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Notices
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Contributors

Numbers in Parentheses indicate the pages on which the author’s contributions begin.
A.F. Barrero (1), Institute of Biotechnology, University of Granada, Avda.
Fuentenueva, Granada, Spain
R. Braz-Filho (231), Laboratório de Ci^encias Quı́micas, Centro de Ci^encias e
Tecnologia, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos
dos Goytacazes; ICE, Universidade Federal Rural do Rio de Janeiro, Seropedica,
Brazil
S.M. Cardoso (65), CERNAS, School of Agriculture, Polytechnic Institute of Coimbra
Bencanta, Coimbra; University of Aveiro, Aveiro, Portugal
M.D. Catarino (65), CERNAS, School of Agriculture, Polytechnic Institute of
Coimbra Bencanta, Coimbra, Portugal
G. Chen (209), School of Life Science and National Glycoengineering Research
Center, Shandong University, Jinan; Center for Gene and Cell Engineering,
Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced
Technology, Chinese Academy of Sciences, Shenzhen, PR China
K. Chen (209), School of Life Science and National Glycoengineering Research
Center, Shandong University, Jinan; Anhui Provincial Engineering Research Center
for Polysaccharide Drugs, Wannan Medical College, Wuhu, PR China
A.R. de Carvalho Jr. (231), Laboratório de Ci^encias Quı́micas, Centro de Ci^encias e
Tecnologia, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos
dos Goytacazes, Brazil
M.G. de Carvalho (231), ICE, Universidade Federal Rural do Rio de Janeiro,
Seropedica, Brazil
D. Dı́ez (137), Facultad de Ciencias Quı́micas, Universidad de Salamanca, Salamanca,
Spain
P.W. Dhore (287), Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, India
V. Domingo (1), Institute of Biotechnology, University of Granada, Avda.
Fuentenueva, Granada, Spain
I. Duttagupta (29), Indian Association for the Cultivation of Science, Kolkata, West
Bengal, India
B. Fenert (399), Apteka “Dbam o Zdrowie”, Szczecinek, Poland
H. Gao (347), Institute of Traditional Chinese Medicine and Natural Products, College
of Pharmacy, Jinan University, Guangzhou, PR China

xi
xii Contributors

K.C. Ghosh (29), Indian Association for the Cultivation of Science, Kolkata,
West Bengal, India
A. Gil-Mesón (137), Facultad de Ciencias Quı́micas, Universidad de Salamanca,
Salamanca, Spain
J.N. Jacob (101), Organomed Corporation, Coventry, RI, United States
V. Karuppiah (417), Marine Biotechnology Laboratory, State Key Laboratory of
Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai
Jiao Tong University, Shanghai, PR China
D.M. Kokare (287), Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, India
U.R. Lal (263), Birla Institute of Technology, Ranchi, Jharkhand, India
C. Li (209), Anhui Provincial Engineering Research Center for Polysaccharide Drugs,
Wannan Medical College, Wuhu, PR China
J. Li (347), State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants
Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry,
Chinese Academy of Sciences, Urumqi, PR China
Z. Li (417), Marine Biotechnology Laboratory, State Key Laboratory of Microbial
Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong
University, Shanghai, PR China
H. Makabe (323), Sciences of Functional Foods, Graduate School of Agriculture,
Shinshu University, Kami-ina, Nagano, Japan
I.S. Marcos (137), Facultad de Ciencias Quı́micas, Universidad de Salamanca,
Salamanca, Spain
R.F. Moro (137), Facultad de Ciencias Quı́micas, Universidad de Salamanca,
Salamanca, Spain
J.F. Quilez del Moral (1), Institute of Biotechnology, University of Granada, Avda.
Fuentenueva, Granada, Spain
A. Rabahi (65), Centre de Recherche Scientifique et Technique en Analyses Physico-
Chimiques CRAPC, Bou-Ismail, Tipaza, Algeria
N.A. Raut (287), Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, India
S.D. Saoji (287), Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, India
A.M.S. Silva (65), University of Aveiro, Aveiro, Portugal
A. Singh (263), Herbal Consultant, Phase-VII, Mohali, Punjab, India
S. Sinha (29), Indian Association for the Cultivation of Science, Kolkata, West Bengal,
India
W. Sun (417), Marine Biotechnology Laboratory, State Key Laboratory of Microbial
Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong
University, Shanghai, PR China
O. Talhi (65), University of Aveiro, Aveiro, Portugal
I.J.C. Vieira (231), Laboratório de Ci^encias Quı́micas, Centro de Ci^encias e
Tecnologia, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos
dos Goytacazes, Brazil
Contributors xiii

