Rethrosyntehsis of Natural Products

Retrosynthetic Analysis and Synthesis
of Natural Products 1
Series Editor
Max Malacria
Retrosynthetic Analysis and

Synthesis of Natural
Products 1
Synthetic Methods and Applications
Olivier Piva
First published 2019 in Great Britain and the United States by ISTE Ltd and John Wiley & Sons, Inc.
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Contents
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi
Chapter 1. Total Synthesis: Some Elements to Contemplate . . . . . . . . . 1

1.1. Total synthesis – why and for what purpose? . . . . . . . . . . . . . . . . . . . 1
1.2. The different approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.3. Efficiency, selectivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
1.4. The essential reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
1.5. Towards a sustainable total synthesis . . . . . . . . . . . . . . . . . . . . . . . 11
1.6. What about tomorrow? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
1.7. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Chapter 2. Squamostolide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
2.1. Structure, isolation and properties . . . . . . . . . . . . . . . . . . . . . . . . . 21
2.2. Bond disconnections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
2.3. Approach according to M.J. Wu . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.3.1. Bond disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.3.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
2.3.3. Key reaction: Claisen–Ireland rearrangement . . . . . . . . . . . . . . . . 27
2.3.4. Key reaction: functionalization of true alkynes . . . . . . . . . . . . . . . 29
2.3.5. Supporting synthetic transformations . . . . . . . . . . . . . . . . . . . . . 31
2.4. Approach according to K.J. Quinn . . . . . . . . . . . . . . . . . . . . . . . . . 33
2.4.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
2.4.3. Key reaction: alkene metathesis and tandem processes . . . . . . . . . . . 37
2.5. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
vi Retrosynthetic Analysis and Synthesis of Natural Products 1
Chapter 3. Rubrenolide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
3.2. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
3.3. Approach according to H. Fujioka . . . . . . . . . . . . . . . . . . . . . . . . . 53
3.3.1. Disconnection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
3.3.2. Synthesis, developed by the Fujioka group . . . . . . . . . . . . . . . . . . 54
3.3.3. Key reaction: iodoetherification . . . . . . . . . . . . . . . . . . . . . . . . 56
3.3.4. Key reaction: oxidation of aldehydes to carboxylic acids . . . . . . . . . . 57
3.4. Approach according to B. Zwanenburg . . . . . . . . . . . . . . . . . . . . . . 59
3.4.1. Retrosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
3.4.2. Synthesis, Zwanenburg’s approach . . . . . . . . . . . . . . . . . . . . . . 60
3.4.3. Key reaction: Wolff rearrangement . . . . . . . . . . . . . . . . . . . . . . 62
3.4.4. Key reaction: dehydration of alcohols according to Grieco . . . . . . . . . 63
3.5. Approach according to N. Kommu . . . . . . . . . . . . . . . . . . . . . . . . . 65
3.5.1. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
3.5.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
3.5.3. Key reaction: diastereoselective alkylation of oxazolidinones . . . . . . . 68
3.5.4. Key reaction: enantioselective reduction of ketones – CBS method . . . . 71
3.5.5. Key reaction: alkyne formation according to Ohira–Bestmann . . . . . . . 73
3.6. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Chapter 4. Bipinnatin J . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
4.2. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
4.3. Approach according to D. Trauner (racemic synthesis) . . . . . . . . . . . . . 83
4.3.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
4.3.2. Key reaction: ene reaction between alkynes and alkenes . . . . . . . . . . 86
4.3.3. Key reaction: Stille coupling . . . . . . . . . . . . . . . . . . . . . . . . . . 88
4.3.4. Key reaction: Nozaki–Hiyama–Kishi reaction . . . . . . . . . . . . . . . . 90
4.4. Approach according to V.H. Rawal . . . . . . . . . . . . . . . . . . . . . . . . 94
4.4.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
4.4.2. Key reaction: Negishi coupling . . . . . . . . . . . . . . . . . . . . . . . . 97
4.5. Enantioselective approach according to G. Pattenden . . . . . . . . . . . . . . 99
4.5.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
4.6. Approach according to D. Trauner – enantioselective version . . . . . . . . . . 102
4.6.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Contents vii

4.7. Comparison of the four syntheses . . . . . . . . . . . . . . . . . . . . . . . . . 106
4.8. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Chapter 5. Tubingensin B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

5.2. Bond disconnections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
5.3. Approach according to N.K. Garg . . . . . . . . . . . . . . . . . . . . . . . . . 113
5.3.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
5.3.3. Key reaction: Sonogashira reaction . . . . . . . . . . . . . . . . . . . . . . 116
5.3.4. Key reaction: Suzuki coupling . . . . . . . . . . . . . . . . . . . . . . . . . 118
5.3.5. Key reaction: cycloaddition [2+2] of arynes . . . . . . . . . . . . . . . . . 120
5.3.6. Key reaction: radical cyclization and Baldwin’s rules . . . . . . . . . . . . 122
5.3.7. Key reaction: enantioselective hydrogenation of ketones . . . . . . . . . . 122
5.4. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
Chapter 6. Polygonatine A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127

6.2. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
6.3. Synthesis according to S.M. Allin . . . . . . . . . . . . . . . . . . . . . . . . . 128
6.3.1. Disconnection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
6.3.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
6.3.3. Key reaction: radical cyclization of selenoesters . . . . . . . . . . . . . . . 130
6.4. Synthesis by J.P. Michael . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
6.4.1. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
6.4.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
6.4.3. Key reaction: Vilsmeier–Haack–Arnold reaction . . . . . . . . . . . . . . 135
6.5. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Chapter 7. (+)-Intricatetraol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143

7.2. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
7.3. Approach according to Morimoto . . . . . . . . . . . . . . . . . . . . . . . . . 145
7.3.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
7.3.2. Key reaction: epoxidation according to Katsuki–Sharpless . . . . . . . . . 149
7.3.3. Key reaction: asymmetric epoxidation according to Shi. . . . . . . . . . . 151
7.4. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
viii Retrosynthetic Analysis and Synthesis of Natural Products 1
Chapter 8. Enigmazole A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159

8.2. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
8.3. Approach according to T. Molinski . . . . . . . . . . . . . . . . . . . . . . . . 160
8.3.1. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
8.3.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
8.3.3. Key reaction: 1,2-enantioselective addition of dialkylzinc to aldehydes . . 166
8.3.4. Key reaction: reduction of β-aldols to 1,3-diols . . . . . . . . . . . . . . . 168
8.4. Approach according to A. Fürstner. . . . . . . . . . . . . . . . . . . . . . . . . 172
8.4.1. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
8.4.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
8.4.3. Key reaction: diastereoselective alkylation according to Myers . . . . . . 177
8.4.4. Key reaction: Yne-yne ring-closing metathesis (RCAM) . . . . . . . . . . 179
8.4.5. Key reaction: sigmatropic rearrangement [3,3] of propargyl esters . . . . 180
8.5. Approach according to A.B. Smith III . . . . . . . . . . . . . . . . . . . . . . . 183
8.5.1. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
8.5.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
8.5.3. Key reaction: dithiane, umpolung and relayed reactions . . . . . . . . . . 189
8.5.4. Key reaction: Petasis–Ferrier rearrangement . . . . . . . . . . . . . . . . . 191
8.6. Approach according to H. Fuwa . . . . . . . . . . . . . . . . . . . . . . . . . . 194
8.6.1. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
8.6.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
8.6.3. Key reaction: Tishchenko–Evans reaction . . . . . . . . . . . . . . . . . . 199
8.6.4. Key reaction: Meyer–Schuster and Rupe rearrangement . . . . . . . . . . 201
8.7. Comparative assessment of the different syntheses . . . . . . . . . . . . . . . . 205
8.8. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
Chapter 9. Biyouyanagin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

9.2. Synthesis according to K.C. Nicolaou . . . . . . . . . . . . . . . . . . . . . . . 214
9.2.1. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
9.2.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
9.2.3. Key reaction: 1,4-addition and organocatalysis . . . . . . . . . . . . . . . 220
9.2.4. Shapiro reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
9.3. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
Contents ix
Chapter 10. Elatol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233

10.1. Structure, isolation and properties . . . . . . . . . . . . . . . . . . . . . . . . 233
10.2. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
10.3. Approach according to B. Stoltz . . . . . . . . . . . . . . . . . . . . . . . . . 234
10.3.1. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
10.3.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
10.3.3. Key reaction: Tsuji–Trost reaction . . . . . . . . . . . . . . . . . . . . . . 237
10.3.4. Key reaction: ring-closing metathesis of hindered olefins . . . . . . . . . 241
10.3.5. Key reaction: reduction of enones according to Luche . . . . . . . . . . . 242
10.3.6. Supporting synthetic diagrams . . . . . . . . . . . . . . . . . . . . . . . . 243
10.4. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
Chapter 11. Thiomarinol H . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249

11.1. Structure, isolation and properties . . . . . . . . . . . . . . . . . . . . . . . . 249
11.2. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
11.3. Approach according to D.G. Hall . . . . . . . . . . . . . . . . . . . . . . . . . 250
11.3.1. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
11.3.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
11.3.3. Key reaction: hetero-Diels–Alder enantioselective reaction . . . . . . . . 254
11.3.4. Supporting synthetic transformations . . . . . . . . . . . . . . . . . . . . 256
11.4. Approach according to S. Raghavan . . . . . . . . . . . . . . . . . . . . . . . 258
11.4.1. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
11.4.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
11.4.3. Key reaction: Kirmse–Doyle rearrangement . . . . . . . . . . . . . . . . 262
11.4.4. Key reaction: Julia–Lythgoe and Julia–Kocienski reaction . . . . . . . . 264
11.5. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
Chapter 12. Oblongolides A and C . . . . . . . . . . . . . . . . . . . . . . . . . . 273

12.1. Structures, isolation and properties . . . . . . . . . . . . . . . . . . . . . . . . 273
12.2. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
12.3. Synthesis of oblongolide A according to Shing . . . . . . . . . . . . . . . . . 275
12.3.1. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
12.3.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
12.3.3. Key reaction: intramolecular Diels–Alder reaction . . . . . . . . . . . . . 278
12.4. Shishido’s approach to oblongolide C . . . . . . . . . . . . . . . . . . . . . . 281
12.4.1. Disconnections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
12.4.2. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
12.4.3. Key reaction: intramolecular [3+2] cycloadditions . . . . . . . . . . . . . 287
12.5. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291
x Retrosynthetic Analysis and Synthesis of Natural Products 1
List of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
Preface
Through a dozen molecules isolated from living organisms, the field of total
synthesis is presented to the reader by analyzing for each target compound:
– its structure and known biological properties;
– the retrosynthesis envisaged;
– the various syntheses completed, briefly discussed step-by-step and compared
with one other.
An overview of several key steps is found at the end of each chapter, explaining
the mechanisms and describing various applications.
Similarly, the set of reactions involved in each synthesis are grouped together in
a text box and thus form a compendium of practical methods, mostly referring to the
publications referenced in the original articles.
Learning about retrosynthesis can certainly be based on the monitoring of laws

and general rules, most often gathered in difficult studies. We have chosen to avoid
this limitation and instead favor an approach using examples, which we hope is
nevertheless pleasant to read and follow.
Other examples will follow…
Olivier PIVA
June 2019
1
Total Synthesis: Some Elements to

Contemplate
1.1. Total synthesis – why and for what purpose?
Nature is an immeasurable source of rather complex molecules, which have

always attracted the curiosity of chemists. Since Friedrich Wöhler prepared urea
from ammonium cyanate in 1828, vital force theory has been challenged, allowing
the synthesis of organic compounds from the simplest to the most complex, such as
spongistatin 1 [HUD 07, HUA 18], and thereby the emergence of organic synthesis.
In less than two centuries, this branch of chemistry has reached a certain degree
of maturity that has made it possible to prepare a considerable number of the most
complex compounds, whose exact structures have been revealed as a result of the
concomitant development of purification, analysis or characterization techniques
(HPLC and UPLC, 1D and 2D NMR, mass spectrometry, X-ray diffraction, etc.).
The isolation and structural determination of natural products is most often

guided by the existence of biological properties of interest to human health. In order
to confirm or invalidate the proposed structures [NIC 05, MAR 17a] and also to
identify the functional groups responsible for, or even essential to, these activities, it
is necessary to carry out structure-activity studies. This assumes there are significant
quantities of these natural compounds as well as different analogues with regard to
their structure or even the spatial arrangement of these same functional groups; it is
also one of the roles assigned to chemical synthesis [WIL 07]. Does this mean that
organic synthesis becomes a simple tool available to researchers in the life sciences?
No, of course not [HOF 13, NIC 18].
Retrosynthetic Analysis and Synthesis of Natural Products 1: Synthetic Methods and Applications,
First Edition. Olivier Piva.
© ISTE Ltd 2019. Published by ISTE Ltd and John Wiley & Sons, Inc.
2 Retrosynthetic Analysis and Synthesis of Natural Products 1
OH
AcO
Cl
O
OH O H
H AcO
O
OH
O
O H
H O
O HO
H H OMe
O O
HO
O HO
H2N NH2
OH Spongistatin 1
Urea (F. Wöhler)
1828 Syntheses: D.A. Evans, A.B. Smith III,

I. Paterson, Y. Kishi, S. V. Ley
Figure 1.1. Evolution of target complexity in just over 150 years. For a color
version of the figures in this chapter, see www.iste.co.uk/piva/analysis1.zip
With increasing ecological awareness, organic synthesis can also indirectly

dispose of the required molecules, in order to preserve certain endemic species and
their biotopes.
To minimize the impact of chemical synthesis on the environment, it is also

important to develop new methods and concepts that produce less waste; this is all
the more true since those generated using so-called fine chemistry are generally very
numerous. This trend is commendable but remains difficult to achieve; the E factor,
defined as the ratio of kg of waste per kg of product formed, is between 25 and 100
for the most advanced products (pharmaceuticals), while for base chemicals, this
number is closer to 1 [SHE 07, ROS 15].
Number of
Annual tonnage as Annual tonnage as
Industry Factor E people of
products waste
steps
Petrochemical 106–108 t 0.1 107 t separation
5 6
Heavy chemistry 10 –10 t <1–5 5.106 t 1–2
Fine chemistry 100–104 t 5–50 5.105 t 3–4
5
Pharmaceutical 10–1000 t 25–> 100 10 t >6
Table 1.1. Environmental impact factors across chemical industries

Total Synthesis: Some Elements to Contemplate 3
1.2. The different approaches
There are two distinct conflicting approaches: the approach developed in the
academic world and that recognized in industry.
Of course, the effectiveness criterion, which can be correlated to the number of

steps and overall performance, remains common to both.
For academic syntheses, in addition to these efficiency criteria, there is

the primacy of experiment, which is often reflected in publications by the words
“first total synthesis of…”. In many cases, to reach the target, teams use
methodologies that they have developed themselves. The choice of target may be the
result of:
– direct application of this method;
– interest in the compound’s properties, or its unique and even fascinating
structure.
Last but not least, training young researchers through research is obviously a
factor. A thesis in total synthesis undoubtedly makes it possible to “see” more
chemistry and probably to test one’s character by being faced with a challenge at
each stage [NIC 11].
The success and effectiveness criteria for the approaches implemented in

industry are: cost reduction (in reagents and human resources), a minimum number
of operations (for processing and purification), the reduction in associated waste and
risks.
For complex targets, particularly those with several stereocenters,

stereochemistry control can be performed:
– By hemisynthesis: one of the most well-known cases is that of taxol,
a diterpene initially isolated from the bark of Taxus baccata and known for its
highly cytotoxic properties. To collect sufficient quantities, Françoise Guéritte and
Pierre Potier’s team at the ICSN in Gif-sur-Yvette succeeded in isolating
10-deacetylbaccatin III from yew tree needles, a precursor with the same
taxane skeleton; it was possible to regioselectively graft the appropriate side
chain onto the hydroxy group at the C-13 position of the taxane skeleton [DEN 88,
DAN 96].
R1O O OH HO O OH
NHR2 10
O
Ph
O O HO O
HO H 13 H
HO OBz OAc HO OBz OAc
Taxol (R1 = Ac, R2 = Bz)
10-Deacetylbaccatine III
Taxotere (R1 = H, R2 = tBu-CO)
Figure 1.2. Taxol and Taxotere® from 10-deacetylbaccatin III
– According to a chiron approach: it is a question of benefiting from molecular

platforms and carrying out various selective transformations. Stephen Hanessian
is one of the researchers who has made the most out of this concept [HAN 12,
BRI 17]. In the synthesis of dihydromevinolin, L-glutamic acid was used as a
molecular block to prepare the lactone synthon with two stereogenic centers, which
after several steps, gives rise to the key precursor of cycloaddition according to
Diels–Alder [HAN 87, HAN 90].
O
HO O R1O
O-PG
O
O O
+ NO2
O
H R2O R2O
D1 H D2 H
H
H H
Dihydromevinolin
O O
OTBS
O NH2
H O
D3 D4
O CO2H
CO2H
H O
OMOM L-glutamic acid
Figure 1.3. Dihydromevinolin from L-glutamic acid
LEGEND OF FIGURE 1.3.–

D1: ring enlargement (Baeyer–Villiger reaction).
D2: introduction of the cyclopentanone unit (1,4-addition of a nitronate anion).
D3: functionalization of the tricyclic lactone.

D4: formation of the tricyclic structure (intramolecular Diels–Alder reaction in
exo mode).
De novo syntheses are generally based on well-established processes but are also
an impetus to the discovery of new reactions or catalysts [MEN 16]. In addition to
the expected formation of the carbon skeleton and the functional groups present, it is
necessary to master the configuration of the stereogenic centers by addressing the
3D aspect. There are a plethora of diastereoselective and enantioselective
asymmetric syntheses which make it possible to reach selectivities close to those in
biocatalysis (e.g. > 99%).
Natural products represent a significant source of inspiration in the genesis of

drug candidates. Thanks to structure-activity studies, it is possible to identify
sub-units responsible for the expected activity. Eribulin is exemplary in this respect.
This anti-cancer molecule, now marketed by Eisai in Japan, has a common fragment
with halichondrin B, itself isolated from marine sponges. Its synthesis requires no
less than 62 steps and is currently one of the most successful examples of a
pharmaceutical synthetic molecule on the market [BAU 16].
Figure 1.4. Marine polyethers for cancer treatment

Establishing a retrosynthetic scheme is the first step in the long journey to the
synthesis of any target molecule. A convergent synthesis from fragments obtained in
parallel pathways is preferred over a linear synthesis, which will take longer to
implement and has a lower overall yield. In the event that the proposed scheme fails,
a linear synthesis may prove to be ineffective; it will then be necessary to reconsider
the overall strategy rather than just that of a fragment.
Linear synthesis
w% w% w% w% t%
Linear sequence : Yield = (w%)4 x t%
S"1 S"2 S"3 S"4 S"5
Convergent synthesis
S1 x% S2
The shortest convergent sequence :
S4 t'% S1 -S2 -S4 -> Target : Yield : x% x z% x t%
S'1 S'2 S'3
z%
The longest convergent sequence :
y% y% S'1 -S'2 -S'3 -S4 -> Target : Yield :( y%)2 x z% x t'%
Figure 1.5. Convergent or linear synthesis
Even though very recently some syntheses have been effectively carried out
without the involvement of protective groups, this solution is uncommon; the higher
the number of functional groups present the truer this statement [YOU 09, SAI 14].
Introduction and deprotection can lead to a significant number of steps, which can
however be reduced by simultaneously cutting off some of them in a single process.
A very large number of protective groups have been defined [WUT 14]; the most
commonly used ones meet the following criteria:
– their accessibility (cost);
– obtaining the highest possible yields when attaching them;
– the possibility of avoiding the creation of new stereogenic centers;
– stability under reaction conditions;
– their selective and effective deprotection.
In order to minimize the number of steps to obtain a given target molecule,

performing multiple transformations in the same reactor is highly tempting
(Figure 1.6). Such processes avoid dealing with unstable or volatile intermediates;
they also avoid one or more time-consuming solvent purifications. A distinction
should be made here:
– sequential reactions for which different reagents are introduced as the starting
substrates are transformed and consumed to create a new entity capable of reacting
itself. This process is automatically retained since the second reagent involved R2
could itself interact with the substrate S [EPP 15];
– tandem, domino or cascade reactions, which allow a high level of complexity
to be reached, by deliberately placing all reagents in the same reactor, will ideally
react step-by-step until the target compound is obtained [NIC 06, LU 12, PEL 13a,
PEL 13b, HON 15, SZÖ 18]. If competitive reactions were to take place, it would
then be possible to modulate the reactivity by altering the physical parameters, such
as temperature (heating/cooling) or the possibility of generating excited species
(photochemical activation).
R1
Classical synthesis
S Pi In two distinct stages :
- Action of reagent R1
R2
- Isolation of Pi
Pi Pf - Action of reagent R2
R1 R2 One-pot sequential approach :

R1 reacts at first with S to deliver the
S Pi Pf intermediate Pi
then R2 is added to furnish product Pf
R1 + R2 One-pot cascade approach :

R1 and R2 are introduced simultaneously : R2
S Pi Pf doesn't interfere and R1 reacts first. Once
formed in situ, Pi reacts with R2 leading to Pf
Figure 1.6. Classic, sequential or cascade synthesis
1.3. Efficiency, selectivity
For an author, the synthetic pathway he has conceived and carried out will
probably always be preferred. An external examiner has a less subjective view to
compare different reaction pathways leading to the same target molecule and
measure their effectiveness. The number of steps and overall performance are two
important criteria, but they can also be weighted by negatively considering the use
of protective groups or changes in the degree of oxidation of specific functional
groups [HEN 75, GAI 10].
Thus, the percentage towards the ideality of a synthesis can be expressed in the
form:
[No. Of constructive reactions] + [No. Of strategic redox processes]

Ideality (%) =
[Nr. of total steps]
To obtain. the highest possible percentage, the chemist can and must rely on the
extraordinary number of reactions at his disposal, allowing him to control the regio-,
diastereo- and enantioselectivity.
An ideal synthesis must be possible to carry out a large-scale synthesis, while

minimizing the production of by-products (always selectivity) and the quantity of
waste. As such, reactions with atomic economy (cycloadditions, condensation
(aldolic), isomerizations) are of great help [TRO 91].
In order to reduce the number of steps, cascade reactions will also be an asset to
move closer to absolute ideality. To achieve this, the combination of catalytic
reactions (organometallic(s), organocatalyzed and/or involving biocatalysis) is
essential [XIO 10, WEN 13, VOL 14, BIE 18, IND 18, BAR 19, REE 13].
Benefiting from the symmetry of a substrate, for a more advanced stage, to

achieve desymmetrization using a chiral or non-chiral reagent, is also an interesting
strategy, often leading to spectacular results [HO 95, ZEN 16, MER 17, YOS 17].
O
N
OH PG
PG N
Br N HN
N
Br Br
O O HO2C N
KHCO3 O
O
AcOEt, r.t. O
OH
Desymmetrization
Actinophyllic acid
Figure 1.7. Desymmetrization and synthesis of actinophyllic acid [YOS 17]
Planning the synthesis of a single target molecule or achieving an intermediate

structure that will allow different targets to be synthesized is the challenge of
target-oriented synthesis (TOS) rather than a divergent approach (DOS) [LI 18,
SZP 10, SER 13]. Figure 1.9 shows the interesting nature of the DOS approach;
from diketone I, itself obtained by ozonolysis of a cyclohexenone, it has been
possible through the set of post-functionalizations to obtain no less than 11 indole
alkaloids, differing by the size of the adjacent rings and the nature of the grafted
substituents [XU 15].
Target oriented synthesis (TOS) :

Diversification by parallel synthesis
Target 1
Target 2
Target 3
Target n
Divergent oriented synthesis (DOS) :

Implication of a common intermediate I
Target 1
I Target 2
Target n
Figure 1.8. Target-oriented or divergent-oriented synthesis
N
O
OH
HO
N
N
N (-)-Mersicarpine
O
(-)-Scholarisine G
O N3
N3
O
CO2Me O
H
N O
NO2 OMe
NO2
N
Key intermediate I O
(+)-Arboloscine
O
Figure 1.9. Route to different indole alkaloids from the same diketone I [XU 15]
1.4. The essential reactions
The chemist has an ever-increasing arsenal of methods that allow him to consider
multiple transformations accompanied by the control of selectivities (regio-,
diastereo- and enantioselectivities). It would be unrealistic to want to create an
exhaustive list of them. However, some of them are unavoidable and widely
involved in synthesis. Thus, since the late 1970s, pallado-catalyzed C-C coupling
reactions (Stille, Suzuki, Heck, Sonogashira or Negishi) have greatly facilitated
access to complex targets, requiring only a small quantity of organometallic
complexes and always with very high selectivities [BAT 12, WU 10]. Moreover, due
to the availability of unsaturated compounds, the metathesis reactions ene-ene,
ene-yne, yne-yne and their variants have allowed the formation of very diverse
structures, whether cyclic or not, and always highly functionalized. Moreover,
extremely mild operational conditions have led to their association with subsequent
transformations in sequential processes [GRU 15, COS 10, HAN 15, CHE 18,
TUR 19]. Olefinization reactions of carbonyl compounds are also strongly present in
the construction of carbon units, obtained via the reactions of Wittig, Wittig–Horner
[ROC 18], Peterson [VAN 02], Julia–Kocienski [BLA 02], Tebbe [HAR 07], etc.
The same is true for achieving alkynes (Corey–Fuchs or Ohira–Bestmann reaction).
In addition to organometallic cycling processes (e.g. RCM), thermal or
photochemical cycling reactions [HOF 08, BAC 11, KÄR 16, LIU 17] often remain
popular routes to produce cyclic structures, while also allowing relative and absolute
control of the created stereogenic centers.
Asymmetric synthesis is now essential. Here too, spectacular advances have been
made thanks to the development of chiral copulas (Evans’ oxazolidinones [HER 16,
HER 13], amides derived from ephedrine [LAR 79, MYE 94], Enders’ hydrazones
[JOB 02] and many others) and their involvement in alkylation, addition-1,4 or
aldolization reactions. The 1,2-addition is also one of the most important. In this
field, reactions using organozinc compounds are very attractive both from a
compatibility point of view and in terms of asymmetric induction [KIT 99,
NUG 02, TRO 06], chirality amplification or asymmetric autocatalysis [KAG 11,
SOA 96, SOA 17]. The reactivity of allyl metals is also a key factor in processes,
widely used to access exceptional synthons such as homoallylic alcohols [BRO 87,
ROU 85, DEN 03].
Since the 2000s, the chemistry of enamines has been brought back to the
forefront and organocatalysis, in the broad sense, is an effective way to form C-C or
C-heteroelement bonds [BER 05, GRO 10]. A dual catalysis approach has recently
emerged through the combination of these organocatalyzed reactions with other
processes, in particular involving metals [AFE 16]. Finally, more recently, C-H
activation involving noble metals [JAZ 10, PIN 17] as well as photoredox catalysis
has been added to this panel [NAR 11].
Also worth mentioning are all selective reduction or oxidation methods,

including:
– reductions via oxazaborolidines (CBS method) [COR 98];

– enantioselective hydrogenations [MAR 17b];
– the selective oxidation of alcohols to carbonyl derivatives [COR 75, MAN 78,
LEY 94, DES 91];
– enantioselective epoxidation processes [HER 15, WAN 97, ZHA 90];
– enantioselective dihydroxylation of alkenes [HER 17, KOL 94].
and all esterification and macrocyclization methods [PAR 13].
The applications of any of the reactions mentioned and their mechanisms will be
described in detail in the following chapters but can also be found in various books
[KÜR 05].
1.5. Towards a sustainable total synthesis
Preventing Promoting
Avoiding
the risk atom
waste economy
of accidents
e
tim r les Favo
e al- is fo s rin
s
R l y on ch haza g
a ti e rd
an ollu ntion sy m
nth ical ous
p ve es
e is
pr
Designing
12 Principles Designing
degradable
products
of green safer
products
chemistry
Promoting Achieving
catalytic less noxious
processes solvents
Minimizing Using Minimizing

the number renewable the energy
of steps feedstocks requirements
Figure 1.10. The 12 principles of green chemistry

The 12 principles of green chemistry are now at the heart of the concerns of all
chemists [ANA 10, FED 09]. Still, it is not easy to follow them throughout the entire
multi-step sequence. However, some of these principles are now well established
(involvement of catalysis, development of bioresources into synthons, waste
minimization, involvement of flow chemistry, etc.); this development is going strong
and will undoubtedly dictate the strategies deployed to achieve future targets
[NOY 09]. The combination of chemical and biological processes (biocatalysis) is
also an underestimated approach, at least in academic research.
1.6. What about tomorrow?
With the invention of artificial intelligence and by integrating thousands of

referenced reactions into databases, it is possible by mobilizing powerful computers
to obtain retrosynthetic pathways for targets of moderate complexity, with a certain
degree of success [SCH 18, MAR 18]. What about the future? If machines replace
chemists not only on the bench but also in the design of synthesis pathways, then the
discipline would lose a little more of its soul.
By relying solely on the relative intelligence of a brain, whose neurons are

silicon-based, there is a risk that we will no longer be able to detect fortuitous
results, which only experienced or insightful – human – minds can detect. This
source of unpredictable discoveries related to serendipity is, however, at the basis of
considerable progress in the recent past in many fields, from therapeutic chemistry
(penicillin, Viagra, etc.) [MON 14] to the development of new materials (Teflon,
post-it®, etc.).
In conclusion, total synthesis, like chemistry as a whole, remains a promising

field with a societal demand that remains as strong as ever in terms of products and
applications. It is up to chemists to make it more efficient, always as elegant and
with as little impact on the environment as possible [NOY 05, NOY 18].
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2
Squamostolide
2.1. Structure, isolation and properties
Squamostolide belongs to acetogenins, a class of polyoxygenated compounds,

typified by a fatty long chain, with a terminal γ-lactone subunit [XIE 03]. These
compounds, isolated from tropical plants, have various biological activities such as
antimalarial, antibiotic or antitumor [BER 05].
OH O
O
O
Figure 2.1. Structure of squamostolide. For a color version of the figures

in this chapter see, see www.iste.co.uk/piva/analysis1.zip
ANALYSIS.– γ-Valerolactone substituted at α position by a long chain of 13 carbon

atoms. Its tip has a secondary alcohol functional group and a second saturated
lactone unit.
2.2. Bond disconnections
For each of the two approaches, bond disconnections are carried out along the
carbon chain linking the two butyrolactones. The first is based on a Sonogashira
coupling between a terminal alkyne and a vinyl iodide catalyzed by palladium (0)
[LEE 05, MAK 06]. For the second, a tandem process of cyclization and
cross-coupling by metathesis allows both the formation of one of the lactone units
and the formation of the carbon chain linking them [QUI 07]. To finalize the
syntheses, a selective reduction of double bonds is required while preserving or
regenerating the one present in butenolide.
OH O
I
+ ( )5
O
O H
O
Sonogashira coupling
OH
O
( )5
O
O
O RCM / CM
OBn
+ O
PhS
O
( )5
O
O
Figure 2.2. Key disconnections

Squamostolide 23
2.3. Approach according to M.J. Wu
2.3.1. Bond disconnections
OH O
D1
( )5
O
O
OH O
I
( )5
O
+
O
O
1-A1 1-B1
D2 D5
I
( )5 I
CO2Et SiMe3
1
1-C1 1-E
D3 +
O
OH PhS
SiMe3
1-D1 1-F1
D4 OH
4-pentyn-1-ol
Figure 2.3. Disconnections recommended by Wu

D1: ene/yne coupling (Sonogashira reaction followed by reduction).
D2: formation of a hydroxy-butyrolactone (dihydroxylation/lactonization).
D3: formation of an γ,δ-unsaturated ester (Claisen rearrangement).

D4: allyl alcohol (1,2-addition of vinylmagnesium to an aldehyde).
D5: butenolide (coupling of an anion stabilized by a thiophenyl group and an
alkyl iodide/elimination).
2.3.2. Synthesis
2.3.2.1. Access to hydroxylactone 1-A1
OH
OH OHC
a b
SiMe3 SiMe3
OH
EtO2C
c d
SiMe3
SiMe3
SiMe3
e f
O O O
O
OH OH
1-A1
Figure 2.4. Synthesis of hydroxylactone 1-A1

a. Triple bond protection – 71%: (i) n-BuLi, THF, 0°C; (ii) TMS-Cl, 0°C -> r.t.
b. Oxidation of primary alcohol to aldehyde – 96%: Complex SO3.py, Et3N,
DMSO, CH2Cl2, −10°C, 1 h.
c. 1,2-Addition of vinylmagnesium chloride – 98%: CH2=CH-MgCl, THF, 0°C.
d. Claisen rearrangement – 64%: CH3-C(OEt)3, propionic acid, 150°C.
e. Asymmetric dihydroxylation and lactonization – 94%: AD-mix-β, CH3SO2NH2,
t-BuOH/H2O, 0°C.
f. Deprotection at the terminal position of the alkyne – 95%: TBAF, THF, 0°C.
Squamostolide 25
2.3.2.2. Access to vinyl iodide 1-B1

OH OH
I
g h, i
OTHP
OH OTHP
I
j k
OTHP OH
I I
l m
OTs I
1-E1
O O
PhS I
O n, o O
1-F1 1-B1
Figure 2.5. Synthesis of vinyl iodide 1-B1

g. Monoprotection of 1,6-hexandiol – 67%: dihydropyran, TsOH.
h. Tosylation of a primary alcohol: TsCl, pyridine, CH2Cl2.
i. Formation of a primary iodide – 81% (two steps): NaI, NaHCO3, acetone.
j. Introduction of the alkyne functional group by nucleophilic substitution – 83%:
lithium acetylide, ethylenediamine, DMSO.
k. Hydrozirconiation/iodination/deprotection of THP ether – 81%: (i) Cp2ZrHCl,
THF; (ii) I2, THF, 0°C; (iii) Conc. HCl, MeOH.
l. Protection of the primary alcohol function – Tosylation: Ts-Cl, pyridine.
m. Substitution of the tosyl group by iodide – 79% (two steps): NaI, NaHCO3,
acetone.
n. Coupling – 45%: (i) NaHMDS, THF/HMPA; (ii) 1-E1.
o. Generation of the double bond by sulfoxide elimination – 67%: (i) m-CPBA,
CH2Cl2; (ii) Ph-Me, Δ.
2.3.2.3. Coupling of the two fragments – termination of the synthesis

OH
O
O I
O
O
+
1-A1 1-B1
p
OH
O O
O
OH O
O
O
O
Figure 2.6. Sonogashira coupling and finalizing the synthesis

p. Sonogashira reaction – 58%: PdCl2(PPh3)2 (5 mol%), CuI (10 mol%), Et3N,
Ph-H, 8 h.
q. Reduction of both unsaturated bonds – 62%: Ts-NH-NH2, AcONa,
EtOCH2CH2CH2OEt.
Number of steps: 11 (from 1.6-hexandiol) – Overall yield: 3.1%.
A Sonogashira reaction between a true acetylene and a vinyl iodide makes

it possible to build the carbon skeleton; the hydroxy group tolerates the conditions
of this coupling and avoids the use of a protective group. The selective reduction
of enyne, without affecting the unsaturation present on a lactone unit, is ensured
by diimide.
Squamostolide 27
2.3.3. Key reaction: Claisen–Ireland rearrangement
The Claisen rearrangement of allylic esters allows direct access to

γ,δ-unsaturated acids. It is a concerted sigmatropic process [3,3] that takes place
in an acyclic series, according to a 6-membered chair transition state. From
esters derived from cyclic unsaturated alcohols, the transition state for this
transformation is of boat type [CHA 02, MAJ 07, FER 13]. In order to decrease the
activation energy of the reaction, deprotonation of the ester by a lithiated base was
recommended by R.E. Ireland, thus generating enolate, trapped by trimethylsilyl
chloride [IRE 72]. From the ketene acetal thus formed, the rearrangement of
Claisen–Ireland takes place at room temperature.
O R1
1) LDA, THF O
R2 O R2
-78°C
R1 2) TMS-Cl OTMS
Enolate (E)
R1 R1
R2 OH
O
H R2 O
OH
anti
Figure 2.7. Claisen rearrangement of acyclic allylic esters
The process has been successfully applied many times in total synthesis. The
acid can then be trapped by diazomethane to make the methyl ester easier to handle
[RED 13].
O O
1) LiHMDS, TMSCl CO2H
O THF, -78°C -> r.t., 15h H3CO
2) CH2N2, Et2O CO2H

N
0°C, 30 min H
OPMB OPMB Kainic acid
BnO BnO
79%
Figure 2.8. Claisen rearrangement, a key step towards kainic acid

The mild conditions of this reaction made it possible to combine it with other
reactions conducted sequentially and generate the required intermediate in situ
[ERN 17, ERI 95, SER 16].
F F
Ph
FSO2CF2CO2-SiMe3
Ph Ph
(3 equiv.) Ph
O NaF (0.1 equiv.) O
OPMB OPMB
Diglyme, 120°C
O O
F
F Ph F
Ph F
1) KHMDS H [3,3]
(4 equiv.) O -78°C -> r.t. Ph
TMS-Cl O 2) NH4Cl
OTMS Ph PMBO CO2Me
(4 equiv.) 3) CH2N2
PMB
MeOH, PhMe
73% (d.r. >96/4)
Figure 2.9. Difluorocyclopropanation and Claisen–Ireland rearrangement [ERN 17]
O-TMS
O CO2H
1) Me2CuLi, Li-I 2) Et3N, r.t.
TMS-Cl, Et2O 3) HCl (3M)

-78°C, 4h
O Ketene acetal (Z) 93% syn Major
d.r. = 82 : 18
O
O-TMS
O CO2H
2) Et3N, r.t.
1) MeCu, Li-I
3) HCl (3M)
TMS-I, Et2O
-78°C, 4h 68% anti Major
Ketene acetal (E) d.r. = 83 : 17
Figure 2.10. Tandem Michael addition/Claisen rearrangement [ERI 95]

Squamostolide 29
2.3.4. Key reaction: functionalization of true alkynes
Before the advent of palladium catalyzed reactions, the coupling of aromatic or

vinyl derivatives with alkynes, known as Castro–Stephens reactions, could be
carried out under fairly harsh conditions (involvement of strong bases, high
temperatures, reactions under inert atmosphere) requiring stoichiometric quantities
of copper acetylides [STE 63].
I
pyridine Ph
+ Cu Ph
125°C, 7h O
OH
88%
Figure 2.11. Castro–Stephens coupling
From an application point of view, the reaction has some disadvantages: the
instability of copper acetylides gives them potential explosion risks, as well as the
homocoupling of alkynes leading to diynes (Eglinton–Glaser reaction). As for the
exact mechanism, it is still controversial; the most commonly accepted model is the
one involving a transition state with four centers, although the possible involvement
of Cu(III) species is not totally excluded [ROV 14].
Cu-I
R
L
Cu
L I
L
R'
L L
Cu L Cu
R L
I L
R
R'
L
R' Cu L
I L
R
Figure 2.12. Mechanism of the Castro–Stephens reaction

The reaction can be carried out intramolecularly to produce enynes [COL 01,
HAA 03]. The coupling studied in the synthesis of oximidine II led to low yields and
was accompanied by the isomerization of the E double bond to Z; thanks to the
presence of sodium formate, enyne can be reduced stereoselectively and form the
expected triene with very significant yields. The effectiveness of the second step
depends on the phosphine present in the medium; further studies have shown that
phanephos allows a better stabilization of the reductive species, copper hydride
(Cu-H) [LI 15].
OTBDPS
OMe O OMOM
O
K2CO3, CuI
OTBDPS PPh3, DMF
120°C Z
OMe O 18%
OMOM OTBDPS
O
OMe O OMOM
E I
K2CO3, CuI
H-CO2Na O
PPh3, DMF
120°C
H H
67%
Figure 2.13. Intramolecular coupling sequence and alkyne reduction
Since its discovery, the Sonogashira reaction has superseded the Castro–
Stephens reaction. Catalyzed by palladium Pd(0), it eliminates the need for
stoichiometric quantities of copper acetylides, is produced at a lower temperature
and tolerates the presence of many functional groups [MIL 97].
O
O Pd(Ph3)2Cl2 (5% mol.)
I + CuI (10% mol.) O
O iPr2NH, THF, 0°C
OTBS
OTBS 54%
Figure 2.14. Sonogashira reaction – Harveynone synthesis

Squamostolide 31
The Sonogashira reaction creates a C-C bond between an alkyne and an aryl or
vinyl halide. Like most pallado-catalyzed processes, it involves three classic steps:
oxidative addition, transmetalation and reductive elimination.
Pd(0)L2
L R1-X
L Pd R2
R1
L
L 1
R1 R2 R Pd X
1 2
R Pd R L
L
Cu+ R2
X- Cu
H R2 Base
2
H R
+ -
Cu X
Figure 2.15. Catalytic cycle of the Sonogashira reaction
2.3.5. Supporting synthetic transformations
2.3.5.1. Oxidation of alcohols to aldehydes according to Parikh–von Doering

[BOU 10, CAR 06, PAR 67]
SO3, pyridine
O O
OMe DMSO, Et3N OMe
MeO2C MeO2C
OH H O
90%
2.3.5.2. Asymmetric dihydroxylation according to Sharpless [AHM 06]

OH
AD-mix β (2 mol%)
C11H23 MeSO2NH2 (1 equiv.)

O C11H23
MeO O
t-BuOH / H2O (1 : 1)
O
86%
e.e. > 95%
2.3.5.3. Preparation of phenylsulfonyl butyrolactone 1-F1 [IWA 77]

O
2)
1) LDA (2 equiv.) CO2H
CO2H
THF, -78°C
SPh OH SPh
SPh
TsOH (cata.) Ni Raney
O
O O
Ph-H, Δ O MeOH
82% 78%
2.3.5.4. Sulfoxide removal – access to butenolides [REN 01, MOG 96]
Ph
O H O
O O
O O
Ar LDA Ph H Ar
S O S O
THF, -78°C
O O
Ph O
H OH
O
H2SO4 (2M) PhMe, Δ O
Ar
THF, Δ S OH
O Ph
79% e.e. = 93%
Squamostolide 33
2.4. Approach according to K.J. Quinn
OH O
O
O
O
D1
OBn O
PhS
( )7
O
O
O 1-A2
D2
OBn O
PhS
( )8
O
+
O
O
1-B2 1-C2
D3
D4
O
OH OH OH PhS
D5 O
OH OH OH
Propylene O
D-mannitol oxide 1-D2
Figure 2.16. Disconnections recommended by K. J. Quinn [QUI 07]

D1: reduction of two C=C bonds and the regeneration of one C=C bond
(reduction by hydrogenation/elimination of a sulfoxide).
D2: formation of the carbon skeleton (tandem ring-closing metathesis

(RCM)/cross-metathesis (CM)).
D3: C2 symmetric chiral 1-B2 synthon (functionalization of D-mannitol).
D4: α-alkylated butyrolactone (enolate anionic coupling with an iodoalkyl
derivative).
D5: chiral lactone 1-D2 (functionalization of propylene oxide).
2.4.2. Synthesis
2.4.2.1. Access to ester 1-B2
OH OH OH OAc OAc Br OAc

a b
OH OH OH Br OAc OAc OAc

D-Mannitol
OBn
OH OBn
c d e
O
OH OH
O
1-B2
Figure 2.17. Synthesis of polyunsaturated ester 1-B2

a. Bromoacetylation – 67%: AcBr, Ac2O, pyridine.
b. β-Elimination: Zn, AcONa, AcOH.
c. Saponification – 80% (two steps): MeONa, MeOH.
d. Monoetherification – 88%: (i) Bu2SnO, nBu4NI, Ph-H, Δ; (ii) PhCH2-Br, Δ.
e. Esterification – 83%: acryloyl chloride, iPr2Net, CH2Cl2.
Squamostolide 35
2.4.2.2. Synthesis of dodec-11-en-1-ol triflate 1-E2

O
f OMe g, h OTf
( )8 H ( )8 ( )8
1-E2
Figure 2.18. Access to triflate (trifluoromethanesulfonate) 1-E2

f. Wittig reaction: Ph3P=CHOMe, THF.
g. Hydroxymercuration and reduction of enol ether – 44% (two steps):
(i) Hg(OAc)2, THF; (ii) NaBH4, MeOH.
h. Protection of alcohol in triflate – 84%: Tf2O, 2,6-lutidine, CH2Cl2.
2.4.2.3. Access to butyrolactone 1-A2

O
PhS
1-D2 i
OBn
O
PhS
( )8
O O
O 1-B2 1-C2
j
OBn OBn O
PhS
O
O + O
O 1-F2 O 1-A2
Figure 2.19. Access to lactone 1-A2 by RCM/CM coupling


i. Alkylation of α-phenylthiobutyrolactone – 80%: (i) KHMDS, THF, 0°C;
(ii) 1-E2, 0°C -> r.t., 16 h.
j. Tandem RCM/CM – 77%: Hoveyda–Grubbs catalyst (10 mol%), CH2Cl2,
40°C.
2.4.2.4. Termination of the synthesis

OBn O
PhS
O
O
O 1-A2
k-m
OBn O
O
O
O 1
Figure 2.20. Termination of the synthesis

k. Hydrogenation of the two double bonds and hydrogenolysis of the benzyl
ester: H2, Pd/C, AcOEt.
l. Conversion of α-phenylthiolactone to butenolide (oxidation to sulfoxide):
m-CPBA, CH2Cl2, 0°C.
m. Thermal β-elimination of sulfoxide – 53% (three steps): PhCH3, 110°C.
Number of steps: 9 (from D-mannitol) – Overall yield: 12.7%.
Squamostolide 37
The synthesis is convergent and uses as a key reaction a double metathesis

process (RCM and CM) carried out in tandem [QUI 07, QUI 05, SCH 18];
the most efficient catalyst here is that of Hoveyda–Grubbs which minimizes the
formation of non-functionalized 1-F2 butenolide. Chirality is controlled by using
D-mannitol as a synthon. The appropriate choice of benzyl group to protect the
hydroxy group – allows, during the double bond reduction step, to regenerate at the
same time as the free alcohol functional group. The presence of the phenylsulfanyl
group in the 1-D2 compound is also essential to introduce butenolide unsaturation
(by oxidation to sulfoxide and β-elimination); it also helps to stabilize the anion
during the alkylation step with triflate 1-E2.
2.4.3. Key reaction: alkene metathesis and tandem processes
Since the discovery of catalysts, capable of reacting in the presence of

many functional groups, the metathesis reaction has taken off and is no
longer restricted to the field of petrochemistry or polymerization processes
[LIU 18]. The metathesis of alkenes is declined in several modes [YET 16].
Cross-coupling is a key tool but remains the most difficult to control in terms
of regio- and E or Z stereo-selectivity. Ring-closing metatheses, on the contrary,
have undergone extraordinary development and have truly revolutionized
the strategy for the synthesis of macrocyclic compounds. Instead of breaking
the bonds at or near well-established functional groups, it is quite easy and
now common to cleave the molecule between two sp3 carbon atoms of an alkyl
chain, even though it means subsequently reducing (by selective hydrogenation)
the newly created double bond.
Over the past two decades, significant progress has been made. Now even
tetrasubstituted alkenes can be achieved with highly active catalysts; control
of selectivity to Z alkenes is also possible with other well-defined catalysts.
Regio-selectivity can also be controlled by involving either tether groups
(silylated or phosphate) or by implementing relayed reactions. In order to reduce
the steps of a synthesis, the combination of different metathesis reactions
(CM, RCM or ROM) through cascade or domino processes allows access to
complex structures [ZIE 16]. In addition, the extremely mild conditions also lend
themselves to the implementation of tandem reactions combining at least two
distinct transformations and resulting in the formation of molecules produced in a
single vessel.
2.4.3.1. Cross-metathesis – access to tetrasubstituted alkenes [WHI 08,

CHU 08, PAE 12]
N N
Cl
Ru
Cl
O
O
O
5 mol% Cl
Cl
Ph-H, 60°C, 18h O
O
97%
Figure 2.21. Key step in the synthesis of elatol
2.4.3.2. Cross-metathesis – Z selectivity [MEE 11, END 11, WER 15]

adamantanamine
or
2,6-dimethylaniline
.. ..
NH2 N N
N N
Mo R1 Rotation Mo R1
O around C-O
Br R2 Br O R2
Br Br
RO
R O
(OR = OTBS)
R1 R2
.. .N
..
N N
N Mo
Mo
R1 CH2
O
O R2 Br
Br
Br
RO Br TBS O
Selectivity Z/E > 96 /4
Figure 2.22. Cross-coupling and Z selectivity

Squamostolide 39
2.4.3.3. Ring-closing metathesis and silylated ethers [EVA 16, CUS 12]
GBII (2 x 1 mol%) PMPO

PMPO OBn O
O O CH2Cl2, 40°C Si O OBn
Si
i-Pr i-Pr i-Pr i-Pr
86% (Z / E > 19:1)
Figure 2.23. Silylated ethers allowing Z-selective metathesis coupling
2.4.3.4. Ring-closing metathesis and ether phosphates [VEN 12]

O O
1) HGII (4 mol%)
O P P OTBS
O benzoquinone O O
O CH2Cl2, reflux O
2) OTBS
H H
HGII (6 mol%)
52%
3) Diimide
Figure 2.24. RCM/CM and selective hydrogenation
2.4.3.5. Domino process: RCM/CM [VIR 03, DRA 06, CRO 10]
O
N N Mes O
Mes
O Cl
Ru Ph O
Cl
PCy3 (5% mol.)
+ C11H23
CH2Cl2, 40°C, 4h
C11H23 75%
Figure 2.25. Domino reaction RCM/CM

2.4.3.6. Domino process: RCM/CM and transfer of alkenyl groups [VIR 04]
N N Mes O O
O Mes
Cl
Ru Ph
Cl O O
O +
PCy3 (5% mol.)
C5H11
CH2Cl2, 40°C, 4h
C5H11
65% 16%
Figure 2.26. Metathesis cyclization and transfer of alkenyl groups
2.4.3.7. Domino process: ROM/Double RCM [HAL 14]
O
1) GBI
O
(10mol%)
( )4 O then
THF, -78°C 2) GBII

O-Li O (5 mol%)
-> r.t. O O
PhMe, Δ O
79% 42%
Figure 2.27. Access to bicyclic macrolides
2.4.3.8. One-pot synthesis: CM/hydrogenation [ZIE 18]

O
O H O
1) GBII (4 mol%)
THF, 40°C, 2h O H
+
2) NaH (0.2 equiv) CO2Me
CO2Me
HCO2H (50 equiv.)
62%
(3 equiv.) 80°C, 90h
Figure 2.28. Tandem cross-metathesis and reduction of the alkene formed

Squamostolide 41
2.4.3.9. Migration of C=C double bonds induced by ruthenium hydrides

[CLA 13, SCH 13]
N N
Mes Mes
Cl
Ru H
OTBS OC OTBS
PCy3
OH OH
n-BuOH
Ph-Me, 95°C, 8h
76%
N N Mes
Mes
Cl
Ru Ph +
Cl
PCy3 OSiMe3
Figure 2.29. Isomerization induced by a ruthenium hydride complex
2.4.3.10. Sequential process: RCM/Oppenauer oxidation/hydrogenation

[LOU 01]
(R)-Citronellal
OH
OH
GBII (7 mol%)
DCE
50°C, 12h
c = 3,4 10-4M
O O
O
H2
NaOH (1.5 equiv.) (800 psi)
OH 80°C, 24h
(R)-Muscone 57%
Figure 2.30. One-pot synthesis of (R)-muscone

2.4.3.11. Domino process: RO–double RCM [MAO 14]
N N Mes H
Mes
Cl N H
Boc 1) Ru Ph CF3CO2
Cl
N PCy3
(15% mol.) TFA
N CH2Cl2, r.t. CH2Cl2, r.t. H
N
Boc H
CF3CO2
54%
Figure 2.31. Access to bipiperidines
2.4.3.12. Alkylation/RCM/Claisen rearrangement [CHA 14]

O O
O
Ph Ph Ph
1) LiTMP ( 3 equiv.) GBII
S Br S THF S
O reflux
O O O O O
(2 equiv.), THF
S
O O 55%
Figure 2.32. Formation of vinylcyclopropanes
2.4.3.13. CM/oxa-Michael reaction [WAL 13, SAN 17]

OH
Et
OH OH
O O
O (20 equiv.)
HG (10 mol%) Et O Et
DCE (0.2M), 80°C
76% (d.r. = 10:1)
Figure 2.33. Tandem CM double reaction and oxa-Michael monoaddition

Squamostolide 43
2.4.3.14. CM/aza-Michael reaction [FUS 12, SAN 17]

PMB
O
O N PMB
H HG (5 mol%) N O
+ F
O
F ( )n Ti(OiPr)4 (10 mol%) ( )n OMe
F
F CH2Cl2, reflux, 8h
OMe
n = 1 - 61%
n = 2 - 51%
Figure 2.34. Tandem cross-metathesis (CM) reaction/aza-Michael addition
2.4.3.15. Alkane group cross-metathesis (AGCM) by dual catalysis

[DOB 13, HAI 12]
R
R
+ + CH3-CH3
[Ir] [Ir]
Dehydrogenation Hydrogenation
[Ir]H2 [Ir]H2
R
R Cross-metathesis
+ + CH2=CH2
Metathesis
catalyst [W]
[Ir] :(tBuPCP) Ir (C2H4)

[W] : W(NAr)(C3H6)(py)(OHIPT)
Figure 2.35. Tandem dehydrogenation/metathesis/hydrogenation reaction
2.4.4.1. Selective reduction of enol ethers [CRO 99, TOH 83]

Hg(OAc)
OCH3 Hg(OAc)2 OH
CHO NaBH4
THF,H2O K2CO3 aq.
C4H9 C4H9 C4H9
82%
2.4.4.2. Bromoacetylation [BEN 92, EL 93]

OH OH OH 1) Ac-Br 2) Ac2O Br OAc Br
(3 equiv.) py
1,4-dioxane
OH OH r.t., 16h OAc OAc
74%
OH
Br Br
O O
O O
2.4.4.3. Mono-etherification of 1,2-diols [RAM 87]
n-Bu n-Bu
Sn OH
OH
O O
Bu2SnO Bn-Br
DMF, 100°C OBn

OH
77%
2.4.4.4. Reduction of alkenes by diimide [SIN 10]
NH2-NH-COO NH2-NH3
O H2O2 O
O O
EtOH, THF, r.t., 12h
72%
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Squamostolide 49
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3
Rubrenolide
Rubrenolide 1 and rubrynolide 2 are two isolated metabolites of Nectandra

rubra, the red louro, a tree endemic to the Amazonian and Guyanese forests. These
butyrolactones differ from each other only by the nature of the unsaturation at the
end of the chain and have insecticidal (larvicidal) properties [FRA 71]. The relative
and absolute configuration of the centers (2S, 4R, 2R') was confirmed by total
synthesis [THI 04].
O O
2'R 2'R
HO HO
2S 2S O
O HO
HO
4R 4R
1 2
Figure 3.1. Structure of rubrenolide 1 and rubrynolide 2. For a color version

of the figures in this chapter see www.iste.co.uk/piva/analysis1.zip
ANALYSIS.– A molecule with 17 carbon atoms with a disubstituted butyrolactone

moiety: a long chain of carbon 10 atoms, fixed at position 5; a chain of three carbon
atoms with a 1,2-diol unit is bonded at the α position of the carboxylic group.
3.2. Disconnections
The butyrolactone unit is common in a large number of natural compounds,

some of which are shown in Figure 3.2 and which have a variety of properties such
as anti-cancer, antiviral, antibacterial, antifungal or anti-inflammatory.
O O
O O
O
O ( )3 N ( )3
H
γ-Decalactone Dubiusamine
H
H
HO2C O O O H
O O O
H
O
H
Cephalosporolide I Arglabin
Figure 3.2. Examples of natural compounds

possessing a butyrolactone framework
As a result, a significant number of methods to prepare the butyrolactone unit

have been reported in the literature [MAO 17, KIT 09]. This diversity is also
reflected in the three approaches described to synthesize rubrenolide.
Figure 3.3. Key disconnections for the lactone structure

Rubrenolide 53
3.3. Approach according to H. Fujioka [FUJ 05, FUJ 08]
3.3.1. Disconnection
The synthesis is based on the involvement of a chiral cyclic ketal 3-C1 in a

double iodoetherification, allowing the stereo-controlled formation of a new bicyclic
ketal 3-B1 whose regioselective cleavage leads to the formation of a butyrolactone
precursor. 1,2-Diphenyl ethanediol (hydroxybenzoin) was chosen for various
reasons:
– easy access by Sharpless asymmetric dihydroxylation of (E)-stilbene;
– the selective cleavage which allows the formation of both a lactol, easily
oxidized to lactone, and also an epoxide, facilitating the subsequent introduction of
an unsaturated carbon chain.
OH I
2'R O
OH Ph
2'R O H
O O
O Ph
2R
D1 D2
2S
O O O
4S I 2'R
4R H 4S
5
( )8 I
5
1 MT ( )8 1
1 3-A 3-B
Ph Ph
O H
O O
D3 D4
3-D1
3-C1
Figure 3.4. Disconnection involving double iodoetherification
LEGEND OF FIGURE 3.4.-

D1: lactone cleavage and functionalization to the diol (tandem epoxide ring
opening/translactonization and further reformation of an epoxide on the lateral
chain).
D2: terminal epoxide from a β-iodoether and a lactone from a lactol (epoxide
cyclization and oxidation).
D3: ketal cleavage and concomitant formation of a five- and eight-membered ring
(bis-etherification and desymmetrization).
D4: ketalization (from a diol of C2 symmetry).
3.3.2. Synthesis, developed by the Fujioka group
Ph Ph Ph
H
CHO O
I O Ph
O O
a b O
H
I
3-C1 3-B1
OH I O Ph
I O Ph O
c OH O OH
O d
H Ph Ph
I I
O I O
O O
e f OH
I
O
( )7
3-C1
O O
O O
g h HO
O OH
( )7 ( )7
Figure 3.5. Synthesis according to Fujioka

a. Ketalization – 83%: (R,R)-hydroxybenzoin, TMS-OTf, TMS-OMe, THF.
b. Bisiodoetherification – 62%: NIS (2.5 equiv.), H2O, CH3CN, -40°C, 3 h.
Rubrenolide 55
c. Ketal cleavage: DDQ, CH3CN, H2O.

d. Oxidation of lactol – 84% (two steps): NaClO2, NaH2PO4, 2-methylbutene,
t-BuOH/H2O.
e. Formation of a benzyl radical at the terminal position/β-elimination/epoxidation
– 80%: (i) CAN, CH3CN, H2O; (ii) K2CO3, CH3CN.
f. Ring opening of the epoxide: CH2=CH2-(CH2)7-MgBr, CuI.
g. Relactonization – 63% (two steps): K2CO3, AcOEt.
h. Ring opening of the epoxide by water – 75%: Bi(OTf)3, CH3CN, H2O.
Number of steps: 8 – Overall yield: 16.3%.
The overall yield of the synthesis is more than appreciable. The crucial step is a
double iodoetherification. The first cyclization stereoselectively delivered a transient
bicyclic oxonium species I, which is directly attacked by water. The free hydroxyl
group of the remaining ketal II further reacts with a second iodonium intermediate.
This second cyclization is assumed to be faster than the cleavage of the hemiketal
which would result in the formation of an aliphatic γ-hydroxyaldehyde.
Ph Ph Ph Ph I
+
O O O
I I
O O Ph
H2O O I+ O H
I+ Ph Ph H-O
H Ph
O O
+ H O
H I I
I II
Figure 3.6. Mechanism of bisiodoetherification
The transformation of the bicyclic diiodo compound requires three successive

oxidation steps to produce a butyrolactone 3C1 possessing two additional
electrophilic sites. Organocuprate reacts mainly with the terminal epoxide. The
alcoholate formed under these conditions is then able to open the existing lactone
ring; a new lactonization occurs and is accompanied by the formation of an epoxide.
This strained three-membered ring is finally opened by water in the presence of
bismuth triflate as a catalyst. It is interesting to note that the (potentially
competitive) attack of the same cuprate on carbon linked to the iodine atom,
followed by the opening of the terminal epoxide ring, would have led to a very
similar structure (in fact the enantiomer) of the expected product (Figure 3.7).
O O
O O
O O
I
R-MT
R R
O
O
I
O
O
R O O
R-MT O
O
O
R
Figure 3.7. Epoxy ring opening versus direct alkylation
3.3.3. Key reaction: iodoetherification
Haloetherification of alkenes allows the functionalization at the vicinal positions

of a double bond. In intermolecular mode, regioselectivity depends on steric
hindrance and electronic effects related to the nature of the substituents present on
the double bond. The intramolecular process is much more attractive because the
formation of cyclic structures can be predicted by Baldwin’s rules [BAL 76, ALA
13]. Out of all the processes involving halogens, iodoetherification (and
lactonization) has developed most strongly [FUJ 12, SIM 94, ROU 97]. The
electrophilic species may be the diiode itself, as well as more elaborate complexes
such as Rousseau’s reagent (bis(sym-collidine)iodonium perchlorate or
hexafluorophosphate). Hydroiodic acid is most often neutralized by sodium
carbonate, in order to avoid any subsequent reaction. In addition to its ease of
implementation, the reaction is most attractive because of its stereospecificity; by
controlling the E or Z configuration of the double bond that will be activated, the
relative stereochemistry of the two new contiguous centers can be predicted. These
different aspects reflect the interest in accessing tetrahydrofuran or tetrahydropyran
subunits widely present in natural products.
Ph Ph Ph Ph
Ph Ph
O O
O O I(coll)2ClO4
O O+
Bn-OH, CH2Cl2 I O
-78°C -> r.t. - I
ClO4 Ph
Ph OH
74% (dr 90/10)
Figure 3.8. Ketal-assisted iodoetherification

Rubrenolide 57
3.3.4. Key reaction: oxidation of aldehydes to carboxylic acids
The direct oxidation of primary alcohols to carboxylic acids very often requires
drastic conditions that are difficult to reconcile with the presence of labile functions.
The conversion of alcohol into aldehyde followed by a second oxidation step into
the expected acid is nowadays the most commonly applied strategy in synthesis. The
use of sodium chlorite (NaClO2) was initially reported by B. O. Lindgren for the
oxidation of vanillin to vanillic acid [LIN 73]. G. A. Kraus significantly improved
the modus operandi by associating 2-methyl-2-butene, an electron-rich alkene, to
trap hypochlorous acid formed in situ [KRA 80].
Na+ ClO2- + NaH2PO4 H-O-Cl=O + Na2HPO4
H
O
H
O
O R H H O
R H + Cl R Cl
O O
O O
Cl
H
O
Cl
O OH
H
R O
+
HO-Cl
Figure 3.9. Oxidation mechanism according to Lindgren–Kraus–Pinnick
The subsequent work of H. W. Pinnick, whose contribution somewhat evaded

that of the first inventors, showed the general nature of the process, which has since
been very widely applied to the synthesis of molecules of interest and in total
synthesis [BAL 81, MAT 11, ZHA 15].
OMe O OMe O
Cl NaClO2 (3 equiv.) Cl
H NaH2PO4 (3 equiv.) OH
2-methyl-2-butene
BnO (4 equiv.) BnO
Cl THF/t-BuOH/H2O Cl
25°C, 3h 95%
Figure 3.10. Oxidation of an aldehyde to benzoic acid

H NaClO2 (3 equiv.) H
NaH2PO4 (3 equiv.)
2-methyl-2-butene
(4 equiv.)
OHC H O HO2C H O
t-BuOH/H2O
25°C, 3h
91%
Figure 3.11. Access to spiculoic acid
3.3.5.1. Ketalization [FAU 01, TSU 80]

O
O O
TMSO OTMS
TMSOTf
O O
CH2Cl2, -30°C
O O 82%
3.3.5.2. Hydrolysis of ketals under oxidizing conditions [FER 95, TAN 92]
O HO
O HO O
HO O DDQ (1 equiv.) HO
O CH3CN / H2O, O
O 20°C, 48h O
100%
3.3.5.3. Opening of epoxides by zinc compounds [DEL 03, PIN 04]

(CH3)2Zn
OH
O O
P
O
65%
Cu(OTf)2 e.e. > 90%
PhMe, -78°C -> 0°C (1.5 mol%)
Rubrenolide 59
3.3.5.4. Opening of epoxides catalyzed by Bi(OTf)3 [OLL 04, MOH 00]

NH2
OH
Bi(OTf)3 10% mol. in water
O +
hexanes or Et2O
NHPh
25°C, 7-9h
83%
3.4. Approach according to B. Zwanenburg

3.4.1. Retrosynthesis
The retrosynthesis envisaged involves a post-functionalization at α of the lactone
functional group [THI 04]. In order to control the relative stereochemistry between
the substituents at position 3 and 5, a three-step process has been chosen: it requires
an aldolization, crotonization and hydrogenation reaction of the double bond on the
less cluttered side, the aldehyde used during condensation being the appropriately
protected glyceraldehyde. Access to the five-membered heterocyclic compound
results from the lactonization of the γ-hydroxyester 3'C. The latter is derived from
the Wolff photochemical rearrangement of an α'-diazo-α, β-epoxyketone. This diazo
reagent is obtained by the Arndt–Eistert reaction, from the α,β-epoxy acid 3'-F,
itself derived from the trans epoxy alcohol 3'-G.
D1
OH HO D2 O
OH D1 D2 O
8( )
O
O ( )8 O
O
3-A2
OR OR
RO
D3 D4 D5
O
( )8 CO2Et ( )8
( )8 O
O
O
OH
2 2
3-B 3-C 3-D2
OR OR OR
D6 N2 D7 D8
( )8 ( )8 X ( )8 OH
O O O
O O
2 2 2
3-E 3-F 3-G
Figure 3.12. Retrosynthesis envisaged by the Zwanenburg group

D1: generation of the terminal double bond (elimination).
D2/D3: cleavage of α- of the lactone functional group (introduction of the side

chain via an alkenylation followed by the reduction of the double bond).
D4: butyrolactone formation (hydrogenation/cyclization under acidic medium).
D5: formation of unsaturated γ-hydroxyester (epoxyketene alcoholysis).
D6: epoxyketene (Wolff rearrangement of an epoxy α-diazoketone).
D7: generation of epoxy-α-diazoketone (action of CH2N2 on an activated ester).
D8: obtaining an acid from an epoxy alcohol (Pinnick’s oxidation).
3.4.2. Synthesis, Zwanenburg’s approach
3.4.2.1. Access to lactone 3-B2

HO ( )8 OH a Br ( )8 OH b Br ( )8 OTHP
OH
c THPO ( )8 d THPO ( )8
OH
O O
e THPO ( )8 f,g THPO ( )8 CO2H
OH
O O
O O
h THPO ( )8 i THPO ( )8
O
N2
i-Bu-O O 3-E2
OH
8 8
j HO () OEt k, l, m ()
O
O
THPO
2 O 2
3-C 3-B
Figure 3.13. Synthesis of lactone 3-B2

a. Bromination – 73%: HBr (48% aq.), hexanes, 80–100°C, 60 h.
b. Protection of alcohol as a THP ether – 94%: DHP, TsOH, CH2Cl2, 0°C, 2 h.
c. Nucleophilic substitution – 99%: LiNH2 (6 equiv.), 2-propyn-1-ol (1,3 equiv.),
THF, -40°C then r.t.
d. Reduction of the triple bond – 99%: LiAlH4, Et2O/THF, -60°C -> r.t. -> 40°C, 12 h.
Rubrenolide 61
e. Sharpless epoxidation – 69%: (-)-DET, Ti(OiPr)4, t-BuOOH, CH2Cl2, −25°C,

12h.
f. Oxidation according to Swern: (i) Oxalyl chloride, DMSO, CH2Cl2, −60°C;
(ii) Et3N, CH2Cl2, -60°C r.t.
g. Oxidation of the aldehyde into acid according to Lindgren–Kraus–Pinnick
process: NaClO2, t-BuOH, isobutene, NaH2PO4, H2O, r.t.
h. Activation of acid by formation of mixed anhydride: Isobutyl chloroformate,
Et3N, Et2O, 0°C.
i. Formation of diazoketone 3-E2 – 68% (four steps): CH2N2, Et2O, −30°C.
j. Photorearrangement of diazoketone 3-E2: hν (300 nm), EtOH (10-2 M), 4 h.
k. Reduction of conjugated double bond – 57% (two steps): Ni(OAc)2,
NaBH4, EtOH.
l. Lactonization – 99%: TsOH (cat.), PhH, Δ.
m. Protection of primary alcohol: DHP, TsOH, CH2Cl2, 0°C, 2 h.
3.4.2.2. Completion of the synthesis

O O
HO
O O
n o O
3-B2 O ( )8
( )8 O
O
OTHP OTHP
OH
O
OH O
p O q, r O
( )8 ( )8
O O
OH OH
3-A2
O
OH
O OH
s, t u
O 8( )
O
O
8( ) O
1
Figure 3.14. Completion of the synthesis

n. Aldolization – 26%: (i) LDA, HMPA, THF, -70°C; (ii) (S)-isopropylidene
glyceraldehyde, 16 h.
o. Elimination via mesylate – 72%: (i) Ms-Cl, Et3N, CCl4; (ii) DBU, ether, r.t.
p. Deprotection of the acetonide group and THP – 70%: MeOH, TsOH, r.t.
q. Diastereoselective hydrogenation – quantitative: H2, Pd/C, MeOH.
r. Reprotection of the 1,2-diol as an acetonide – 73%: acetone, TsOH, 30 min.
s. Arylselenation – 91%: o-nitrophenyl-selanyl cyanide, PBu3, THF, 2 h, r.t.
t. Oxidation/β-elimination of selenoxide: H2O2, THF, r.t.
u. Acetonide deprotection – 60% (two steps): p-TsOH, MeOH, r.t.
Butyrolactone is obtained via the acid-catalyzed cyclization of a chiral

γ-hydroxyester. The control of this center is ensured from the fifth stage thanks to
the Sharpless epoxidation of a trans-allyl alcohol. A second center at the base of a
hydroxy group and located on the side chain at position 3 comes from the chiral pool
(glyceraldehyde). The step with the lowest yield (aldolization with only 26% yield)
is followed by crotonization. The presence of the side chain at position 5 allows a
diastereoselective hydrogenation to be carried out, which leads to a product that is
mainly syn. The terminal unsaturated bond is generated from an alcohol and the use
of selenium derivatives that are quickly removed under mild conditions (Grieco’s
reaction).
The major disadvantage of this synthesis is that it is totally linear, which results
in a very low overall yield.
3.4.3. Key reaction: Wolff rearrangement
The Wolff rearrangement allows the formation of a ketene from an α-diazo

ketone. Its decomposition can be thermally initiated by UV light or by
organometallic catalysis (silver salts); the intermediate is most often trapped by a
nucleophilic species, such as ethanol, used as a solvent [KIR 02, FOR 15, FUS 17].
O hν O
O
R2 or Δ R2
R1 R1
R1
or Ag+ N
N
R2
N N
O
R1
Nu-H R2
C O Nu
R2 R1 H
Figure 3.15. The Wolff rearrangement

Rubrenolide 63
Diazoketones from α,β-epoxyacids similarly lead to epoxyketenes, which after

nucleophilic attack by an alcohol result in unsaturated γ-hydroxyesters [THI 90].
H Et
O
1) iBuCO-Cl N2 O
O O
Et3N, ether hν O
R C
R CO2H 2) CH2N2 R EtOH
O
OH
EtOH OEt
R 46-63%
1,5-2h H
O
Figure 3.16. The Wolff rearrangement of α,β-epoxyacids
3.4.4. Key reaction: dehydration of alcohols according to Grieco
NO2 NO2 OH
R
CN
Se Se
PBu3
PBu3 CN
H-CN
H
O
Se-Ar R PBu3
R
O Se
H2O2 P
Bu Bu
Bu NO2
H O
Se-Ar R + Ar-Se-OH
R
Figure 3.17. The Grieco elimination mechanism
A very effective method of forming terminal alkenes from the corresponding

primary alcohols was reported by Paul Grieco in 1976 [GRI 76]. It consists of the
formation of an aryl selenide with the irreversible formation of a tributylphosphine
oxide. At room temperature, the selenide is oxidized by hydrogen peroxide or
m-CPBA to produce a selenoxide, which is immediately syn-eliminated and results
in the formation of the expected alkene. This efficient method is far preferable to
acid eliminations that may be accompanied by migration or Wagner–Meerwein-type
rearrangements. It can also be highly regioselective; all of these factors have

contributed to its reputation as a total synthesis [MAR 79, ZHO 02].
OH SeAr
O O
O O
O O OH
OH OH H 2 O2
Ar-SeCN (30%)
H H
PBu3 H r.t.
THF
MeO2C MeO2C
MeO2C
86% 98%
O O
N OH 1) Se-CN N
2) NaIO4
NaHCO3
NO2
N H PBu3, THF, r.t. CH3OH N H

O O
50°C
CH3 CH3
86%
Figure 3.18. Applications of Grieco’s reaction in total synthesis
3.4.5.1. Formation of bromoalcohols from 1,n-diols [KAD 03, END 91,

CHO 00]
HBr aq. 48%
HO ( )n OH HO ( )n Br
n-Bu4NBr, μυ, 5min
n = 1-8 75-80%
3.4.5.2. Enantioselective epoxidation according to Sharpless [KON 07,

KAT 80, HER 15]
HO CO2iPr
(-)DIPT
HO CO2iPr
OH Ti(OiPr)4, t-BuOOH OH
CH2Cl2, -30°C, 3h O
75% (e.e. = 93.6%)

Rubrenolide 65
3.4.5.3. Reduction of α,β-unsaturated esters [RUS 71]
Ni(OAc)2, EtOH, H2
CO2Et NaBH4 CO2Et
100%
3.5. Approach according to N. Kommu [MAD 14]
3.5.1. Disconnections
The synthesis is based on the direct construction of a lactone subunit by

oxidation of a 1,4-diol. The two stereogenic centers present on the five-membered
ring are created respectively by an alkylation reaction involving an Evans
oxazolidinone, and by a stereo-controlled reduction of a ketone. The terminal
1,2-diol group on one of the two side chains results from a chironic approach from
ascorbic acid. The terminal double bond is generated by partial hydrogenation of a
triple bond, itself accessible from an aldehyde by the Ohira–Bestmann reaction, an
alternative to the Corey–Fuchs reaction.
HO RO
HO RO
O ( )8 HO ( )8
O HO
3-A3
RO RO
RO RO
R'O R'O
O O
P OMe
( )7 OMe
O
CHO
3-B3 3-C3
O O
O O CO2H
O NX*
3-D3 3-E3
Figure 3.19. Disconnection according to N. Kommu

3.5.2. Synthesis
3.5.2.1. Access to β-ketophosphonate 3-C3

O O
CO2H
a, b N O
O O
O O
Ph
3-D3
OTPS OTPS
c, d O e O
O O H
O
OMe
OMe
P OMe HN O P OMe
f, g O
O O O O
Ph
TPSO XN* 3-F3
3-C3
Figure 3.20. Synthesis of β-ketophosphonate 3-C3

a. Formation of acyl oxazolidinone – 88%: Piv-Cl, Et3N, XN*, LiCl, THF, −20°C.
b. Diastereoselective alkylation – 65%: (i) NaHMDS, THF, -78°C, 1 h; (ii) Allyl

bromide, -45°C, 4 h.
c. Reduction in primary alcohol – 88%: LiBH4, MeOH, ether, 0°C - r.t., 3 h.
d. Protection of the alcohol as a silyl ether – 94%: TPS-Cl, imid., CH2Cl2, 0°C.
e. Ozonolysis in reducing medium – 85%: O3, CH2Cl2, -78°C, then Me2S, r.t., 14 h.
f. Addition of methylphosphonate to the aldehyde: 3-F3, n-BuLi, THF, −78°C.
g. Oxidation of β-hydroxyphosphonate to ketone – 84% (two steps): DMP,

NaHCO3, CH2Cl2, r.t., 1 h.
Rubrenolide 67
3.5.2.2. Continuation of the synthesis

h i H ()6 OBn
HO ()6 OH HO ()6 OBn
O
3-G3
O O
O O
j ()6 k-m
( )7 OH
O OBn OTBS
TPSO TPSO
O O
MeO P
O O OMe
MeO
O O N2 3-H3
n o
( )7 ( )7
OTBS CHO OTBS

TPSO TPSO
3-I3
Figure 3.21. Access to alkyne 3-I3

h. Mono-etherification – 84%: NaH, BnBr, DMF, -10°C -> r.t., 6 h.
i. Oxidation of primary alcohol according to Swern – 87%: (i) (COCl)2, DMSO,
CH2Cl2, -78°C; (ii) Et3N, CH2Cl2, -78°C, 1 h.
j. Wittig–Horner condensation – 76%: (i) phosphonate 3-C3, Ba(OH).8H2O, THF,
2 h; (ii) aldehyde 3-G3, THF/H2O (40: 1), r.t., 6 h.
k. Enantioselective reduction of enone to allyl alcohol – 83% (d.r. = 95:5):
(R)-CBS (1 equiv.), BH3. Me2S (1.5 equiv.), THF, -40°C, 8 h.
l. Alcohol protection – 93%: TBS-OTf, 2,6-lutidine, CH2Cl2, 0°C, 2 h.
m. Hydrogenation of the double bond and hydrogenolysis of benzyl ether – 86%:
H2, Pd/C (10 mol%), AcOEt, r.t., 6 h.
n. Oxidation of alcohol to aldehyde: DMP, NaHCO3, CH2Cl2, 0°C, 2 h.
o. Ohira–Bestmann reaction – 78% (two steps): Reagent 3-H3, MeOH, K2CO3, r.t.,
1 h.
O O
O O
( )8 p
OTBS OH
TPSO HO
3-I3 3-A3
O HO
O HO
q r, s
O ( )8 O ( )8
O O

p. Deprotection of the two silylated ethers – 76%: TBAF, THF, 0°C -> r.t., 12 h.
q. Oxidation of diol to lactone – 90%: TEMPO, BAIB, CH2Cl2, r.t., 6 h.
r. Ketal cleavage – 92%: HCl (2 M), THF, r.t., 2 h.
s. Reduction of alkyne to alkene according to Lindlar – 90%: H2, Pd/ BaSO4,
quinoline, r.t., 9 h.
3.5.3. Key reaction: diastereoselective alkylation of oxazolidinones
Evans’ oxazolidinones are the chiral auxiliaries of choice for the creation of
stereo-controlled centers in α-position of a carboxylic group [EVA 82]. Prepared
from β-aminoalcohols from (2S)-amino acids such as valine, or alkaloids
(norephedrine) and trisphogen, they are easily grafted onto an acid chain. The
deprotonation of acyloxazolidinones results in enolate structures with
Z configuration, the metal being chelated to the oxo group. This conformation favors
the selective approach at low temperature of an electrophile to one of the two sides
of the enolate. The highest selectivities are achieved with methyl iodide, allyl or
benzyl bromides and are in the range of 90–99%; with other less activated or more
cluttered electrophiles, higher reaction temperatures are required to collect products
with similar yields, but at the expense of selectivities.
Rubrenolide 69
O
NH2 NH2
O H
LiAlH4 trisphosgene O N
HO THF HO
O O O O
2)
H R1 R1
O N 1) n-BuLi Cl O N
THF, -78°C
Li O O
O O O
O
R1
R1 R1 O N
O N LDA O N E
E
THF THF
-78°C -30°C
76% < d.e. < 98%
Figure 3.23. Alkylation involving an Evans oxazolidinone from (S)-valinol
During the deprotection step of the chiral auxiliary, the lithium hydroxide
associated with H2O2 makes it possible to generate a nucleophilic reagent that is less
basic than hydroxide ions, thus minimizing the risk of racemization of the new
center created.
Alternatively, direct product reduction allows access to primary alcohols without

a significant variation in selectivity.
In order to obtain the α-substituted carboxylic derivative with the opposite

configuration, two complementary methods can be considered:
– Use a chiral auxiliary with the opposite configuration; instead of involving
unnatural (2R)-amino alcohols, the simplest way is to consider commercial
derivatives of norephedrine, whose use is sadly regulated because of their potential
precursors to synthetic drugs.
– Do not change the initial auxiliary, but modify the order of electrophile
introduction, i.e. first graft the R2 group on the acid chain, and then introduce the R1
group via a suitable electrophile.
Li
O O O O O O O O
R1 R1 R1 R1
O N a O N b O N O N
R2 + R2
92 8
Li
O O O O O O O O
R2 R2 R2 R2
O N a O N c O N O N
R1 + R2
92 8
Conditions: (a) LiHMDS, THF, -78°C then 0°C; (b) R2-X (1.1 equiv.) or (c) R1-X (1.1 equiv.)
Figure 3.24. Reversal of the configuration of the new center

from the same Evans oxazolidinone
Li
O O O O O O O O
Ph Ph Ph Ph
O N a O N b O N O N
+
(S)-valinol series 92 8
Li
O O O O O O O O
Ph Ph Ph Ph
O N O N O N O N
a b
+
(S)-t-leucinol series 98.5 1.5
Li
O O O O O O O O
Ph Ph Ph Ph
O N a O N b O N O N
+
(S)-dimethylvalinol series
97 3
Conditions: (a) LiHMDS, THF, -78°C then 0°C. (b) Me-I (1.1 equiv.)
.
Figure 3.25. Evans’ oxazolidinones from (S)-valinol and SuperQuat®

Rubrenolide 71
In the case of β-amino alcohols, it is expected that the excesses will be greater
the bulkier the grouping fixed to α- of the nitrogen atom. Thus, the selectivities
obtained from t-leucine derivatives are very impressive, the disadvantage being to
the detriment of the precursor. D. Seebach and S. Davies have in turn developed
chiral reagents called “SuperQuat®” derived from the same inexpensive amino
acids, but with almost as good a selectivity as with the t-leucine derivative [HIN 98,
BUL 00, BUL 06, DAV 19].
The significant difference in selectivity between the valinol derivative and the
one with two additional methyl groups (without creating a new stereogenic center)
could be explained by measuring NOE effects in 1H-NMR spectrometry from
lithium enolate structures. In valinol series, in order to minimize interactions with
the enolate part, the hydrogen atom Ha is placed in the bisector plane derived from
the two methyl groups of the isopropyl group. In SuperQuat series, due to the
presence of the two methyl groups at the base of the oxygen atom, it is the hydrogen
atom Hb which is placed in the median plane with the effect of bringing the
isopropyl group closer to the nucleophilic site, thus allowing a better facial
discrimination of an electrophile.
Li O
Li O H3C O H
H O H O N H
O N H
H3C CH3
H3C Hb
Ha H
NOE NOE CH3
H3C
Valinol series Super Quat series
Figure 3.26. Change in conformation due to the introduction of a

gem-dimethyl group on the heterocycle compound
3.5.4. Key reaction: enantioselective reduction of ketones – CBS

method
The CBS method – Corey–Bakshi–Shibata – allows the enantioselective

reduction of ketones by the action of a chiral oxazaborolidine (most often derived
from diphenylprolinol) and borane [COR 98, CHO 06]. The catalyst can be prepared
in situ from amino alcohol and an alkylboronic acid in toluene and using a
Dean–Stark apparatus [COR 87].
The reaction is extremely efficient when the carbonyl substrate has a very
marked substitution difference, ideally bonded at α to a hybridized carbon atom sp3
and in α’ to a hybrid carbon atom sp2.
Enantiomer excess (ee) can be increased by altering the nature of the group fixed
to the boron atom, that of the associated reducing reagent (Borane–THF,
catecholborane, etc.), and also the temperature. Selectivity at the transition state
level results from the minimization of interactions (typically of a steric nature)
between the substituent attached to the boron atom of the chiral auxiliary and the
least bulky group Rs of the carbonyl compound.
H
H Ph
Ph HO OH Δ N Ph
N Ph + B
H Ph-Me B O
HO Alk
Alk
(S)-CBS
H Ph
Ph
O
BH3
O
(S)-CBS N+ RS RL
B
H 3B
- Alk
OH
RS RL #
Ph Ph
H
H O
N - H RL
+ BO
C
B
H RS
Alk
H Ph
Ph
+ O H RL
N
B
- O RS
H 2B
CH3
Figure 3.27. Enantioselective reduction of ketones via the CBS method
This method published in 1987 by Corey et al. is similar to a process published a

few years earlier by Itsuno and his team on the reduction of ketones and imines,
involving an acyclic aminoalcohol derived from (S)-valine [ITS 83].
Nevertheless, the very large excesses and ease of implementation of this reaction
have led to its very high profile and widespread use in total synthesis.
Rubrenolide 73
3.5.5. Key reaction: alkyne formation according to Ohira–Bestmann
The Ohira–Bestmann reaction allows access to a terminal alkyne from an

aldehyde with an additional unit at the end of the carbon chain. Initially described in
1989 by Ohira, the reaction was carried out in two stages: (i) preparation of the
reagent from 2-oxopropylphosphonate; (ii) action of the reagent on an aldehyde in a
basic medium [OHI 89]. The modifications made by Bestmann allowed the reagent
to be generated in situ and access the alkyne in one step with a similar yield
[ROT 04, PIE 06].
O O O O
1) NaH, PhMe P
MeO P MeO
MeO 2) Ar-SO2-N3 MeO
N
THF, 0°C
N 77%
Figure 3.28. Ohira–Bestmann reaction
From a mechanistic point of view, a retro-Claisen reaction by the action of

sodium methoxide leads to a phosphonium ylide which immediately interacts with
an aldehyde to give an oxaphosphetane whose decomposition leads to an acetylide,
which is reprotonated using a protic solvent.
O
O O O O O
H R
MeO P MeO P MeO P R
MeO MeO-K MeO MeO H
N MeOH N N
N N N
O O H R H R
N2 R R
MeO P R
C C MeO-K
MeO H
N N N
H K+
N N N
Figure 3.29. Ohira–Bestmann reaction mechanism
It is also possible to prepare the carbonyl compounds from benzyl alcohols using
MnO2, then subjecting them to the Ohira–Bestmann reaction to directly access the
expected alkynes [QUE 06].
OH O O
CHO
MeO P
Br Br MeO Br
MnO2, THF N2
THF, 4-24h MeOH, K2CO3

r.t., 12h 94%
Figure 3.30. Tandem oxidation reaction/Ohira–Bestmann reaction
3.5.6.1. The Swern oxidation [MAN 78, TID 90]

O
Cl O
1) Cl
OH + DMSO H
O
CH2Cl2, - 65°C
2) Base, - 65°C
Et3N 72%
iPr2NEt 85%
3.5.6.2. Wittig–Horner reaction [PAT 93]

O O
P
MeO
MeO
Ba(OH)2
+
THF (40:1) OBn O O O
60°C, 20h Si
CHO t-Bu t-Bu
OBn O O 72%
Si
t-Bu t-Bu
3.5.6.3. Oxidation of 1,4-diols by TEMPO/DAIB [NOM 14, HAN 03]
HO O O
OTPS TEMPO, BAIB OTPS
HO
CH2Cl2 / H2O (1:1)
0°C -> r.t., 5h 81%
Rubrenolide 75
3.5.6.4. Oxidation of 1,4-diols to butyrolactones [LEY 94]

OH TPAP O
(Pr4N)[RuO4]
O
(5 mol%)
NMO (1.5 equiv.)