M.B. Zarzycka (399), Apteka “Bursztynowa”, Koszalin, Poland

P.K. Zarzycki (399), Section of Toxicology and Bioanalytics, Koszalin University of
Technology, Koszalin, Poland
H. Zhao (347), Institute of Traditional Chinese Medicine and Natural Products,
College of Pharmacy, Jinan University, Guangzhou, PR China
J. Zou (347), Institute of Traditional Chinese Medicine and Natural Products, College
of Pharmacy, Jinan University, Guangzhou, PR China
Preface

The exploration of bioactive molecules from natural resources continues to

play a major role in developing novel natural products of therapeutic signifi-
cance. Volume 48 of Studies in Natural Product Chemistry presents many
interesting classes of natural products with exciting biological activities.
In the past century, remarkable creativity has been achieved in the synthesis
of structurally complex natural products. In the first chapter, Domingo et al.
have presented some recent accomplishments in the total synthesis of different
families of natural products through C–H functionalization strategies.
Nonribosomal peptides (NRPs) comprise a large group of pharmacologi-
cally important natural products, mostly isolated from microorganisms. Now-
adays, special importance has been given to their isolation and chemical
synthesis for their use as antibiotics, immunosuppressants, etc. Sinha et al.
have discussed the chemical synthesis of these NRPs in Chapter 2.
Flavonoids are polyphenolic compounds with very diverse roles. They
occur ubiquitously in food plants and vegetables. In Chapter 3, Cardoso
et al. have discussed the basic chemistry of flavonoids, structure–affinity rela-
tionship between flavonoids and key inflammatory markers, as well as an
approach to some synthetic strategies targeting the enhancement antiinflam-
matory properties of flavonoids.
The two major rhizomes, turmeric (Curcuma longa) and ginger (Zingiber
officinale), originated from the same family, Zingiberaceae, are known to
have a variety of medicinal and biological properties. In Chapter 4, Jacob
has provided a comparative account of the structural and biochemical proper-
ties of volatile and nonvolatile fractions of turmeric and ginger.
Marcos et al. have discussed a complete biogenetic classification of diter-
penes that have a 7-6-5 tricarbocyclic system in Chapter 5. A biosynthetic
approach to each group and synthetic approaches that have not been reported
previously are presented.
Fructooligosaccharides (FOSs) are oligosaccharides that are composed of
linear chains of fructose units, linked by beta (2-1) bonds. They exhibit a num-
ber of interesting properties, including a low sweetness intensity; they are also
calorie free, noncariogenic and are considered as soluble dietary fibers. Chen
et al. have reviewed the mechanism of action and effects of FOSs with empha-
sis on the relationship between the prebiotic effects and the benefits to health in
Chapter 6.

xv
xvi Preface

In Chapter 7, Vieira et al. have provided a review on the world’s largest

genus, Psychotria, with nearly 2000 species, mainly found in tropical and sub-
tropical regions of the globe. They have presented the chemical, biological,
and synthetic aspects of compounds found in this genus.
The diseases that are mostly prevalent in tropical and subtropical regions
can be cured efficiently by the natural product-based drugs. Lal and Singh
have discussed, in Chapter 8, the trends during the last 5 years (2008–13) in
the discovery and development of natural product-based drugs against tropical
diseases.
The epidemic rise in the number of patients suffering from Diabetes
mellitus requires prompt action for discovering new remedies especially from
bioactive natural resources. In Chapter 9, Raut et al. have presented a review
focusing the importance of bioactive natural products for the treatment of this
disease. Prodelphinidins have many significant biological activities such as
antitumor, antiviral, and antiinflammatory. A comprehensive discourse on iso-
lation, synthesis, and biological activities of prodelphinidins is presented by
Makabe in Chapter 10. Gao et al. have presented a detailed review on the
source, chemistry, bioactivities, and biosynthetic pathway of natural products
from endolichenic fungi in Chapter 11.
Cyanobacteria (blue-green algae) are photosynthetic prokaryotes that are
excellent source of vitamins and proteins. Many cyanobacteria produce com-
pounds with potent biological activities. In Chapter 12, Zarzycki et al. have
provided general information about active metabolites from cyanobacteria
and particularly about the use of such biological materials as the ingredients
in food and pharmaceutical formulations.
Actinomycetes are one of the most efficient groups of secondary metabo-
lite producers which play a significant role in pharmaceutical applications.
Around 150 natural products have been isolated so far from these ubiquitous
actinobacteria. Li et al. have presented a review on the natural products
isolated from marine actinomycetes.
I am confident that this volume will prove to be of great interest to scien-
tists working in the field of medicinal chemistry and natural product
chemistry.
I would like to thank Ms. Taqdees Malik and Ms. Humaira Hashmi
for their assistance in the preparation of this volume. I am also grateful to
Mr. Mahmood Alam for the editorial assistance.