OH CH3CN / CH2Cl2 (9:1)
90%
3.5.6.5. Controlled hydrogenation of alkynes to alkenes [UEM 07]

O
O
H2
O O OBn
MPMO Lindlar MPMO
OBn catalyst
O O
AcOEt
99%
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Rubrenolide 77
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Rubrenolide 79
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4
Bipinnatin J
Isolated from gorgonians of the genus Pseudopterogorgia, bipinnatin J 1 belongs

to the furanocembrane family of natural products and has cytotoxic activities against
colon cancer or certain melanomas. It is considered a biosynthetic precursor of other
complex polycyclic compounds such as intricarene 2 [TAN 06, ROE 06b].
OH
O O
H O
O H O
O
O
1 2
Figure 4.1. Structures of bipinnatin J 1 and intricarene 2. For a color

version of the figures in this chapter see www.iste.co.uk/piva/analysis1.zip
ANALYSIS.– Fourteen-membered macrocycle with a butenolide moiety, a furan ring

and a trisubstituted double bond. The molecule has three stereogenic centers, two of
which are contiguous, one united in a homoallylic alcohol subunit characteristic of
cembranoids.
4.2. Disconnections
The four syntheses described are all based on two main disconnections:
the closure of the large cyclic ring from the same 4-A substrate via a
Nozaki–Hiyama–Kishi reaction, on the one hand, and the stereo-controlled
formation of a Z-trisubstituted C=C double bond directly linked to the furan unit, on
the other hand.
OH
CHO
O O
Br
D1
O O
O O
4-A
D2
X
OR
M CHO
O
O
4-C
O
4-B
Figure 4.2. Key disconnections included for the four approaches
D1: ring closure (intramolecular Nozaki–Hiyama–Kishi reaction).

D2: stereo-controlled fixation of a furan to a double bond with Z configuration
(organopalladium coupling).
Bipinnatin J 83
4.3. Approach according to D. Trauner (racemic synthesis) [ROE 06a]
4.3.1. Synthesis
The synthesis of this cembranoid is based on the construction of the

14-membered ring, by intramolecular Nozaki coupling between an aldehyde and an
allyl bromide involving chromium (II) salts. The triple-substituted double bond of
configuration (Z) is obtained by the carboalumination of butynol, the alcohol
functional group being involved in the control of selectivity. The butenolide subunit
is achieved by the ene reaction catalyzed by ruthenium salts between a γ-hydroxy
ester propiolic and an alcohol. A Stille coupling is also involved to synthesize the
precursor of macrocyclization. This is accompanied by selectivity in favor of the
expected compound.
4.3.1.1. Access to 4-B1 lactone

H
a b
OH O
OH
I I
OH CO2Et
OH
c d
I
I CO2Et
OH
O CHO O
OH
O O
e f, g
I I
4-B1
Figure 4.3. Formation of the lactone pattern 4-B1


a. Carboalumination/iodination of butynol – 60%: (i) Me3Al, Cp2ZrCl2, CH2Cl2;
(ii) I2.
b. Oxidation according to Dess–Martin: (i) Periodinane DMP (1.05 equiv.),
CH2Cl2, 15 min.; (ii) NaHCO3 aq.
c. Addition of an acetylide to aldehyde – 66% (two steps): ethyl propiolate, LDA,
THF, −78°C.
d. Ene reaction: allyl alcohol, catalyst A-2 (5%), THF/acetone, 50°C.
e. In situ Lactonization – 52%: CSA, THF/acetone.
f. Wittig reaction – 71%: Ph3P=CH(CH3)CHO, PhH.
g. Reduction of unsaturated aldehyde to allyl alcohol – 99%: NaBH4,
MeOH, r.t.
+
Catalyst A-2 : Ru(N C-CH3)3

PF6
4.3.1.2. Access to the synthon 4-C1
a' OLi
Li
O
CHO Bu3Sn CHO
O N O
OMe
1
4-C
Figure 4.4. Synthesis of the synthon 4-C1

a'. Protection and ortholithiation of 3-methylfurfural – 85%: (i) n-BuLi,
MeONHMe, THF, −40°C; (ii) Me3Sn-Cl; (iii) NH4Cl aq.
Bipinnatin J 85
O OH O Br
O O
h i O
4-B1 O 10
O O
H H
4-A1
O
O
O
OH
j 1'
O +
O
OH
O
OH
1"

h. Stille coupling – 92%: 4-C1 (1.3 equiv.), Pd(Ph3)4 (4%), CuI (8%), CsF
(2 equiv.), DMF, r.t., 20 min.
i. Conversion of alcohol to bromide – 87%: NBS (1.1 equiv.), PPh3 (1.1 equiv.),
CH2Cl2, −5°C, 20 min.
j. Nozaki–Hiyama–Kishi reaction – 59%: CrCl2 (12 equiv.), NiCl2 (3 equiv.),
4 Å sieves, THF, 12 h, r.t. Ratio (1/1'/1'' = 73/12.7/5.8).
4.3.2. Key reaction: ene reaction between alkynes and alkenes
H R1 R2
+
R2 R3 + R3
R1 E'
H
Ru
+
L L
R1 R3 L
R2 R1 > R2
E A
Reductive
elimination
+ + + +
R3 R3 R1 R3 R3
Ru H
+ Ru H Ru + R2 Ru
R2 R1
R2 R1
R1 D' R2 D B B'
+
H
Ru
R1
Hydride R3 Oxidative
β-elimination cyclization
C
R2 +
+
H
Ru
R2
R3
R1 C'
Figure 4.6. An ene reaction involving an alkyne and an olefin
The ene reaction between an alkyne and an olefin results in the formation of
1,4-dienes. Trost et al. showed that cationic ruthenium complexes were able to
catalyze the reaction. This is accompanied by high regio- and stereoselectivity,
which makes it an attractive method, particularly for the synthesis of trisubstituted
olefins. The proposed catalytic cycle includes four steps: (1) an exchange of ligands
around the metal; (2) the formation of a metallacycle by oxidative cyclization; (3) a
β-elimination leading to a ruthenium-hydride complex; (4) an irreversible reductive
elimination step, regenerating the catalyst and leading to dienes E and E' [TRO 99,
TRO 02].
Regioselectivity in favor of alkene E depends on the favored obtaining of

metallacycle C rather than C' which corresponds to a minimization of interactions
between the largest substituent R1 and the terminal site of the alkene [TRO 02]. The
catalyst A-2 [CpRu-MeCN)3]PF6 is much more active than A-1 CpRu(COD)Cl and
Bipinnatin J 87
allows the desired transformation to be carried out at room temperature instead of at

65°C, in a polar solvent such as DMF. In the case of propiolic acid derivatives,
regioselectivity is reversed and the carbon chain is fixed on α-position to the ester
subunit.
OH
OH
Ru(N C-CH3)3
PF6 H
H
A-2 (10% mol.)
+ ( )7
H DMF, r.t. H CO2Me
CO2Me
( )7
91%
OH
( )14 O
O OH
CO2Me
H A-2 (10% mol.)
( )14
DMF, r.t.
OH
83%
Figure 4.7. Separate regioselectivities according to alkyne substitution
R3 R2 R3
R2
R3 R2
A-3
+
(10% mol.) Ru R1
O
Ru
HO HO R1 DMF, r.t. H O
O R1 O
H H
H
R3 R2
A-3 : Cp* Ru(N C-CH3)3 R1

PF6 OHC
68-92% OH
Figure 4.8. An ene reaction between an allyl alcohol and a propargyl alcohol
The coupling between two alcohols makes it possible, via hydrogen bonds, to
promote the regioselective formation of hydroxyaldehydes (reduced in situ by
NaBH4) [RUM 17].
4.3.3. Key reaction: Stille coupling
The synthetic interest of coupling halogenated (or pseudohalogenated) aryl and

vinyl derivatives with organotin compounds, catalyzed by palladium salts, was
demonstrated by the Stille group in 1978 [MIL 78].
O O
Ph-CH2Pd(PPh3)2Cl
Cl Me
Me3Sn-Me (0.0005 equiv.)
+
(1.01 equiv.)
NC HMPA, 65°C NC
99%
Figure 4.9. Initial Stille reaction: ketone formation
The reaction tolerates the presence of many functional groups and despite the
relative toxicity of tin salts, it has been widely used for the synthesis of bioactive
molecules, with various procedures now available to ensure that the final products
are minimally contaminated with stannylated residues [COR 15, HER 18]. Using
proven methods, whether through the ortholithiation of aromatic derivatives, or the
regio- and stereoselective hydrostannylation of terminal alkynes, the synthesis of
precursors is relatively easy and controlled. All these factors have contributed to its
development. The (simplified) reaction mechanism can be represented according to
a conventional catalytic cycle for palladocatalyzed reactions involving an oxidative
addition step, a trans-metalation followed by isomerization, and then a reductive
removal to regenerate the catalyst. It seems that depending on the nature of the
starting group, that of the reaction medium (solvent, presence of additives), several
reaction paths must be considered.
A synergistic effect of copper(I) salts and fluoride ions has been demonstrated
when the Stille reaction is carried out in a polar solvent such as DMF. Copper(I)
iodide participates in transmetalation with the stannyl derivative to give a more
reactive organocopper derivative, while the fluoride ion participates in the
precipitation of tin salts in the medium, making the transmetalation reaction
irreversible [MEE 04, MEE 05]. These same fluorides also affect the reducing
elimination step [GRI 17].
Bipinnatin J 89
R1-X
PdLn
R1-R2
Oxidative
addition
Reductive
elimination Isomerization
R1 R1
R2 Pd L L Pd L
L X
Isomerization Transmetalation R2-SnBu3
R1
X-SnBu3
L Pd L
R2
Figure 4.10. Catalytic cycle of the Stille reaction
L R1 R1
(II) L (II)
Pd Pd
R2 L X L
Cu-X R2-Cu Cu-I
CsF
F-Sn(R3)3 I-Sn(R3)3 R2-Sn(R3)3
+ Cs-I
Figure 4.11. Synergy of copper(I) salts and

fluoride ions during the transmetalation step
OPMB OH OPMB OH
Me4Sn (7.6 equiv.)
CO2Me Pd(PPh3)4 (0.05 equiv.) CO2Me
CuI (0.2 equiv.) Me

I
CsF (2.0 equiv.)
DMF, 45°C, 1h 75%
Figure 4.12. Stille reaction: introduction of a methyl group [HAL 14]
OMe OMe
Br
O Bu3Sn O
Ac Ac
N Pd(Ph3)4, CsF N
H H
OMe O CH3CN, 100°C, 6h OMe O
O O
88%
Figure 4.13. Stille reaction: key step in the synthesis of clavilactones
SnBu3
O O Pd2(dba)3, LiCl O O
DMF, r.t.
OTBS OMe OTBS OMe

94%
Figure 4.14. Stille reaction: macrocyclization [SAT 16]
4.3.4. Key reaction: Nozaki–Hiyama–Kishi reaction
The nucleophilic addition of alkenylchromium reagents to carbonyl compounds

was initially described by the Nozaki and Hiyama group in 1977 [OKU 77].
Bipinnatin J 91
OH
R1 R2
OH OH
R1 R2 R1 R2
O
OH R1 H OH
R1 R1
R2 OH R2
R1
R2
Figure 4.15. Access to allyl, homoallyl and propargyl alcohols
The success of the coupling depends on the quality of the chromium salts used.
The presence of catalytic quantities of nickel (II) chloride is essential to achieve
effective coupling [TAK 83, TAK 86, JIN 86]. Its role is explained in the catalytic
cycle shown below. The nickel (0) generated in situ contributes to the oxidative
addition in the C-X bond. The alkenyl nickel undergoes transmetalation with
chromium (III) salts to provide the species responsible for the 1,2-addition.
Ni X
Cr(III) R-CHO
X R
Cr(III)
X = I, Br, NHTK
OTf OH
Ni(0) Ni(II)
(III) (II)
2 Cr 2 Cr
Figure 4.16. Dual catalysis of the Nozaki–Hiyama–Takai–Kishi reaction

To control the configuration of the new stereocenter, the enantioselective version

was studied. Of all the ligands tested, the one described by White and Shaw gives
excellent results [WHI 11, TIA 16].
N
N
Cr
O
R1 O O
OH
t-Bu
+
Br t-Bu t-Bu t-Bu Mn (3 equiv.) R1
e.e. > 97%
THF
Figure 4.17. Enantioselective version of the Nozaki–Hiyama–Takai–Kishi reaction
H
MeO
TBSO
O O
TBSO OTBS
O
H
O
TBSO
O OTBS
O
CHO
CrCl2 /NiCl2
THF / DMF
H
MeO
TBSO
O O
TBSO OTBS
O
H
O
TBSO
O OTBS
O OH
95%
Figure 4.18. Eribulin synthesis – a key macrocyclization step

Bipinnatin J 93
The reaction was widely used in total synthesis in both intermolecular and
intramolecular modes to access macrocyclic structures [FÜR 99, GIL 17].
Researchers at Eisai in Japan used this reaction to synthesize eribulin, a complex
anti-cancer molecule inspired by halichondrin B [YU 13].
4.3.5.1. Carboalumination of homopropargyl alcohols [MA 97]
CH3
Me3Al
H I2
Cp2ZrCl2 (1 equiv.)
H HO
CH2Cl2
OH O Al I
60%
4.3.5.2. Dess–Martin oxidation [THO 05, WIR 99, ZHD 02]
CO2H Oxone
OH
OH (0.2 equiv.) 1.3 equiv.
O
acetonitrile/H2O, 70°C, 6h
94%
4.3.5.3. Ortholithiation of furans [DON 94]
n-BuLi
Li
O THF, -80°C -> 0°C, 2h O
4.3.5.4. Lithium–tin exchange [HUC 98, GRA 02]
SnMe3
S 1) n-BuLi (2.5 equiv.) S
O TMEDA / THF, -60°C O
2) Me3Sn-Cl
S S 95%
SnMe3
4.4. Approach according to V.H. Rawal [HUA 06]
4.4.1. Synthesis
Macrocycle formation always involves an intramolecular Nozaki reaction (with

the same selectivities). Different couplings, in particular that of Negishi and that
between a butenolide enol ether and an allylic iodide, lead to the key precursor of
macrocyclization [HUA 06].
4.4.1.1. Access to butenolide 4-B2

4.4.1.1.1. Synthesis of 5-iodo-2-methyl-pent-2-enol protected 4-D2
Br Br OH I OMOM
a b, c
4-D2
Figure 4.19. Access to the synthon 4-D2
a. Allylic oxidation – 67%: SeO2 (0.5 equiv.), t-BuOOH (2 equiv.), r.t., 6 h.

b. Protection of the alcohol function – 91%: MOM-Cl (1.5 equiv.), iPrNEt2
(1.1 equiv.), 0°C -> r.t., CH2Cl2, 3 h.
c. Bromine/iodine exchange – 99%: NaI/acetone, r.t., 12 h.
Bipinnatin J 95
4.4.1.1.2. Butyrolactone alkylation and access to 4-B2

O O MOMO O MOMO
d e, f
O O O
O
MOMO
TBSO OMOM
g O
h
O
4-B2
Figure 4.20. Synthesis of the precursor 4-B2

d. Deprotonation and alkylation of butyrolactone – 72%: (i) LDA, THF, HMPA
(0.2 M), −78°C, 1.5 h; (ii) 4-D2.
e. α-Selenation – 66%: (i) LDA, THF, −78°C; (ii) PhSeCl, 10 min.
f. Oxidation and elimination of selenoxide – 82%: H2O2, THF, 10 min.
g. Formation of 2-silyloxyfuran – 99%: (i) LDA, THF, −78°C; (ii) TBDMS-Cl,
20 min.
h. Alkylation of enol ether – 60%: 3-Iodo-2-methyl-1-bromopropene (1.3 equiv.),
Ag(O2CCF3) (1.2 equiv.), −40°C -> r.t. CH2Cl2, 4 h.
4.4.1.2. Preparation of the zinc reagent 4-E2

O O
O O
a' ClZn
O O
4-E2
Figure 4.21. Ortholithiation – access to the reagent 4-E2

a’. Formation of the organozinc: (i) t-BuLi, THF, −78°C, 1.5 h; (ii) ZnCl2.
4.4.1.3. Finalization of the synthesis

MOMO Br
O O
O O
i j, k
4-B2 O 10 O
O O
O H
O
O
O
OH
l 1'
+
O
O
OH
O
OH
1"
Figure 4.22. Access to bipinnatin J 1

i. Negishi coupling – 99%: 4-E2, PdCl2(dppf), THF, 0°C, 2 h.
j. Acid hydrolysis of dioxolane and MOM ether – 81% (two steps): PPTS,
t-BuOH, 60–80°C, 18 h.
k. Conversion of alcohol to bromide – 68%: CBr4, PPh3, CH2Cl2, 0°C, 5 min.
l. Nozaki–Hiyama–Kishi reaction – 91.5% (1/1'/1''= 73/12.7/5.8): CrCl2
(20.6 equiv.), THF, 4 Å sieve.
Bipinnatin J 97
4.4.2. Key reaction: Negishi coupling
In its initial form, the Negishi reaction corresponded to the coupling between an
unsaturated halide (aromatic or vinyl) and an organozinc compound, a process
catalyzed by palladium (0) salts. The accessibility of organozinc reagents as well as
their low toxicity have made this reaction highly prized in synthesis. The catalytic
cycle is very similar to that described for other palladocatalyzed reactions
(Stille, Kumada–Corriu or Suzuki); it has been shown that the transmetalation step
was faster with organozinc compounds than with organomagnesium compounds
without the significant formation of products resulting from dehalogenation or
β-elimination [NEG 80, NEG 11].
n-Bu-MT
I Pd(Ph3)4 (5 mol %) n-Bu H
+
THF, r.t., 2h
MT = ZnCl 76 2
MT = MgCl 25 51
Figure 4.23. Formation of 1,5-dienes according to Negishi
The use of lithium chloride is now recommended to improve the solubility of the
organometallic compound, as well as to remove oxides from the zinc surface. In
addition, other catalysts based on iron, cobalt, nickel or copper instead of palladium
may also be involved, making it possible to extend the scope of cross couplings
while reducing the cost of the overall process [HAA 16].
(2 mol%)
I ZnI N
+ N N
NiCl2.glyme (2 mol%)
THF, 60°C, 20h 96%
Figure 4.24. Coupling involving a secondary organozinc derivative [JOS 11]
Particular attention was also given to couplings between aryl halides and primary
[HAU 18, PAN 18] or secondary [JOS 11] zinc species. The efficiency of the
coupling depends particularly on the polarity of the solvent medium as well as on
the nature of the metal and the ligands that stabilize it.
O
Bn
O N
OMe
I
Bn N
OMOM
H I
t-BuLi, MeO
ZnCl2 OMOM H
TBSO THF, -78°C Pd-SPhos
THF, DMA,
40°C TBSO
49%
Figure 4.25. Coupling from a primary organozinc derivative [HAU 18]
The creation of new stereogenic centers has been studied. G. Fu’s work has thus
provided access to coupling products with excellent yields and enantioselectivities.
The C2 symmetric PyBox complexes have proven extremely successful [SON 08,
QUR 17].
O
O O
N
O ZnBr
N N
NiCl2 O
1.2 equiv.
glyme
Bn (5.5%) Bn
+ O
Cl (S)-BnCH2-PyBox
NaCl (4.0 equiv.), 93%
DMA/DMF (1:1), -10°C e.e. = 90%
Figure 4.26. Asymmetric coupling of allylic chlorides and organozinc compounds
4.4.3.1. Allylic oxidation by SeO2 [ZOU 07, FUJ 02]
O O
SeO2 (3 equiv.)
dioxane, μν
110°C, 10 min. HO 83%
Bipinnatin J 99
4.4.3.2. Formation and elimination of selenoxides [RÜE 82]

PhSe H
H2O2, pyridine
CO2Me CO2Me
N CH2Cl2, 0°C -> r.t. N
Cbz Cbz
87%
4.5. Enantioselective approach according to G. Pattenden [TAN 06]
4.5.1. Synthesis
4.5.1.1. Access to 4-B3

OH
O OH
OH a, b c OH
OH
OH
O O
d O e
S
I O
I
4-B3
Figure 4.27. Synthesis of butenolide 4-B3

a. Opening of (R)-glycidol – 97%: TMS-acetylene, n-BuLi, BF3.OEt2, THF,
−78°C -> −30°C.
b. Regeneration of the terminal alkyne – 92%: K2CO3, MeOH/THF, r.t.
c. Carboalumination: (i) Cp2ZrCl2, AlMe3, Cl-CH2-CH2-CH2-Cl, r.t., then reflux,
3 days; (ii) I2, THF, −30°C −> 0°C.
d. Tosylation of primary alcohol – 48% (two steps): TsCl, pyridine, 0–3°C.
e. Formation of the epoxide – 73%: K2CO3, MeOH.
4.5.1.2. Precursor synthesis 4-A3

SePh
MeO OH f, g MeO
O O OTBS
MeO2C SePh O TBSO
O
h i SePh
OTBS
HO
I
I
O TBSO O OH
O O
j k
I I
4-A3
Figure 4.28. 4-A3 Precursor synthesis of 4-A3

f. Protection of primary alcohol – 90%: TBS-Cl, imidazole, DMF, 0°C.
g. α-Phenylselenation – 97%: (i) LDA, THF, −78°C; (ii) PhSe-Br, TMS-Cl,
−78°C -> r.t.
h. Epoxide ring opening 4-B3 – 60%: (i) NaHMDS, THF, −78°C; (ii) 4-B3,
BF3.OEt2, -> r.t.
i. Lactonization: TsOH cata. CH2Cl2, r.t.
j. Formation and elimination of phenylselenoxide: H2O2, THF, 0°C -> r.t.
k. Deprotection of TBS ether – 62% (three steps): PPTS (cata.), CH2Cl2/MeOH.
Bipinnatin J 101
O O Br
OH
O O
l, m
I O CHO
4-A3
O O
O O
n
O + O
OH OH
1 1' / 1"

l. Stille coupling: 4-C1, Pd(PPh3)4, CuI, CsF, DMF.
m. Conversion of primary alcohol to bromide – 72% (two steps): NBS, PPh3.
n. Cyclization by Nozaki–Hiyama–Kishi reaction – 70%: CrCl2 (10 equiv.), 4 Å
MS, THF, r.t.
Pattenden’s synthesis was the first enantioselective synthesis. The source of

chirality is (R)-glycidol whose stereogenic center is in the five-membered lactone.
The macrocycle closure process is based, as with other approaches, on an
intramolecular Nozaki reaction.
4.5.2.1. Epoxy ring opening [HEA 03, MAC 01]

SiMe3 OH
O K2CO3
OTES n-BuLi PPTS OH
BF3.OEt2 MeOH / THF MeOH / THF
THF, -78°C 73%
4.5.2.2. Stille coupling [ELO 08]

Br
NO2 NO2
Pd(Ph3)4
+ SnBu3
PhMe, 80°C, 16h
NO2 NO2
65%
4.6. Approach according to D. Trauner – enantioselective version
4.6.1. Synthesis [ROE 06b]
4.6.1.1. Access to butenolide 4-B4

OH H
a b O
OH
I I
OH OH
c d, e
I SiMe3 I SiMe3
O CHO
OH
j O
f-i
I CO2Et
I
4-B4
Figure 4.30. Synthesis of butenolide 4-B4

Bipinnatin J 103

a. Carboalumination/iodization of butynol – 60%: (i) Me3Al, Cp2ZrCl2; (ii) I2.
b. Dess–Martin Oxidation: Periodinane, CH2Cl2, NaHCO3, 15 min, r.t.
c. Addition of an acetylide to the aldehyde: Li-C=C-TMS, THF, −78°C, 15 min.
d. Dess–Martin Oxidation – 60% (two steps): Dess–Martin periodinane, CH2Cl2,
NaHCO3, 30 min.
e. Enantioselective reduction of ynone – 91% (two steps): (i) (S)-Alpine borane,
THF, 0°C -> r.t., 22 h; (ii) propionaldehyde, NaOH, H2O2, 16 h, r.t.
f. Deprotection of the alkyne TMS group: MeOH, K2CO3.
g. Protection of the hydroxy group: TES-OTf, lutidine, THF, 20 min.
h. Functionalization of the terminal position of the alkyne: (i) LiHMDS, THF,
−78°C; (ii) Cl-CO2Et, −50°C -> r.t.
i. Deprotection of the TES group – 85% (four steps): HF aq., MeCN, 0°C.
j. Ene alkyne/alkene reaction according to Trost and in situ lactonization – 52%:
(i) allyl alcohol, 4-R catalyst (5%); (ii) CSA, THF/acetone.
4.6.1.2. Finalization of the synthesis

OH OH
OH O
O O
k, l m, n
4-B4
10
I I
OH Br
O O
O O
o p
O O
O O
H H
4-A4
O O
O O
O + O
OH OH
1 1' / 1"


k. Wittig reaction – 84%: Ph3P=CH(CH3)CO2Et, CH2Cl2, r.t.
l. Reduction of the unsaturated ester to allyl alcohol and lactone to lactol:
DIBAL-H, CH2Cl2, −78°C.
m. Oxidation to lactone and unsaturated aldehyde: PDC, CH2Cl2.
n. Reduction of aldehyde to allyl alcohol – 70% (three steps): NaBH4, MeOH.
o. Stille coupling – 92%: 4-C4 (1.3 equiv.), Pd(Ph3)4 (4 mol.), CuI (0.8 equiv.),
CsF (2 equiv.), DMF.
p. Conversion of alcohol to bromide – 87%: NBS (1.1 equiv.), PPh3 (1.1 equiv.),
CH2Cl2, −5°C, 20 min.
q. Nozaki–Hiyama–Kishi reaction – 72%: CrCl2, NiCl2, THF, 4 Å MS, r.t., 16 h.
4.6.1.3. Access to the synthon 4-C4
a' OLi
Li
CHO O Bu3Sn CHO
O O
N
OMe
4-C4
Figure 4.32. Synthesis of the synthon 4-C4
a'. Protection and ortholithiation of 3-methylfurfural – 85%: (i) n-BuLi,

MeONHMe, THF, −40°C; (ii) Me3Sn-Cl; (iii) NH4Cl aq.
In this synthesis, stereochemistry control is achieved through the enantioselective

reduction of an ynone by Alpine borane®. The strategy is similar to the first
synthesis described by the same team (see the synthesis in section 4.3).
Bipinnatin J 105
4.6.2.1. Enantioselective reduction of ynones by Alpine borane® [MID 84,

BRO 95]
H
O H OH
Alpine borane
(2.2 equiv.)
THF, r.t., 48h
72%
# (e.e. = 85%) + pinene
B
H O
RL
CH3 Rs
4.6.2.2. Appel reaction [BER 07]
O
CCl4
P P
+ Ph Me + Ph Me
OH Ar PhMe, 4Å MS Cl Ar
(+/-) -78°C -> r.t., 12h
e.e. = 50%
> 95%
106
Key Racemic or stereo-

Corresponding Number Overall controlled synthesis
Section Year Key reaction 1 reaction 2,
author (University) of steps yield
Key reaction 3 Source of chirality
4.3.3. Stille
4.3.2. Ene reaction reaction
D. Trauner Univ. of
4.3 2006 9 6.8% catalyzed by – racemic synthesis
California, Berkeley 4.3.4. Nozaki
ruthenium
reaction
V.H. Rawal Univ. of 4.4.2. Negishi 4.3.4. Nozaki
4.4 2006 9 11.5% – racemic synthesis
Chicago reaction reaction
4.7. Comparison of the four syntheses
– stereo-controlled
G. Pattenden Univ. of 4.3.3. Stille 4.3.4. Nozaki synthesis:
4.5 2006 12 5.8%
Nottingham reaction reaction
(R)-glycidol = chiron
– stereo-controlled
4.3.2. Ene reaction synthesis:
Retrosynthetic Analysis and Synthesis of Natural Products 1
D. Trauner Univ. of 4.3.4. Nozaki

4.6 2006 18 4.9% catalyzed by Enantioselective
California, Berkeley reaction
ruthenium reduction with
Alpine borane®
Table 4.1. Syntheses

Bipinnatin J 107
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[ROE 06a] ROETHLE P.A., TRAUNER D., “Expedient synthesis of (+/-)-bipinnatin J”, Organic
Letters, vol. 8, pp. 345–347, 2006.
[ROE 06b] ROETHLE P.A., HERNANDEZ P.T., TRAUNER D., “Exploring biosynthetic
relationships among furanocembranoids: Synthesis of (-)-bipinnatin J, (+)-intricarene,
(+)-rubifolide, and (+)-isoepilophodione B”, Organic Letters, vol. 8, pp. 5901–5904,
2006.
[RÜE 82] RÜEGER H., BENN M.H., “The preparation of (S)-3,4-dehydroproline from
(2S,4R)-4-hydroxyproline”, Canadian Journal of Chemistry, vol. 60, pp. 2918–2920,
1982.
[RUM 17] RUMMELT S.M., CHENG G.-J., GUPTA P. et al., “Hydroxy-directed
ruthenium-catalyzed alkene/alkyne coupling: Increased scope, stereochemical
implications, and mechanistic rationale”, Angewandte Chemie: International Edition,
vol. 56, pp. 2599–3604, 2017.
[SAT 16] SATO E., TANABE Y., NAKAJIMA N. et al., “Total synthesis of biselyngbyolide B”,
[SON 08] SON S., FU G.C., “Nickel-catalyzed asymmetric Negishi cross-couplings of
secondary allylic chlorides with alkylzincs”, Journal of the American Chemical Society,
vol. 130, pp. 2756–2757, 2008.
[TAK 83] TAKAI K., KIMURA K., KURODA T. et al., “Selective Grignard-type carbonyl
addition of alkenyl halides mediated by chromium (II) chloride”, Tetrahedron Letters,
vol. 24, pp. 5281–5284, 1983.
[TAK 86] TAKAI K., TAGASHIRA M., KURODA T. et al., “Reactions of alkenylchromium
reagents prepared from alkenyl trifluoromethanesulfonates with chromium (II) chloride
under nickel catalysis”, Journal of the American Chemical Society, vol.108,
pp. 6048–6050, 1986.
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(+)-intricarene”, Tetrahedron Letters, vol. 47, pp. 6401–6404, 2006.
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o-iodobenzoic acid (IBX) and the catalytic use of it in oxidation reactions in the presence
of oxone as a co-oxidant”, Organic Letters, vol. 7, pp. 2933–2936, 2005.
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reaction”, Synthesis, vol. 48, pp. 4038–4049, 2016.
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5
Tubingensin B
Tubingensin B 1 was isolated in 1989 from the fungus Aspergillus tubingensis

and its structure was confirmed by X-ray diffraction [TEP 89]. This secondary
metabolite appears to play a role in protecting the fungus when predatory organisms
attack. It has some cytotoxicity to HeLa cancer cells with an IC50 of 4μg. mL−1.
OH
N
H
Figure 5.1. Structure of tubingensin B. For a color version of

the figures in this chapter see www.iste.co.uk/piva/analysis1.zip
ANALYSIS.– A hexacyclic structure comprising a carbazole unit fused with a

bicyclo[3.2.2]nonane structure. Five stereogenic centers including three quaternary
centers, two of which are contiguous. An alcohol functional group fixed to a
six-membered ring.
5.2. Bond disconnections
The synthesis of tubingensin B 1 and its isomer 2 were both carried

out by Neil K. Garg et al., taking advantage of a cyclization between a silylated
enol ether and a carbazolyne species generated from an aryl brominated derivative
[COR 17, GOE 14]. In parallel, the synthesis of compound 2 was carried
out by K.C. Nicolaou et al. on the basis of the electrocyclization of a triene
[BIA 12].
OH
OH
N
H
N
H
1 2
Aryne Electrocyclization
OSiR3 OH
( )n
N N
Gp Gp
R
Figure 5.2. Key disconnections for tubingensin 1 and 2
These syntheses highlight the recently revived interest in the potential of arynes
to form polycyclic molecules. In particular, these successes are based on the way in
which these intermediates are generated from ortho-silylated aromatic triflates by
treatment with fluoride ions.
Tubingensin B 113
5.3. Approach according to N.K. Garg
OH O
Y
D1
N N
H
Gp
1 5-A
OH OSiR3
D2 D3
Y Y
N N
Gp Gp
5-B 5-C
X
X N
O X'
5-E Gp
O
D4 N D5 +
Gp
OH
5-D
5-F
Figure 5.3. Disconnection according to Garg
D1: formation of the bicyclo[3.2.2]nonane structure by radical cyclization.

D2: opening of benzocyclobutanol.
D3: cycloaddition [2+2] between an aryne and an enol ether.
D4: formation of an enol ether by 1,4-addition and trapping.
D5: formation of the 5-D enone by two successive cross couplings.
5.3.2. Synthesis
Br
Br
a
N
TfO N HO MOM
MOM
Br Br
b I c, d I
N N
HO MOM MOM
Figure 5.4. Functionalization of carbazole

a. Sonogashira reaction – 84%: Propargyl alcohol, Pd(PPh3)4, CuI, Et3N, DMF,
60°C.
b. Cupromethylation/iodination – 71%: (i) MeMgBr, CuI, THF, −78°C, then
23°C; (ii) I2, THF, −78°C, then 23°C.
c. Alcohol mesylation: Ms-Cl, Et3N, CH2Cl2, 0°C, then r.t.
d. Mesylate reduction – 81% (two steps): LiBHEt3, THF, −78°C, then 23°C.
O ODMIPS ODMIPS
e, f g
Br
DMIPSO
h N
MOM
Figure 5.5. Suzuki coupling

Tubingensin B 115

e. 1,4-Addition: VinylMgBr, CuI, THF, −78°C.
f. Enolate trapping – 92% (two steps): DMIPS-Cl, HMPA, −78°C, then r.t.
g. Hydroboration of the vinylic double bond: 9-BBN, THF, −78°C, then 50°C.
h. Suzuki coupling – 76% (two steps): Pd2(dba)3, AsPh3, K3PO4, DMF, 23°C.
ODMIPS O
Br Br
i, j
N N
MOM MOM
OTES
SePh
OH
k Br l
SePh
N
MOM
N
MOM
Figure 5.6. Generation of the aryne and [2+2] cycloaddition

i. Access to dimethylaminoketone: [Me2N=CH2]+ I-, 18-Cr-6, KF, THF, 35°C.
j. Oxidation/Cope elimination – 62% (two steps): m-CPBA, CH2Cl2, 0°C.
k. 1,4-Addition of the PhSeCH2 fragment/enolate trapping – 61%:
PhSe-CH2-SePh, n-BuLi, CuCN.2 LiCl, TES-Cl, THF, −78°C, then 23°C.
l. Formation/cycloaddition of aryne – 47%: NaNH2, t-BuOH, THF, 1.5 h, 23°C.
OH O
SePh
m
SePh
N N
MOM MOM
O OH
n o, p
N N
MOM H
1
Figure 5.7. Completion of the synthesis by Garg
m. Regio-controlled opening of benzocyclobutenol – 53%: [Rh(OH)cod]2,

Ph-Me, 100°C.
n. 6-exo-trig radical cyclization – 54%: Bu3SnH, AIBN, Ph-Me, 110°C.
o. Stereoselective reduction of ketone – 43%: (S)-Ru(OAc)2(DM-SEGPHOS),
H2, KOH, i-PrOH, 23°C.
p. Deprotection of the MOM ether – 67%: HCl (3 N), ethylene glycol/THF, 55°C.
The synthesis requires 13 steps for the longest sequence and is carried out with
an overall yield of 0.53%. It combines both palladium-catalyzed coupling reactions,
a cyclization reaction via an aryne, and a 6-exo-trig radical cyclization process to
reach the bicyclo[3.2.2]nonane structure with a good yield of 47%.
5.3.3. Key reaction: Sonogashira reaction
The Sonogashira reaction creates a C-C bond between an alkyne and an aryl or
vinyl halide. The pallado-catalyzed process involves three classical steps for this
type of coupling.
Tubingensin B 117
Pd(0)L2
L R1-X
L Pd R2
1
R
L
1 L 1
R R 2 R Pd X
R1 Pd R2 L
L
Cu+ R2
X- Cu
H R2 Base
2
H R
+ -
Cu X
Figure 5.8. Catalytic cycle of the Sonogashira reaction
An oxidative addition step results in the formation of an organopalladium

complex of oxidation degree (2), stabilized by two ligands, most often phosphines. It
undergoes transmetalation involving copper acetylide generated by pre-complexing
the terminal alkyne with copper (I) salts and in the presence of a base (a tertiary
amine, for example). The final step is a reductive elimination, leading to the creation
of the disubstituted alkyne and the regeneration of the Pd(0) catalyst. This reaction is
widely used to create alkynes as well as alkenes of controlled configurations, by the
selective reduction of the double bond, to the Z-isomer by hydrogenation in the
presence of the Lindlar catalyst or the E alkene by reduction with LiAlH4. For safety
reasons and ease of use, acetylene is often replaced by the trimethylsilyl derivative, a
liquid for which the protective group can be selectively removed by fluoride ion
action or in a basic medium.
SiMe 3
F 3C Br TMS F3C
Cl Pd(Ph 3)4 Cu-I, Et 3N Cl
Figure 5.9. Regioselectivity for the Sonogashira reaction

O Ar O
I
HN NH
Ar
O N N O
O O Pd(PPh3)4 O O
Si Cu-I, Et3N Si
O O DMF, 25°C O O
Si Si
70%
Figure 5.10. Sonogashira coupling [SKO 06]
5.3.4. Key reaction: Suzuki coupling
R1-X
R1-R2
Pd(0)
Oxidative
addition
Reductive
elimination
R1-Pd-R2 R1-Pd-X
NaOH
transmetallation
B(OR)2
(OH)2 R1-Pd-OH
R2
B(OR)2
NaX
OH
NaOH
R2-B(OR)2
Figure 5.11. Suzuki reaction catalytic cycle

Tubingensin B 119
The Suzuki coupling is currently the most popular pallado-catalyzed reaction for
creating C-C bonds between a boron derivative and an aryl or vinyl
halide/pseudohalide. Its main advantages are mild conditions, low catalyst loading,
(E) or (Z) stereoselectivity maintained when vinyl compounds of established
configuration are used. The reaction takes place in three phases: (1) generation of
the organopalladium species of oxidation degree (II) by oxidative addition of the
Carbon-Halogen bond; (2) transmetalation of the boron derivative involving anions
that forms a chelate with the boron atom; and (3) reductive elimination resulting in
the expected bond and regeneration of the catalyst to oxidation degree (0).
Since its discovery in 1979, many developments have been reported for
Suzuki coupling. Today, this reaction can be conducted from crowded boranes for
Csp3-Csp2 couplings. In order to overcome their tendency to form trimeric boroxins,
potassium trifluoroborates or MIDA derivatives are preferred over boronic acids,
which are deprotected just before coupling.
B(OMe)3 KHF2, H2O

MgBr BF3K
THF
CHO CHO
PdCl2(dppf) (2% mol.)

Br BF3K
Et3N, n-PrOH, Δ, 3h
65%
Figure 5.12. Suzuki reaction involving potassium trifluoroborates
In addition to the very classical Friedel–Crafts reactions involving the

nucleophilic properties of the aromatic ring with respect to electrophilic species such
as carbocations, the functionalization of aromatic rings via arynes is now an
alternative route. These highly constrained intermediates are likely to interact with
different nucleophiles (Grignard reagents, enolates, alcoholates, etc.) or to perform
thermal [4+2] or [2+2] cycloadditions. Access to these structures required extreme
conditions until recently (use of strong bases such as sodium amide and/or use of
high temperatures) [GRE 86].
Recently, o-silylaryl triflates have been shown to be excellent precursors. The

action of potassium fluoride in the presence of a crown ether to enhance the
-
nucleophilic properties of the F ion results in the formation of an aryne, which can
undergo cocyclization [2+2+2], for example [SAT 07].
5.3.5. Key reaction: cycloaddition [2+2] of arynes [HUT 11, GRE 86,
TDA 12]
OTBS OTBS
H H
NaNH2 (10.5 equiv)
O t-Bu-OH (3.5 equiv.) O

Br
THF, 23°C
N N
Me Me
TBSO OTBS
H
O
H
O +
N N
Me Me
33% 13%
Figure 5.13. Cyclization of benzyne/enolate
These same fluoride ions are capable of generating the carbanion of a

β-ketoester; a cycloaddition between the two species leads to benzocyclobutane
which then opens spontaneously after protonation to form a disubstituted aromatic
compound.
Tubingensin B 121
O SiMe3 O
-
F
O OTf O
OMe
+ O N
MeO N
O
O O
O
O [Pd2(dba)3] (5 mol %)
P(o-tol)3
Cs-F (6 equiv.)
MeCN, r.t., 4h O
O
O
O 61%
Figure 5.14. Co-cyclization between an aryne and a diyne
R1
SiMe3 O O O
+
R1 R2
OTf
O R2
KF, 18-Cr-6
DME
R1 R1
O O-M
M
+
O R2
R2
O
Figure 5.15. Cyclization of an aryne and β-ketoester

5.3.6. Key reaction: radical cyclization and Baldwin’s rules
Long overlooked in synthesis, radical reactions are now part of the synthetic
chemist’s arsenal to access specific (poly)cyclic structures. The propensity of a
radical to cyclize depends on many factors related to operational conditions as well
as to the very structure of the starting products (sp or sp2 hybridization of the
attacked centers, size of the cyclic compound formed, etc.). Professor Jack Baldwin
defined rules that make it possible to consider the preference to form a cyclic
compound by considering the two competitive exo or endo attacks [BAL 76]. The
ratio observed 98:2 following the cyclization of a hexenyl radical is directly related
to the kinetics of these two processes [BEC 92, ALA 13].
k6-endo = 4. 103 s-1 k5-exo = 2. 105 s-1
2 98
6-endo trig 5-exo trig
Figure 5.16. Radical cyclization of the 5-hexenyl radical
5.3.7. Key reaction: enantioselective hydrogenation of ketones
The enantioselective hydrogenation of ketones to secondary alcohols

in the presence of ruthenium complexes is a preferred alternative to
reactions involving hydrides. The success of this method is largely linked to the
discovery of highly efficient ligands both in terms of enantiomeric excesses and
consequent turnover number (TON). In addition, its ease of implementation,
operating conditions and low cost have made it possible to scale it up to industrial
scales [SHI 07]. Axial symmetrical ligands, such as BINAP, have proven their
effectiveness [OHK 98]. Subtle variations in the biphenyl system have allowed the
design of new and even more active derivatives. Among them, SEGPHOS has
proven to be very effective in reducing many ketones, possessing a second chelating
group [SAI 01].
Tubingensin B 123
O H2 OH
OH [NH2Me2] [{RuCl (R)-segphos)}2(u-Cl]3] OH
(S/C = 10000)
e.e. = 98.5%
O
PPh2 PPh2 MeO PPh2 O PPh2

PPh2 PPh2 MeO PPh2 O PPh2
BINAP BIPHEMP MeO-BIPHEP SEGPHOS
θ 73.5° 72.0° 68.6° 65.0°
e.e. 89% 92.5% 96.0% 98.5%
θ θ'
P P P P
M M
O O
Y Y
R R
a) b)
Figure 5.17. Enantioselective hydrogenation of hydroxyketone
This increase in selectivity is correlated with a decrease in angle θ, which then

leads to stronger interactions between the aryl substituents attached to the
phosphorus atoms and the substrate to be reduced.
5.3.8.1. Access to α-methylene ketones according to Eschenmoser

[DUD 01]
O 1) LHMDS (1.5 equiv.) O
H
2) N
I (3 equiv.) N
THF, -78°C then r.t.
m-CPBA (2 equiv.)
+ N
CH2Cl2, NaHCO3 (2:1) OH
70%
5.3.8.2. Opening of benzocyclobutenols catalyzed by Rh(OH)(cod)2 [ISH 12]

Rh
OH [Rh(OH)(cod)]2 O
Ph Rh
Ph (2.5 mol %) O
Ph-Me, 100°C
Ph
Ph
Ph
Ph O Rh
Ph
Ph OH
82%
5.3.8.3. 5-exo-trig radical cyclization [UYE 96]
Bu3Sn-H
Br O (1.6 equiv.) O O
+
AIBN (0.1 equiv.)
Ph-H, 80°C, 2h
42% 25%
Tubingensin B 125
5.3.8.4. Enantioselective reduction of ketones [TRA 97, TAN 03]

O (P*P)RuBr2 OH
(2 mol %)
SPh SPh
H2 (30 bars), r.t.
MeOH, 24h Quantitative
(e.e. = 98%)
P*P : MeO P(Ph)2

(S)-MeO-Biphep MeO P(Ph)2
5.4. References
[ALA 13] ALABUGIN I.V., GILMORE K., “Finding the right path: “Baldwin Rules for ring
closure” and stereoelectronic control of cyclizations”, Chemical Communications, vol. 49,
pp. 11246–11250, 2013.
[BAL 76] BALDWIN J.E., “Rules for ring-closure”, Journal of Chemical Society, Chemical
[BEC 92] BECKWITH A.L.J., “The pursuit of selectivity in radical reactions”, Chemical
Society Reviews, pp. 143–151, 1992.
[BIA 12] BIAN M., WANG Z., XIONG X. et al., “Total syntheses of anominine and tubingensin
A”, Journal of the American Chemical Society, vol. 134, pp. 8078–8081, 2012.
[COR 17] CORSELLO M.A., KIM J., GARG N.K., “Total synthesis of (-)-tubingensin B enabled
by the strategic use of an aryne cyclization”, Nature Chemistry, vol. 9, pp. 944–949, 2017.
[DUD 01] DUDLEY G.B., TAN D.S., KIM G. et al., “Remarkable stereoselectivity in the
alkylation of a hydroazulenone: Progress towards the total synthesis of guanacastepene”,
[GOE 14] GOETZ A.E., SILBERSTEIN A.L., CORSELLO M.A. et al., “Concise enantiospecific
total synthesis of tubingensin A”, Journal of the American Chemical Society, vol. 136,
pp. 3036–3039, 2014.
[GRE 86] GREGOIRE B., CARRE M.-C., CAUBERE P., “Arynic condensation of ketone enolates.
New general access to benzocyclobutene derivatives”, Journal of Organic Chemistry,
vol. 51, pp. 1419–1427, 1986.
[HUT 11] HUTERS A.D., QUASDORF K.W., STYDUHAR E.D. et al., “Total synthesis of
(-)-N-methylwelwitindolinone C isothiocyanate”, Journal of the American Chemical
Society, vol. 133, pp. 15797–15799, 2011.
[ISH 12] ISHIDA N., SAWANO S., MASUDA Y. et al., “Rhodium-catalyzed ring opening of
benzocyclobutenols with site-selectivity complementary to thermal ring opening”,
[OHK 98] OHKUMA T., KOIZUMI M., DOUCET H. et al., “Asymmetric hydrogenation
of alkenyl, cyclopropyl, and aryl ketones. RuCl2(xylbinap)(1,2-diamine) as a
precatalyst exhibiting a wide scope”, Journal of the American Chemical Society, vol. 120,
pp. 13529–13530, 1998.
[SAI 01] SAITO T., YOKOZAWA T., ISHIZAKI T. et al., “New chiral diphosphine ligands
designed to have a narrow dihedral angle in the biaryl backbone”, Advanced Synthesis &
Catalysis, vol. 343, pp. 264–267, 2001.
[SAT 07] SATO Y., TAMURA T., KINBARA A. et al., “Synthesis of biaryls via
palladium-catalyzed [2+2+2] cocyclization of arynes and diynes: Application to the
synthesis of aryl-naphtalene lignans”, Advanced Synthesis & Catalysis, vol. 349,
pp. 647–661, 2007.
[SHI 07] SHIMIZU H., NAGASAKI I., MATSUMURA K. et al., “Developments in asymmetric
hydrogenation from an industrial perspective”, Accounts of Chemical Research, vol. 40,
pp. 1385–1393, 2007.
[SKO 06] SKOROBOGATYI M.V., USTINOV A.V., STEPANOVA I.A. et al., “5-Arylethynyl-2’
-deoxyuridines, compounds active against HSV-1”, Organic & Biomolecular Chemistry,
vol. 4, pp. 1091–1096, 2006.
[TAD 12] TADROSS P.M., STOLTZ B.M., “A comprehensive history of arynes in natural
product total synthesis”, Chemical Review, vol. 112, pp. 3550–3577, 2012.
[TAN 03] TANG W., ZHANG X., “New chiral phosphorous ligands for enantioselective
hydrogenation”, Chemistry Review, vol. 103, pp. 3029–3069, 2003.
[TEP 89] TEPASKE M.R., GLOER J.B., WICKLOW D.T. et al., “The structure of tubingensin
B: A cytotoxic carbazole alkaloid from the sclerotia of Aspergillus tubingensis”,
[TRA 97] TRANCHIER J.-P., RATOVELOMANANA-VIDAL V., GENET J.-P. et al., “Asymmetric
hydrogenation of phenylthio ketones with chiral Ru(II) catalysts”, Tetrahedron Letters,
vol. 38, pp. 2951–2954, 1997.
[UYE 96] UYEHARA T., MURAYAMA T., SAKAI K. et al., “Formal substitution at both
bridgeheads of a bicyclo[2.2.2]oct-5-en-2-one and its application to a synthesis of
modhephene”, Tetrahedron Letters, vol. 37, pp. 7295–7298, 1996.
6
Polygonatine A
Polygonatine A is an alkaloid isolated in 1997 from Polygonatum sibiricum of

the lily family [SUN 05]. It is used in traditional Chinese medicine to treat bronchial
diseases. It has a low activity against different microorganisms, suggesting that its
real effectiveness needs to be weighed up.
OH
Figure 6.1. Structure of polygonatine A. For a color version of

the figures in this chapter see www.iste.co.uk/piva/analysis1.zip
ANALYSIS.– An alkaloid with a 6,7-dihydro-8(5H)-indolizinone skeleton; the

presence of a hydroxymethyl group on the pyrrole ring.
6.2. Disconnections
Access to the indolizinone skeleton was considered starting from the same pyrrole
precursor substituted on the nitrogen atom by an appropriate side chain, possessing a
free carboxylic acid group; one approach is based on the cyclization of an acyl radical
on the aromatic ring [ALL 01] while the other involves a Friedel–Crafts reaction via
an acylium ion [DIN 06]. The hydroxymethyl group results from the reduction of an
aldehyde group, introduced by a Vilsmeier–Haack reaction.
O D2
O
N O
D1 OH
R
N
N O
N
CHO
HO
R
D2' N
D1: hydroxymethyl group derived from an aldehyde (Reduction).

D2: formation of indolizinone (Radical cyclization).
D2': formation of indolizinone (Intramolecular Friedel–Crafts acylation).
6.3. Synthesis according to S.M. Allin
6.3.1. Disconnection
O O O
SePh
D1 D2
N N N
OH CHO CHO
O
OCH3
D3 D4 CO2Me
+ N
N Br H
CHO
CHO
Figure 6.3. Disconnection

Polygonatine A 129
D1: obtaining the hydroxymethyl group from an aldehyde (reduction).

D2: formation of the cycle with six centers adjacent to the pyrrole ring (radical
cyclization and rearomatization).
D3: access to the precursor of radical cyclization (conversion of the ester to acyl
selenide).
D4: functionalization of the nitrogen atom of the pyrrole ring (N-alkylation).
6.3.2. Synthesis
The key reaction is the formation of the six-membered ring from pyrrole
carboxaldehyde by radical cyclization according to a 6-exo-trig process. In the
absence of carbon monoxide, the acyl radical leads to the expected product with a
yield of only 20%. The intermediate is also likely to undergo decarbonylation
resulting in the production of a new primary alkyl radical that can be cyclized to
pyrrolizidine. The reaction conducted in a carbon monoxide atmosphere avoids
decarbonylation and leads to the expected bicyclic compound. It should also be
noted that the rearomatization of the pyrrole is accompanied by the reduction of the
formyl group.
CO2Me CO2H
N a b N
N
H
CHO CHO CHO
H
O CHO
N O
O
SePh
c d
N N
H O
CHO O
N HO
Figure 6.4. Synthesis of polygonatine A and radical cyclization

a. Alkylation of the nitrogen atom of the pyrrole: (i) NaH, DMF, 30 min, r.t.;
(ii) Br-(CH2)3-CO2Me, 0°C, 2 h, then r.t.
b. Saponification of methyl ester – 95% (two steps): LiOH/EtOH/H2O, r.t., 4 h.
c. Access to acyl selenide – 57%: Bu3P (2.5 equiv.), PhSe-SePh (1.5 equiv.),
CH2Cl2, r.t.
d. Reducing radical cyclization – 65%: Bu3SnH (2.2 equiv.) slow addition over
5–6 h, 80°C, CH3CN/cyclohexane in CO atmosphere (sealed tube).
6.3.3. Key reaction: radical cyclization of selenoesters
Phenylselenoesters are excellent precursors of acyl radicals by homolytic

cleavage of the C-Se bond [BOG 92]. When the substrate includes a substituted or
unsubstituted C=C double bond, the addition takes place and results in the formation
of a new cycle. The regioselectivity in favor of the observed 5-exo, 6-exo or even
7-exo-trig process obeys Baldwin’s rules. The reaction is usually not disrupted by
decarbonylation, except when the resulting radical would be highly stabilized
(benzyl, for example).
O O
SePh Bu3Sn-H (1.2 equiv.) R

AIBN (0.1 equiv.)
( )n R Ph-H, 80°C ( )n
n=0,R=H 81% (5-exo-trig)

n = 1 , R = CO2Me 84% (6-exo-trig)
Figure 6.5. Radical cyclization and exo-trig process

Polygonatine A 131
O SePh
Bu3Sn-H
37% CO2Me
(1.2 equiv.)
+
CO2Me AIBN
(0.1 equiv.)
Ph-H, 80°C CO2Me
42%
6-exo-trig 5-exo-trig
O
CO
CO2Me CO2Me
benzyl radical
Figure 6.6. Decarbonylation/cyclization versus direct radical cyclization
Conversely, with all other things being equal, the cyclization of acyl radicals on
a triple bond is less favorable in terms of trajectory; in this case, reduction takes
precedence over cyclization [CRI 89, BOG 92].
O O
SePh Bu3Sn-H (1.2 equiv.) H

AIBN (0.1 equiv.)
Ph-H, 80°C
Ph Ph
61%
Figure 6.7. Reduction versus radical cyclization
These cyclizations could be carried out in tandem mode on polyunsaturated

compounds. The studies conducted show that cyclizations are irreversible processes
under kinetic control, preferably in an exo mode and not involving rearrangements
of the newly formed radical. In the case of relatively crowded substrates at position
5, cyclization in the exo mode is more difficult for steric reasons and may be
replaced by the endo mode, involving the formation of a more stable tertiary radical
[BOG 92].
PhSe Bu3Sn-H
O
(1.2 equiv.) O H
O
AIBN
(0.1 equiv.)
Ph-H, 80°C 5-exo-dig Me

6-endo-trig H
Ph Ph
Ph
80%
(cis/trans 97/3)
Figure 6.8. Radical tandem reaction
Finally, these selenium-containing substrates were exploited during the total

synthesis of indole alkaloids and the formation of bridged structures [BEN 08,
ZAI 12].
MeO2C
N
N O
N H
MeO2C
6-endo-trig
Bu3SnH
SePh
Et3B MeO2C
N
N O C = 0.07M
H
H Ph-H, r.t.
71%
(ratio: 1:1) O
N
H
5-exo-trig
Figure 6.9. Non-regioselective radical cyclization in indole series

Polygonatine A 133
6.3.4.1. Formation of acyl selenide [NIC 85]

O
O
CO2H N SePh + Bu3P
SePh
O
O O
CH2Cl2, -20 -> 25°C
O O
75%
6.3.4.2. Carbonylation and radical cyclization [MIR 99, KIM 04]
H
n-Bu3SnH + AIBN H
N O
(addition in small portions) N C
O
CO (80 atm.), PhH, 100°C O
I C = 0.02M
30%
6.4. Synthesis by J.P. Michael
O O O
D1 D2
N N N
OH CHO
O
MeO
OH
D3 D4 CO2Me
+ O
N NH2
OMe
Figure 6.10. Disconnections

D1: obtaining the hydroxymethyl group from a formyl group (reduction).

D2: introduction of a formyl group on an aromatic ring (Vilsmeier–Haack
reaction).
D3: formation of the six-membered ring (Friedel–Crafts acylation).
D4: formation of the N-substituted pyrrole ring (condensation of a primary
amine and a bis-acetal – Clauson-Kaas reaction).
6.4.2. Synthesis
O
CO2H
MeO + O
C
+ a
NH3 + O
N N
-
Cl OMe
Cl O O
b c d
N N N
CHO CHO
HO
Figure 6.11. Synthesis of polygonatine A and Friedel–Crafts acylation
a. Formation of pyrrole – 61%: polyphosphoric acid, r.t., 16 h.

b. Vilsmeier–Haack reaction – 54%: DMF, POCl3, PhMe, 0°C, then 4 h.
c. Hydrolysis of vinyl chloride – 100%: HClO4 (60%)/HCO2H.
d. Reduction of aldehyde to alcohol – 78%: Zn(BH4)2, THF, -10°C, 30 min.
Condensation between a primary amine (γ-substituted by a carboxylic acid

group) and 2,5-dimethoxytetrahydrofuran gives a pyrrole which by simple heating in
an acid medium undergoes intramolecular acylation according to Friedel–Crafts.
The introduction of the hydroxymethyl group could not be carried out successfully
Polygonatine A 135
via a SEAR reaction with formaldehyde or its equivalent. A Prins reaction via an
azafulvenium intermediate then takes place to give bis-arylmethyl structures.
6.4.3. Key reaction: Vilsmeier–Haack–Arnold reaction
The formylation of aromatic and heteroaromatic molecules has attracted the

interest of chemists since the end of the 19th Century. Like the reactions of
Reimer–Tiemann, Gattermann–Koch or Duff, the Vilsmeier–Haack reaction,
initially reported in 1925, represents a very effective method for obtaining aromatic
aldehydes from electron-rich aromatic hydrocarbons [BEN 15]; it was later extended
to certain alkenes such as enol ethers by the Czech chemist Z. Arnold [REI 99]. The
Vilsmeier–Haack reagent is prepared by the action of an acid chloride (most often
phosphoryl chloride (POCl3) or oxalyl chloride) against an N,N-disubstituted
formamide, typically DMF. It then interacts in an aromatic electrophilic substitution
reaction (SEAR) to produce an intermediate iminium chloride which is hydrolyzed at
the end of the reaction.
O - O
O
Cl P
P Cl P Cl
Cl O Cl
Cl O Cl
O Cl
+ N H
N H Cl
N H
POCl2 Cl -
Cl Cl
O
- N H
N H Cl N H
- Vilsmeier-Haack
O-POCl2 reagent
Cl
OH OH H
H N OH Cl
-
Cl N
NMe2
H
-
Cl
OH OH H-NMe2, HCl OH O
H2O N H
H
H
-
Cl
Figure 6.12. Mechanism of the Vilsmeier–Haack reaction applied to phenol

The reaction has been widely applied in the synthesis of natural products,
particularly in indole series. Thus, access to CDE cycles of aspidospermatan-type
alkaloids could be achieved by combining a Vilsmeier–Haack reaction with a
1,3-dipolar cycloaddition involving an azomethine ylide [HAU 17].
O TfO
CN 1) Tf2O TfO CN
H N N
O DTBMP O
OAc OAc
CH2Cl2, t.a.
CO2Me CO2Me
TfO
CN CN
TfO N N
O
OAc OAc
O
TfO CO2Me CO2Me
OMe
CN
N
2) i-Pr2NEt N
OAc NC
O
PhCl OAc
125°C CO2Me O
O
OMe NC
N
N OMe
NC MeO2C
OAc
O AcO
O 47%
N N
N N
H
MeO2C Condylocarpine Condyfoline
Figure 6.13. Tandem Vilsmeier–Haack/[3+2] cycloaddition reaction

Polygonatine A 137
More traditionally, the introduction of a formyl group was carried out as the last
step in the synthesis of indiacen A [ANA 17].
+ H
- O
1) POCl3, DMF N Cl
Cl H
0°C, 15 min
2) H2O
N N
H H
Indiacen A
58%
Figure 6.14. Last step in the synthesis of indiacen A
6.4.4.1. Pyrrole formation – Clauson-Kaas reaction [ELM 52, ROC 06,

MÜL 98]
CO2Me CO2Me
HN Cl HN
NH2 OMe
N
+
O N+ -
Cl
H
MeO 1,4-dioxane
100°C
F F
90%
6.4.4.2. Alkylation according to Friedel–Crafts [ERK 90, BAN 04]

OH Me
OH O
CH2Cl2, OH
CO2Me -10°C * CO2Me
56%
e.e. = 84%
ZrCl3
6.4.4.3. SEAR involving an azafulvenium ion [DIN 06, ABE 99]
O O O
OEt
Cl
N N N
SnCl4 +
EtO
O
PhH
N
Ph
6.4.4.4. Vilsmeier–Haack reaction [MIK 06, JON 97, TAS 03]

O
H
N H
+ - N
1) POCl3, DMF N Cl
Cl
Cl Cl , -78°C
OMe 2) H2O
OMe
82%
6.4.4.5. Aromatic hydrocarbon formylation – Gattermann–Koch reaction

[CRO 49]
Polygonatine A 139
6.4.4.6. Aromatic hydrocarbon formylation – Duff reaction [GHO 13, GRI 16]
N
OH OH
N N CHO
N
HMTA
CO2Me CO2Me
TFA, 75°C, 8h
85%
6.4.4.7. Aromatic hydrocarbon formylation – Reimer–Tiemann reaction

[VUO 12]
OH OH
CHO
CHCl3, NaOH
Cl N O H2O, 80°C, 20h Cl N O

H H
46%
6.4.4.8. Chemo-selective reduction by Zn(BH4)2 [TAK 80, CRA 73, OIS 99]
O O
O O
O CCl3 O CCl3
O O
O O O O
Zn(BH4)2
ether, r.t.
O OH
73%
6.5. References
[ABE 99] ABELL A.D., NABBS B.K., “Properties and reactions of ring-deactivated deuterated
hydroxymethylpyrroles”, Organic Letters, vol. 1, pp. 1403–1405, 1999.
[ALL 01] ALLIN S.M., BARTON W.R.S., BOWMAN W.R. et al., “Acyl radical cyclisation onto
pyrroles”, Tetrahedron Letters, vol. 42, pp. 7887–7890, 2001.
[ANA 17] ANANTOJU J.K., MOHD B.S., MARINGANTI T.C., “An efficient and concise
synthesis of indiacen A and indiacen B”, Tetrahedron Letters, vol. 58, pp. 1499–1500,
2017.
[BAN 04] BANDINI M., MELLONI A., UMANI-RONCHI A., “New catalytic approaches in the
stereoselective Friedel-Crafts alkylation reaction”, Angewandte Chemie: International
Edition, vol. 43, pp. 550–556, 2004.
[BEN 08] BENNASAR M.-L., ROSA T., GARCIA-DIAZ D., “A new acyl radical-based route to
1,5-methanoazocino[4,3-b]indole framework of uleine and strychnos alkaloids”, Journal
of Organic Chemistry, vol. 73, pp. 9033–9039, 2008.
[BEN 15] BENIWAL M., JAIN N., “Review article on Vilsmeier Haack reaction and its
applications”, European Journal of Biomedical and Pharmaceutical Sciences, vol. 2,
pp. 1340–1374, 2015.
[BOG 92] BOGER D.L., MATHVINK R.J., “Acyl radicals: Intermolecular and intramolecular
alkene addition reactions”, Journal of Organic Chemistry, vol. 57, pp. 1429–1443, 1992.
[CRA 73] CRABBÉ P., GARCIA A., RIUS C., “Synthesis of novel bicyclic prostaglandins by
photochemical cycloaddition reactions”, Journal of Chemical Society, Perkin Transaction
vol. 1, pp. 810–816, 1973.
[CRI 89] CRICH D., FORTT S.M., “Acyl radical cyclizations in synthesis. Part 1. Substituent
effects on the mode and efficiency of cyclization of 6-heptenoyl radicals”, Tetrahedron,
vol. 45, pp. 6581–6598, 1989.
[CRO 49] CROUNSE N.N., “The Gattermann-Koch reaction. The formylation of
isopropylbenzene under pressure”, Journal of the American Chemical Society, vol. 71,
pp. 1263–1264, 1949.
[DIN 06] DINSMORE A., MANDY K., MICHAEL J.P., “Total synthesis of two novel
5,6,7,8-tetrahydroindolizine alkaloids, polygonatines A and B”, Organic & Biomolecular
Chemistry, vol. 4, pp. 1032–1037, 2006.
[ELM 52] ELMING N., CLAUSON-KAAS N., “The preparation of pyrroles from furans”, Acta
Chemica Scandinavica, vol. 6, pp. 867–874, 1952.
[ERK 90] ERKER G., VAN DER ZEIJDEN A.H., “Enantioselective catalysts having a new
zirconium trichloride-Lewis acid with dibornaneannulated cyclopentadienyl ligand”,
[GHO 13] GHOSH K., KARMAKAR R., MAL D., “Total synthesis of neo-tanshinlactones
through a cascade benzannulation-lactonisation as the key step”, European Journal of
Organic Chemistry, pp. 4037–4046, 2013.
[GRI 16] GRIMBLAT N., SAROTTI A.M., KAUFMAN T.S. et al., “A theoretical study of the
Duff reaction: Insights into its selectivity”, Organic & Biomolecular Chemistry, vol. 14,
pp. 10496–10501, 2016.
[HAU 17] HAUDUC C., BELANGER G., “General approach toward aspidospermatan-type
alkaloids using one-pot Vilsmeier-Haack cyclization and azomethine ylide
cycloaddition”, Journal of Organic Chemistry, vol. 82, pp. 4703–4712, 2017.
[JON 97] JONES G., STANFORTH S.P., “The Vilsmeier reaction of fully conjugated carbocycles
and heterocycles”, Organic Reactions, vol. 49, pp. 1–330, 1997.
Polygonatine A 141
[KIM 04] KIM S., “Free radical-mediated acylation and carboxylation reactions”, Advanced
Synthesis & Catalysis, vol. 346, p.19–32, 2004.
[MIK 06] MIKHALEVA A.I., ZAITSEV A.B., IVANOV A.V. et al., “Expedient synthesis of
1-vinylpyrrole-2-carbaldehydes”, Tetrahedron Letters, vol. 47, pp. 3693–3696, 2006.
[MIR 99] MIRANDA L.D., CRUZ-ALMANZA R., PAVON M. et al., “A tandem
carbonylation/cyclization radical process of 1-(2-iodoethyl)indoles and pyrrole”,
[MÜL 98] MÜLLER P., POLLEUX P., “Synthessis of a ketorolac model via aromatic carbenoid
insertion”, Helvetica Chemica Acta, vol. 81, pp. 317–323, 1998.
[NIC 85] NICOLAOU K.C., PETASIS N.A., CLAREMON D.A., “N-phenylselenophtalimide
(NPSP), a valuable selenenylating agent”, Tetrahedron, vol. 41, pp. 4835–4841, 1985.
[OIS 99] OISHI T., Handbook of Reagents for Organic Synthesis – Oxidizing and Reducing
Agents, BURKE S.D., DANHEISER R.L. (eds.), Wiley, pp. 513, 1999.
[REI 99] REICHARDT C., “Vilsmeier-Haack-Arnold formylation of aliphatic substrates with
N-chloromethylene-N,N-dimethylammonium salts”, Journal für Praktische Chemie,
vol. 341, pp. 609–615, 1999.
[ROC 06] ROCHAIS C., LISOWSKI V., DALLEMAGNE P. et al., “Synthesis and biological
evaluation of novel pyrrolopyrrolizinones as anticancer agents”, Bioorganic & Medicinal
Chemistry, vol. 14, pp. 8162–8175, 2006.
[SUN 05] SUN L.-R., LI X., WANG S.-X., “Two new alkaloids from the rhizome of
Polygonatum sibiricum”, Journal of Asian Natural Products Research, vol. 7,
pp. 127–130, 2005.
[TAK 80] TAKANOBU N., NAKATA T., AKITA H. et al., “Synthesis of (+/−)-cinnamodial and
(+/−)-cinnamosmolide”, Chemistry Letters, vol. 9, pp. 445–446, 1980.
[TAS 03] TASNEEM, “Vilsmeier-Haack reagent”, Synlett, pp. 138–139, 2003.
[VUO 12] VUONG S., BRONDEL N., LEN C. et al., “Formal synthesis of TMC-69-6H via a one-
pot enantioselective domino proline-mediated aldol/olefin homologation procedure”,
[ZAI 12] ZAIMOKU H., TANIGUCHI T., ISHIBASHI H., “Synthesis of the core of actinophyllic
acid using a transannular acyl radical cyclization”, Organic Letters, vol. 14,
pp. 1656–1658, 2012.
7
(+)-Intricatetraol

(+)-Intricatetraol is a triterpenic polyether member of the oxasqualenoid family.
It was isolated in 1993 by Suzuki et al. from the red sponge Laurencia intricata,
harvested from the coasts of Hokkaido. This tetraol has moderate cytotoxic activities
against P388 leukemic cells with an IC50 of 12.5 μg.mL-1. The synthesis described
here confirmed the allocation of all stereogenic centers initially based on a
biogenesis study [SUZ 93].
Br OH OH
12 H
Cl O
O Cl
H 13
HO OH Br
Figure 7.1. Structure of intricatetraol. For a color version of the

figures in this chapter see www.iste.co.uk/piva/analysis1.zip
ANALYSIS.– A molecule with a C2 axis of symmetry between the C12 and C13 carbon
atoms, characterized by 2 x 5 stereogenic centers. The presence of halogen atoms
(bromine and chlorine) indicates its marine origin. Two identical syn-2,5-
disubstituted tetrahydrofuran units are present on this compound containing, as its
name indicates, four hydroxyl groups (two tertiary and two secondary).
7.2. Disconnections
The retrosynthesis envisaged by Morimoto is extremely convergent, based on the
intrinsic symmetry of the target [MOR 07]. By breaking the bond between the two
carbon atoms C12 and C13, it is possible to consider a metathesis homodimerization
of the alkene 7-B, followed by the selective reduction of the new double bond while
preserving the halogenated substituents.
Cl Br
Cl Br
HO
H O
12 D1
HO
OH
2 RO
H O
13
O H
OH RO
1 7-A
Br Cl
O OR'
R'O
D2 D3 OH
O
H O
RO OR H
HO OH
7-B 7-C
R'O OAc
R'O
D4 D5
O O
OH
7-D 7-E

D1: symmetric molecule (homodimerization by metathesis and reduction).
D2: 1,2-dihalogenated derivative from an epoxide (regioselective opening and
functional transformations).
D3: terminal alkene from a primary alcohol (oxidation/methylenation).
D4: THF from a Payne rearrangement (cascade cyclization from a bis-epoxy
alcohol).
D5: polyoxygenated sesquiterpene structure (double epoxidation and
enantioselective dihydroxylation of farnesyl acetate).
The challenge is to prepare tetrahydrofuran 7-C by controlling the configuration

of four centers, two of which are quaternary. This was achieved by taking advantage
of the stereospecific opening of a bis-epoxide via a Payne reaction followed by a
(+)-Intricatetraol 145
Wittig reaction to reach the required alkene. The two epoxide functional groups
were introduced respectively by means of an asymmetric Sharpless epoxidation of
an allyl alcohol and a Shi epoxidation of a trisubstituted alkene. The bromine atom
results from the ring opening of a third epoxide generated from a 1,2-diol.
Farnesyl acetate 7-E, a commercial terpene, was used as a starting material.
7.3. Approach according to Morimoto

7.3.1. Synthesis
7.3.1.1. Synthesis of fragment 7-C
p-MeOC6H4
O
O
a,b
OAc
OAc
7-E
p-MeOC6H4
O
O
c,d O
e
OH
p-MeOC6H4
O O
O
O
O
O O O O
O
OH
D-Fructose 7-D
f
p-MeOC6H4
O p-MeOC6H4
O O
O OH
O
+
O OH
H
HO O
OH
7-C 7-C'
Figure 7.3. Synthesis of fragment 7-C


a. Regioselective asymmetric dihydroxylation – 34%: AD-mix-β, 0°C, 24 h.
b. Ketalization: p-MeO-C6H4-CH(OMe)2, PPTS, CH2Cl2, 0°C -> r.t., 16 h.
c. Methanolysis of the ester – 99% (two steps): MeOH, K2CO3, r.t., 7 h.
d. Regio- and enantioselective epoxidation according to Sharpless – 95%
(d.r. > 20/1): t-BuOOH, Ti(OiPr)4, L-(+)-DET, 4 Å MS, CH2Cl2, -20°C, 21 h.
e. Enantioselective epoxidation according to Shi – 87% (r.d. > 6/1): Shi reagent,
oxone, Bu4NHSO4, CH2(OMe)2/CH3CN/H2O, pH = 10.5, 0°C, 2.5 h.
f. Payne rearrangement and 5-exo-tet cyclization – 7-C (67%) and 7-C' (23%):
LiOH aq. (1 M), 1,4-dioxane, 100°C, 7 h.
7.3.1.2. Synthesis of fragment 7-F

Ar Ar
O O
O O
OH OTBS
g,h
O O
H H
HO OH MOMO OMOM
7-C
Ar
HO
O
O
i,j k-m HO
CHO
O O
H H
MOMO OMOM MOMO OMOM
7-F
Ar = p-MeO-Ph
Figure 7.4. Synthesis of fragment 7-F

g. Protection of the primary hydroxy group – 96%: TBDMS-Cl, Et3N, DMAP,
CH2Cl2, r.t., 26 h.
h. Protection of the two secondary alcohols as MOM ethers – 96%: MOM-Cl,
iPr2NEt, CH2Cl2, 0°C, then r.t., 36 h.
i. Deprotection of silyl ether – 99%: nBu4NF, THFaq, 0°C -> r.t., 15 h.

j. Oxidation of primary alcohol to aldehyde according to Parikh–von Doering –
99%: SO3.pyr, Et3N, DMSO/CH2Cl2, 0°C, 30 min.
k. Methylenation – 90%: Ph3P=CH2, THF, 0°C, 1 h.
l. Conversion of ketal to p-methoxybenzoate: DDQ, H2O, CH2Cl2, r.t., 2 h.
m. Reduction of benzoate to alcohol – 96% (two steps): LiAlH4, THF, 0°C,
1.5 h.
7.3.1.3. Access to fragment 7-A

7-F
Br
O
HO
O o O
H H
MOMO OMOM MOMO OMOM
7-B
Br p,q
Cl
O
H
HO OH
7-A
Figure 7.5. Synthesis of fragment 7-A

n. Conversion of 1,2-diol to epoxide – 90%: (i) Ms-Cl, pyridine, CH2Cl2, 0°C,
then r.t., 14 h; (ii) MeOH, K2CO3, r.t., 3 h.
o. Regioselective opening of epoxide in bromohydrin – 76%: Li2[NiBr4], THF,
r.t.
p. Conversion of tertiary alcohol to chloride: SOCl2, DMPU, 0°C, 30 min.
q. MOM ether deprotections – 55% (two steps): HCl, MeOH, r.t., 1 h.
7.3.1.4. Homologous coupling and finalization of the synthesis

Br
Cl
O
H
HO OH
7-A
Br OH OH
H
Cl O
O Cl
H
HO OH Br
Br OH OH
H
Cl O
O Cl
H
HO OH Br
1
Figure 7.6. Finalization of the synthesis of intricatetraol

r. Metathesis – 86%: GBII, CH2Cl2, 40°C, 7 h.
s. Reduction of double bond by diimide – 56%: KOOC-N=N-COOK, AcOH,
MeOH, MeOH, r.t., 70 h
The symmetry of the molecule led the authors to favor metathesis coupling
between two identical 7-A subunits. The reduction of the double bond is
subsequently achieved by diimide action in the absence of transition metals that
would interact with bromine or chlorine atoms. These two steps were carried out on
substrates without protective groups demonstrating the catalyst’s action spectrum
and synthetic power. The different stereogenic centers were controlled by a
Sharpless dihydroxylation step and two successive epoxidation reactions,
respectively: first, a reaction involving only allyl alcohols (enantioselective
Sharpless epoxidation) and then an organocatalyzed epoxidation reaction initially
developed by Shi. From bisepoxyalcohol 7-D, a Payne rearrangement leads, in a

single step, to the formation of the 7-C syn-disubstituted five-membered ring,
including the functionalities necessary for the elaboration of the unsaturated
synthon. During this step, by-product 7-C' with a 7-cycle is also isolated with a
significant yield. It results from the intramolecular attack of the alcoholate formed
during the crucial 5-exo-tet cyclization stage. In order to minimize its formation, a
high concentration of lithium oxide (1 M), initiating the Payne rearrangement, was
recommended.
7.3.2. Key reaction: epoxidation according to Katsuki–Sharpless
The enantioselective epoxidation reaction of allyl alcohols was developed by

K. B. Sharpless et al. in the 1980s and has been very successful in both academia
and industry [RAM 06, HER 15]. Its impact in synthesis is such that it earned
Professor Sharpless the Nobel Prize in Chemistry in 2001 (with W. S. Knowles and
R. Noyori) [SHA 2002]. It is usually carried out in dichloromethane at -20°C in the
presence of Ti(OiPr)4, t-butyl hydroperoxide as oxidizing agent and a tartaric acid
diester (ethyl ester, or even better, isopropyl ester) as chiral inducer. Since both
enantiomers are available at non-prohibitive costs, it is possible to access
epoxyalcohols in their two enantiomeric forms. Selectivities are generally very high,
exceeding 90% or even 95% in the case of allyl alcohols of configuration E. The
reaction requires anhydrous conditions; when carried out in the presence of 4 Å
molecular sieves, the kinetics are faster and it can therefore take place with clear
substoichiometric quantities of reactants [HIE 08]. It has been widely used for
region- and enantioselective access to many synthons: the presence of the alcohol
functional group allows many post-functionalizations, while the oxirane pattern can
easily undergo a regio- and stereoselective ring opening.
O
HO HO
(-)-DET, Ti(OiPr)4
t-BuOOH, 4Å MS
CH2Cl2, -20°C, 3h
81% (e.e. = 96%)
Figure 7.7. Regioselective epoxidation according to Sharpless
A predictive model has been proposed to anticipate synthesis one of the two
enantiomers, the “L model”, depending on the tartrate used.
Figure 7.8. Mnemonic: epoxidation and configuration of tartrates
Various mechanistic models have been proposed for this transformation, including
one using a dimeric structure where a titanium atom is bound to both the substrate by a
metal-oxygen bond and to the oxidant. The chiral environment created by tartrate entities
allows the highly selective approach of one of the two sides of the C=C double bond.
HO R3
R1
(+)-DET (R' = Et)
R2 R1 R2
OR O
R'O2C R'O2C
RO RO
CO2R' CO2R' R3
RO O O RO O O
Ti Ti Ti Ti
OR O O O-O
O O t-Bu
C C
OR' O OR'
O
R'O R'O
O O
HO R3
Activation
O
R2 R1 of peroxide
R1 R1
R2 R2
O
O R3 R'O2C
R'O2C RO
RO CO2R'
CO2R' O transfer of an R3
RO O O
RO O O oxygen atom Ti
Ti Ti O
Ti O O
O O
CO2R' O CO2R'
O
R'O t-Bu
R'O t-Bu O
O
Figure 7.9. Enantioselective epoxidation – model

On the basis of the same model, with a considerable difference in reactivity rate,
the kinetic resolution of racemic allyl alcohols could be established to access one of
the two enantiomers of the starting product. Deriving from these studies, a
regioselective epoxidation reaction was used in the synthesis of (-)-laulimalide by
both Ian Paterson’s team in Cambridge and Johann Mulzer’s team in Vienna
[PAT 01, MUL 01, MUL 01, MUL 04]. The two allylic alcohol subunits differ in the
configuration of the stereogenic center at the base of the hydroxy group and are
considered as pseudoenantiomer subunits. In the presence of diisopropyl (+)-tartrate
as a chiral ligand, only one of the two alkenes reacts (match), the other remaining
unchanged (mismatch).
OH
H
OH O O O
H H
O
TBHP, Ti(OiPr)4
(+)-DIPT
CH2Cl2, -27°C, 15h
OH
O H
OH O O O
H H
O
73%
(one sole diasteromer)
Figure 7.10. Regioselective epoxidation: match and mismatch effect
7.3.3. Key reaction: asymmetric epoxidation according to Shi
The epoxidation of alkenes can easily be carried out by dioxiranes, formed in situ
by the action of an oxidant such as potassium persulfate (KHSO5) on a ketone. Once
the transfer of an oxygen atom has been completed, the ketone is regenerated, the
latter being most often the solvent itself (acetone or trifluoromethyl ketone).
R1
R
R O HSO5-
O
R2
in situ
R1
O
R HSO4
-
R O
R2
Figure 7.11. Transfer of an oxygen atom from dioxirane to an alkene
In order to achieve an asymmetric reaction, different chiral ketones could be

tested including fluoroketones derived from terpenes as well as sugar derivatives
such as D-fructose duly protected by different groups. The reactions are carried out
in a polar solvent such as acetonitrile by introducing quantities between 5 and 300%
of chiral dioxirane precursor [ZHU 14].
The reaction performed on 1,2-disubstituted alkenes of E configuration results in
a very high enantiomeric excess (ee) greater than 93%, unlike Z-isomers for which
the ee does not exceed 60% at best. In the “spiro” transition state leading to the
major enantiomer, the most favorable approach is the one, which as a first
approximation places the largest substituent (R2) furthest from the rest of the
oxidizing species, then involving the weakest possible interaction between the
“small” substituent R1 and the axial hydrogen atom attached to C2 of the sugar. This
model can be transposed to trisubstituted alkenes of E configuration.
R2 R1
R2
R1
O
#
e.e. > 93 %
O
O R2
H R1
O
O
O
O
O
Figure 7.12. Epoxidation according to Shi of alkenes with E configuration
By taking advantage of the nature of the protective groups attached to the chiral
ketone, the epoxidation of different classes of alkenes can be achieved always with
high selectivities. Thus, 1,1-disubstituted olefins undergo effective oxidation in
terms of yields and enantiomeric excesses in the presence of the required catalyst. A
planar transition state was assigned to reflect the selectivities and configuration
observed [WAN 08].
O
O
N
O O
O
O
OH (0.3 equiv.)
OH
Oxone (1.6 equiv.)
1,4-dioxane, -10°C, 2h 47% ( e.e. = 72%)
K2CO3 / AcOH pH = 9.3
O # O #
O Ar Ph O Ar
N N
R
O O R
O O Ph
O O
O O
O O
planar T.S. spiro T.S.
Figure 7.13. Epoxidation of 1,1-disubstituted alkenes
7.3.4.1. Enantioselective dihydroxylation [VID 93, SHA 92, COR 93]

OAc
OH
OH
OAc 34%
AD-mixβ
+
acetone/water OH OAc
0°C, 24h
conversion
80% OH
16%
+ tetrol 27%
7.3.4.2. Payne rearrangement [MOR 02]
NaOH (1M)
O
1,4-dioxane O
HO O O OH HO O
100°C, 1h
HO
HO HO OH
O O O
H H H H OH
HO HO
94%
7.3.4.3. Wittig reaction [HAN 09]

OTBS OTBS
O CH2=PPh3 O
O
O O
PhMe
H -40°C -> 0°C, 30 min.
57%
7.3.4.4. Protection of ketals by DDQ [OIK 82]
O O
DDQ (1.5 equiv.)