Atta-ur-Rahman, FRS
International Center for Chemical and Biological Sciences
H.E.J. Research Institute of Chemistry
University of Karachi
Karachi 75270
Pakistan
Chapter 1

Recent Accomplishments in the

Total Synthesis of Natural
Products Through C–H
Functionalization Strategies
V. Domingo*, J.F. Quilez del Moral and A.F. Barrero*
Institute of Biotechnology, University of Granada, Avda. Fuentenueva, Granada, Spain

Chapter Outline
Introduction 1 Miscellaneous 15
Radical C–H Functionalization 3 Azidation of
(
)-Leuconoxine 3 Tetrahydrogibberellic Acid 15
Ouabagenin 5 (+)-Myrrhanol C 17
Gracilioether F 7 Complanadines A and B 20
Metal-Catalyzed C–H (+)-Hongoquercin A 23
Functionalization 9 Concluding Remarks 25
Podophyllotoxin 9 References 26
Dictyodendrin A and
Dictyodendrin B 10

INTRODUCTION
C–H functionalization is the term used to describe the ability to cleave a C–H
bond in a molecule regio- and stereoselectively and thereby transform it into
new C–C, C–X (X ¼ nitrogen, oxygen, or halogen), or C–metal bonds.
These transformations can be also classified according to the chemical
species generated as radical, radical-cationic, radical-anionic, carbenic, cat-
ionic, or metal-catalyzed transformations (the term C–H activation is used
in the last case). A considerable number of reactions and their applications
in synthesis have already been described and reviewed covering different
types of processes [1–5]. The field of C–H functionalization appears to offer
the synthetic chemist the opportunity to find new disconnections almost at

*
Co-authors of this chapter.

Studies in Natural Products Chemistry, Vol. 48. http://dx.doi.org/10.1016/B978-0-444-63602-7.00001-1

© 2016 Elsevier B.V. All rights reserved. 1
2 Studies in Natural Products Chemistry

will within a multitude of covalent C–H bonds. Most C–H transformations

have been uncovered relatively recently. As a result, these modes of activation
are being applied at present in material science, agrochemistry, drug develop-
ment, perfumery, and the realm of natural products discussed in this chapter
(Fig. 1.1). The steady growth and refinement of C–H functionalization is
based mainly on the high level of originality and creativity in the disconnec-
tion approach to complex organic architectures.
In another sense, the transformation of a C–H bond into a bond with a dif-
ferent function is nothing new. It has been present in natural processes for
millennia and in natural product synthesis we are simply trying to emulate
the level of synthetic efficiency found in the natural world. Nature can gener-
ate hydroxyls (P450 oxidases) [6–9], halides (halogenases) [10–12], amines
(transaminase and aminoacid dehydrogenase enzymes) [13–16] or construct
new C–C bonds (cyclases) [17–21] with surgical precision.
Technologically, the most powerful synthetic strategy would be to take an
enzyme and use it in every reaction in a synthetic sequence as a simple chemi-
cal. However, enzyme engineering has not yet achieved the levels of efficiency
that are needed to transform diverse molecular cores and experimentation in
enzyme engineering and direct evolution are still mandatory [22,23].
Historically, the application of C–H functionalization in natural products
dates from the early studies of steroids. In the early 1960, the Nobel prize
winner Sir Derek Barton (1969 for his contribution to “conformational analy-
sis”) found a wide range of new reactions applicable to hydrocarbons. In par-
ticular, the discovery of a remote nitrite radical functionalization enabled him
to obtain aldosterone acetate in scalable amounts for the first time [24].
The birth of C–H functionalization was also assisted at that stage by other
chemists including Breslow, Corey, Arigoni, and Woodward (For a review
see Ref [25] and references cited therein).
From those times to the present era, C–H functionalization has been increas-
ingly exploited in the synthesis of natural products and reviewed recently
[3,26,27], so the aim of this chapter is to highlight the most recent achievements
in this field. A number of molecules have been selected to illustrate the

Natural product
Pharmaceutical synthesis Material
targets science

Perfumery C–H activation Agrochemistry

C–C, C–X

FIG. 1.1 C–H activation field.

 Recent Accomplishments in the Total Synthesis Chapter 1 3

diversification that has taken place in terms of the range of natural products
(their biosynthetic origin) and the C–H functionalization strategies executed
in their construction. Although highly desirable, it is impossible to cover all
the contributions that have appeared, and the authors apologize for any
omissions.

RADICAL C–H FUNCTIONALIZATION

(2)-Leuconoxine
(
)-Leuconoxine (1) is grouped as a monoterpene indole alkaloid (over 2000
described) [28] that is characterized by a singular congested diaza[5.5.6.6]
fenestrane skeleton (Fig. 1.2). Leuconoxine (1) belongs to the subfamily of
Aspidosperma alkaloids, and this natural product was first found in the leaves
and stems of plants of the genus Leuconotis (eugenifolius and griffithii) in
Malaysia and Indonesia [29,30]. Due to their important range of bioactivities
(anticancer, antimalarial, and antiarrhythmic) as well as the challenging
scaffolds, indole alkaloids have stimulated the synthetic community and the
interest in (
)-leuconoxine (1) has resulted in five syntheses [31]. In 2015,
Gaich’s group synthesized this molecule using as its key strategy a novel pho-
toinduced domino macrocyclization/transannular cyclization [31] (Scheme 1.1).
The congested ABC-ring system of 1 was assembled in a late stage using a
Witkop cyclization, a photochemical C–H functionalization process. The syn-
thetic sequence commenced with the synthesis of the quiral methyl ketone 1a
using previously described methods. 1a was afterward transformed into the
b-ketosulfide 1b via conversion to the silyl enol ether, electrophilic addition
of bromine, and treatment of the bromoketone with dimethylsulfide (90%
yield, three steps) (Scheme 1.1). Then, 1b was submitted to Gassman’s indole
synthesis conditions obtaining the indole core 1c in excellent yield (77%).
After experimenting with several conditions to remove the thiol in 1c and
applying a routine set of reactions, they were ready to orchestrate the Witkop
photochemical reaction in the a-chloroacetamide 1f.
Irradiation of 1f at 254 nm enabled the Witkop photocyclization, affording
a regioisomeric mixture of compounds, including indolophanes (2,4) 1g and

Witkop cyclization

H N BN
C
A
N N
D
O

(–)-Leuconoxine (1) Diaza [5.5.6.6] fenestrane skeleton

FIG. 1.2 (
)-Leuconoxine.

4 Studies in Natural Products Chemistry

(a) NEt3, TMSOTf,

O O CH2Cl2 O O (d) aniline, –45°C, CH2Cl2, SMe O
(b) NBS, THF MeCN, tBuOCl OEt
MeS
OEt (c) SMe2, toluene, 80°C OEt then NEt3, then H3PO4
N
90% 77% H
1a 1b 1c

O
(e) TFA, thiosalicylic acid, 88% CN NH
(f) DIBAL-H; (g) DMSO, SO3.Py Cl (l) BH3.SMe2, THF,
(h) Ph3P K CHCN, toluene, 80°C (i) Mg, MeOH, 85% then NaBO3, 51%

73% (3 steps) N N
H H
(j) LiAlH4, Et2O
O
1d (k) Cl 1e
OH DIC, DMAP
73% (2 steps)

O
NH Cl O O
Cl
(m) hu (254 nm), Na2CO3, Witkop Transannular
HN HN
MeOH, rt cyclization cyclization
N N
H 49% N –
H –Cl H
5:2.5:1:1
HO HO HO
1f
O
NH

O HN OH
O HN
N
H
Transannular H 1h
HN 1g
cyclization HO
+
N O O
H H H
HO N N
Transient iminium ion N N
H H

HO
1i OH
1j

SCHEME 1.1 Synthetic sequence.

O O O
H H H
N (n) TPAP, NMO, MeCN N N

N N N
H 50%

HO HO O
1j (–)-Leuconoxine (1)

SCHEME 1.2 (
)-Leuconoxine end game.

(2,7) 1h together with the desired cyclized product at position C-3 in the
heterocycle 1j.
The key C–H functionalization step features a photoinduced electron trans-
fer from the excited state of the indolic system to the chloroacetamide moiety.
Thus, the diradical cation cyclises forming a transient iminium ion that
is trapped intramolecularly affording compounds 1i and 1j (Scheme 1.2).
 Recent Accomplishments in the Total Synthesis Chapter 1 5

It should be noted that the global yield for this transformation was modest;
however, in this case, the power of the C–H functionalization lies in the rapid
assembly of the terpene-indolic system in one chemical operation in a cascade
fashion.
At the end of the synthesis to obtain (
)-leuconoxine (1), 1j was oxidized
with catalytic TPAP (tetrapropylammonium perruthenate) which establishes
the final fenestrane skeleton of (
)-leuconoxine in 50% yield (Scheme 1.2).