O HO O
CH2Cl2 / H2O
OMe (17/1), r.t., 1h OMe

74%
7.3.4.5. Formation of bromohydrins [DAW 84, MOH 03]
HO
O Li2NiBr4, THF
25°C, 5h Br
NC CN NC CN
99%
7.3.4.6. Synthesis of chlorides from alcohols [CHE 02]

H H
OH SOCl2 Cl
O O
DMAP, THF
0°C -> r.t.
71%
7.3.4.7. Cross-metathesis [YAM 08]
H Boc N N
N Mes Mes
Cl
OMe Ru Ph
Cl H Boc
P OMe PPh3 N
OCbz O C13H27 OMe
(3% mol.)
P OMe
+
(E) OCbz O
CH2Cl2, 40°C, 7h
C13H27
(4 equiv.)
68%
7.3.4.8. Reduction of alkenes by diimide [ARM 05]
H H2O2 + N2H4 H H
N N N
+
N N O O
O H H
15 1
7.4. References
[ARM 05] ARMSTRONG P., O’MAHONY G., STEVENSON P.J. et al., “Stereoselective synthesis
of (8R,8S)-8-methylhexahydroindolizin-5-one”, Tetrahedron Letters, vol. 46,
pp. 8109–8111, 2005.
[CHE 02] CHEN B., KO R.Y.Y., YUEN M.S.M. et al., “A tandem metal carbene cyclization-
cycloaddition approach to the pseudolaric acids”, Journal of Organic Chemistry, vol. 68,
pp. 4195–4205, 2002.
[COR 93] COREY E.J., NOE M.C., SHIEH W.-C., “A short and convergent enantioselective
synthesis of (3S)-2,3-oxidosqualene”, Tetrahedron Letters, vol. 34, pp. 5995–5998, 1993.
[DAW 84] DAWE R.D., MOLINSKI T.F., TURNER J. V., “Dilithium tetrabromonickelate (II) as
a source of soft nucleophilic bromide: Reaction with epoxides”, Tetrahedron Letters,
vol. 25, pp. 2061–2064, 1984.
[HAN 09] HANDE S., M., UENISHI J.-I., “Total synthesis of aspergillide B and structural
discrepancy of aspergillide A”, Tetrahedron Letters, vol. 50, pp. 189–192, 2009.
[HER 15] HERAVI M.M., LASHAKI T.B., POORAHMAD N., “Applications of sharpless
pp. 405–495, 2015.
[HIE 08] HIEBEL, M.A., PELOTIER B., LHOSTE P. et al., “Synthesis of bistramide A and
analogues: Stereoselective access to normethyl tetrahydropyran subunit”, Synlett,
pp. 1202–1204, 2008.
[MOH 03] MOHR P.J., HALCOMB R.L., “Total synthesis of (+)-phomactin A using a B-alkyl
Suzuki macrocyclization”, Journal of American Chemical Society, vol. 125,
pp. 1712–1713, 2003.
[MOR 02] MORIMOTO Y., IWAI T., NISHIKAWA Y. et al., “Stereospecific and biomimetic
synthesis of CS and C2 symmetric 2,5-disubstituted tetrahydrofuran rings as central
building blocks of biogenetically intriguing oxasqualenoids”, Tetrahedron: Asymmetry,
vol. 13, pp. 2641–2647, 2002.
[MOR 07] MORIMOTO Y., OKITA T., TAKISHI M. et al., “Total synthesis and determination of
the absolute configuration of (+)-intricatetraol”, Angewandte Chemie: International
Edition, vol. 46, pp. 1132–1135, 2007.
[MUL 01] MULZER J., ÖHLER E., “An intramolecular case of Sharpless kinetic resolution:
Total synthesis of laulimalide”, Angewandte Chemie: International Edition, vol. 40,
pp. 3842–3846, 2001.
[MUL 04] MULZER J., MARTIN H.J., “Lessons learned from macrolide synthesis”,
The Chemical Record, pp. 259–270, 2004.
[OIK 82] OIKAWA Y., YOSHIOKA T., YONEMITSU O., “Protection of hydroxyl groups by
intramolecular oxidative formation of methoxybenzylidene acetals with DDQ”,
[PAT 01] PATERSON I., DE SAVI C., TUDGE M., “Total synthesis of the microtubule-stabilizing
agent (-)-laulimalide”, Organic Letters, vol. 34, pp. 3149–3152, 2001.
[RAM 06] RAMON D.J., YUS M., “In the arena of enantioselective synthesis, titanium
complexes wear the laurel wreath”, Chemical Reviews, vol. 106, pp. 2126–2208, 2006.
[SHA 02] SHARPLESS K.B., “Searching for new reactivity”, Angewandte Chemie:
International Edition, vol. 41, pp. 2024–2032, 2002.
[SHA 92] SHARPLESS K.B., AMBERG W., BENNANI Y.L. et al., “The Osmium-catalyzed
asymmetric dihydroxylation: A new ligand class and a process improvement”, Journal of
[TU 96] TU Y., WANG Z.-X., SHI Y., “An efficient asymmetric epoxidation method for trans-
olefins mediated by a fructose-derived ketone”, Journal of American Chemical Society,
vol. 118, pp. 9806–9807, 1996.
[SUZ 93] SUZUKI M., MATSUO Y., TAKEDA S. et al., “Intricatetraol, a halogenated triterpene
alcohol from the red alga Laurencia intricata”, Phytochemistry, vol. 33, pp. 651–656,
1993.
[VID 93] VIDARI G., DAPPIAGGI A., ZANONI G. et al., “Asymmetric dihydroxylation of
geranyl, neryl and trans, trans-farnesyl acetates”, Tetrahedron Letters, vol. 34,
pp. 6485–6488, 1993.
[WAN 08] WANG B., WONG O.A., ZHAO M.-X. et al., “Asymmetric epoxidation of 1,1-
disubstituted terminal olefins by chiral dioxirane with a planar-like transition state”,
[YAM 08] YAMAMOTO T., HASEGAWA H., ISHII S. et al., “Syntheses of sphingomyelin
methylene, aza, sulfur analogues by the versatile olefin cross-metathesis method”,
[ZHU 14] ZHU Y., WANG Q., CORNWALL R.G. et al., “Organocatalytic asymmetric
epoxidation and aziridination of olefins and their synthetic applications”, Chemical
Reviews, vol. 114, pp. 8199–8256, 2014.
8
Enigmazole A
Enigmazole A is an 18-membered macrolactone isolated from the sponge

Cinachyrella enigmatica, collected in Papua New Guinea by Gustafson and his team
at the University of San Diego [OKU 10]. It showed cytotoxic activity against a
panel of 60 cancer cell lines. It is a target for the development of new cancer
therapies for gastrointestinal tumors and certain leukemias.
HO P O O
HO OMe
O
N
O
O
OH
Figure 8.1. Structure of enigmazole A. For a color version of the

figures in this chapter see www.iste.co.uk/piva/analysis1.zip
ANALYSIS.– An 18-membered macrolactone with a THP subunit included in the

ring, a disubstituted oxazole unit attached to C17, two hydroxy groups on the C5
(one of which is esterified with phosphoric acid) and C15 carbon atoms. The
molecule has eight stereogenic centers and an exo-methylene group.
8.2. Disconnections
The most obvious construction for the enigmazole consists of creating the
lactone structure in the last step by intramolecular esterification according to, for
example, a Steglich–Keck or Yamaguchi reaction [SKE 10, AI 15, AI 18].
Alternatively, the same large cycle can be achieved via a ring-closing metathesis of
a diene ester [SAK 18] or with two alkyne units [AHL 16], followed by the
reduction of unsaturated bonds, by hydrogenation. The tetrahydropyran subunit, in
most cases, was created before macrocyclization; in only one case, it was obtained
via a transannular process [AHL 16].
D1 : Ene-ene RCM C13-C14 D1 : Macrolactonization C1-O17

D2 : Esterification C1-O17 D2 : Wittig reaction C12-C13
D3 : THP : Tandem CM/Oxa-Michael C7-C8 D3 : THP via Hetero-Diels-Alder
H. Fuwa (2018) T. Molinski (2010)
HO P O O
HO 5 OMe
6 1 O 17
N
7 O 7
13
O
OH
12 14
D1 : Macrolactonization C1-O17 D1 : THP via transannular sigmatropic

D2 : THP via Ferrier-Petasis rearrangement
rearrangement D2 : Yne-yne ring-closing metathesis C12-C13
A. B Smith III (2015) A. Fürstner (2016)
Figure 8.2. The four disconnections reported for enigmazole
8.3. Approach according to T. Molinski
The first synthesis of enigmazole A was published by T. Molinski and his team
at the University of San Diego, directly following K.R. Gustafson’s article on
determining its structure [OKU 10, SKE 10].
Enigmazole A 161
HO P O O
HO OMe
O
N
O
O
OH
O-Gp O
D1
OH
OMe
D3 O OH
D2
N
TBSO O
Ph3P OH
O

D1: simplification into two acid and alcohol subunits (regioselective
esterification).
D2: creation of a C-C bond (Wittig reaction and hydrogenation).
D3: formation of the THP heterocycle (hetero Diels–Alder reaction).
8.3.2. Synthesis
8.3.2.1. Functionalization of oxazole by the Negishi reaction
O I OMe I
HO a, b c,d
H H H
8-A1
OMe
O O
O
e ZnI
I
N EtO2C N
EtO2C LiCl N
EtO2C
8-B1
Figure 8.4. Synthesis of disubstituted oxazole 8-B1


a. Formation of 2-methyl-3-iodo-propenol – 38%: (i) MeMgBr, CuI, Et2O,
0°C -> r.t.; (ii) I2, 0°C -> r.t.
b. Oxidation of allyl alcohol to aldehyde – 82%: MnO2, CH2Cl2, r.t., 1 h.
c. Enantioselective addition of dimethylzinc – 60%: (+)-MIB, Me2Zn, hexanes,
0°C -> r.t., 12 h.
d. O-Methylation of alcohol – 80%: (i) NaH, THF, imidazole (cat.), 0°C -> r.t.,
2 h; (ii) Me-I, 1 h 30.
e. Negishi reaction – 86%: (i) Zn, LiCl, THF, r.t., 10 min; (ii) 8-A1, Pd(PPh3)4,
r.t., 1 h.
8.3.2.2. Synthesis of Wittig reaction precursor 8-C1
OMe OMe
O OBz O
f, g
N N
EtO2C
1
8-B OH
OMe OMe
OBz O OBz O
h i
N N
O OH OH OH
OMe OMe
I
+
I O PPh3 O
j-l N m N
O O O O
Ph Ph
1
8-C
N N
Ts Ts
SnBu3 B
BzO
8-D1 R-1 Br
Figure 8.5. Synthesis of Wittig reaction precursor 8-C1

Enigmazole A 163

f. Reduction of the ester to aldehyde – 89%: DIBAL, CH2Cl2/PhMe, -90°C, 2 h.
g. Enantioselective allylation according to Corey – 88% (ratio 24:1): (i) Reagent
R-1, allylstannane 8-D1, 0°C -> r.t., 16 h; (ii) addition to aldehyde, -78°C, 1 h 30.
h. Oxidative cleavage of the alkene – 60%: (i) OsO4, K3Fe(CN)3, K2CO3,
NaHCO3, DABCO, t-BuOH/H2O, r.t., 2 h 30; (ii) NaIO4, THF/H2O, 0°C -> r.t.,
30 min.
i. Reduction of β-aldol to syn-1,3-diol: Et2BOMe, NaBH4, THF, MeOH, -78°C,
4 h.
j. Diol protection – 89% (two steps): 2,2-Dimethoxy-propane, CSA, r.t., 1 h.
k. Benzoate reduction – 80%: DIBAL, DCM, toluene, -78° -> -10°C, 2 h.
l. Conversion of primary alcohol to iodide – 89%: PPh3, imid. THF, 0°C, 1 h.
m. Phosphonium salt formation – 75%: PPh3, Li2CO3, MeCN, toluene,
microwave, 130°C, 30 min.
8.3.2.3. Synthesis of aldehyde 8-E1
HO2C CO2H a' b' HO2C CO2Me
O O O
O RO2C CO2R
c' CO2Me d' CO2Me

HO H O O
B
R-2
OTBS O OTBS (R = i-Pr)
e', f' CO2Me g' CO2Me

H
1
8-E
Figure 8.6. Synthesis of aldehyde 8-E1

a’. Conversion of diacid to anhydride – 99%: AcCl, 50°C, 30 min.
b’. Opening of symmetric anhydride C2 – 87%: MeOH, py, CH2Cl2, 3 h.
c’. Reduction of acid to alcohol – 82%: BH3.DMS, B(OMe)3, THF, 0°C, 3 h.
d’. Swern oxidation – 85%: (i) Cl(CO)2Cl, DMSO, CH2Cl2, -78°C, 30 min.;
(ii) alcohol, -78°C, 30 min.; (iii) Et3N, -78°C -> 0°C, 2 h.
e’. Allylation according to Roush – 85% (d.r. 9:1): allylboronate R-2, PhMe,
-78°C, 2 h.
f’. Alcohol protection – 90%: TBS-Cl, imidazole, DMF, 17 h.
g’. Oxidative cleavage of the double bond – 99%: (i) O3, CH2Cl2, -78°C;
(ii) PPh3, CH2Cl2, -78°C -> r.t., 1 h.
8.3.2.4. Construction of the tetrahydropyran pattern

O OMe O OMe O OMe
TBSO TBSO TBSO

OBn OBn OBn
n
O O + O
8-E1
MeO OMe MeO OMe

OTBS
1 1
8-F 8-G
OMe
CO2Me
TBSO
CO2Me
TBSO O
1 o, p q N
8-G O
CHO
O O
MeO MeO O
OMe
MeO
8-H1
Figure 8.7. Hetero Diels–Alder reaction and Wittig coupling

n. Cycloaddition[4+2] and hydrolysis of enol ether – 81% (ratio cis-8-F1/trans-
8-G1: 4.2/1): (i) BF3.OEt2 (0.2 equiv.), CH2Cl2, -78°C, 40 min.; (ii) MeOH,
CH(OMe)3, CSA, -78°C -> r.t., 1 h.
o. Hydrogenolysis of benzyl ether – 94%: H2, Pd/C, AcOEt, 3 h.
p. Swern oxidation – 99%: (i) Cl(CO)2Cl, DMSO, CH2Cl2, -78°C, 30 min.;
(ii) alcohol, -78°C, 30 min.; (iii) Et3N, -78°C -> 0°C, 2 h.
q. Wittig coupling – 71%: (i) Phosphonium salt 8-C1, LHMDS, THF, -78°C,
30 min.; (ii) Aldehyde 8-H1, -78°C, 1 h 15, then 0°C, 45 min.
Enigmazole A 165
8.3.2.5. Macrolactonization and finalization of the synthesis

R R
O O
CO2Me CO2H
TBSO N TBSO N
O r, s OH
O O O OH
MeO MeO
MeO 8-I1 MeO
R R
N N
O O
O O O O
OAc
OAc
TBSO TBSO
t u, v
O O
MeO OMe
O
R
O N
O
O
HO OAc
w, x
O y, z
O
KO P O O
HO OMe
H2 C O
N
O
O 1
OH
Figure 8.8. Macrolactonization and access to enigmazole 1


r. Saponification of methyl ester 8-I1: LiOH, MeOH/H2O, 80°C, 1 h.
s. Ketal cleavage: CSA, MeOH, r.t., 1 h.
t. Regioselective macrolactonization according to Keck/Acylation of alcohol in
position C-15 – 35% (three steps): (i) DCC, DMAP, DMAP.HCl, CHCl3, reflux,
15 h 30; (ii) AcOH, MeOH.
u. Hydrogenation of the double bond – 70%: H2, Rh(PPh3)3Cl, THF/t-BuOH
(1:1), 50°C, 5 h.
v. Ketal cleavage 82%: CSA, acetone, r.t., 4 h 30.
w. Takai–Lombardo methylenation – 78%: (i) Zn, CH2Br2, TiCl4, THF, -78°C ->
0°C, 2 days. (ii) Ketone, CH2Cl2, 0°C -> r.t., 30 min.
x. Deprotection of silyl ether – 72%: HF/MeCN/H2O (5/86/9), r.t., 2 days.
y. Phosphatation – 61%: (i) i-Pr2N(OFm)2, 1H-tetrazole, MeCN/CH2Cl2, r.t.;
(ii) H2O2 30%, 0°C, 10 min.
z. Hydrolysis of phosphate and acetate – 98%: K2CO3, MeOH, H2O, r.t., 25 h.
The synthesis requires 26 steps for the longest sequence (from propargyl alcohol)
with an overall yield of 0.1%.
8.3.3. Key reaction: 1,2-enantioselective addition of dialkylzinc to

aldehydes
The addition reaction of organozinc compounds on aldehydes is a much slower

process than the action of organolithium or organomagnesium compounds.
However, the kinetics can be significantly increased when a β-aminoalcohol is
added to the reaction medium. In order to distinguish between one of the two
enantiotopic faces of the substrate, the involvement of such non-racemic chiral
compounds (derived from amino acids or alkaloids) has nevertheless proved very
promising. The reaction is all the more effective when two equivalents of the
organometallic species are used. Aminoalcohols are deprotonated by the zinc
species to generate a chiral zinc complex in situ that can then enhance like a Lewis
acid and enhance the electrophilic character of the substrate. A second molecule of
the organozinc species bonds to the oxygen atom. The chiral environment thus
created by this complex induces a selective attack on one side of the carbonyl group.
Soai’s work has shown that proline derivatives can achieve very high selectivities
[SOA 87].
Enigmazole A 167
Figure 8.9. Enantioselective addition of organozinc compounds
By using aminoalcohols prepared from camphor, enantioselectivities can reach

values close to the detection limit [KIT 89, NUG 99]. The 1,2-addition process was also
combined with a cyclopropanation reaction according to Simmons–Smith, itself
controlled by the new stereogenic center. Cyclopropane alcohols are isolated with high
yields and high stereoselectivities [KIM 05].
O
N F3C
1) OH O
O Zn HO
ZnMe
(-)-MIB (4 mol%) O 2) Me
I
H + Me2Zn (2 equiv.)
Me
3) H2O
76%
e.e. = 99%
d.r. > 20:1
Figure 8.10. Tandem addition/cyclopropanation reaction
In addition, when non-optically pure aminoalcohols are used, a chirality

amplification phenomenon has been observed [KAG 01]. This can be explained by the
formation of different dimeric species; the heterochiral species would have a slower rate
of dissociation than the predominant homochiral species too. The minor amino alcohol
would thus be trapped (reservoir tank model) and would not be able to catalyze the
reaction, with the opposite effects that could be expected. The transition state proposed
by R. Noyori and D.A. Evans has been refined through molecular modeling [KIT 89,
EVA 88, GOL 98].
Unlike Grignard’s reagents, organozinc compounds are less easy to manipulate: few
are commercial and must therefore be prepared in situ, while the simplest (Me2Zn) is
pyrophoric. Despite these limitations, the addition reaction of organozinc compounds
remains a process particularly adapted to the synthesis of chiral secondary alcohols.
NMe2
O OH OH
Et2Zn ee 15%
+
Ph H Ph Et
(8% mol)
e.e. 95%
NMe2 NMe2 Me2N

OH OH HO
15% 42.5% 42.5%
Et2Zn Et2Zn
N N Et
Et
Zn Zn
O O O
O
Zn Zn
N Et N
Et
Homochiral
dimeric species Non reactive dimeric heterochiral species
rapid Minimization of #
steric interactions
N Et2Zn N
Zn Zn H
O O
O
Zn
Et Ph
Et
Figure 8.11. Catalysis by aminobornanols and nonlinear effects
8.3.4. Key reaction: reduction of β-aldols to 1,3-diols
The reduction of β-hydroxyketones to 1,3-diols can be controlled to selectively

obtain either the anti compound or the syn compound; Narasaka and Pai reported
access to the latter by precomplexing the two oxygen atoms with a trialkyl borane
[NAR 84, KAT 86, BOD 06]. The species, doubly chelated at the two oxygen
atoms, adopts a chair conformation by minimizing 1,3-diaxial interactions. A
hydride added into the reaction medium is then able to selectively attack the less
hindered face.
Enigmazole A 169
O HO H OH OH OH OH H
1) n-Bu3B H
THF, r.t. Bu
H O
+ B
2) NaBH4 R1 O Bu
H
-100°C
86% (syn) 5% (anti)
Figure 8.12. Diastereoselective reduction according to Narasaka and Pai
8.3.5.1. Oxidation of allyl alcohols by MnO2 [GRA 69, TAY 05, PAR 11]
HO OHC
MnO2
CHCl3, r.t.
OH OH
80%
8.3.5.2. Negishi reaction [DUT 06]

F Br
Ph
O
Pd(OAc)2,
MeO-Ph H (2.5 mol. %) F HCl (1N) F
+ OEt
THF, 10°C r.t. Ph
OEt
MeO-Ph H MeO-Ph H
Ph
ClZn 93%
8.3.5.3. Alkylation/iodination of alkynes [DUB 79, NEG 79, LU 06]

n-C5H11 OH
92
1) CuI (0.5 equiv.)
OH
-78°C -> r.t. I
+ n-C5H11MgBr + I OH
(3.5 equiv.) 2) I2 (3 equiv.), THF
8
-40°C, 30 min. n-C5H11
66%
8.3.5.4. Desymmetrization of meso anhydrides [CHE 00]

O DHQD
OMe
O
O DHQD
CO2H
(5 mol %) OH
O
N
MeOH (10 equiv.) CO2Me
O Et2O, -20°C N
DHQD
97% (e.e. = 97%)
8.3.5.5. Enantioselective allylation according to Roush [ROU 90, HOF 89]

OH
CO2iPr
O OTBDPS
B CO2iPr
O OTBDPS
O
(1 equiv.) syn : 89
H 71%
° MS
Ph-Me, -78°C, 4 A OH
OTBDPS
anti : 11
8.3.5.6. Enantioselective allylation according to Singaram [HIR 05]

HO NHMe
Br
In
+ pyridine Ph Ph
O OH
(2 equiv.) (2 equiv.)
Ph H Ph
THF / n-hexane, -78°C, 1h30
Conversion > 99%
e.e. = 93%
8.3.5.7. Enantioselective hetero Diels–Alder reaction [DOS 99]

Ad
1)
Ad
N O
OSiEt3 Cr O
O SbF6
O Me
(3 mol %)
+ H
OTBS
OTBS acetone, r.t. Me O
2) TBAF, AcOH, THF
97% (d.e. > 97%)
Enigmazole A 171
8.3.5.8. Esterification according to Steglich [BOD 85]

O O
DCC (2 equiv.)
OH HO O
DMAP (3 equiv.)
DMAP.HCl (2 equiv.)
CHCl3 : THF (5:1)
95%
In the absence of DMAP.HCl, the yield is only 4%.
8.3.5.9. Transesterification [PAT 98]

PMB
O O O
1 O OTIPS
OMe 25
MeO OH
Ti(OiPr)4
CH2Cl2, 20°C, 24h
PMB
O O O
TIPSO
HO
1 O
MeO
23
MeO
macrolide 24 / macrolide 26 = 3 : 1
8.3.5.10. Methylenation – Takai–Lombardo reagent [TAK 80]

O CH2Br2 (3 equiv.) CH2
C7H15 Zn (9 equiv.) - TiCl4 (1 equiv.) C7H15
, 25°C
THF, r.t.,
89%
8.3.5.11. Phosphate synthesis [WAT 97]
P O Fm R-OH R P Fm
N O O
O O
Tetrazole
H H
CH2Cl2
O
R P Fm O
O O
m-CPBA O DBU R P OH
O
H OH
CH2Cl2
95% 90-95%
8.4. Approach according to A. Fürstner

With a view to developing a DOS approach, Aloïs Fürstner et al. carried out the
synthesis of the enigmazole based on their very fruitful experience of ring-closing
metatheses, particularly those involving diynes [AHL 16]. The THP cycle is constructed
by a transannular reaction requiring prior sigmatropic rearrangement [3,3].
MeO MeO
N D3 N
O O
O O O O
1 17
OH OR
R
O 5
D2
O R"O
6
7 11
D1 D4
OR'
1 8-A2
1 OH
OMe
8-C2 OH
+
R'O N
O 17
O
10 H 11
OR
MT
8-B2 8-D2
Figure 8.13. Disconnections retained by A. Fürstner

Enigmazole A 173

D1: C7-O11 bond cleavage (tetrahydropyran formation by transannular
cyclization).
D2: disconnection C5-C6: ring-closing metathesis of diyne and reduction.
D3: disconnection of the C1-O17 bond: esterification.
D4: homoallyl alcohol: stereoselective allylation of aldehyde 8-D2.
8.4.2. Synthesis
8.4.2.1. Synthesis of aldehyde 8-D2
MeO OMe
OMe I
O
a N b-d
O N
2 EtO2C
8-E OBoc
OMe
OMe
O
I
e f, g O
N
O O N
O
OTBS
O
OMe
O O OMe CHO
O
O
h, i j
N
N
OTPS OTBS
OTPS OTBS 2
8-D
Figure 8.14. Synthesis of aldehyde 8-D2

a. Coupling by C-H activation – 74%: 8-E2, Pd(OAc)2 (5 mol%), Ligand
CyJohnPhos (10 mol%), Cs2CO3, 1,4-dioxane, 110°C.
b. Reduction of ethyl ester to aldehyde – 80%: DIBAL, CH2Cl2, -90°C.
c. Keck allylation – 98% (diastereomeric ratio > 95: 5): AllylSnBu3, Ti(OiPr)4
(10 mol%), (S)-BINOL (10 mol%), 4 Å MS, CH2Cl2, -20°C.
d. Protection of alcohol as a t-butyl carbonate – 92%: (Boc)2O, DMAP, CH3CN.

e. Iodocarbonation – 54–73%: IBr, toluene, -90°C.
f. Carbonate removal and SNi – 79% (d.r. > 95: 5): K2CO3, MeOH.
g. Alcohol protection – 98%: TBS-Cl, imid. DMAP (10 mol%), THF.
h. Regioselective epoxide opening – 92%: Reagent 8-F2, CuI (20 mol%), THF,
-78°C -> -40°C.
i. Protection of secondary alcohol as TPS ether – 88%: TPS-OTf, 2,6-lutidine,
CH2Cl2, 0°C.
j. Deprotection of the ketal – 97%: TMS-OTf, 2,4,6-trimethylpyridine, CH2Cl2, 0°C.
O MgBr
Cy2P
Reagent 8-F2 Ligand CyJohnPhos
Figure 8.15. Reagent 8-F2 and Ligand CyJohnPhos
8.4.2.2. Conversion of aldehyde 8-D2 to acetylenic alcohol 8-G2

AcO
Cl
Cl Cl a' Bu3Sn Cl b', c'
AcO OMe
SnBu3 CHO
d', e'
O
k-m
N
OTPS OTBS
Ph Ph
8-D2
TsN NTs OMe

B
Br R-1 AcO O
OTroc OTPS OH
8-G2
Figure 8.16. Access to alcohol 8-G2

Enigmazole A 175

a’. Access to stannane by nucleophilic substitution – 49%: (i) LDA, Bu3SnH,
THF/pentane, 0°C; (ii) 3-chloro-2(chloromethyl)-1-propene, pentane, -78°C.
b’. Enantioselective 1,2-addition – 84%: butynal, Ti(OiPr)4 (10 mol%),
(S)-BINOL (10 mol%), 4 Å MS, CH2Cl2, -20°C.
c’. Acylation of propargyl alcohol – 93%: Ac2O, Et3N, DMAP (10 mol%), CH2Cl2.
d’. Conversion of allyl chloride to allyl iodide – 88%: NaI, acetone, 70°C.
e’. Stille Coupling with a bistannane – 73%: Bu3Sn-SnBu3, [Pd2(dba)3]
(2 x 1.7 mol%), THF, 55°C.
k. Allylation according to Corey – 95% (d.r. > 10: 1): 8-D2, Reagent R-1, CH2Cl2,
-78°C.
l. Protection of homoallyl alcohol in trichloromethylcarbonate – 99%: Troc-Cl,
DMAP (10 mol%), pyridine, CH2Cl2.
m. Cleavage of TBS ether – 61%: CSA (20 mol%), CH2Cl2/MeOH (3:1),
0°C -> r.t.
8.4.2.3. Access to diyne 8-A2

O
Ph O
N
Ph
OH n N OTBS
2
8-H
OH
I OTBS
O
o, p q, r
H OTBS OTBS
O
s, t
OH
u
O
OMe
O O
N
O TrocO
O
OTPS
8-A2
Figure 8.17. Access to diyne 8-A2


n. Alkylation according to Myers – 98% (d.r. = 96:4): (i) 8-H2, LDA, LiCl, THF,
-78°C -> r.t.; (ii) alkyl iodide.
o. Reduction of amide by LAB – 89%: (i) LDA, THF; (ii) BH3.NH3, 0°C.
p. Oxidation of alcohol to aldehyde – 88%: TPAP, NMO, 4 Å MS, CH2Cl2.
q. Formation of 1,1-dibromoalkene – 74%: CBr4, PPh3, Zn, CH2Cl2.
r. Corey–Fuchs alkylating reaction – 97%: (i) n-BuLi (2 equiv.), THF; (ii) MeI,
THF, -78°C -> r.t.
s. Deprotection of silyl ether – 96%: TBAF, THF.
t. Oxidation of alcohol to acid – 92%: TPAP (10 mol%), NMO, H2O, MeCN.
u. Esterification according to Yamaguchi – 99%: (i) 8-G2, 2,4,6-trichlorobenzoyl
chloride, Et3N; (ii) DMAP, toluene, 0°C.
8.4.2.4. Cyclization of diyne 8-A2 by metathesis

O
OMe
O
C6H4OMe
N
AcO TrocO
Mo
Ph3SiO OSiPh3
O
OTPS Ph3SiO OSiPh3
K
8-A2
v, w R-3
O O O
OMe
O
TPSO N
HO O
2
8-I
Figure 8.18. Access to cycloalkyne 8-I2

v. Yne-yne ring-closing metathesis – 79%: Molybdenum catalyst R-3
(0.31 equiv.), 4Å MS, toluene, Δ.
w. Deprotection of trichloromethylcarbonate – 93%: Zn, AcOH, ultrasound.
Enigmazole A 177
O O O
OMe
O
TPSO N
HO O
8-I2
x
Ar
OAc O Ar
OMe MeO P AuCl
O MeO P AuCl
Ar
N Ar
O
O t-Bu
OTPS
Ar : OMe
y-z, aa-ab
O t-Bu
R-4
HO P O O
HO
OMe
O
N
O
O
OH
1
Figure 8.19. Formation of tetrahydropyran subunit and access to 1

x. Sigmatropic rearrangement [3,3] – 91%: Gold (R)-R4 complex (17 mol%),
AgSbF6 (34 mol%), CH2Cl2.
y. Saponification of enol acetate – 95%: MeOH, K2CO3.
z. Reduction of carbonyl to alcohol – 61% (+ epimer C5: 33%): NaBH4, MeOH,
-40°C.
aa. Formation of protected phosphate – 99%: (i) (FmO)2PNiPr2, tetrazole,
MeCN; (ii) H2O2 aq., 0°C.
ab. Deprotection of the Fmo groups and the TPS group – 82%: TBAF, AcOH,
THF, 40°C.
This synthesis requires 28 steps for an overall yield of 2.2%.
8.4.3. Key reaction: diastereoselective alkylation according to Myers

The α-alkylation of a carboxylic acid derivative may be accompanied by very
high stereoselectivities when carried out successfully from esters or amides derived
from alcohols or chiral amines. Following the work of Larchevêque and Husson, the
Myers group reported various stereoselective functionalizations by using
pseudoephedrine as a chiral auxiliary [MYE 97]. By the action of two equivalents of
a lithiated base, the enolate from the amide reacts with an electrophile to give the
α-substituted derivative after hydrolysis, with excellent stereoselectivities.
O O
Cl 1) LDA (2 equiv.) Cl
N LiCl N
OH 2) Ph-CH2-Br, OH
-45°C Ph
88%
d.e. = 90%
Figure 8.20. Myers alkylation
The cleavage of amides into acids requires often drastic conditions that could
lead to a partial racemization of the α-center. The action of the LAB allows the
amide to be easily reduced to aldehyde without loss of selectivity [SU 09].
O
Ph
N O O O
BH3.NH3, LDA
OH
O THF H
0°C -> r.t., 2h TPSO
OTPS
O 97%
Figure 8.21. Non-epimerizing reduction by LBA
Selectivities and easy access to carbonyl derivatives make this asymmetric

process very attractive, even though an excess of base is required compared to other
well-established asymmetric alkylations. A model has been proposed to rationalize
the approach of the electrophile species towards the (Z)-enolate of the amide.
O-Li
H
H
O Li
H3C N
H3C R
H
+
E
Figure 8.22. Enantioselective alkylation according to Myers: model

Enigmazole A 179
8.4.4. Key reaction: Yne-yne ring-closing metathesis (RCAM)

The metathesis of alkynes is a catalytic process that allows cyclic alkynes to be
synthesized from diynes [FÜR 13]. Initially developed on relatively simple
compounds, it is now possible to involve substrates with multiple functionalities.
Most probably inspired by the classic catalytic cycle of alkene metathesis, published
by Chauvin, Katz and McGinnis proposed a mechanism for the cross-metathesis of
alkynes involving a carbyne [KAT 75]. This was confirmed by the detection of
metallacyclobutadiene structures by the Schrock group using spectroscopic methods.
The process is in equilibrium; in order to move it towards the formation of the
expected alkyne, the addition of 5 Å molecular sieves is necessary. The but-2-yne is
trapped in the cavity which has the optimal size; this method is preferable to vacuum
evaporation, which can also affect the solvent used and contribute to an increase in
concentration that is detrimental to the reaction. Since Mortreux’s initial work on
homogeneous catalysis [MOR 74], an impressive number of catalysts have been
synthesized based around tungsten or molybdenum. In the presence of
dichloromethane, the molybdenum complex leads to the formation of a new
Mo-carbyne species in the reaction medium, which has proven to be very effective
and widely used in total synthesis. The major disadvantage, however, is its very high
sensitivity to air oxidation or hydrolysis. It therefore requires working exclusively
under argon and not under molecular nitrogen, to which the complex can react,
leading to nitrides.
R
[M] R
N
N Mo
Ar N Ar
Ar
Mo-complex
CH2Cl2
R R R
[M] [M] [M] [M]
H
R R R R
Mo N
N
Ar N Ar
Ar [M] R
Mo-carbyne
R
R
Figure 8.23. Yne-yne ring-closing metathesis

A very important step forward in the development of air-stable catalysts has been
made by the Fürstner group, the ate complex intermediates prepared in a few steps
from Mo(CO)6 can be transformed into pre-catalysts bound by 1,10-phenanthroline.
Decomplexing, carried out under mild conditions in the presence of MnCl2 or ZnCl2
at 80°C, results in the release of the true catalyst into the reaction medium [HEP 12].
Mo(CO)6 Ar Ar
Ph3SiO Mo OSiPh3
5 steps Mo
Ph3SiO OSiPh3 Ph3SiO N
Ph3SiO OSiPh3 Phenanthroline N
K
Ar stable
MnCl2 or ZnCl2
Toluene, 80°C
Mo
Ph3SiO
OSiPh3
Ph3SiO Ar = Ph, p-MeOPh
Figure 8.24. Access to air-stable molybdenum-based catalysts
The cyclization process has been extended to the direct formation of cyclic
1,3-diynes by the intramolecular reaction of bis(diynes) and has found an application
for the convergent synthesis of the ivorenolide carbon skeleton [UNG 15].
OMe
TBSO
OTBS Mo
Ph3SiO
OSiPh3
O Ph3SiO
(40 mol%) O
O
Toluene, 4Å/5Å MS
O
82%
Figure 8.25. Ring-closing metathesis of a bis(diyne)
8.4.5. Key reaction: sigmatropic rearrangement [3,3] of propargyl esters

The rearrangement of propargyl esters known as Saucy and Marbet reaction
allows access to the corresponding allenic isomers. Silver tetrafluoroborate (AgBF4)
Enigmazole A 181
as well as platinum (PtCl4) or gold (HAuCl4) salts used as catalysts considerably

reduce the reaction temperature (35–95°C) [SCH 73, KUS 11, MAR 07, MER 11].
From cyclopropane analogues and in the presence of gold salts, the Nevado group
showed that sigmatropic migration could be accompanied by ring enlargement and
lead to cyclopentenones [ZOU 08, GAR 10].
R1 R3
R2 R1 C
R3 + R2
Ag O
O O
O
R4 R4
O
O 1) Au(PPh3)SbF6
O 1 mol%
CH2Cl2, r.t., 5 min
2) K2CO3, MeOH
r.t., 4h
88%
AcO
AcO OAc
Au Au
Figure 8.26. Rearrangement of propargyl cyclopropane acetates

8.4.6.1. C-H activation – direct functionalization of oxazoles [VER 09]
Pd(OAc)2
EtO2C EtO2C
N Br (5 mol%) N
+ PCy2
Cs2CO3 O
O
(2 equiv.)
(1 equiv.)
L, dioxane 92%
110°C, 18h L
8.4.6.2. Enantioselective allylation according to Keck [KEC 93]

1) (R)-BiNOL 2) SnBu3 OH
Ti(OiPr)4
CHO
CH2Cl2 -78°C -> -20°C, 70h
reflux, 1h
89% (e.e. = 96%)
8.4.6.3. Iodocarbonation [DUA 93]

O
O-t-Bu
O O
O O
I-Br I
OBn
OBn
Ph-Me
-85°C, 70h
syn, syn anti, syn
85% 13,9 1
8.4.6.4. Enantioselective allylation according to Corey [COR 89, WIL 98,

WIL 04]
Ts
Ph N
Ts
B Br
Ph
N N
Ph OH R1
B R2-CHO
Ts
+ N
Ph
CH2Cl2 CH2Cl2 R2
Bu3Sn Ts R1
0°C -78°C
95%
e.e. > 96%
R1
# #
O R2 Ts
Ts N O R2
N B
B Ph R1
Ph H N
N Ts H
Ts R1
Ph
Ph
The most favorable
8.4.6.5. Deprotection of trichloromethylcarbonates [NEU 14]

O O
O O HO
Zn, DMF / AcOH
O 0°C, 45 min
Cl Cl
Cl
84%
Enigmazole A 183
8.5. Approach according to A.B. Smith III

MeO OMe
N N
OH
O O
O O OH
O
OH
O OH PMBO
P OH
O
RO
O O
CH2 CH2
1 8-A3
OMe
OTPS MeO
OR N
O OR N
X O
OTIPS HO
PMBO
+
O O
PMB
TIPSO
3
O 8-C
HO
O
O 8-B3 HO2C 8-D3
Figure 8.27. Disconnections according to A.B. Smith III

D1: breakdown of the lactone functional group (macrolactonization).
D2: formation of dihydropyran (Petasis–Ferrier rearrangement).
D3: dioxanone disconnection (Condensation of a β-hydroxy acid and an aldehyde).
8.5.2. Synthesis
The approach envisaged by A. B. Smith and his team is based on a lactonization
step, according to Yamaguchi, to synthesize the macrocycle while methylene
tetrahydropyran results from the combination of Petasis and Ferrier reactions. The
linear fragments were prepared by the application of anionic reactions from a
2-trialkylsilyl-1,3-dithiane [AI 15, AI 18].
8.5.2.1. Access to epoxide 8-E3
SS OH H H OH
S S
a' b'
TBS OPMB OPMB
TBS-O TBSO
OTBS OTBS
OTBS OH OTBS
O
c' d'
TBSO TBSO
OH 8-E3
OTBS O
OPMB
O
3 3
8-F 8-G
Figure 8.28. Synthesis of epoxide 8-E3

a’. Double alkylation of dithiane involving Brook rearrangement – 90%:
(i) n-BuLi, Et2O, 0°C; (ii) epoxide 8-F3, Et2O, -30°C; (iii) epoxide 8-G3, DMPU, -
78°C -> r.t.
b’. Reduction of dithiane by Raney nickel – 95%: Ni(Ra), H2, EtOH, 80°C.
c’. PMB ether cleavage – 87%: Ni(Ra), H2, EtOH, 80°C.
d’. Epoxide formation from 1,2-diol – 99%: NaH, Tris-imid., THF, 0°C.
8.5.2.2. Synthesis of dithiane 8-H3

OMe
N
OH
a, b c MeO2C
O
OMe
I
N Cl
S N
d, e S MeO2C
O O
H OMe
8-H3 8-I3
Figure 8.29. Access to dithiane 8-H3

Enigmazole A 185

a. Copper–magnesium iodination: (i) MeMgBr, Cu-I, toluene. (ii) I2, -78°C -> r.t.
b. O-Methylation – 77% (two steps): NaH, 15-Cr-5, Me-I, Et2O, r.t.
c. Negishi coupling – 80%: (i) t-BuLi, ZnCl2, pentane, Et2O, THF, -78°C -> r.t.; (ii)
Pd(PPh3)4, 8-I3, THF, 65°C.
d. Reduction of the ester to aldehyde – 87%: DIBAL, CH2Cl2, -78°C.
e. Conversion of aldehyde to dithiane – 96%: 1,3-propanedithiol, BF3.OEt2, CH2Cl2.
8.5.2.3. Synthesis of acid 8-D3

OMe OMe
OTBS HO
S S S S
N f N
H
O O
OTBS
3
8-H
OMe
OTBS HO O
g N
O h, i
OTBS
PMB OMe
OTBS O O
N
j, k O
OTBS
PMB OMe
O OTBS O O
N
HO
O l, m
OMe
PMB
O OH O OH
N
HO
O
8-D3
Figure 8.30. Synthesis of acid 8-D3


f. Condensation of the dithiane anion on epoxide 8-E3 – 77%: (i) n-BuLi, Et2O,
0°C; (ii) epoxide 8-E3, Et2O, -78°C.
g. Dithiane deprotection – 75%: Fe(acac)2, NaI, H2O2, AcOEt.
h. Selective syn reduction – 95% (20:1): Et2BOMe, NaBH4, THF/MeOH, -78°C.
i. Protection of 1,3-diol: p-Anisaldehyde dimethylacetal, CSA, CH2Cl2.
j. Deprotection of primary silyl ether – 88% (two steps): TBAF, AcOH, THF.
k. Oxidation of alcohol to acid – 95%: TEMPO, NaClO, NaClO2, THF, H2O,
CH3CN, r.t.
l. Regioselective ketal opening – 93%: DIBAL, CH2Cl2, hexanes, -78°C.
m. Deprotection of silyl ether – 88%: TBAF, AcOH, THF.
8.5.2.4. Access to aldehyde 8-C3

O
OTPS OH OTPS OH
Ph
N n, o p, q
OH
8-J3
OTPS OTIPS OTPS
r-t I
O
8-C3 8-K3
Figure 8.31. Synthesis of aldehyde 8-C3

alkylation according to Myers: (i) Amide 8-J3 (2.1 equiv.),
N. Diastereoselective
LDA (4 equiv.), LiCl (12.6 equiv.), THF, -78°C; (ii) iodide 8-K3 (1 equiv.),
-78°C -> r.t.
O. Reduction of amide to alcohol – 99% (two steps, d.r. > 20:1): LDA
(3.9 equiv.), BH3.NH3 (4 equiv.), THF, -78°C -> r.t.
P. Oxidation of primary alcohol: SO3.pyr, iPr2Net, DMSO, CH2Cl2.
q. Allylation according to Brown – 91% (two steps, d.r. > 20:1): (-)-Ipc2BOMe,
allyl-MgBr, Et2O, -78°C.
r. Alcohol protection – 91%: TIPS-OTf, lutidine, CH2Cl2.
Enigmazole A 187
s. Dihydroxylation of the double bond: K2OsO4 (8 mol%), NMO (3 equiv.),

t-BuOH, H2O, acetone.
t. Oxidative cleavage of 1,2-diol – 75% (two steps): NaIO4, acetone, r.t.
8.5.2.5. Formation of the 4-methylene tetrahydropyran structure

OMe
OTPS MeO
OTPS N
N O
O OTMS
OTIPS HO
PMBO
O
+ PMB
O
3 u, v TIPSO
8-C
O
HO
O
HO2C 8-D3 O
OMe OMe
OTPS N TMS OTPS N TMS

O O O O
PMBO PMBO
TIPSO x,y TIPSO

w
O O
CH2 CH2 8-L3
Figure 8.32. Access to the 4-methylene tetrahydropyran structure 8-L3

u. Silylation of the oxygenated functions of 8-D3: HMDS, THF.
v. Dioxanone condensation – 95%: 8-C3, TMS-OTf, H2O, CH2Cl2, -78°C.
w. Enol ether formation – 87%: Tebbe reagent, toluene, THF, microwave,
100°C, 3 h.
x. Ferrier rearrangement: Me2AlCl, CH2Cl2, -78°C, 30 sec.
y. Wittig reaction methylenation – 84% (two steps, d.r. > 20:1): Ph3P=CH2.
8.5.2.6. Access to acid 8-A3

OMe OMe
OTPS N OH N
O OTMS O OH
O
PMBO PMBO
TIPSO TIPSO
O z, aa O
CH2 CH2
8-L3 8-A3
Figure 8.33. Access to acid 8-A3

z. TMS and TPS ether removal – 84%: KOH, 18-CR-6, H2O, THF.
aa. Oxidation of primary alcohol to acid – 75%: TEMPO, NaClO, NaClO2,
t-BuOH, CH3CN, H2O, r.t.

MeO MeO
N N
O O
O O O O
OH
OPMB O OH OH
P
HO O
ab, ac ad-af
8-A3 O O
CH2 CH2
1

Enigmazole A 189

ab. Esterification according to Yamaguchi – 89%: 2,4,6-trichlorobenzoyl
chloride, iPr2Net, DMAP, toluene, Δ.
ac. Deprotection of TIPS ether – 70%: HF/pyr (1:6), THF.
ad. Formation of bisfluorenylmethyl phosphate: (i) iPr2NP(OFm)2, 1H-tetrazole,
CH3CN, CH2Cl2; (ii) H2O2.
ae. Deprotection of PMB ether – 61% (two steps): DDQ, pH =7, CH2Cl2.
af. Cleavage of fluorenylmethyl groups: (i) Na2CO3, H2O, MeOH; (ii) TFA,
CH3CN, H2O.
8.5.3. Key reaction: dithiane, umpolung and relayed reactions
1,3-Dithiane, a commercial reagent, can undergo a deprotonation reaction in the

presence of a strong organometallic base, thus leading to a stabilized carbanion by
delocalizing the charge in the free d orbitals of sulfur atoms. This species formally
constitutes a “formyl carbanion” synthon whose potential was revealed in 1972 by
E.J. Corey and D. Seebach, which since then has been widely used in synthesis
[SEE 72, BUL 88, KIR 07].
S S S
S O O
R1 R2
R3 R2 R3 R2
R2 X
O
S S R2 Cl R2-CHO S S
S S
R1 R2 R1 R2
R1
O HO
R2
R2
S S
R2 S S
N R2
R1 O R1
NHTs Ts
HO
Figure 8.35. Reactivity of 1,3-dithiane

Many deprotection methods to release the carbonyl derivative have been
reported. Compared to the initial use of mercuric chloride (HgCl2) or other heavy
metal-based reagents, more eco-friendly processes are now preferred, such as
activation by methyl iodide, the use of oxidants or photochemical methods. While
the monofunctionalization of dithiane is easily achieved, the introduction of a
second group is sometimes more difficult. Amos B. Smith III and his team were able
to overcome this barrier by developing a strategy based on the regeneration of the
base through a Brook rearrangement [SMI 97].
O
R
SiR3 SiR3 SiR3 O
Base
H GSA GSA GSA R
ASG : Anion
stabilizing group
SiR3 SiR3
O E O
Brook rearrangement E+
GSA R GSA R
1,4-migration
Figure 8.36. Principle of relayed anionic reactions
This very elegant strategy has been successfully used to access many natural
products and extrapolated to other methodological umpolung procedures.
S S S TBS S
TBS S S
OTBS O
TBS O
t-BuLi BnO OTBS OTBS

Et2O
BnO BnO
OTBS
O TBS TBS TBS
O O OH O
S S
HMPA/Et2O OBn
69%
Figure 8.37. Synthesis of polyols by multicomponent coupling of a silyl dithiane

Enigmazole A 191
8.5.4. Key reaction: Petasis–Ferrier rearrangement

The methylenation of 1,3-dioxan-4-ones by the Tebbe reagent results in
exocyclic enol ethers. In the presence of a Lewis acid such as trialkylaluminum
salts, they undergo a σ-1,3-sigmatropic rearrangement to generate, after a series of
steps, a tetrahydropyranone, whose ketone function is finally reduced
stereoselectively by transfer of a hydride [PET 96, SMI 01, SMI 06, SMI 08].
O CH2 OH
R2 R2 R2
O O
Cp2TiMe2 Al(i-Bu)3
R1 O R3 THF, 65°C R1 O R3 PhMe

R1 O R3
-78°C
H H H
O Al(i-Bu) R1 R2 O
R3 R1 R2 O R3
R 1 R2 O R3 3
O O
H H
(i-Bu)3Al (i-Bu)3Al
R1 H H Al(i-Bu)3
O H H O
R3 R2 R1 R2 O R3 R1
R2
O R3
Al
O HO
H H
Figure 8.38. Petasis–Ferrier rearrangement

8.5.5.1. Reduction of sulfides, disulfides and dithianes [MOZ 43]
Ni(Ra)
MeS CO2H H CO2H
MeOH, reflux, 5h
95%
8.5.5.2. Deprotection of para-methoxybenzyl ethers [HOR 86]
O
NC Cl
OMe
O O
NC Cl
O DDQ O
O
(1.5 equiv.)
O OBn HO OBn
CH2Cl2/H2O/i-PrOH
5°C, 40 min.
97%
8.5.5.3. Direct conversion of 1,2-diols to epoxides [HIC 74]
H H
H H
Ph O H O Ph O
N-Tosyl O
O imidazole O O
HO H H
OH NaH / DMF
H OCH3 H OCH3
78%
H
H
Ph O H O
O
HO H
OTs
H OCH3
8.5.5.4. Deprotection of dithianes [KIR 13]
O
Fe(acac)3 (0.1 equiv.)
S S
NaI (1 equiv.) S S
H2O2 (30%) - 4 equiv.)
+
THPO
THPO AcOEt/Buffer (1 : 1)
r.t., 20 min 93%
Enigmazole A 193
8.5.5.5. Oxidation of primary alcohols to carboxylic acids [HIR 09]
OH
OH
4-acetamidoTEMPO O O
O
O NaClO/NaClO2 O
HO O HO O
OH pH = 6.8 OH
n n
40°C, 3d
84%
8.5.5.6. Access to the synthon 8-K3 from Roche ester [Li 10]
MeO OH 1) Ts-Cl, DMAP, Et3N MeO OTs
O CH2Cl2, r.t.,12h O
98%
+ -
3) CH3P(Ph)3 Br
2) DIBAL H OTs n-BuLi, THF, 0°C I
Ph-Me, -90°C 4) Li-I, Et2O

O
reflux, 4h 78% (3 steps)
8.5.5.7. Brown enantioselective allylation [NZO 05, BRO 82]
t-BuOK/n-BuLi (+)-Ipc2B-OMe B(+Ipc)2

THF, Et2O, -78°C
-78°C -> -45°C
20 min
OH
O
B(+Ipc)2
TBSO
TBSO H
Et2O, -78°C
80% (e.e. > 95%)
8.5.5.8. Oxidative breakdown of alkenes according to Lemieux and Johnson

[PAP 56]
O
Ph 1) OsO4, dioxane
Ph
2) NaIO4, dioxane
Ph H
1h30 85%
8.6. Approach according to H. Fuwa

The most recent synthesis carried out jointly by M. Sasaki and H. Fuwa involves
a ring-closing metathesis reaction to reach the macrocycle [SAK 18]. The precursor
8-D4 results from the combination of a cross-metathesis reaction and an oxa-Michael
reaction, performed in the same pot.
MeO
OGp O
OMe
N O
O
O O N
O
OH
O OH
P OH O O
GpO
O
8-A4
O
OMe
OGp O
OH
CH2 OH N
1
O + O
GpO
X
4 4
8-B 8-C
OGp
OGp O OGp
S S
OH +
CHO GpO
GpO
4
8-D 8-E4 8-F4
Figure 8.39. Disconnection according to H. Fuwa

Enigmazole A 195
8.6.2. Synthesis
8.6.2.1. Access to tetrahydropyran 8-D4
OH OH OTPS S OTPS
CO2Me
a-e f-g S
8-G4
Bz
OPMB OH OTPS OPMB O OH TPSO
S S
h i, j
OH TPSO OH TPSO
k OH l O
CHO
PMBO PMBO
OTBS OH OTBS OH
m-o O p, q O
PMBO PMBO
8-D4
O
OPMB
8-E4
Figure 8.40. Synthesis of tetrahydropyran 8-D4

a–e. Synthesis of 8-G4 – 77% (five steps): see, sections 8.5.2.4 and 8.5.5.6.
f. Swern oxidation: (i) (COCl)2, DMSO, CH2Cl2; (ii) Et3N, CH2Cl2, -78°C, then
-30°C, 30 min.
g. Dithiane formation – 85% (two steps): HS-(CH2)3-SH, BF3.OEt2, CH2Cl2
-78°C, then 0°C, 1 h.
h. Alkylation of dithiane – 76%: (i) t-BuLi, HMPA, THF, -78°C; (ii) 8-E4 -78°C
-> -50°C, 2 h.
i. Oxidative deprotection of dithiane – 78%: NaClO2, NaH2PO4, Me2CH=CHMe,

EtOH/H2O (10:1), 0°C, 50 min.
j. Evans–Tishchenko reaction – 99% (d.r. > 20:1): SmI2, PhCHO, THF, -10°C,
2 h.
k. Benzoate reduction – 95%: DIBAL, CH2Cl2, -78°C, 2 h.
l. Tandem cross-metathesis/oxa-Michael reaction – 77% (d.r. > 20): HGII, CSA,
crotonaldehyde, 1,2-DCE, r.t., 14 h.
m. Olefin according to Wittig – 78%: CH3-PPh3+ Br-, NaHMDS, THF, 0°C, 1 h 30.
n. Protection of secondary alcohol – 96%: TBS-OTf, 2,6-lutidine, CH2Cl2, 0°C, 1 h
20.
o. Deprotection of primary silyl ether – 77%: TBAF, AcOH, THF, 0°C, 17 h.
p. Oxidation of alcohol to aldehyde: SO3.py, Et3N, DMSO, CH2Cl2, 0°C, 35 min.
q. Oxidation of aldehyde to acid – 88% (two steps): NaClO2, NaH2PO4,
Me2CH=CHMe, t-BuOH/H2O (5:1), 0°C, 2 h.
8.6.2.2. Access to oxazole 8-C4

OMe
OMe
EtO2C
a' N
I O
OMe OMe
OTBS O OTBS
b'-d N e', f' N

H
'
O O
OMe OH OMe
OTBS OTBS
g' N h' N
O O
O-Bz OMe
OH EtO2C
N
i', j' N
8-H4 O
8-C 4 O
Figure 8.41. Synthesis of oxazole 8-C4

Enigmazole A 197

a’. Coupling by C-H activation – 74%: Ester 8H4, Pd(OAc)2 (5 mol%), Ligand
CyJohnPhos (10 mol%), Cs2CO3, 1,4-dioxane, 110°C.
b’. Reduction of ethyl ester to aldehyde – 80%: DIBAL, CH2Cl2, -90°C.
c’. Keck allylation – 98% (diastereomeric ratio > 95: 5): AllylSnBu3, Ti(OiPr)4 (10
mol%), (S)-BINOL (10 mol%), 4 Å MS, CH2Cl2, -20°C.
d’. Protection of silyl ether alcohol – 97%: TBS-Cl, imidazole, DMF, 0°C.
e’. Dihydroxylation of the double bond: OsO4, NMO, THF/H2O (1:1), r.t., 3 h.
f’. 1,2-Diol cleavage – 99% (two steps): NaIO4, THF/H2O (1:1), r.t., 2 h.
g’. Corey–Fuchs reaction – 88%: (i) CBr4, PPh3, Et3N, CH2Cl2, 0°C, 1.5 h;
(ii) n-BuLi (2.1 equivalent), THF, -78°C, 2 h.
h’. Alkylation of alkyne – 67%: n-BuLi, CH3-CHO, THF, -78°C -> 0°C, 1 h 30.
i’. Protection of alcohol to benzoate: BzCl, py, DMAP, CH2Cl2, 0°C -> r.t.
j’. Deprotection of silyl ether – 92% (two steps): TBAF, AcOH, THF, 0°C.
8.6.2.3. Coupling of fragments 8-C4 and 8-D4 and formation of the

macrocycle
OMe OTBS O
OMe
OH
O
N
N
O
O
r O
PMBO
OBz
OBz
8-C4 s
OTBS O
OMe
O
N
O
O O
PMBO
8-A4
t
OTBS O
OMe
O
N
O
O O
PMBO
Figure 8.42. Formation of macrolactone by ring-closing metathesis


r. Esterification according to Yamaguchi – 96%: (i) 8-D4, 2,4,6-trichlorobenzoyl
chloride, Et3N, THF, 0°C, then r.t., 1 h 30; (ii) DMAP, toluene, r.t., 15 h.
s. Meyer–Schuster rearrangement – 82%: iPrAuCl, AgSbF6, THF/H2O (10:1),
microwave, 80°C, 7 h.
t. Ring-closing metathesis – 81% (E/Z: 20/1): GBII, toluene, 40°C, 11 h.
MeO MeO
O N O N
O O
O O
TBSO O TBSO OAc

u-x
O O
PMBO HO
MeO MeO
N
O N O
O
O O O
OH
TBSO OAc
y-z aa-ac
O O
O P
O
HO OH
H2C 1
CH2

Enigmazole A 199

u. Hydrogenation of the double bond – 91%: H2, RhCl(PPh3)3, toluene, 50°C,
1 h.
v. Reduction of ketone function – 86% (d.r. = 3:1): L-selectride, THF, -78°C, 2 h.
w. Protection of alcohol as acetate – 90%: Ac2O, py. 0°C -> r.t., 11 h.
x. Deprotection of PMB ether – 93%: DDQ, CH2Cl2, pH 7 buffer, 0°C.
y. Oxidation of alcohol to ketone – 88%: DMP, NaHCO3, 1,2-DCE, 0°C, 1 h 20.
z. Ketone methylenation – 83%: CH2Br2, Zn, TiCl4, CH2Cl2, 0°C -> r.t., 30 min.
aa. Deprotection of silyl ether – 48%: HFaq, CH3CN, 0°C -> r.t., 20 h.
ab. Formation of fluorenylmethyl phosphate – 77%: (i) iPr2NP(OFm)2, 1H-
tetrazole, CH3CN/CH2Cl2 (7:1); (ii) H2O2, 0°C, 30 min.
ac. Access to free phosphate and cleavage of the acetate – 87%: K2CO3,
MeOH/H2O (10:1), r.t., 16 h.
The synthesis is based on the potential of two metathesis reactions: a

cross-coupling reaction associated with an oxa-Michael reaction and a ring-closing
metathesis to reach the macrocycle. All the processes implemented are accompanied
by excellent yields, except for the step aa of deprotection of a silyl ether at the end
of the sequence.
8.6.3. Key reaction: Tishchenko–Evans reaction
Stereo-controlled access to 1,3-diols is of primary importance because this

pattern is found in many cyclic and acyclic natural products. To achieve them, the
stereoselective reduction of β-hydroxyketones was considered by taking advantage
of the proximal stereogenic center already present. The required substrates are easily
reached via a diastereoselective aldolization reaction involving, for example, Evans’
oxazolidinones followed by transamidation with the Weinreb amine and finally the
addition of an organometallic species [EVA 03]. At low temperature, in the presence
of an aldehyde and a catalytic amount of samarium (II) salts, the β-aldols yield
protected 1,3-diols in the form of monoesters in less than one hour. The reaction is
accompanied by very high selectivities in favor of the anti-derivative. These values
are not affected by the presence of a methyl group at α-, which significantly
increases its potential [EVA 90, RAL 12].
BHex2
O O OH O O
R1 R2-CHO
N R2 N
O O
R1
OH O OH O
AlMe3 OMe R3-MT
R2 N R2 R3
HNMe(OMe) R1 Me R1
O
OH O
R4-CHO R4 O HO H
R2 R3 SmI2 (15 mol%)
R1 R2 R3
THF, -10°C
R1
Figure 8.44. Tishchenko reaction
The mechanism accepted for this transformation is based on the prior formation of a
hemiketal between the aldehyde and the substrate, a reaction catalyzed by the samarium
salts possibly brought to the oxidation degree +3, via a pinacolization reaction of the
aldehyde introduced in excess (the disappearance of the intense blue color of the solution
clearly indicates the disappearance of the samarium (II) salts). The carbonyl group
chelated by the metal is then activated and can be attacked intramolecularly by a hydride.
This mechanism, supported by isotopic studies, is to be compared with the Verley–
Meerwein–Ponndorf reduction [CHA 07]. It should also be noted that such a
transformation was developed by the Heathcock group using nickel salts [BUR 90].
O
OH O R2 O OH
R2-CHO
SmI2 (15 mol%)
R1 R1
THF, -10°C
O R2
R1 H
H
O O
Sm
Figure 8.45. Transition state for Evans–Tishchenko reaction

Enigmazole A 201
The reaction was applied in synthesis including on highly functionalized

substrates [END 07, RAL 15].
O OH OTBS O OH OAc OTBS
SmI2
H
THF, -15°C
90% - d.e. > 96%
Figure 8.46. Application of the Evans–Tishchenko

reaction to the synthesis of pironetin
8.6.4. Key reaction: Meyer–Schuster and Rupe rearrangement
The Meyer–Schuster rearrangement corresponds to the conversion of a propargyl

alcohol (secondary or tertiary) into an α,β-unsaturated carbonyl compound. It is
made possible by the use of Bronsted or Lewis acid catalysts [ENG 09].
Mechanically, the reaction carried out in a protic medium takes place via alcohol
protonation followed by a σ-1,3 sigmatropic rearrangement, to form an allenol,
which is tautomerized into the corresponding carbonyl compound [ZHU 14,
ROY 18]. Depending on the substitution of alkyne, the reaction leads either to
unsaturated aldehydes (R3 = H) or enones (R3 = alkyl, aryl).
OH
R1 O
R1
R2 R2 R3
R3
+
H
H H
O H H R1
O + R3
R1 C
R1 OH
R2 C R3 R2
R3 allenol
R2
H+
Figure 8.47. Meyer–Schuster rearrangement mechanism

The rearrangement can be assisted by a nucleophile such as an ester function; the

allenic structure can then interact with an internal nucleophile such as an aromatic
ring to form bicyclic structures [THA 17, FÜR 07, FÜR 14].
EtO O
EtO
O
TsOH O
(cat.) RO2C
C
CH2Cl2
O 55°C R = Et : 80%
H
H+ and R = H : 10%
Figure 8.48. Cascade Meyer–Schuster and Friedel–Crafts reactions
A very close rearrangement, that of Rupe can take place from tertiary
propargyl alcohols with at least one hydrogen atom on one of the carbon atoms in
position α.
R1 H
OH H
R1 H
H R2 O
H
R2
R1 H H2 O
+
H
H
+
R2 H
H H R1
O R1
H
R1
H R2 H
H R2
R2 enyne
Figure 8.49. Rupe rearrangement mechanism
Instead of Bronsted acids, Gold and Silver salts catalyzed these isomerizations
which can be combined in a sequential process with other reactions such as 1,4-
additions catalyzed by rhodium [HAN 13].
Enigmazole A 203
OH
O
IPrAuNTf2
(3 mol%)
MeOH/H2O
Rh-L*
1-3h, r.t. (2.5 mol%)
p-Tol-B(OH)2
O p-Tol (2 equiv.)
KOH
(0.05 equiv.)
CO2-(2-Naphtyl)
2-3h, 50°C
97%
RhCl/2 Rh-L* (e.e. = 93%)
Figure 8.50. Tandem process Meyer–Schuster rearrangement/1,4-addition

8.6.5.1. Deprotection of dithianes [ICH 04]
NaClO2 (6 equiv.)
OH O OH
S S NaH2PO4
TBSO (2 equiv.) TBSO

OPMB OPMB
87%
(10 equiv.)
MeOH : H2O (3:1), r.t.
8.6.5.2. Tandem metathesis reaction/oxa-Michael addition [FUW 10]

OTIPS OTIPS
O O
(1.5 equiv.)
OH O
HG-II (10 mol %)
CH2Cl2, 100°C (μν)
OTPS OTPS
94%
cis/trans : 7/1
8.6.5.3. Corey–Fuchs reaction [GRA 94, DUM 17, PAR 11, COR 72]
CBr4 (2 equiv.) Br Br
OTBS OTBS OTBS Br
PPh3 ( 2 equiv.) NaHMDS
CHO
Et3N ( 1 equiv.) THF, -100°C
O O O
CH2Cl2, -60°C
80% 92%
O O
Boc N n-BuLi Boc N
O O ( )6 ( )6
CBr4 / PPh3 (2 equiv.)
Boc N
( )7 H THF, -90°C
Br Br
90%
8.6.5.4. Relayed ring-closing metathesis [WAN 04, GRA 06]
OPMB Mes N N Mes

Cl Ru OPMB
OTBS O Cl
OTBS O
O 10% mol. O
O O
O
DCE
50°C
[Ru]
OPMB
OTBS O
O
O
71%
Section Corresponding Year Number Global Key reaction 1 Key reaction 2, Key process
author (University) of steps report Key reaction 3
8.3 T.F. Molinski 2010 27 0.1% 8.3.3. Enantioselective 8.3.4. Reduction - Macrolactoniztaion
Univ. of California, addition of organozinc of β-aldols to - Wittig
San Diego compounds 1,3-diols - THP: Hetero Diels–
Alder
8.4 A. Fürstner Max 2016 28 2.2% 8.4.3. Alkyne 8.4.4. Gold - Yne-yne RCM –
THP: transannular
Planck Institute, metathesis cycling
sigmatropic
Mülheim 8.4.5. rearrangement
Rearranged [3,3]
propargyl esters
8.5 A. B. Smith III 2015 31 1.95% 8.5.3. Dithiane, 8.5.4. Petasis– - Macrolactonization
Univ. of umpolung and relayed Ferrier Retreat - THP: Ferrier–Petasis
rearrangement
Pennsylvania reactions
8.6 H. Fuwa Tohoku 2018 29 1.4% 8.6.3. Tishchenko– 8.6.4. Meyer– - ene-ene RCM
University Evans reaction Schuster and - THP: cross-
8.7. Comparative assessment of the different syntheses
metathesis and oxa-

Rupe’s reagent
Michael
Table 8.1. Syntheses

Enigmazole A
205
8.8. References
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9
Biyouyanagin A
Biyouyanagin A was isolated in 2005 from St. John’s Wort (Hypericum

chinense L.) and has inhibitory activity against HIV virus replication in
H9 lymphocytes [TAN 05]. Its synthesis and that of analogues was carried out
by K. C. Nicolaou and his group [NIC 07, NIC 08, SAV 16].
H H H O
O
O
H
O
Figure 9.1. Structure of biyouyanagin A. For a color version of the

figures in this chapter, see www.iste.co.uk/piva/analysis1.zip
ANALYSIS.– Pentacyclic structure including three rings linearly joined respectively

six-membered, four-membered and five-membered and a butyrolactone entity
linked to the last cycle by a spiranic center. The molecule has eight stereogenic
centers, four of which are around the cyclobutane, according to a cis/anti/cis
sequence.
9.2. Synthesis according to K.C. Nicolaou
9.2.1. Disconnections [NIC 07, NIC 08]
H H H O
H O
D1
O +
O O
H O
O Ph
O
9-A 9-B
H H
D2 D3
9-A +
O
O
(R)-citronellal
O
OR Ph OR OR
O O
D4 D5 D6
9-B O O
O HO O
O
Ph
O O
O
9-C 9-D 9-E
OH
L-malic acid CO2H

HO2C

D1: disconnection of cyclobutane (intermolecular [2+2] photocycloaddition
between two known compounds: sesquiterpene 9-A and hyperolactone C 9-B).
D2: formation of a trisubstituted alkene from a ketone (Shapiro reaction).
D3: synthesis of a cyclohexenone (1,4-addition/crotonization).
Biyouyanagin A 215
D4: double bond from β-elimination (R=H) (Grieco elimination).

D5: disconnection of the spiranic subunit (Pallado-catalyzed rearrangement
of a propargyl alcohol into furanone).
D6: formation of propargyl alcohol (1,2-addition on an α-ketolactone from
malic acid).
9.2.2. Synthesis
9.2.2.1. Synthesis of cyclohexadiene 9-A
CHO H
H
a' Ph
- +
O N Ph
OMe
H H H
H H
b' c', d'
O O
O
9-A
CO2Et
Ph
R1 R2
Ph
N (S)-Diphenyl(methoxy) HO Ethyl 3,4-dihydroxy-
OMe methyl-pyrrolidine
H benzoate
OH
Figure 9.3. Synthesis of precursor 9-A

a’. Formation of enamine from citronellal and 1,4-addition: (i) Reagent R1
(5 mol %), methylvinyl ketone (1.5 equiv.); (ii) Reagent R2 (20 mol %), 0°C, 24 h.
b’. Aldol reaction/crotonization – 68% (two steps) d.e. = 86%: KOH [0.1 N aq.],
(1.0 equiv.), nBu4N+OH- [40% aq.] catalytic, Et2O/THF/H2O (3/1/3).
c’. Formation of enol triflate: (i) KHMDS, THF, −78°C, 3 h; (ii) Comins’
reagent (1.5 equiv.), THF, −78°C, 1 h.
d’. Functionalization of the double bond C=C – 80% (two steps): CH3MgI: [3.0
M in ether] (1.5 equiv.), CuI (2 mol %), THF, 0°C, 15 min.
9.2.2.2. Synthesis of the precursor ketolactone 9-E
MeO2C
HO2C MeO2C
OH
OH OH
a, b c
CO2Me
CO2H CO2Me
OBn
HO O
d, e f
OBn OBn
O O O O
9-E
Figure 9.4. Synthesis of ketolactone 9-E

a. Esterification of malic acid – 98%: MeOH, BF3, OEt2, r.t.
b. Diastereoselective methylation – 86% (anti/syn = 12/1): (i) LHMDS
(2 equiv.), THF, −78°C; (ii) MeI.
c. Enolate alkylation and creation of the quaternary center – 58%: (i) LDA
(2 equiv.), THF, −78°C; (ii) BnOCH2CH2CH2-I.
d. Regioselective saponification – 97%: KOH, MeOH, H2O.
e. Selective acid reduction and lactonization – 75%: LiEt3BH (Superhydride®),
THF, −78°C.
f. Oxidation of α-hydroxylactone – 92%: DMP (2 equiv.), CH2Cl2, r.t., 5 h.
Biyouyanagin A 217
9.2.2.3. Synthesis of the spiranic precursor 9-B

O
Ph
g HO h HO
9-E
OBn OBn
O O O O
9-D
Ph
O
O
O Ph
O O
O OBn
O O
OBn
O O
9-C
O O
Ph Se Ph
i, j k O
O
O O O
O O2N
9-B
Figure 9.5. Synthesis of the spiranic precursor 9-B

g. Diastereoselective addition of acetylene – 79% (d.r. = 3:1): acetylene, n-BuLi,
THF, −78°C, 1 h.
h. Pallado-catalyzed carbonatation and rearrangement of a propargyl alcohol
into furanone – 77%: Pd(Ph3)4 (5 mol %), Ph-I, CO (200 psi), CO2 (200 psi), Et3N,
100°C, 5 h.
i. Deprotection of benzyl ether: BBr3 (1.5 equiv.), CH2Cl2, −78°C, 30 min.
j. Selenation: o-NO2PhSe-CN, P(n-Bu)3, THF, 25°C, 4 h.
k. Generation of the double bond by oxidation of the selenide and
β-elimination/Grieco’s reaction – 73% (three steps): H2O2 (30% aq.) in excess,
THF, 25°C, 1 h.
H H H O
9-A l
+
O O
O
Ph H Ph O
O
1
O O
9-B
Figure 9.6. Intermolecular [2+2] cycloaddition: final step of synthesis

l. Photosensitized [2+2] cycloaddition – 46%: 9-A (4 equiv.), 9-B (1 equiv.),
2-acetonaphthone (1 equiv.), CH2Cl2, 25°C, 5 h.
The synthesis made it possible to determine the relative and absolute

configuration of numerous stereogenic centers, in particular the cis/syn/cis
arrangement initially assumed for cyclobutane had to be revised. Two molecules
from the “chiral pool” (R)-citronellal and L-malic acid were chosen for the control
of the absolute configuration of two target centers. Thanks to a suitable proline
derivative, an organocatalyzed 1,4-addition allowed the stereocontrol of a new
center crucial for the key diastereoselective intermolecular cycloaddition.
A tandem carbonylation reaction of a propargyl alcohol followed by an

oxa-Michael reaction and then the rearrangement of a cyclic carbonate into furanone
results in the expected spiro derivative 9-B.
Biyouyanagin A 219
O O R2
R2 R2
O
H R1
O
R1 R1 O
HO O O
O
O
O O O O O O
+ -
CO2 Pd O- O
R2
R2 R1
R1 +
Pd
O O
O O O
O
R2 O O
R1 R2 R1
O
Pd O
O O O
O
Figure 9.7. Formation of a furanone by pallado-catalyzed coupling
The formation of cyclobutane by the photochemical route could be considered

according to an exo- or endo-approach. Based on NMR studies (NOE effect),
the exo-approach has to be considered to minimize interactions between the side
chain attached to the 9-A cyclohexadiene and the 9-B butyrolactone subunit.
According to this approach, the adduct obtained has the relative configuration
cis/anti/cis, that of the natural product. The photochemical process is carried out in
the presence of a sensitizing agent, in this case 2-acetonapthone, which makes it
possible to reach the triplet stage of hyperolactone C 9-B by intersystem crossing,
thus avoiding the formation of by-products from the singlet state (reached in the case
of direct irradiation). The reaction is performed at 320 nm, which does not require
the use of special quartz glassware.
H
H
O
O
O
O O
O
O
O
Exo approach Endo approach
Figure 9.8. Facial discrimination during [2+2] cycloaddition
9.2.3. Key reaction: 1,4-addition and organocatalysis
The functionalization at β-position of α,β-unsaturated carbonyl or carboxylic

compounds gives access to important synthons. The introduction of alkyl groups is
generally carried out via a Michael reaction involving organocopperlithium
compounds. Enamines, on the contrary, lead to 1,5-dicarbonyl derivatives, in
particular precursors of cyclohexenones, from the same substrates. The first
enantioselective study was reported by Yamada and Otani and required the prior
formation of nucleophilic species and therefore stoichiometric quantities of chiral
amines [YAM 69]. Modest ee up to 37% have significantly increased thanks to
D’Angelo’s work involving α-methylbenzylamine, both enantiomers of which are
commercially available [PFA 85, DAN 92].
Ph
N
O
N
O
Ph
Ph
H+, H2O
NH2 O
NH
Ph
88% O
e.e. = 91%
Figure 9.9. 1,4-Addition of a chiral enamine to methylvinyl ketone

Biyouyanagin A 221
With the renaissance of organocatalysis in the 2000s [PEL 07, MUK 07],
catalytic versions have been reported by Jorgensen, Gellman or List involving
reagents derived from proline or cyclic derivatives (imidazolidinones) from
(S)-phenylalanine [MEL 03, FRA 05, CHI 05, PEE 05, FON 04, JEN 12].
Ph
Ph
N
O O O O
H OMe
+ (5 mol%)
H H
neat, 4°C, 24h
Bn Bn
conversion 90%
e.e. = 98%
Figure 9.10. Enantioselective addition of an aldehyde to methylvinyl ketone
O
N
O O
O Ph N O
H2 - H
Cl
H (10 mol%)
THF, r.t.
15-24h
99% (e.e. = 97%)
anti / syn : 20:1
Figure 9.11. Organocatalyzed intramolecular Michael addition
Two activation processes have been proposed:

– one involving the formation of an enamine, a nucleophilic species likely to
attack the electrophilic position of the enone; in this case, the accepting character
of the latter can be enhanced by the use of additives such as Bronsted acids
(e.g. phenols).
– the other involving the formation of an iminium ion from the unsaturated
carbonyl compound increasing the accepting character of the substrate.
E+ Nu-H
Ar
Ar Ar
Ar OTMS
OTMS
N
N
R R'
E+ Nu-H
Figure 9.12. Possible activation modes for the organocatalyzed 1,4 addition
9.2.4. Shapiro reaction
The Shapiro reaction, initially described in 1967, makes it possible to create an

unsaturation from a carbonyl compound (aldehyde or ketone) via the initial
formation of an arylsulfonyl hydrazone [SHA 67, ADL 83], which undergoes double
deprotonation using a lithium base, to generate a dianion, stable below −65°C.
By allowing the temperature to rise, it irreversibly decomposes to generate a vinyl
anion, which can then be hydrolyzed or used to attack an electrophilic E+ species
(I2, Me3Si-Cl, aldehyde).
R3 R3 R3 R3
O O
O S +
O S Li
+
N R3 N Li R3 N Ar
N H R-Li, THF N R-Li N S
O
-78°C -30°C O
H H +
R1 R1 R1 Li
R2 R2
R2
R-H R-H
+
Li
Ar-SO2-Li N2 E
N Li
N +
E
R1 R1
R1
R2 R2
R2
Figure 9.13. Mechanism of the Shapiro reaction

Biyouyanagin A 223
In order to limit the risks of ortholithiation during the deprotonation step,

a trisyl group substituted at positions 2, 4 and 6 of the aromatic ring will be
preferred over the phenyl or toluyl group not substituted at the ortho and ortho’
positions. In addition, with such a crowded sulfonylhydrazone, a better E/Z
selectivity is observed, which is crucial to control the regioselectivity of the second
deprotonation, which is performed on the same side as the nitrogen branch
[CHA 79, FUN 15].
This reaction has undergone many developments in total synthesis, as shown

by the following example to generate a key synthon for taxoid synthesis [LET 16,
NIC 93].
OMe
2)
OMe
O
O CHO
TMSO
1) t-BuLi (+/-)
THF 3) HCl aq
OH OH
N -78°C
NHTris 70% (2 diastereo
- isomers)
Figure 9.14. Shapiro reaction – a key step in taxoid synthesis
The dianion, at very low temperature, can react with an initial electrophile
to achieve a first functionalization at position 2. The action of one equivalent of
a base allows the regeneration of the dianion; by slowly increasing the temperature
to −30°C, its decomposition with loss of a dinitrogen molecule provides the
expected vinyl anion [CHA 79]. Nakai and Mimura used this reaction sequence
to perform the 1,2-transposition of a keto group from different cyclohexanones
and terpene derivatives [NAK 79].
SO2Ar
O N
N H
1) NH2-NHSO2Ar H
SO2Ar
SO2Ar
N
N Li+
2) n-BuLi N
N
(2 equiv.) 3) CH3S-S-CH3
SCH3
T < -30°C H
SO2Ar
N Li+ N Li+
N N
SCH3 SCH3
4) BuLi
SCH3 O
H+/H2O
48% 98%
Figure 9.15. 1,2-Transposition of oxo groups by the Shapiro reaction
As the Shapiro reaction allows the synthesis of vinyllithium compounds, these

can be easily transformed into their boronic derivatives by adding a trialkylborate.
These can then sequentially undergo a Suzuki coupling catalyzed by palladium
[PAS 96, COR 97].
Biyouyanagin A 225
O2S
N B(OiPr)2
N H
H 1) n-BuLi (3 equiv.) 2) B(OiPr)3
TMEDA/hexane 1h
-78°C -> 0°C (5 min)
Br
Pd(OAc)2
(5 mol%)
Na2CO3, P(Ph)3 (10 mol%)
Ph-Me, reflux, 14h
55%
Figure 9.16. Sequential process: Shapiro reaction and Suzuki coupling
9.2.5.1. Formation of enol triflates [GHO 06, COM 92]

Cl
O OSO2CF3
2) CF3SO2
N N
1) KHMDS SO2CF3
N N
Boc THF, -78°C -30°C Boc
92%
9.2.5.2. Coupling triflates with organocoppermagnesium compounds

[KAR 98]
OTf Me
Me-MgBr (1.5 equiv.)
Ph Cu-I (10 mol %), 0°C, THF Ph

Ph Ph
95%
9.2.5.3. Dess–Martin oxidation [BAC 01, DES 83, TOH 04]

AcO OAc
I OAc
O
OH O O O O O
DMP O
O (1.3 equiv.) O
CH2Cl2, 25°C
98%
9.2.5.4. 1,2-Addition of acetylides – chelation control [MEA 87, GUI 06]

OH OH
CHO
Li Ph
OBn OBn Ph OBn Ph
1,2-syn 1,2-anti
THF, -78°C 45 55
Et2O, -78°C + ZnBr2 95 5
9.2.5.5. Palladium-catalyzed carbonylation [FUK 05, SAN 06]

O
CO PdCl2(PPh3)2
I
(1 mol %)
+
Ph (bmim)PF6, Et3N Ph
F F
120°C, 1h, 20 atm.
81%
Biyouyanagin A 227
9.2.5.6. Deprotection of p-methoxybenzyl ethers [ONO 97, KIM 03]

OMe
MgBr2, OEt2
(3 equiv.)
Me2S (10 equiv.) OH

O CH2Cl2, r.t. OMe
OMe 76%
9.2.5.7. Grieco elimination [HAY 04, GRI 76]
1) NO2
H H
HO SeCN
N (n-Bu)3P, THF, r.t. N
2) m-CPBA
PMBO THF, r.t. PMBO
86%
9.2.5.8. Intermolecular photocycloaddition [ZHO 15, BAC 11]

MeO2C
MeO2C
H H
O O
O
hν = 313 nm
CO2Me H
H H
(15 equiv.)
CH3CN, acetone
r.t., 5h
98%
ratio: 5 2 + 0,2
(head-to-tail
regioisomer)
9.2.5.9. Intramolecular photocycloaddition [HAT 94, BAC 11]

O
MeO2C O O
hν MeO2C
(350 nm)
CO2Me
O hexane O O
(c = 4. 10-3M) 64%
9.2.5.10. Asymmetric photocycloaddition and ether groups [FAU 02]

O
H
O
H
O
hν
(366 nm) MeONa
O O
CH2Cl2, 20°C O MeOH
O
O O O
O
O
O
81% (d.e. = 94%) 69%
(e.e. = 94%)
9.2.5.11. Enantioselective intermolecular photocycloaddition [POP 18]
Ar
Ar
N O
O B O
Br3Al H
F F
hν (366 nm)
+
CH2Cl2
-75°C, 24h H
F
(0.5 equiv.) 72% - e.e. = 93%
(Ar : 2,3-dimethylphenyl)
Biyouyanagin A 229
9.3. References
[ADL 83] ADLINGTON R.M., BARRETT A.G.M., “Recent applications of the Shapiro reaction”,
[BAC 01] BACH T., KIRSCH S., “Synthesis of 6-substituted 4-hydroxy-2-pyrones from
aldehydes by addition of an acetoacetate equivalent, Dess-Martin oxidation and
subsequent cyclization”, Synlett, pp. 1974–1976, 2001.
[BAC 11] BACH T., HEHN J.P., “Photochemical reactions as key steps in natural product
[CHA 79] CHAMBERLIN A.R., BOND F.T., “Regiochemical control in alkenyllithium
generation from arenesulfonylhydrazones”, Synthesis, pp. 44–45, 1979.
[CHI 05] CHI Y., GELLMAN S.H., “Diphenylprolinol methyl ether: A highly enantioselective
catalyst for Michael addition of aldehydes to simple enones”, Organic Letters, vol. 7,
pp. 4253–4256, 2005.
[COM 92] COMINS D.L., DEGHANI A., “Pyridine-derived triflating reagents: An improved
preparation of vinyl triflates from metallo enolates”, Tetrahedron Letters, vol. 33,
pp. 6299–6302, 1992.
[COR 97] COREY E.J., ROBERTS B.E., “The application of a Shapiro reaction – Suzuki
coupling sequence to the stereoselective synthesis of E-trisubstituted olefins”,
[DAN 92] D’ANGELO J., DESMAELE D., DUMAS F. et al., “The asymmetric Michael addition
reactions using chiral imines”, Tetrahedron: Asymmetry, vol. 3, pp. 459–505, 1992.
[DES 83] DESS D.B., MARTIN J.C., “Readily accessible 12-I-51 oxidant for the conversion of
primary and secondary alcohols to aldehydes and ketones”, Journal of Organic
Chemistry, vol. 48, pp. 4155–4156, 1983.
[FAU 02] FAURE S., PIVA-LE BLANC S., BERTRAND C. et al., “Asymmetric intramolecular
[2+2] photocycloadditions: α− and β−hydroxy acids as chiral tether groups”, Journal of
[FON 04] FONSECA M.T.H., LIST B., “Catalytic asymmetric intramolecular Michael reaction
of aldehydes”, Angewandte Chemie: International Edition, vol. 43, pp. 3958–3960, 2004.
[FRA 05] FRANZEN J., MARIGO M., FIELENBACH D. et al., “A general organocatalyst for direct
a-substitution of aldehydes: Stereoselective C-C, C-N, C-F, C-Br, and C-S bond-forming
reactions. Scope and mechanistic insights”, Journal of the American Chemical Society,
vol. 127, pp. 18296–18304, 2005.
[FUK 05] FUKUYAMA T., YAMAURA R., RYU I., “Synthesis of acetylenic ketones by a
Pd-catalyzed carbonylative three-component coupling reaction in [bmim]PF6”, Canadian
Journal of Chemistry, vol. 83, pp. 711–715, 2005.
[FUN 15] FUNES-ARDOIZ I., LOSANTOS R., SAMPEDRO D., “On the mechanism of the Shapiro
reaction: Understanding the regioselectivity”, RCS Advances, vol. 5, pp. 37292–37297,
2015.
[GHO 06] GHOSH S., KINNEY W.A., GAUTHIER D.A. et al., “Convenient preparation of
aryl-substituted nortropanes by Suzuki-Miyaura methodology”, Canadian Journal of
Chemistry, vol. 84, pp. 555–560, 2006.
[GRI 76] GRIECO P.A., GILMAN S., NISHIZAWA M., “Organoselenium chemistry. A facile
one-step synthesis of alkyl aryl selenides from alcohols”, Journal of Organic Chemistry,
vol. 41, pp. 1485–1486, 1976.
[GUI 06] GUILLARME S., PLE K., BANCHET A. et al., “Alkynylation of chiral aldehydes:
Alkoxy-, amino-, and thio-substituted aldehydes”, Chemical Reviews, vol. 106,
pp. 2355–2403, 2006.
[HAT 94] HATAKEYAMA S., KAWAMURA M., TAKANO S., “Total synthesis of (-)-paeoniflorin”,
[HAY 04] HAYAKAWA I., ARIMOTO H., UEMURA D., “Synthesis of the tricyclic core of
halichlorine”, Chemical Communications, pp. 1222–1223, 2004.
[JEN 12] JENSEN K.L., DICKMEISS G., JIANG H. et al., “The diarylprolinol silyl ether system: A
general organocatalyst”, Accounts of Chemical Research, vol. 45, pp. 248–264, 2012.
[KAR 98] KARLSTRÖM A.S.E., RÖNN M., THORARENSEN A. et al., “A versatile route to
2-substituted cyclic 1,3-dienes via a copper(I)-catalyzed cross-coupling reaction of dienyl
triflates with Grignard reagents”, Journal of Organic Chemistry, vol. 63, pp. 2517–2522,
1998.
[KIM 03] KIM J.D., HAN G., JUNG Y.H., “Deprotection of benzyl and p-methoxybenzyl
ethers by chlorosulfonyl isocyanate-sodium hydroxide”, Tetrahedron Letters, vol. 44,
pp. 733–735, 2003.
[LET 16] LETORT A., DE-LIANG L., PRUNET J., “Study of cascade ring-closing metathesis
reactions en route to an advanced intermediate of taxol”, Journal of Organic Chemistry,
vol. 81, pp. 12318–12331, 2016.
[MEA 87] MEAD K.T., “Syn-selective additions of acetylide anions to α-alkoxyaldehydes”,
[MEL 03] MELCHIORRE P., JORGENSEN K.A., “Direct enantioselective Michael addition of
aldehydes to vinyl ketones catalyzed by chiral amines”, Journal of Organic Chemistry,
vol. 68, pp. 4151–4157, 2003.
[MUK 07] MUKHERJEE S., YANG J.W., HOFFMANN S. et al., “Asymmetric enamine catalysis”,
Chemical Reviews, vol. 107, pp. 5471–5569, 2007.
[NAK 79] NAKAI T., MIMURA T., “A facile procedure for regioselective 1,2-carbonyl
transposition. One-pot conversion of ketone tosylhydrazones to enol thioethers of
transposed ketones”, Tetrahedron Letters, vol. 20, pp. 531–534, 1979.
Biyouyanagin A 231
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2007.
[NIC 08] NICOLAOU K.C., WU T.R., SARLAH D. et al., “Total synthesis, revised structure and
biological evaluation of biyouyanagin A and analogues thereof”, Journal of the American
[NIC 93] NICOLAOU K.C., YANG Z., SORENSEN E.J. et al., “Synthesis of ABC taxoid ring
systems via a convergent strategy”, Journal of the Chemical Society, Chemical
[ONO 97] ONODA T., SHIRAI R., IWASAKI S., “A mild and selective deprotection of
p-methoxybenzyl (PMB) ether by magnesium bromide diethyl etherate-methyl sulfide”,
[PAS 96] PASSAFARO M.S., KEAY B.A., “A one-pot in situ combined Shapiro-Suzuki
reaction”, Tetrahedron Letters, vol. 37, pp. 429–432, 1996.
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pp. 4237–4240, 1969.
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pp. 6062–6065, 2015.
10
Elatol
Elatol is a dihalogenated spirosesquiterpene, initially isolated from the red alga

Laurencia elata collected from the coasts of New South Wales in Australia [SIM 74]
and whose structure has been determined by studying the R-X-ray diffraction of its
acetate. Tests on biological targets revealed cytotoxic activity and also against
leishmaniasis [CAM 12, DOS 10].
Cl
HO
Br
Elatol α-Chamigrene
Figure 10.1. Elatol structure. For a color version of the figures

in this chapter see www.iste.co.uk/piva/analysis1.zip
ANALYSIS.– Elatol is a spiro dihalogenated molecule (spiro[5.5]undecane); one of

the two six-membered rings has a chlorine atom attached to a tetrasubstituted
endocyclic double bond. The second cycle includes an exo methylene group, two cis
hydroxy and bromo groups and also two methyl groups in a geminal position.
10.2. Disconnections
The key reaction to form the six-membered unsaturated cycle is a ring-closing

metathesis from a diene [WHI 08, WHI 10].
O
B
A Cl
Cl
HO
Br RO
10.3. Approach according to B. Stoltz
O
B
Cl D1 D2
A Cl
Cl
HO O
Br RO
O
O X
butenone
D3 D4 O
+
RO
A dimedone
HO
Figure 10.3. Disconnection according to Stoltz

D1: functional arrangement around cycle A (α and γ’-halogenation, reduction of
carbonyl group and SN' by hydride).
D2: cycle B with six disconnected bonds at the tetrasubstituted double bond (RCM
between two terminal double bonds including one substituted by a chlorine atom).
Elatol 235
D3: stereo-controlled introduction of an allylic chain (enantioselective

Tsuji–Trost reaction).
D4:introduction of a chain of four carbon atoms (Michael reaction between an
enolate from dimedone and butenone (methylvinyl ketone)).
10.3.2. Synthesis
O O O
a, b
HO i-Bu-O
10-C
Cl
O
O
O O
c d
i-Bu-O
i-Bu-O
O
O
e f
Cl
Cl
i-Bu-O
i-Bu-O
10-B 10-A
Figure 10.4. Formation of the spiranic structure 10-A
LEGENDS OF FIGURE 10.4.–

a. Protection of 1,3-dione to enol ether – 90%: isobutanol, TsOH cat. PhH, Δ.
b. α-Alkylation of the ketone – Michael reaction: (i) LDA, THF, −78°C;
(ii) methylvinyl ketone.
c. Methylenation of non-conjugated carbonyl – Wittig reaction – 74% (two
steps): CH3PPh3Br, t-BuOK, THF, 0-> 70°C.
d. Formation of enol carbonate – 73%: (i) LDA, THF, −78°C; (ii) TMEDA,
Cl-CO-O-CH2(CCl=CH2).
e. Enantioselective alkylating decarboxylation – 82%: Phosphinooxazoline

PHOX-2 (12.5 mol%), Pd(dmdba)2 (10 mol%), PhH, 11°C.
f. Ring-closing metathesis – 97%: Stewart–Grubbs catalyst (5 mol%), PhH, 60°C.
The selected process requires from dimedone (including the gem-dimethyl group
present on ring A) the introduction of two unsaturated chains at a position adjacent
to the first quaternary center. The chain with four carbon atoms is easily introduced
via a Michael addition involving methylvinyl ketone. The chloroallylic chain is
attached via an enantioselective Tsuji–Trost reaction involving a PHOX ligand, a
phosphinooxazolidine derived from t-leucine.
Ring-closing metathesis allows the formation of the B cycle. If the Grubbs II
catalyst (2.5 mol%) is effective, it only results in an incomplete conversion of the
substrate (85% after 22 hours of heating at 60°C). The so-called Stewart–Grubbs
catalyst (5 mol%) has been used here and leads to better results (total conversion in
only 5 hours).
OH
g h
10-A Cl Cl
i-Bu-O O
Br
i j Cl
Cl
HO
O
Br
Br
1
CF3
N N
Cl [Ru]
O Cl
O
(p-CF3-C6H4)2-P N
PHOX-2 Stewart-Grubbs catalyst
Figure 10.5. Synthesis of elatol

Elatol 237

g. 1,2-Addition: MeLi, CeCl3, THF, −78°C -> 0°C.
h. Deprotection of enol ether and dehydration – 89% (two steps): HCl aq.
(10%), 0–23°C.
i. Double α-bromination of the carbonyl and at the allylic position: Br2, HBr
48%, AcOH, 23°C.
j. Diastereoselective reduction of carbonyl group and SN2' – 32% (two steps):
DIBAL (2 equiv.), THF, −78°C -> 60°C.
Number of steps: 9 – Overall yield: 11%.
For the functionalization of ring A, the addition of methyllithium followed by

acid hydrolysis conventionally generates the corresponding enone. In a single step,
two brominations are then carried out: the first, the α-bromination of the carbonyl
group with a stereoselectivity of 6 to 1; the second, at the allylic position.
Chemo- and stereo-selective reduction (syn/anti = 3.9/1) of the ketone is possible by
treatment with DIBAL at low temperatures. In the same step, the bromine atom in
allyl position is substituted mainly by a hydride ion from the same reducing agent
(SN'/SN = 11/1) according to an SN' process.
10.3.3. Key reaction: Tsuji–Trost reaction
The Tsuji–Trost reaction discovered in the 1970s was widely used to create a
C-C bond as well as a carbon-heteroatom bond from compounds with a
leaving group (bromide, acetate, carbonate, etc.) in the allylic position.
Depending on the nature of the nucleophile and the operating conditions,
regiocontrol and diastereoselectivity now place this reaction at the forefront of
coupling processes. It involves a π-allyl-palladium complex whose formation is
conditioned by the stereocenter of the leaving group. Depending on the nature of the
nucleophile, the nucleophilic attack can be carried out on the opposite side to
that coordinated to the metal (with soft nucleophiles such as malonates); conversely,
in the presence of harder nucleophile (hydrides from ammonium formate, stannanes,
etc.), a pre-coordination with the metal leads to the nucleophilic attack on the same
side (Figure 10.6).
R1 X
R1 Nu Pd0L2
Decoordination Coordination
L2Pd(0)
R1 Nu L2Pd(0)
R1 X
Nu Oxidative
R1 addition
(soft reagents)
II
Pd R1
L Nu
Nucleophilic Pd
II
attack
Nu L L X
R1
(hard
reagents) PdII
L X L
Figure 10.6. Catalytic cycle of the Tsuji–Trost reaction
In order to further increase the potential of this reaction, different groups have
focused on developing an enantioselective version. Some of the most effective
ligands grouped together in Figure 10.7 belong to classes including
phosphinooxazolines PHOX [LOI 00], C2-symmetric diphosphines or
atropoisomeric biaryl structures [LEB 16].
Elatol 239
CF3
O
O
(C6H5)2-P N
(p-CF3-C6H4)2-P N
PHOX-1 PHOX-2
O O
P P NH HN
PPh2 Ph2P
(R,R)-Me-DUPHOS (S,S)-Trost-stilbene
OMe O O O O
O Me
Ph2P
PPh2
(Ar)2 P P (Ar)2
(R,R)-MeO-BIPHEP (S)-DTBM-SEGPHOS
Figure 10.7. Chiral ligands associated with the enantioselective Tsuji–Trost reaction
PHOX ligands, derived from t-leucine and initially developed by the Pfaltz group
at the University of Basel, were taken over by the group of B. Stoltz (Caltech) to
synthesize elatol [WHI 10]. A reaction conducted on the dechlorinated compound
showed that the process was possible with the PHOX-1 ligand. Transposed to the
derivative with a chlorine atom, the reaction was slower and less effective in terms
of yield. Additional studies have shown that the decisive step was alkylation; in the
presence of the PHOX-2 ligand, possessing very strongly electroattractive
fluorinated groups on aromatic rings, the electrophilic character of the complex
π-allyl palladium (II) was largely increased leading to a very significant

improvement in yield. Thus, under optimal conditions (PHOX-2 ligand
(11–13 mol%), benzene, 13°C), the alkylation product is formed with an excellent
yield of 90% and an ee of 87%.
Cl
O Cl
PHOX-1 (12 mol%) O
O O Pd(dmba)2
(10 mol%)
Ph-H, 40°C, 7h i-BuO

i-BuO
53% - e.e. = 78%
Cl
O
O
O O H
PHOX-1 (12 mol%)
HCO2H
Pd(OAc )2 (10 mol%) i-BuO
i-BuO
Ph-H, 40°C, 4Å MS, 3h Total conversion (NMR)
O
PHOX-1 (12 mol%) O
O O Pd(dmba)2
(10 mol%)
Ph-H, 40°C, 1h i-BuO

i-BuO
Total conversion (NMR)
Figure 10.8. Optimization and control of allyl transfer
The catalytic cycle of the reaction as well as the stereochemical course of the
reaction are explained in Figure 10.9.
Elatol 241
(PHOX-2) Pd(dmdba)
Cl
O
Cl
O CF3 O O
90% O
i-BuO i-BuO
e.e. = 87%
N P(Ar)2
C-C Coupling Pd
Coordination
CF3
CF3
O
O
N P(Ar)2
Pd N P(Ar)2
Pd
O Cl Cl O
O
O
CF3 O-iBu
i-BuO
CO2 O
Oxidative
Decarboxylation N P(Ar)2 addition
Pd
O
Cl
O O
i-BuO
Figure 10.9. Enantioselective Tsuji–Trost reaction
10.3.4. Key reaction: ring-closing metathesis of hindered olefins
The formation of tri- and tetra-substituted double bonds has been considered by
metathesis but has long suffered from low conversions and yields. The development
of second-generation ruthenium catalysts substituted by NHC ligands has opened a
new path towards more reactive species. In 2008, Caltech’s R. H. Grubbs and his
team developed a new catalyst for which the mesityl group attached to each of the
two nitrogen atoms is replaced by a less cumbersome tolyl group (Figure 10.9).
This new reagent (called Stewart–Grubbs reagent) has proven to be extremely

effective in reaching highly substituted alkenes while supporting the presence of
many functionalities [STE 07, STE 10]. This field remains very active as evidenced
by recent work published by Cazin and Grela and their groups [URB 13, ABL 14].
E E E E
[Ru] CH2
C = 0.1M, Ph-H, 60°C
N N 95%
Cl [Ru]
[Ru] CH2 : Cl
O
Figure 10.10. Ring-closing metathesis to tetrasubstituted alkenes
10.3.5. Key reaction: reduction of enones according to Luche
Controlling the reduction of enones to allyl alcohols is an important issue in

synthesis. The conditions described by Luche et al. of the University of Grenoble,
combining NaBH4 and lanthanide chloride in methanol, allow very high selectivities
to be achieved by minimizing the formation of possible by-products (ketones or
saturated alcohols). Of all the salts tested, cerium salts were the most effective
[GEM 81].
Ce3+ #
Me
O OH OH O
H
O
NaBH4 + CeCl3
+ R2
MeOH (0.4M) H R1
97 3 R3 B OMe
R4
MeO OMe
Figure 10.11. Luche reduction of cyclopentenone

Elatol 243
The selectivity in favor of the observed 1,2-reduction would result from the in
situ formation of alkoxyborohydrides associated with the Ce3+ cation considered as a
“hard” species. A protic solvent, most often methanol, is essential to activate the
carbonyl group by hydrogen bonding.
To be effective, the process requires more than one equivalent of relatively

expensive cerium salts, which is a major drawback for large-scale implementation.
Variants have been reported combining NaBH4 with calcium triflate or rehydrated
alumina respectively [FOR 12, JON 16]. An enantioselective variant has been
developed involving potassium borohydride and a scandium (III)/chiral L
N,N'-dioxide complex derived from (S)-proline (Figure 10.12) [HE 12].
Figure 10.12. Enantioselective reduction of enones
10.3.6. Supporting synthetic diagrams
10.3.6.1. Organocatalyzed 1,4-addition [PER 00, JHA 02, IKU 07]
Cl-
O O
CO2Me H N
+
MeO2C OH
N *
K2CO3 CO2Me
OMe MeO2C
e.e. -> 90%
Quinine salt
10.3.6.2. Organocatalyzed addition – Rauhut–Currier reaction [ARO 07,

RAU 63, MEL 08]
O O
O
O Ph NHAc O Ph
MeO
Ph SH 0.2 equiv. Ph
t-BuOK (6 equiv.), CH3CN, -40°C
C = 0.05M, 24h
70%
e.e. = 95%
10.3.6.3. Wittig methylenation [CHA 08]
TBDPSO O TBDPSO
+ -
PPh3-CH3 , I
H t-BuOK, THF,
0°C -> -78°C
83%
10.3.6.4. Enantioselective alkyl decarboxylation according to Tsuji–Trost

[MOH 05, TAN 07, MOH 08]
O
O
O
O O
PPh2 N
t-Bu
90%
[Pd2(dba)3], THF, 12°C e.e. 89%
10.3.6.5. Tsuji–Trost decarboxylation and enantioselective protonation [ABO

94, KUK 08, DUH 04]
O
O NH2
O
OH
*
(0.3 equiv.)
O
H2, 5% Pd/C
79%
CH3CN, r.t., 5h e.e. = 50%
Elatol 245
10.3.6.6. Formation of spiranic compounds by double RCM [WYB 04,

KOT 07]
C5H11 Mes N N Mes

.
Cl Ru
Cl Ph
N CF3 C5H11 N
10% PCy3
O PhMe, 80°C O CF3
Quantitative
(ratio dia. 1.5/1)
10.3.6.7. Radical allylic bromination [FUC 07]

O
Br
N Br
AIBN cata.
O
CCl4, Δ, 3h 72%
10.4. References
[ABL 14] ABLIALIMOV O., KEDZIOREK M., MALINSKA M. et al., “Synthesis, structure, and
catalytic activity of new ruthenium(II) indenylidene complexes bearing unsymmetrical
N-heterocyclic carbenes”, Organometallics, vol. 34, pp. 2160–2171, 2014.
[ABO 94] ABOULHODA S.J., HENIN F., MUZART J. et al., “ Production of optically active
ketones by a Palladium-induced cascade reaction from racemic β-ketoesters”,
Tetrahedron: Asymmetry, vol. 5, pp. 1321–1326, 1994.
[ARO 07] AROYAN C.E., MILLER S.J. “Enantioselective Rauhut-Currier reactions by
protected cysteine”, Journal of the American Chemical Society, vol. 129, pp. 256–257,
2007.
[CAM 12] CAMPOS A., BORGES SOUZA C., LHULLIER C. et al., “Anti-tumor effects of elatol, a
marine derivative compound obtained from red algae Laurencia microcladia”, Journal of
Pharmacy and Pharmacology, vol. 64, pp. 1146–1154, 2012.
[CHA 08] CHANDRASEKHAR S., YARAGORLA S.R., SREELAKSHMI L. et al., “Formal total
synthesis of (-)-spongidepsin”, Tetrahedron, vol. 64, pp. 5174–5183, 2008.
[DOS 10] DOS SANTOS A.O., VEIGA-SANTOS P., UEDA-NAKAMURA T. et al., “Effect of elatol,
isolated from red seaweed Laurencia dendroidea, on Leishmania amazonensis”, Marine
Drugs, vol. 8, pp. 2733–2743, 2010.
[DUH 04] DUHAMEL L., DUHAMEL P., PLAQUEVENT J.-C. et al., “Enantioselective
protonations: Fundamental insights and new concepts”, Tetrahedron: Asymmetry, vol. 15,
pp. 3653–3691, 2004.
[FOR 12] FORKEL N.V., HENDERSON D.A., FUCHTER M.J., “Lanthanide replacement in
organic synthesis: Luche-type reduction of α,β-unsaturated ketones in the presence of
calcium triflate”, Green Chemistry, vol. 14, pp. 2129–2132, 2012.
[FUC 07] FUCHS S., BERL V., LEPOITEVIN J.-P., “A highly stereoselective divergent synthesis
of bicyclic models of photoreactive sesquiterpene lactones”, European Journal of
[HE 12] HE P., LIU X., ZHENG H. et al., “Asymmetric 1,2-reduction of enones with potassium
borohydride catalyzed by chiral N,N’-dioxide-Scandium(III) complexes”, Organic
Letters, vol. 14, pp. 5134–5137, 2012.
[IKU 07] IKUNAKA M., “Catalytic, asymmetric carbon-carbon formations: Their evolution
from biocatalysis to organocatalysis over the millennium”, Organic Process Research &
Development, vol. 11, pp. 495–502, 2007.
[JHA 02] JHA S.C., JOSHI N.N., “Catalytic enantioselective Michael addition reactions”,
Arkivoc, vol. 7, pp. 167–196, 2002.
[JON 16] JONES-MENSAH E., NICKERSON L.A., DEOBALD J.L. et al., “Cerium-free Luche
reduction directed by rehydrated alumina”, Tetrahedron, vol. 72, pp. 3748–3753, 2016.
[KOT 07] KOTHA, LAHIRI K., “Synthesis of diverse polycyclic compounds via catalytic
metathesis”, Synlett, pp. 2767–2784, 2007.
[KUK 08] KUKULA P., MATOUSEK V., MALLAT T. et al., “Enantioselective decarboxylation of
β-ketoesters with Pd/amino alcohol systems: Successive metal catalysis and
organocatalysis”, Chemistry: A European Journal, vol. 14, pp. 2699–2708, 2008.
[LEB 16] LE BRAS J., MUZART J., “Production of Csp3-Csp3 bonds through
palladium-catalyzed Tsuji-Trost-type reactions of (hetero)benzylic substrates”, European
Journal of Organic Chemistry, pp. 2565–2593, 2016.
[LOI 00] LOISELEUR O., ELLIOTT M.C., VON MATT P. et al., “Pd-Catalyzed allylic substitution
with enantiomerically pure catalysts and chiral non-racemic substrates: A new approach to
catalyst-based regiocontrol”, Helvetica Chimica Acta, vol. 83, pp. 2287–2294, 2000.
[MEL 08] MELCHIORRE P., MARIGO M., CARLONE A. et al., “Asymmetric aminocatalysis gold
rush in organic chemistry”, Angewandte Chemie: International Edition, vol. 46,
pp. 6138–6171, 2008.
[MOH 05] MOHR J.T., BEHENNA D.C., HARNED A.M. et al., “Deracemization of quaternary
stereocenters by Pd-calatyzed enantioconvergent decarboxylative alkylation of racemic
β-keto esters”, Angewandte Chemie: International Edition, vol. 44, pp. 6924–6927, 2005.
[MOH 08] MOHR J.T., STOLTZ B.M., “Enantioselective Tsuji Allylations”, Chemistry: An
Asian Journal, vol. 2, pp. 1476–1491, 2008.
Elatol 247
[PER 00] PERRARD T., PLAQUEVENT J.-C., DESMURS J.-R. et al., “Enantioselective synthesis
of both enantiomers of methyl dihydrojasmonate using solid-liquid asymmetric
phase-transfer catalysis”, Organic Letters, vol. 2, pp. 2959–2962, 2000.
[RAU 63] RAUHUT M.M., CURRIER H., “Dialkyl 2-methylglutarates”, Brevet U.S. 3074999
19630122, American Cyanamid Co., 1963.
[SIM 74] SIMS J.J., LIN G.H.Y., WING R.M., “Marine natural products X: Elatol, a
halogenated sesquiterpene alcohol from the red sea Laurencia elata”, Tetrahedron
Letters, vol. 15, pp. 3487–3490, 1974.
[STE 07] STEWART I.C., UNG T., PLETNEV A.A. et al., “Highly efficient ruthenium catalysts
for the formation of tetrasubstituted olefins via ring-closing metathesis”, Organic Letters,
vol. 9, pp. 1589–1592, 2007.
[STE 10] STEWART I.C., KELTZ B.K., KUHN K.M. et al., “Nonproductive events in
ring-closing metathesis using ruthenium catalysts”, Journal of the American Chemical
Society, vol. 132, pp. 8534–8535, 2010.
[TAN 07] TANI K., BEHENNA D.C., MCFADDEN R.M. et al., “A facile and modular synthesis
of phosphinooxazoline ligands”, Organic Letters, vol. 9, pp. 2529–2531, 2007.
[URB 13] URBINA-BLANCO C.A., BANTREIL X., WAPPEL J. et al., “Mixed N-heterocyclic
carbine/phosphite ruthenium complexes: The effect of a bulkier NHC”, Organometallics,
vol. 32, pp. 6240–6247, 2013.
[WHI 08] WHITE D.E., STEWART I.C., GRUBBS R.H. et al., “The catalytic asymmetric total
synthesis of elatol”, Journal of the American Chemical Society, vol. 130, pp. 810–811,
2008.
[WHI 10] WHITE D.E., STEWART I.C., SEASHORE-LUDLOW B.A. et al., “A general
enantioselective route to the chamigrene natural product family”, Tetrahedron, vol. 66,
pp. 4668–4686, 2010.
[WYB 04] WYBROW R.A.J., EDWARDS A.S., STEVENSON N.G. et al., “A diastereoselective
tandem RCM approach to spiropiperidines”, Tetrahedron, vol. 60, pp. 8869–8880, 2004.
11
Thiomarinol H
Thiomarinol H 1 was isolated from Alteromonas rava bacteria – strain SANK

73390 [STI 92]. Its structure is close to pseudomonic acids, in particular the C
analogue 2 with a similar carbon skeleton. It is an antibacterial agent that is just as
active against Staphylococcus aureus as streptomycin [MAR 09].
OH OH
HO
O O
H
N
HN O O
O OH
1
OH OH
HO
O O
HO O O
Figure 11.1. Structure of thiomarinol 1 and pseudomonic acid C 2. For a color

version of the figures in this chapter, see www.iste.co.uk/piva/analysis1.zip
ANALYSIS.– A polyhydroxy molecule comprising an amide functional group

connected to an α-cyclic-aminoamide, an α,β unsaturated ester functional group, a
THP unit, four hydroxy groups including one in the homoallyl position, one in the
allyl position and a 1,2-diol subunit.
Julia - Kociensky
Dihydroxylation reaction
HO OH
Esterification HO
O
R
O O
DR DH
OH
NHK Allylation
DR DG
5 X
R2O OR2
B
O
2 O 5 X
+ 2 O OR1
R3-CHO
PhS
HDA
RO
O
R2O OR2
RCM B
X
PhS
+
RO O OR1
O
Figure 11.2. Disconnections considered for thiomarinol H
The two syntheses known to date are based on the functionalization of

dihydropyran entities obtained respectively by ring-closing metathesis (DR pathway)
or by a hetero-Diels–Alder reaction (DG pathway) [RAG 17, GAO 05]. The
functionalization of position 5 is ensured in both cases via a Julia–Kocienski
reaction, while the introduction of the side chain in position 2 involves either a
Nozaki–Hiyama–Takai–Kishi (NHTK) reaction [TIA 16] or an allylation conducted
in sequential mode with a cyclic allylboronate.
11.3. Approach according to D.G. Hall
The first synthesis of the target molecule was carried out by D. G. Hall and his
team, focusing on the classic disconnections D1, D2 and D3 leading to three distinct
Thiomarinol H 251
fragments [GAO 05]. The synthesis of the intermediate dihydropyran 11-F was
considered via an original sequential reaction combining a hetero Diels–Alder
cycloaddition reaction/allylation involving an allylboronate.
D3 HO OH
HO
O D1 O
H D2
N
HN O O
O OH
1
O O O
H OR'
N ( )7 S N
HN OH OHC
N
O + RO2C N N +
O Ph
H 11-C
OGp
11-A 11-B
D4
RO CHO
11-E
R'O OR'
RO2C D5
O OEt + B
H
OH D6
11-D
O OEt
R'O OR'
B 11-F
11-G + 11-H
O OEt

D1: simplification into two acid and alcohol subunits (esterification).
D2: disconnection at the double bond level (Julia–Kocienski olefination).
D3: 1,2-diol obtained from an alkene (asymmetric dihydroxylation).
D4: sulfone from an alkene (oxidative cleavage/reduction/substitution).
D5: disconnection of homoallyl alcohol (allylboration of an aldehyde).
D6: formation of dihydropyran (hetero-Diels–Alder).
11.3.2. Synthesis
11.3.2.1. Synthesis of sulfone 11-B
O
O O
B O O
B EtO CHO
11-E
a
+
H O OEt
O OEt b
11-G 11-H 11-F
( )2
O OH O
c-f
EtO O OEt EtO O OEt
H H
OTIPS OH
11-D
O O
S N
g-i
N
EtO2C N N
O Ph
H
OTIPS 11-B
Figure 11.4. Synthesis of sulfone 11-B

a. Enantioselective hetero-Diels–Alder reaction: Jacobsen catalyst (3 mol%),
20°C.
b. Allylation – 76% (2 steps): aldehyde 11-E, 110°C, 36 h.
c. Protection of allyl alcohol – 93%: TIPS-OTf, 2,6-lutidine, CH2Cl2.
d. Regioselective dihydroxylation: AD-mix-β, t-BuOH, H2O, 0°C, 2 h.
e. Oxidative cleavage of 1,2-diol: NaIO4, THF, H2O
f. Reduction of aldehyde to alcohol – 88%: NaBH4, EtOH.
g. Ketal reduction – 85%: TiCl4, Et3SiH, CH2Cl2, −50°C.
h. Conversion of alcohol to sulfide by the Mitsunobu reaction: 1-phenyl-1H-
tetrazole-5-thiol, PPh3, DIAD, THF.
i. Oxidation of sulfide to sulfone – 91%: (NH4)2MoO4, H2O2, EtOH.
Thiomarinol H 253
11.3.2.2. Julia olefination – functionalization of the side chain

O O ArO2S
S O
N
N O
j,k O
EtO2C N N
O Ph
H
OTIPS EtO O
H
11-B OTIPS
OTIPS
O OTIPS
OHC O
11-C
EtO2C
l O
H
OTIPS 11-I
Figure 11.5. Julia–Kocienski coupling involving sulfone 11-B

j. Dihydroxylation of the less hindered double bond: OsO4, NMO, acetone–water.
k. 1,2-Diol protection – 91% (2 steps): Me2C(OMe)2, TsOH cata., AcOEt.
l. Julia–Kocienski reaction – 76%: (i) KHMDS, THF, −78°C; (ii) 11-C, −78°C -> r.t.
O OTIPS
O
EtO2C
O m
H
OTIPS
11-I O OTIPS
O
HO2C
O
H
n-p OTIPS
OH OH
HO
O O
H
N
HN ( )5 O O
O OH
1
Figure 11.6. Final steps of the synthesis


m. Saponification – 96%: KOSiMe3, Et2O, THF, 45°C.
n. DIC-mediated esterification – 95%: hydroxyamide 11-A, DIC, DMAP, CH2Cl2.
o. Silylether cleavage – 81%: TBAF, THF, r.t.
p. Acetonide deprotection – 90%: AcOH aq., r.t.
Number of steps: 15 – overall yield: 22%.
The key step in the synthesis is the formation of dihydropyran via an
enantioselective hetero-Diels–Alder reaction resulting in an allylboronate directly
involved in a tandem addition process on an aldehyde, here 11-E. The introduction
of the unsaturated carbon chain is achieved by a Julia–Kocienski olefination
between an arylsulfone and a duly protected chiral β-hydroxyaldehyde.
11.3.2.4. Access to fragment 11-A

Hydroxyamide 11-A was prepared in four steps from 1,8-octanediol with an
overall yield of 30%.
OH a' OH
HO BnO
H O
N H
b' c',d' HO ( )5 N
BnO ( )5 CO2H
O
11-A
Figure 11.7. Access to the synthon 11-A

a’. Monoetherification – 56%: (i) NaH, DMF, 0°C; (ii) Bn-Br, THF/DMF.
b’. Oxidation of primary alcohol to acid – 78%: PDC, DMF/H2O, 0°C
c’. Amidation – 72%: CDI, (S)-3-aminopiperidinone, THF, r.t.
d’. Benzyl ether cleavage – 96%: H2, Pd/C, AcOEt, r.t.
11.3.3. Key reaction: hetero-Diels–Alder enantioselective reaction
The hetero-Diels–Alder reaction (HDA) with inverse demand between an

α,β-unsaturated aldehyde and an electron-rich alkene – typically an enol ether –
allows synthesis of the corresponding dihydropyrans with high regio- and
Thiomarinol H 255
stereoselectivities [WEI 82, HER 15]. In order to control the approach of the alkene
to one of the two sides of the unsaturated aldehyde, the reaction was carried out in
the presence of a catalytic amount of a salen derivative, cis-1-amino-2-indanol as the
chiral unit [GAD 02, PEL 09, JOR 00].
(S) N O
Cr CO2Et
CO2Et
Cl
(R) O
(5 mol %)
+
O OEt 4Å MS, no solvent O OEt
90%
e.e. = 95 %
Figure 11.8. Enantioselective hetero-Diels–Alder reaction according to Jacobsen
By using 3-boronoacrolein 11-G, cycloaddition results in a dihydropyran with an

allylboronate chain capable of reacting with an aldehyde in a three-component
sequential reaction [GAO 06].
O O
B n-C7H15
n-C7H15 n-C7H15
R-CHO R
O OEt
OEt H
O OEt OH
#
OR'
H H
B # O #
OR' R'O (R'O)2B C7H15
O R'O O
B OEt H
OR C7H15
R R
O
C7H15
OEt H O OEt
H
ET-1 ET-2 ET-3
Figure 11.9. Hetero Diels–Alder reaction/allylation

The effectiveness of the reaction, however, is highly dependent on the substrate.

When the process is conducted at 20°C in the presence of ethyl vinyl ether, only a
very small amount of catalyst is required (1 mol%) and for a reaction time of 2 h.
With a 2-substituted ether in position 2 of configuration Z, the reaction time exceeds
5 h and the amount of catalyst is tripled. The second allylation step also requires
higher than usual temperatures of 45°C with saturated linear aldehydes or 110°C
with 11-C aldehyde required for target synthesis. The presence of the chiral catalyst
is harmful during the allylation reaction and requires elimination by rapid filtration,
which does not allow the process to be carried out in a stricto sensu sequential
manner. To account for the relative cis,cis stereochemistry observed, different
transition states have been proposed. The ET-1 state appears to be excluded due to
steric interactions between the 6-chain ring and the aldehyde. The second state of
transition of the ET-2 chair results in placing the ethoxy and boronate groups in a
pseudo-axial position, which is prohibitive; on the other hand, with ET-3 adopting a
boat conformation, and for which the alkoxy group is then placed in a
pseudo-equatorial position, it clearly reflects the stereochemistry of the reaction.
11.3.4.1. Enantioselective crotylation [BRO 86, YAM 93]
O
OH
1) H3C H THF, -78°C
(Ipc)2B CH3
2) NaOH, H2O2
prepared from 75%

(-)-pinene d.r. = 99% - e.e. = 95%
11.3.4.2. Dihydroxylation/oxidative cleavage [YU 04]
CH3 OPMB CH3 OPMB CH3 OPMB
OsO4 (0.02 eq.) H O

CH3 CH3 CH3
NaIO4 (4 eq.)
+
OTBS O OTBS OTBS
Dioxane/water (3:1) OH
no base : A : 60-64% B : 30-25%
2,6-lutidine (2 eq.) A : 90% B : 6%

Thiomarinol H 257
11.3.4.3. Reduction of ketals [CRA 95]
OSitBuPh2 OSitBuPh2
Et3SiH, TMSOTf
CH2Cl2
EtO O O
70%
11.3.4.4. Mitsunobu reaction in FBS mode [DAN 02, DEM 04]
O
O2 N CO2H C6F13 O O C6F13 O2 N
OEt
O O
N N
C6F13
NO2 NO2
C6F13
+ 92%
Et-OH P THF After extraction
Ph by MeOH/H2O
11.3.4.5. Julia–Kocienski reaction [BEL 96]
2) S
N OTBS O
1) Li-HMDS
OMe
S SO2 THF, -78°C H
OTBS CHO
S S
O OMe
68% (E,E,E)
H 5% (E,E,Z)
11.3.4.6. Dess–Martin oxidation [NIC 07]
O O O
O
IOAc
AcO OAc
OH (1.2 equiv.)
NaHCO3 ( 3 equiv.) OHC

Br CH2Cl2, 45°C, 4h Br
95%
11.3.4.7. Selective saponification [LAG 84, MIN 05]
O O O
Bn2N Bn2N Bn2N
O-t-Bu O-t-Bu 1) BOP, O-t-Bu
TMSO-Na THF, r.t.
THF 2) NaBH4
r.t., 16h THF
O OCH3 O ONa 0°C -> r.t. OH
74%
11.3.4.8. Esterification of tertiary alcohols mediated by DCI [ZHA 98]
CO2H DCI, DMAP O

Sc(OTf)3
(0.6 equiv.) O CO2Et
O2N + HO CO2Et
CH2Cl2, -8°C
O2N
92%
11.4. Approach according to S. Raghavan
The synthesis of the precursor 11-J, common to thiomarinols, was carried out by
S. Raghavan and his team [RAG 17]. The construction of dihydropyran is based
particularly on a ring-closing metathesis followed by the introduction of a carbon
chain in position 2 via a Kirmse–Doyle reaction involving a diazoester and an allylic
sulfide.
Thiomarinol H 259
Figure 11.10. Key disconnections to synthesize acid 11-J

D1: functionalization of the chain in position 2 (Nozaki–Hiyama coupling).
D2: cis-1,2-diol obtained from an alkene (diastereoselective dihydroxylation).
D3: disconnection at the double bond level (Julia olefination reaction).
D4: sulfone from a chiral β-hydroxyester (asymmetric hydrogenation of a
β-ketoester according to Noyori and post-functionalization).
D5: migration of the double bond and introduction of the carbon chain in position
5 (Kirmse–Doyle rearrangement).
D6: formation of dihydropyran (ring-closing metathesis).
11.4.2. Synthesis
11.4.2.1. Synthesis of sulfone 11-N

O OH OMOM
CO2Et a CO2Et b,c CO2Et
OMOM OMOM N N
N
d e,f
OH S N
O O Ph
11-N
Figure 11.11. Synthesis of sulfone 11-N

a. Enantioselective hydrogenation according to Noyori – 95%: (S)-BINAP-RuCl2
(0.1 mol%), H2 (50 psi), EtOH, 80°C, 8 h.
b. Stereoselective alkylation – 82%: (i) LDA (2.1 equiv.), THF, HMPA, −78°C
then -40°C, 20 min.; (ii) MeI (1.25 equiv.), −78°C then 0°C, 3 h.
c. Alcohol protection – 85%: TBAI (0.05 equiv.), MOM-Cl, DIPEA, CH2Cl2.
d. Ester reduction – 94%: LiAlH4, THF, 0°C then r.t., 3 h 30.
e. Mitsunobu reaction – 76%: 1-phenyl-1H-tetrazole-5-thiol, P(Ph)3, DEAD,
Ph-Me, 0°C then r.t., 20 min.
f. Oxidation of sulfide to sulfone – 86%: m-CPBA, CH2Cl2, -30°C, 3 h.
11.4.2.2. Formation of dihydropyran 11-P

SPh SPh
HO Cl g,h i
OH O
OH
OTPS OTPS
PhS Cl PhS PhS
j k l
O O O
OTPS OTPS OTPS
11-P
Figure 11.12. Synthesis of dihydropyran 11-P

Thiomarinol H 261

g. Substitution of chloride by thiophenol – 86%: PhSH, DBU, MeCN, r.t.
h. Protection of primary alcohol – 92%: TPS-Cl, imid. DMF, 0°C – r.t., 4 h.
i. Allylation of secondary alcohol – 83%: Allyl-Br, NaH, 0°C then r.t., 8 h.
j. Formation of a chlorosulfide (non-isolated): NCS (1.1 equiv.), PhH, r.t., 15 min.
k. Substitution of the chloride by a vinyl group – 65%: vinylMgBr, ZnCl2, THF, r.t.
l. Ring-closing metathesis – 81%: GBII (3 mol %), PhMe, reflux, 8 h.
11.4.2.3. Access to acid 11-J
SPh O SO2Ph
PhS O
CO2Et CO2Et
m n,o
O O O
OTPS OTPS OTPS
11-P
O O
O O
p CO2Et q CHO
O O
OTPS OTPS
11-M
O OMOM O OMOM
O O
r s,t
O OHC O
OTPS
11-L
O OMOM
O
OTBS
u,v
O w-z
O
O OMOM
O
OH
O O
OTBS 11-J
Figure 11.13. Access to acid 11-J


m. Kirmse–Doyle rearrangement – 71%: N2CHCO2Et, Rh2(OAc)4, PhMe.
n. Double oxidation of sulfide to sulfone and alkene to diol – 79%: OSO4, NMO,
aqueous acetone.
o. Protection of the 1,2-diol – 84%: Me2C(OMe)2, TsOH.
p. Desulfonation – 80%: Na(Hg), Na2HPO4, MeOH.
q. Reduction of the ester to aldehyde – 92%: DIBAL-H, CH2Cl2.
r. Julia–Kocienski reaction – 75% (E/Z = 3/1): (i) Sulfone 11-N, KHMDS, THF,
−78°C, 15 min; (ii) Aldehyde 11-L, −78°C then return r.t., 12 h.
s. Deprotection of silylated ether – 88%: TBAF, THF, r.t., 3 h.
t. Oxidation of alcohol to aldehyde – 73%: TEMPO (0.1 equiv.), BAIB
(1.2 equiv.), CH2Cl2, 0°C.
u. Nozaki–Hiyama–Kishi coupling – 81%: iodoalkene 11-K, NiCl2, CrCl2, DMSO,
r.t., 7 h.
v. Oxidation of allyl alcohol to ketone – 84%: DMP, NaHCO3, CH2Cl2, 30 min.
w. Stereoselective reduction of enone to allyl alcohol – 93%: Noyori catalyst,
HCO2Na, n-Bu4NBr, CH2Cl2/H2O.
x. Protection of secondary allyl alcohol in silyl ether – 81%: TBSOTf,
2,6-lutidine, CH2Cl2, -20°C, 3 h.
y. Selective deprotection of silyl ether to primary alcohol – 77%: HF.pyridine,
THF, 0°C.
z. Direct oxidation of primary alcohol to carboxylic acid – 92%: BAIB
(30 equiv.), TEMPO (2.1 equiv.), CH3CN/H2O (1:1), 0°C then r.t., 2 h.
11.4.3. Key reaction: Kirmse–Doyle rearrangement
The decomposition of diazo derivatives catalyzed by copper (I) or rhodium (II)

salts and carried out in the presence of allyl sulfide generates a sulfur ylide, which
can then undergo sigmatropic rearrangement [2,3]. Initially highlighted by Kirmse
and Kapps in 1968 and reinvested by the Doyle group, it provides access to
functionalized homoallyl sulfides [KIR 68, DOY 84].
Thiomarinol H 263
R1
R1
R1
N2 Ph + R2
S R2 Ph
S R3
+ R2 MLn
Ph R3
S R3
Figure 11.14. General mechanism of the Kirmse–Doyle rearrangement
More recently, in order to minimize the risks associated with the handling of
diazo derivatives, their in situ generation has been carried out in water by the action
of nitrous acid on amino acetonitrile hydrochloride. In the presence of the iron (III)
dihydroporphyrin complex (FeTPPCl), the intermediate diazo decomposes into a
carbene, which immediately interacts with an allyl and aryl sulfide, already present.
The ylide formed is rearranged into the corresponding α-arylmercapto valeronitrile
in excellent yields [HOC 17].
CN
S
FeTPPCl (1 mol%) S
+
+ NaNO2 (3 equiv.)
H3 N CN (Slow addition)
- H2O/ CH2Cl2
Cl 96%
Figure 11.15. Kirmse–Doyle rearrangement from aminoacetonitrile
In the presence of chiral catalysts such as Rh2(S-DOSP)4, enantioselective

variants have been reported in particular for the genesis of quaternary stereogenic
centers containing a trifluorosulfanyl unit [ZHA 17].
O Rh
N2 CO2Et N S-CF3
O Rh
SO2Ar CO2Et
Ph
+ (0.13 mol%) Ph
S-CF3
n-pentane, -30°C, 24h 95% - e.e. = 91%
Ar = p-C12H25C6H4-
Figure 11.16. Enantioselective Kirmse–Doyle rearrangement

11.4.4. Key reaction: Julia–Lythgoe and Julia–Kocienski reaction
Initially reported by Marc Julia and Jean-Marc Paris in 1973, the condensation
reaction of an arylalkylsulfone on a carbonyl compound followed by a reductive
elimination, makes it possible to synthesize di-, tri- or even tetrasubstituted alkenes
[CHA 14].
LiO R2
Li
Ph n-BuLi Ph R2-CHO Ph
S R1 S R1 S R1
O2 THF, -78°C O2 O2
O R2
Ac
Ac-Cl Na (Hg) R1
Ph
S R1 R2
EtOH
O2
Figure 11.17. Mechanism of the Julia olefination reaction involving phenylsulfones
The reaction is carried out in two steps; after trapping the lithiated intermediate
as an acyloxysulfone, reduction can be achieved using sodium amalgam. After
removal of the acetate group, the vinyl sulfone is reduced to a vinyl radical with the
E configuration; this is then reduced to the corresponding anion to finally give the
alkene after protonation.
Na + MeOH Ph O
H - + S
MeO Na O Na(Hg)
R2 R2 R2
PhO2S
R1 R1
R1 - PhSO2Na
OAc
Na(Hg) R2
R2 R1
R1
Figure 11.18. Reduction of β-acyloxysulfones by sodium amalgam

Thiomarinol H 265
Alternatively, samarium(II) iodide can be used to synthesize the same alkenes,

according to two consecutive single electron transfer.
Ph Ph-SO2
Ph O O
S S SmIII
R2
O Sm2+ O
H
R2 R2 H
R1 R1 R1
SET
OAc
OAc OAc
free rotation
R2
Sm2+ H
H R2
SET R1 R1
OAc
Figure 11.19. Reduction of β−acyloxysulfones by samarium diiodide
The Sylvestre Julia group developed an approach involving a benzothiazol-2-yl

group directly linked to a sulfone, allowing the formation of an alkene, without the
use of an additional reduction step.
S N S N S N
n-BuLi R2-CHO OLi
S O S O S
O Li
THF R2
O O
O
R1 R1 R1
S N
Li O2S R2
O2S O N
Smiles R1 O
Rearrangement
R1 R2 S
R2 N
+ HO + SO2
R1 S
Figure 11.20. Modified Julia olefination reaction

The intermediate lithium alcoholate is added onto the carbon-nitrogen double

bond to give a spiro intermediate, which undergoes a Smiles rearrangement for
which the SO2 group directs the opening of the five-membered ring leading to the
rearomatization of the benzothiazole ring. The cleavage of the carbon-sulfur bond is
accompanied by the release of a gaseous SO2 molecule and 2-hydroxybenzothiazole
in the form of its anion, which is neutralized at the end of the reaction.
The stereochemistry of the alkene depends on many factors including steric

hindrance and operating conditions (solvent, temperature, nature of the base and
cation involved). With lithiated and apolar bases, selectivity is in favor (weakly) of
compounds with Z configuration; the latter can be correlated with the transition
states represented in Figures 11.21 and 11.22 from anti and syn alcoholates
respectively. In the case of the anti derivative, the chelation of the small lithium
cation with the heteroatoms O and N leads to the development of a gauche
interaction between the substituents R1 and R2, which does not promote an easy
ring-closing to the spiro intermediate. After rearomatization and adoption of a
conformation for which the BTO and SO2Li substituents are anti, the elimination
leads to the compound with E-configuration.
S
N
OLi Li
S N O
R1 Li SO2
R2 O R1
R1 O S slow
SO2Ar O
H R2 H
anti R2
H H
H
SO2Li H
R1 R1
C R1
R2
BT-O R2 R2
H
H
Figure 11.21. Justification of the E stereochemistry from the anti adduct
With the synderivative, the situation is more favorable to the formation of the
spiro intermediate, the two substituents R1 and R2 being in anti. In this way,
elimination gives the Z stereoisomer.
Thiomarinol H 267
S
OLi N
S N Li
R1 Li
R2 O O
fast SO2
R1 O S
SO2Ar O R1
H R2
syn
H H R2
H
R2
R R2
R1 SO2Li R12
C R1
BT-O H H Z
H
H
Figure 11.22. Justification of Z stereochemistry from the syn adduct
By modifying the nature of the sulfone-bound heterocycle, Kocienski et al.

showed that tetrazoles substituted by a t-butyl or phenyl group made it possible to
free themselves, just like the BT derivatives, from the reduction step but with much
greater selectivity, in favor of the E derivative, including with lithiated derivatives.
These sulfones now represent the most commonly used reagents for this method of
olefination [SPE 15].
Ph O O
N S O
O
N TBSO
TBSO O
O N N
KHMDS, THF
CHO
H H
H H -78°C -> r.t.
OTBS
OTBS 70%
E/Z > 95/5
Figure 11.23. Application of tetrazolylsulfones in total synthesis
Usually performed using aldehydes and ketones, the reaction has more recently
been extended to lactones, lactams and imides to synthesize, in the latter case,
bicyclic nitrogen structures [TRI 16, GUE 18].
N O
O O
S
1) LiHMDS, -78°C
S BF3.OEt2, THF N
O
2) DBU (2.5 equiv.)
N
BF3.OEt2, THF
O 79%
Figure 11.24. Intramolecular Julia reaction involving an imide
11.4.5.1. Ring-closing metathesis [RAG 11, JAC 16]
HO HO
GBII
(5 mol%)
( )2 ( )2
C10H21 O OR C10H21 O OR
CH2Cl2, Δ
OBn OBn OBn OBn
R=H 76%
R = TES 85%
11.4.5.2. Desulfonation under reductive conditions [TRO 76]
O
O S H
NC NC
Na(Hg)
Na2HPO4
MeOH, -10°C
7 min. 66%
11.4.5.3. Reduction of β-ketoesters according to Noyori [NOY 87]
O O OH O
RuCl2[(R)-BINAP]
OMe OMe
H2 (100 atm.)
MeOH, 23°C 99% - e.e. > 99%
Substrate/catalyst : 2000
Thiomarinol H 269
11.4.5.4. Nozaki–Hiyama–Kishi reaction [STI 83]

OCH2OBn
Ph
O
O HO
O
Br
CHO CrCl2 (5 equiv.) 4

+
O THF, 25°C, 6h OCH2OBn
64% 1
HO
O
11.4.5.5. Oxidation of alcohols to aldehydes by TEMPO [DEM 97]

AcO OAc
I
N
O
TEMPO BAIB
OH (0.1 equiv.) (1.1 equiv.) O
CH2Cl2, r.t., 1h30
95%
11.4.5.6. Oxidation of alcohols to carboxylic acids [EPP 99]

NH2 NH2
N N
N N
OH
N TEMPO N N
HO N O
O (0.2 equiv.) O
BAIB (2.2 equiv.)

O O O O
CH3CN/H2O
90%
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[BRO 86] BROWN H.C., BHAT K.S., “Enantiomeric (Z)- and (E)-
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[DEM 04] DEMBINSKI R., “Recent advances in the Mitsunobu reaction: Modified reagents and
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[DEM 97] DE MICO A., MARGARITA R., PARLANTI L. et al., “A versatile and highly selective
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electron demand hetero-Diels-Alder reactions of α,β−unsaturated aldehydes”,
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antibiotic”, Journal of the American Chemical Society, vol. 127, pp. 1628–1629, 2005.
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Thiomarinol H 271
[GUE 18] GUEYRARD D., “Extension of the modified Julia olefination on carboxylic acid
derivatives: Scope and applications”, Synlett, pp. 293–295, 2018.
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Diels-Alder reaction in the total synthesis of natural products”, RSC Advances, vol. 5,
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[JAC 16] JACQUES R., PAL R., PARKER N.A. et al., “Recent applications in natural product
synthesis of dihydrofuran and pyran- formation by ring-closing alkene metathesis”,
Organic and Biomolecular Chemistry, vol. 14, pp. 5875–5893, 2016.
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carbonyl compounds and imines”, Angewandte Chmie: International Edition, vol. 39,
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[KIR 68] KIRMSE W., KAPPS M., “Reaktionen des diazomethans mit diallylsulfid un
allyläthern unter kupfersalz-katalyse”, Chemische Berichte, vol. 101, pp. 994–1003, 1968.
[LAG 84] LAGANIS E.D., CHENARD B.L., “Metal silanolates: Organic soluble equivalents for
O2”, Tetrahedron Letters, vol. 25, pp. 5831–5834, 1984.
[MAR 09] MARION O., GAO X., MARCUS S. et al., “Synthesis and preliminary antibacterial
evaluation of simplified thiomarinol analogs”, Bioorganic & Medicinal Chemistry,
vol. 17, pp. 1006–1017, 2009.
[MIN 05] MINTA E., BOUTONNET C., BOUTARD N. et al., “Easy saponification by metal
silanolates: Application in SPPS and in (S)-5-hydroxyvaline preparation”, Tetrahedron
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[NIC 07] NICOLAOU K.C., TANG Y., WANG J., “Formal synthesis of (+/-)-platensimycin”,
Chemical Communications, pp. 1922–1923, 2007.
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β-keto-carboxylic esters. A practical purely chemical access to β-hydroxy esters in
high enantiomeric purity”, Journal of the American Chemical Society, vol. 109,
pp. 5856–5858, 1987.
[PEL 09] PELISSIER H., “Asymmetric hetero-Diels-Alder reactions of carbonyl compounds”,
[RAG 11] RAGHAVAN S., SUBRAMANIAN S.G., “Toward a modular, bidirectional synthesis of
(-)-mucocin”, Tetrahedron, vol. 67, pp. 7529–7539, 2011.
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C46 segment of hemicalide. Assignment of the relative configuration of the C36-C42
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vol. 48, pp. 4786–4788, 1983.
[STI 92] STIERLE D.B., STIERLE A.A., “Pseudomonic acid derivatives from a marine
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reaction”, Synthesis, vol. 48, pp. 4038–4049, 2016.
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12
Oblongolides A and C
12.1. Structures, isolation and properties
The oblongolides are a family of sesquiterpenes (C15) and norsesquiterpenes

(C14) isolated from the fungus Phomopsis oblonga itself growing on halophyte
forage plants such as sweet clover (Melilotus dentata) [BEG 85, DAI 05, BUN 10].
This family has 26 members (A-Z), and only two of them have been synthesized to
date. They differ only in their substitution in position 3a.
O O
O O
H H
3a 3a
9b 9b
H OH
H H
1 2
Oblongolide A Oblongolide C
Figure 12.1. Structure of oblongolides A and C. For a color version of

the figures in this chapter see, www.iste.co.uk/piva/analysis1.zip
ANALYSIS.– Oblongolides A and C have an octahydronaphthalene (trans decalin)

core structure with a butyrolactone group attached. They share an unsaturated bond
present on cycle B and five stereogenic centers including a quaternary center at α on
the carboxylic group.
The decalin skeleton is found in many natural products, and its access has been
the subject of many investigations [DHA 15]. Two approaches have been considered
here to reach the carbon skeleton common to both targets:
– first, involving an intramolecular (or even transannular) Diels–Alder reaction
between a diene and an α,β-unsaturated ester to simultaneously construct cycles
A and B [SHI 95];
– second, according to a [3+2] dipolar cycloaddition between a nitrile oxide and
an alkene already combined on synthon 12-C already containing cycle A [INO 13].
Both intermediates 12-A and 12-C can be prepared from the same natural
compound (-)-citronellol. A [4+2] cycloaddition was also carried out using a
transannular approach based on the macrolactone prepared from 12-A; this approach
is then likely to lead directly to oblongolide A 1.
CO2R
OH
O
O
H C 12-A
OH
A B R (-)-citronellol
O
H H H
N
1/2
N
OH
12-B 12-C
Figure 12.2. Key disconnections: Diels–Alder or [3+2] cycloaddition
Citronellol and the corresponding aldehyde are key substrates for the synthesis of
natural products: the alcohol/aldehyde and alkene functional groups can be
selectively modified while preserving the stereogenic center bearing a methyl group,
and lead to chiral synthons of real importance [LEN 07, HAN 15].
Oblongolides A and C 275
12.3. Synthesis of oblongolide A according to Shing
O
O
CO2R
D1 OH D2 CHO
H
CHO
H
1 12-A 12-D
D3
OH (-)-Citronellol
Figure 12.3. Disconnection according to Shing

D1: formation of the B cycle (intramolecular [4+2] cycloaddition).
D2: double olefinization of bisaldehyde 12-D (classic and vinylogous Wittig–
Horner reaction).
D3: access to dialdehyde (oxidative division of the double bond/oxidation of the
primary alcohol of (-)-citronellol).
12.3.2. Synthesis
12.3.2.1. Intramolecular Diels–Alder reaction

The outcome of the Diels–Alder reaction varies significantly depending on
the reaction time and temperature applied. When 12-A is subjected to heat treatment
at 155°C in toluene (Figure 12.5), cycloaddition provides the target structure 1 as
well as the diastereoisomers 12-E and 12-F in a ratio of 12: 24: 38. In
1,2-dichlorobenzene at 210°C and after 56 h, compounds 1 and 12-E are isolated
with respective yields of 38.8 and 17.2%. By extending the heating by 20 h,
only 1 is isolated with a yield of 55%. It therefore appears that the formation of
the minor diastereoisomer 12-E is reversible at 210°C and that lactonization takes
place at this temperature.
It should be noted that the use of Lewis acids as a catalyst in the last step did
not lead to convincing results, as the 12-A substrate was found to be unstable under
acidic conditions.
O
a b CO2t-Bu
OH OH OH
CO2t-Bu CO2t-Bu
c d
CO2Me
O
O
O
CO2t-Bu
e f
H
OH
H
12-A 1
Figure 12.4. Synthesis of oblongolide A by Diels–Alder reaction

a. Oxidative cleavage: OsO4 (cat.), NaIO4, dioxane/water, r.t.
b. Wittig reaction – 71.3% (2 steps): Ph3P=C(CH3)-CO2t-Bu, CH2Cl2.
c. Oxidation of primary alcohol: PDC, 3Å MS, CH2Cl2.
d. Wittig–Horner homologous reaction – 47% (2 steps): NaHMDS,
(MeO)2P(O)CH2CH=CHCO2Me, THF, −78°C.
e. Regioselective reduction of methyl ester to alcohol – 70%: DIBAL-H

(2 equiv.), THF, −78°C.
f. Intramolecular Diels–Alder reaction – 55%: 1,2-dichlorobenzene, sealed tube,
210°C, 76 h.
CO2t-Bu
OH
12-A
f'
O
CO2t-Bu CO2t-Bu
O H H
OH OH
H + +
H H
H
1 12-E 12-F
Figure 12.5. Optimization of the intramolecular Diels–Alder reaction

f’. Intramolecular Diels–Alder reaction – 71% (1: 12-E12-F = 12: 24: 38):
toluene, sealed tube, 155°C.
12.3.2.2. Transannular Diels–Alder reaction

The transannular version requires two additional steps from the same precursor
12-A. While the cycloaddition reaction is more effective, the overall yield is
strongly affected by the low efficiency of the lactonization step performed under
Yamaguchi conditions (27%). The other methods tested (esterification according to
Mukaiyama or Steglich involving DCC) proved to be even less successful with
respective yields of 12 and 6%.
CO2t-Bu CO2H
a
OH OH
12-A 12-G
O O
O
O
b c H
H
12-H 1
Figure 12.6. Synthesis of oblongolide A by transannular Diels–Alder reaction

a. Saponification of the ester 12-A – 68.5%: NaOH (0.1 equiv.), EtOH, H2O.
b. Esterification according to Yamaguchi – 27%: (i) 2,4,6-trichlorobenzoyl
chloride, Et3N, THF; (ii) DMAP, PhMe.
c. Transannular cycloaddition – 80%: PhMe, reflux.
12.3.3. Key reaction: intramolecular Diels–Alder reaction
Of all the orbital-controlled cycloadditions, the Diels–Alder reaction between

a diene and an electron-depleted dienophile is probably the one that has experienced
the strongest developments in synthesis [JUH 09, PAR 14, HER 15]. Its
intramolecular IMDA version is no exception to the rule and continues to be applied
to the production of complex molecules. By considering the different transition
states, it is possible to rationalize the course of such cycloadditions and predict
the formation of the majority stereoisomer. In the synthesis of oblongolide A from
substrate 12-A, four transition states can be described. Various factors must be taken
into consideration in favor of the endo approach (1), in particular the presence of the
methyl group on the sole stereogenic center which adopts a pseudo-equatorial
position as well as the existence of secondary orbital interactions.
CO2t-Bu
H
CO2t-Bu
OH
(1)
eq. OH
endo
H
CO2t-Bu
H
CO2t-Bu
OH
OH (2)
eq.
H
exo
CO2t-Bu
H
OH
ax. OH
(3)
E
H
endo
CO2t-Bu
H
ax. OH OH
(4)
E
exo H
Figure 12.7. Possible transition states during the cycloaddition of 12-A
However, the formation of the compound 12-E characterized by a relative cis

configuration at the ring junction, resulting from the exo approach (2), should not
be disregarded.
IMDA reactions have been successfully applied in total synthesis,

particularly for the synthesis of (-)-himandrine [MOV 09] and salvinorin A
[WAN 18].
OMe OMe
H
N N
O BHT H O
OHC OHC
Et Et
N CH3CN
TBSO 95°C TBSO
Endo 75%
approach
Figure 12.8. Intramolecular Diels–Alder reaction – towards (-)-himandrine
O O O
O O O
H
O
Ph-Cl, O O
H
200°C
+
BHT
(1.2 equiv.)
MeO2C MeO2C
3.5 days 66% <7%
MeO2C conv. 88% (Via endo approach ) (via exo approach)
Figure 12.9. Intramolecular Diels–Alder reaction – towards salvinorin A
12.3.4.1. Lemieux–Johnson reaction [PAP 56, RAJ 13]

H
OsO4 (1 mol %) O
NaIO4 (2.1 equiv.)
dioxane/H2O
68%
12.3.4.2. Oxidation of primary alcohols by PDC [JOR 06, GAR 06]
HO O
O N O
Cr2O72-
O H+ O
Ph 2 PDC Ph
BnO O CH2Cl2, 4Å MS BnO O

AcOH catalytic, 6h 82%
12.3.4.3. Reduction of esters to aldehydes by DIBAL-H [DON 10]
TIPSO TIPSO
H H
DIBAL-H
Hex N PhMe, -78°C Hex N

CO2Me CHO
H H
82%
12.3.4.4. Yamaguchi esterification – perfluorinated reagent [NIS 16]

Cl O
CO2H OH Cl O
Y Cl O
+
iPr2NEt (1.2 equiv.)
DMAP (1.2 equiv.) Y=H 87%
Ph-H, 25°C, 1h Y = C6F13 98%
12.4. Shishido’s approach to oblongolide C
The synthesis of oblongolide C 2 is based on the construction of the B cycle by

intramolecular [3+2] cycloaddition between a nitrile oxide generated from an oxime
and a terminal double bond, a process resulting in the formation of oxazoline 12-K
whose subsequent opening leads to a β-aldol, precursor of the lactone cycle C.
The stereogenic center present on the citronellal determines the control of the new
center created by favoring the approach of the 1.3 dipole towards one of the two
sides of the alkene.
O
O CO2H OBn CHO
H H H
O
OH D1 OH
D2
H H H
O
N
D3 D4 D5
H N
12-K 12-J O
D6 D7
CO2Me
CHO
CO2Me CO2Me
Citronellal
Figure 12.10. Disconnections according to Shishido

D1: formation of the C cycle (lactonization of a γ-hydroxyacid).
D2: formation of a protected diol (1,2-addition of the ketone) and obtaining the
acid from an aldehyde (oxidation according to Pinnick).
D3: synthesis a ketoaldehyde (oxidation of a β-hydroxyketone) and introduction
of a C=C double bond in α of the ketone (oxidation of an enol ether by IBX).
D4: formation of an isoxazoline ([3+2]cycloaddition).
D5: obtaining a nitrile oxide (homologation of the carbon chain terminating in
an aldoxime functional group).
D6: formation of cycle A (ene – reaction and decarboxylation of a malonate).

D7: formation of an unsaturated bis-ester (Knoevenagel condensation).
12.4.2. Synthesis
12.4.2.1. Access to synthon 12-K by [3+2] cycloaddition of a nitrile oxide
a b
CHO CO2Me CO2Me
CO2Me CO2Me
c d e-f
CO2Me
HO NC
12-I
O
N
g-h i
N
OH
H
12-J 12-K
Figure 12.11. Access to the synthon 12-K by [3+2] cycloaddition

a. Knoevenagel reaction – 82%: dimethyl malonate, piperidine, AcOH, CH2Cl2,
0°C.
b. Intramolecular ene reaction – 86% (ratio 96/4): ZnBr2, (1.1 equiv.), CH2Cl2,
25°C, 30 min.
c. Decarboxylation according to Krapcho – 92%: H2O, NaCl, DMSO, 150°C, 4 h.
d. Reduction of the ester to alcohol: LiAlH4, Et2O, r.t., 2 h.
e. Tosylation of primary alcohol: TsCl, Et3N, 4-DMAP, CH2Cl2, r.t.
f. Nucleophilic substitution by cyanide ions – 89% (3 steps): KCN, KI, DMSO,

H2O, 60°C, 12 h.
g. Reduction of nitrile to aldehyde: DIBAL-H, CH2Cl2, −78°C, 2 h.
h. Oxime formation – 99%: NH2OH. HCl, AcONa, MeOH, r.t., 15 min.
i. Dipole cycling[3+2]Cycloaddition – 81%: NaOCl (aq.), toluene, r.t., 6 h.
12.4.2.2. Alternative synthesis of synthon 12-K from a nitroalkane derivative
e' f'
HO
OH O
12-I NO2
O
N
-
g'-h' O i'
N
+ O
H
12-J' 12-K
Figure 12.12. Alternative synthesis of 12-K

e’. Oxidation of primary alcohol according to Swern: (COCl)2, DMSO, Et3N,
CH2Cl2, −78°C then 0°C, 1 h.
f’. Nitroaldolization: MeNO2, KF, 18-Cr-6, 12 h.
g’. Acetylation of the alcohol functional group: Ac2O, DMAP.
h’. Reduction – 57% (four steps): NaBH4, THF, r.t.
i’. [3+2]Cycloaddition – 84%: 4-ClC6H4-N=C=O, Ph-H, r.t., 3 h.
12.4.2.3. Last steps to the target from isoxazoline 12-K

The synthesis of oblongolide C begins with the formation of cycle A from
citronellal, using a sequence of condensation of Knoevenagel/ene reaction followed
by decarboxylation, a process initially and widely used in total synthesis by

L. F. Tietze’s team at the University of Göttingen [TIE 88]. The configuration of the
two generated stereogenic centers can be explained by the adoption of a chair
transition state where the methyl group is placed in a pseudo-equatorial position.
The intramolecular dipolar [3+2] cycloaddition reaction between nitrile oxide and
alkene results in the formation of the B cycle accompanied by controlling the
stereochemistry of the quaternary center. The transition states (Figure 12.14)
obtained by molecular modeling make it possible to rationalize the formation of the
predominantly observed compound. In the transition state T2 adopting a twisted boat
conformation, a highly discriminating interaction occurs between two hydrogen
atoms, the distance between them (2.2 Å) being less than the sum of their van der
Waals radii (2.4 Å).
O OH OTMS
H N H H
O OTMS
j k
H H H
12-K
CHO CO2H OBn

H H
O
l m,n OH o
H H
O
Bn O
H
O O O Li
OH
O
H 2

j. Isoxazolidine cleavage – 87%: H2, Ni Raney (W2), B(OMe)3, MeOH, CH2Cl2,
H2O, r.t., 1 h.
k. Protection of alcohol and formation of enol ether: TMS-OTf, Et3N, CH2Cl2,
0°C, 30 min.
l. Oxidation of the primary ether to enone – 58% (two steps): (i) IBX.DFO,
CH2Cl2; (ii) IBX, DMSO, CH2Cl2, r.t., 10 h.
m. Oxidation of aldehyde to acid: NaOCl, NaH2PO4, 2-methyl-but-2-ene,
t-BuOH, THF, H2O, r.t., 2 h.
n. Conversion of ketone to monoprotected 1,2-diol – 74% (2 steps):
n-Bu3SnCH2OBn + Bu-Li, THF, 2 h.
o. Cleavage of benzyl ether and lactonization – 82%: (i) Li, NH3 (liq.), THF,
−40°C, 2 h; (ii) hydrolysis under acidic conditions.
Figure 12.14. Modeling of transition states leading

to stereoisomers from 12-J or 12-J'
Alternatively, the formation of nitrile oxide was considered by another route

involving a nitro derivative and quite similar yields (Figure 12.12) [MUK 60].
Cycloaddition generates an isoxazoline, a true analogue of an aldol [CUR 82].
The introduction of the double bond in the cycle B was carried out using a method
developed by K.C. Nicolaou and involves periodinane reagents [NIC 02a, NIC 02b].
The formation of the second quaternary center that completes the synthesis results
from the reaction of an organolithium compound whose reaction is controlled by the
presence of an adjacent chelating carboxylic group.
12.4.3. Key reaction: intramolecular [3+2] cycloadditions
The intramolecular [3+2] cycloaddition reaction between a nitrile oxide and an

alkene (INOC) provides direct access to isoxazolines, precursors in particular of
hydroxyketones [KOZ 84, BRO 11]. 1,3-Dipolar species are most commonly
generated from oximes [MIN 11] or nitroalkanes.
OH R2
N
R1 R1
R2 R2
R1 H R3 O
R1 N O N
NO2
O R3 HO R3
R1
Figure 12.15. Reaction [3+2] between an alkene and a nitrile oxide
In the case of nitroalkanes, the action of a base such as triethylamine provides a

nitronate ion which can then react with an isocyanate [MUK 60], chloroformate or
arylsulfonyl chloride [SHI 86]; the intermediate species then undergoes syn
elimination to provide the dipole species.
R
R
R R
O
O Et3N O H N
Ar-SO2Cl
N N N
O O
O O S
O
Ar
Figure 12.16. Generation of nitrile oxide from nitroalkane
Such a sequence is the key step in the synthesis of sarkomycin described by

Kozikowski [KOZ 82].
N=C=O
O O O O N O
N N Ar N
O
Cl
Et3N, PhH, r.t.

CO2Et CO2Et
CO2Et
N O O
CO2Et CO2H (+/-)-sarkomycine

>97%
Figure 12.17. Synthesis of sarkomycin
12.4.4.1. Knoevenagel condensation [SHI 14]
OH CN NC
CN
O
Amberlyst-15 O O
HO CHO CN
hydrotalcite
HO OH 15 min
Xylulose 99%
12.4.4.2. Alder-ene reaction [NAL 18]
O 2N
O O
N + N O2N
O
HO
Ph Cu(OTf)2 Ph CO2Et
N *
(5 mol%) O
O
+
O CH2Cl2, 0°C, 4h
N
H
OEt 81% (e.e. = 76%)
12.4.4.3. Reduction of nitriles to aldehydes [KIM 12]
Cl Li Cl
Al
CN N CHO
H
(1.3 equiv.) O
Cl Cl
THF, 0°C, 30 min
97%
12.4.4.4. Reduction of nitriles to aldehydes [MOU 18]

CN Ca(H2PO2)2 (1 equiv.) CHO
Ni(OAc)2. 4H2O (0.2 equiv.)

EtO2C Ca(OAc)2. H2O (0.4 equiv.) EtO2C
100°C, ethanol, 7h 94%
12.4.4.5. Reduction of nitro-olefins [WOL 78]

OAc H
CHO 1) CH3-NO2
NO2 NO2
KF, 18-Cr-6
i-PrOH NaBH4
2) Ac2O, DMAP EtOH
Ether
64%
12.4.4.6. Reduction of nitroalkenes [XIA 12]
H2 N NHTs [RhCl2Cp*]2
NO2 NO2
(1.1 mol%) (0.5 mol%)
HCOO- Et3NH+
AcOEt, r.t. 99%
12.4.4.7. Formation of nitrile oxides from oximes [MIN 11]

N
OH O
N t-BuO-Cl (1 equiv.)
NaI (1 equiv.)
O O
H + N
2,6-lutidine (1 equiv.) O O
N
Ph
dioxane, r.t., 24h
Ph
85%
12.4.4.8. Reduction of isoxazolines [CUR 82]

N O O OH
Ni (Raney), H2
B(OMe)3
H
MeOH:H2O (15:1), 25°C
92%
12.4.4.9. Oxidation of enol ethers to enones [NIC 02a, NIC 02b]

O
O OTMS O
OMe
O
1) EtMgBr
I N
CuBr.SMe2 HO O
THF, -78°C O
(1.5 equiv.)
O O O
2) TMS-Cl
O O DMSO, 25°C, 30 min O
TMEDA
-78°C -> 25°C
47%
12.4.4.10. Oxidation of enol ethers to enones according to Saegusa

[ANG 08]
H
OTES O
Pd(OAc)2, DMSO
0°C -> r.t., 12h
O O 81%
12.4.4.11. Formation of 1,2-diols from carbonyl compounds [FER 00, STI 78,
YOS 06]
Me3Si
SEMO
O Bu3Sn O O
HO
+ n-BuLi
(1.25 equiv.)
THF, -78°C
89%
12.4.4.12. Selective deprotection of benzyl ethers in reducing media [LI 15]
O Li O
t-Bu t-Bu
PMBO LiDBB PMBO

(2.4 equiv.)
OBn OH
THF, -50°C, 5 min
81% ( + diol 16%)
12.4.4.13. Deprotection of benzyl ethers by hydrogenolysis [BEN 10]
F3C F3C
H2
O Pd/BaSO4 O
EtOH, TFA
O-Bn OH
99%
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List of Abbreviations
acac: Acetylacetone
AcBr: Acetyl bromide
AcCl: Acetyl chloride
AcOEt: Ethyl acetate
AcONa: Sodium acetate
AD-mix-β: Sharpless dihydroxylation reagent
AIBN: Azobisisobutyronitrile
BAIB: Bis(acetoxyiodo)benzene
9-BBN: 9-Borabicyclo[3.3.1]nonane
BHT: 2,6-di-tert-Butyl-4-methylphenol
BINOL: 1,1’-bis-2-Naphthol
Bmim: 1-Butyl-3-methylimidazolium
Bn: Benzyl
Bn-Br: Benzyl bromide
Bn-OH: Benzyl alcohol
BOP: Benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate
n-BuOH: n-Butanol
t-BuOH: tertioButanol
Bu2SnO: Dibutyltin oxide
Bz: Benzoyl
CAN: Ceric ammonium nitrate
CBS: Corey–Bakshi–Shibata reagent
CM: Cross-metathesis
Coll: Collidine
Comins’ reagent: 2-[N,N-Bis(trifluoromethanesulfonyl)amino]-5-

chloropyridine
15-Cr-5: Ether crown with 15 atoms including 5 oxygen
18-Cr-6: Ether crown with 18 atoms including 8 oxygen
CSA: Camphorsulfonic acid
DABCO: Diazabicyclo [3.3.3]octane
DBA: Dibenzylideneacetone
DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene
DCC: Dicyclohexylcarbodiimide
DCE: 1,2-Dichloroethane
DDQ: 2,3-Dichloro-5,6-Dicyanoparaquinone
DEAD: Diethyl azodicarboxylate
DET: Diethyl tartrate

List of Abbreviations 297
DHP: Dihydropyrane
DHQD: Dihydroquinidine
DIAD: Diisopropyl azodicarboxylate
DIBAL: Diisobutylaluminum hydride
DIC: Diisopropylcarbodiimide
DIPEA: Diisopropylethylamine
DIPT: Diisopropyl tartrate
DMA: Dimethylacetamide
DMAP: 4-Dimethylaminopyridine
DMDBA: Bis(3,5-dimethoxybenzylidene)acetone
DME: Dimethoxyethane, glyme, monoglyme
DMF: Dimethylformamide
DMIPS: Dimethylisopropylsilyl
DMP: Dess–Martin periodinane
DMPU: Dimethylpropyleneurea
DMSO: Dimethyl sulfoxide
DOSP: Dodecylbenzenesulfonyl-(S)-prolinate
Equiv.: Equivalent
Et2O: Diethylether
Et3N: Triethylamine
Fmo: 9-Fluorenylmethyloxy
GBII: Second-generation Grubbs catalyst

HG: Hoveyda–Grubbs catalyst
HGII: Hoveyda–Grubbs catalyst (second generation)
HMPA: Hexamethylphosphoramide
HMTA: Hexamethylenetetramine
Imid.: Imidazole
Ipc: Isopinocampheyl
i-Pr2NEt: Diisopropylethylamine
i-Pr2NH: Diisopropylamine
KHMDS: Potassium bis(trimethylsilyl)amide
LDA: Lithium diisopropylamide
LiHMDS: Lithium bis(trimethylsilyl)amide
LiTMP: Lithium tetramethylpiperidide
L-Selectride: Lithium tri-(2s)-2-butanyl(hydrido)borate
2,6-Lutidine: 2,6-Dimethylpyridine
m-CPBA: meta-Chloroperoxybenzoic acid
MeCN: Acetonitrile
Me-I: Methyl iodide
MeOH: Methanol
MeO-Na: Sodium methoxide
MIB: 3-exo-Morpholinoisoborneol
MOM: Methoxymethyl
Ms-Cl: Methanesulfonyl chloride

List of Abbreviations 299
NaHMDS: Sodium bis(trimethylsilyl)amide
NBS: N-Bromosuccinimide
NIS: N-Iodosuccinimide
NMO: N-Methylmorpholine N-oxide
Oxone: Potassium peroxymonosulfate: KHSO5
PBu3: Tributylphosphine
PDC: Pyridinium dichromate
Ph-H: Benzene
Ph-Me: Toluene
Piv-Cl: Pivaloyl chloride
PMB: p-Methoxybenzyl
PPh3: Triphenylphosphine
PPTS: Pyridinium p-toluenesulfonate
n-PrOH: n-Propanol
RCM: Ring-closing metathesis
r.t.: Room temperature
SET: Single electron transfer
SiMe3: Trimethylsilyl
TBAF: Tetra-n-butylammonium fluoride
TBAI: Tetrabutylammonium iodide
TBHP: tert-Butyl hydroperoxide
TBS or TBDMS: tert-Butyldimethylsilyl

TEMPO: (2,2,6,6-tetramethylpiperidinyl-1-yl)oxy
TES: Triethylsilyl
TFA: Trifluoroacetic acid
Tf2O: Triflic anhydride
THF: Tetrahydrofuran
THP: Tetrahydropyrannyl
TIPS: Triisopropylsilyl
TMEDA: Tetramethylethylenediamine
TMS-Cl: Trimethylsilyl chloride
TMS-I: Trimethylsilyl iodide
TMS-OMe: Methoxytrimethylsilane
TMSOTf: Trimethylsilyl trifluoromethanesulfonate
TPAP: Tetrapropylammonium perruthenate (Steve Ley’s reagent)
TPP: 5,10,15,20-Tetraphenyl-[21H,23H]porphine
TPS: tert-Butyldiphenylsilyl
Tris-imid: Trisimidazole
Troc: 2,2,2-Trichloroethoxycarbonyl
TsOH: p-Toluenesulfonic acid

Index
A, B, C benzocyclobutenols, 124
butyrolactone, 23, 32, 34, 35, 51–53, 55,
acyl selenide, 129, 130, 133
60, 94, 213, 219, 273
addition, 3–5, 10, 24, 28, 31, 37, 43, 56,
C-H activation, 10, 173, 181, 197
88, 90, 96, 113, 117, 118, 120, 122,
carbonylation, 218, 226
130, 162, 163, 166, 167, 175, 179,
Clauson-Kaas reaction, 134, 137
198, 202, 204, 214, 215, 217, 218,
220–223, 236, 237, 243, 244,
D, E, H
254, 282
alkenes, 11, 37, 38, 44, 56, 63, 75, deprotection, 6, 25, 62, 69, 185, 189, 196,
117, 135, 151–153, 155, 193, 242, 199, 254, 262, 291
264, 265 Duff reaction, 139
enol triflates, 225 elimination
Shapiro reaction, 214, 222–225 Grieco elimination, 63, 215, 227
alkylation, 10, 37, 56, 65, 66, 94, 129, ene reaction between alkynes and
177, 178, 184, 186, 216, 239, 260 alkenes, 85
Appel reaction, 105 epoxides, 58, 59, 192
cycloaddition [2+2] of arynes, 120 asymmetric epoxidation according to
diastereoselective alkylation according Shi, 151
to Myers, 177 ester, 24, 27, 34, 36, 60, 83, 87, 104, 129,
diastereoselective alkylation of 130, 146, 149, 160, 163, 166, 173, 185,
oxazolidinones, 68 193, 197, 202, 249, 262, 274, 277, 278,
enantioselective allylation, 193 283
alkynes Mitsunobu reaction in FBS mode, 257
functionalization of true alkynes, 29 saponification, 216, 258
Sonogashira reaction, 23, 26, 30, 31, halogenated, 88, 143
114, 116, 117 bromoalcohols, 64
bromohydrins, 154
I, K, M R, S
intramolecular [3+2] cycloadditions, 287 radical cyclization, 113, 116, 122, 124,
iodoetherification, 53, 55, 56 129–133
ketalization, 54 rearrangement, 24, 27, 28, 42, 59, 149,
Knoevenagel condensation, 283, 288 172, 177, 180, 183, 184, 187, 190, 191,
metathesis, 10, 22, 34, 37–40, 43, 143, 198, 201–203, 205, 215, 217, 218, 259,
144, 148, 155, 176, 179, 180, 194, 196, 262, 263, 266
198, 199, 203, 205, 236, 241, 242, 261, Payne rearrangement, 144, 146,
268, 296, 299 149, 154
domino process, 37 Wolff rearrangement, 60, 62, 63
ring-closing metathesis, 34, 160, 173, reduction, 3, 10, 22, 23, 26, 30, 33, 35,
176, 179, 194, 197, 199, 204, 234, 37, 40, 43, 60, 65, 67, 69, 72, 103–106,
241, 250, 258, 259 114, 116, 117, 125, 128, 129, 131, 134,
139, 143, 144, 148, 160, 163, 168, 169,
N, O, P 173, 178, 186, 196, 199, 200, 216, 234,
237, 242, 243, 251, 252, 260, 262, 264,
Negishi coupling, 96, 97, 185
265, 267, 277
olefination, 251, 253, 254, 259, 264,
enantioselective reduction
265, 267
of ketones, 71
oxazaborolidine, 71
reduction of enones according to
oxazolidinone, 65, 66, 69, 70
Luche, 242
diastereoselective alkylation, 68, 177
rerrangment
oxidation
sigmatropic rearrangement [3, 3] of
of aldehydes to carboxylic acids, 57
propargyl esters, 180
of primary alcohols to
ruthenium, 41, 86, 106, 122, 241
carboxylic acids, 57
ene reaction catalyzed
Swern oxidation, 74, 163, 164, 195
by ruthenium, 83
phosphate, 37, 166, 177, 189, 199
Sonogashira reaction, 23, 26, 30, 31,
protection, 24, 67, 163, 164, 174, 186,
114, 116, 117
253, 260
Stille coupling, 83, 85, 88, 101,
Pyrrole formation, 137
102, 104

Rethrosyntehsis of Natural Products

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Rethrosyntehsis of Natural Products

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Retrosynthetic Analysis and Synthesis

Retrosynthetic Analysis and

Synthetic Methods and Applications

ISTE Ltd John Wiley & Sons, Inc.

© ISTE Ltd 2019

Library of Congress Control Number: 2019943838

British Library Cataloguing-in-Publication Data

Chapter 1. Total Synthesis: Some Elements to Contemplate . . . . . . . . . 1

4.6.2. Supporting synthetic transformations . . . . . . . . . . . . . . . . . . . . . 105

Chapter 5. Tubingensin B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

Chapter 6. Polygonatine A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127

Chapter 7. (+)-Intricatetraol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143

Chapter 8. Enigmazole A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159

Chapter 9. Biyouyanagin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

Chapter 10. Elatol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233

Chapter 11. Thiomarinol H . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249

Chapter 12. Oblongolides A and C . . . . . . . . . . . . . . . . . . . . . . . . . . 273

List of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295

Learning about retrosynthesis can certainly be based on the monitoring of laws

Other examples will follow…

Total Synthesis: Some Elements to

1.1. Total synthesis – why and for what purpose?

Nature is an immeasurable source of rather complex molecules, which have

The isolation and structural determination of natural products is most often

1828 Syntheses: D.A. Evans, A.B. Smith III,

With increasing ecological awareness, organic synthesis can also indirectly

To minimize the impact of chemical synthesis on the environment, it is also

Table 1.1. Environmental impact factors across chemical industries

1.2. The different approaches

Of course, the effectiveness criterion, which can be correlated to the number of

For academic syntheses, in addition to these efficiency criteria, there is

The success and effectiveness criteria for the approaches implemented in

For complex targets, particularly those with several stereocenters,

Figure 1.2. Taxol and Taxotere® from 10-deacetylbaccatin III

– According to a chiron approach: it is a question of benefiting from molecular

Figure 1.3. Dihydromevinolin from L-glutamic acid

LEGEND OF FIGURE 1.3.–

D3: functionalization of the tricyclic lactone.

Natural products represent a significant source of inspiration in the genesis of

Figure 1.4. Marine polyethers for cancer treatment

Figure 1.5. Convergent or linear synthesis

In order to minimize the number of steps to obtain a given target molecule,

R1 R2 One-pot sequential approach :

R1 + R2 One-pot cascade approach :

Figure 1.6. Classic, sequential or cascade synthesis

1.3. Efficiency, selectivity

[No. Of constructive reactions] + [No. Of strategic redox processes]

An ideal synthesis must be possible to carry out a large-scale synthesis, while

Benefiting from the symmetry of a substrate, for a more advanced stage, to

Figure 1.7. Desymmetrization and synthesis of actinophyllic acid [YOS 17]

Planning the synthesis of a single target molecule or achieving an intermediate

Target oriented synthesis (TOS) :

Divergent oriented synthesis (DOS) :

Figure 1.8. Target-oriented or divergent-oriented synthesis

1.4. The essential reactions

Also worth mentioning are all selective reduction or oxidation methods,

– reductions via oxazaborolidines (CBS method) [COR 98];

1.5. Towards a sustainable total synthesis

Minimizing Using Minimizing

Figure 1.10. The 12 principles of green chemistry

1.6. What about tomorrow?

With the invention of artificial intelligence and by integrating thousands of

By relying solely on the relative intelligence of a brain, whose neurons are