Ouabagenin
Ouabagenin (2) is the aglycon of ouabain. The glycoside steroid was isolated
in 1888 from the bark of the African ouabio tree (Acokanthera ouabio), and
the aglycon was subsequently isolated in 1942 by Mannich and Siewert
[32–34]. Ouabagenin (2) is encompassed in the family of the cardenolides
(from Greek kardia ¼ heart), a subtype of the family of steroids. Steroids are
described as modified (nor) polycyclic triterpenoids lacking from three methyl
groups (two in position C-4 in the A ring and one at the junction of the B–C
rings), and they are biosynthetically formed from the mevalonic acid pathway
(Fig. 1.3).
From the medicinal point of view, ouabagenin (2) displays cardiotonic
activity through inhibition of the Na+/K+-ATPase, an enzyme found in the
plasma membrane of all eukaryotic cells. For this reason, it has proved to
be of great value in developing potent inotropic agents for the treatment of
congestive heart failure. Topologically speaking, cardenolides possess a
6-6-6-5 carbocyclic skeleton where both A/B and C/D ring fusions are cis
in contrast to the typical steroid structure. In the D ring, a characteristic bute-
nolide framework is found at C-17, and this motif is in part responsible for the
high bioactivity of this molecules.
However, despite its promising bioactive profile, the first total synthesis
of this molecule was not achieved until 2008 due to its complexity [35].
The impressive synthetic composition carried out by Deslongchamps et al.
employed a polyanionic cyclization as key step that afforded a few milligrams
of product at the end of the sequence.

O
C–H oxidations
O O
19
O 11
HO 1 C H
H B D
HO HO 14
OH 5
HO A
HO
Ouabagenin (2) Steroid skeleton (cardenolide)

FIG. 1.3 Ouabagenin.

6 Studies in Natural Products Chemistry

As an example of the advantages of employing “C–H functionalization

logic,” Baran et al. recently accomplished a scalable synthesis of ouabagenin
(>100 mg obtained, >500 mg obtained using the more direct precursor) by
using a classical semisynthetic approach starting from a cheap precursor, cor-
tisone acetate. Shortly afterward, they published a full account describing the
synthesis of 2 and the approach toward C-19-hydroxylated corticosteroid ana-
logs [36,37].
The authors tackle the synthesis through two relay elements: redox relay
(oxidations set at C-19, C-14) and oxidative stereochemical relay (oxidations
set at C-1, C-5) (Scheme 1.3). By means of this strategy, the degree of oxida-
tion and complexity is progressively increased in the carbon skeleton of the
steroid during the synthesis.

O O
O O O
HO O O
H (a) H+, ethylenglycol H I
(c) NIS, Li2CO3 H
81% 85%
H H O H H
O H H
O
(b) hυ 3–5 days O O
Adrenosterone (2a) solid-state (68%) 2b 2c
solution (43%)

O O O
O O (g) H2O2 O O
(d) TiCl4; AgOAc HO O (e) H2O2
HO
O HO
19 H 50% (3 steps) O H
71% (f) SeO2 H

H H H H H H
O O O
2d O 2e O 2f

O O
O O O
HO O O (k) Li, NH3
O HO
HO H H (l) PPTS, O
(i) PPTS, Me2CO O H
(h) Al-Hg, H2O 56% Me2CO O
H H (j) LiBEt3H
5 H H H H
O
HO 63% (2 steps) O 69% (2 steps)
O O O
B B
2g Et 2h 2i O
Et
O
O O
HO HO (p) N2H4; I2; Et3N
(m) TMSOTf, PdII O O 17 (q) CuTC, HO
O H O H O
(n) SiO2, DIPEA (o) O2, Co(acac)2 Pd(PPh3)4, A O H
14
H H OH
F H OH
86% 42% (2 steps)
F3C F O O O O
B B O O
B
Et 2j Et 2k 2l
F F Et
F (Protected ouabageninone)
55% (2 steps)
O
O
O
O
O A
(r) [Co2B]
O
(s) Me2N NtBu HO
HO HO Bu3Sn
NMe2 O HO H
O H
(t) HCl H OH
70% (2 steps) H OH
90% HO HO
O O
B
Ouabagenin (2)
Et 2m

SCHEME 1.3 Synthetic sequence.

 Recent Accomplishments in the Total Synthesis Chapter 1 7

Adrenosterone (2a) obtained from cortisone acetate was the starting point of
the synthetic sequence (Scheme 1.3). Ketalization of the less-hindered ketones
(rings A and D) and abstraction of the g hydrogen in a Norrish type II photo-
chemical transformation functionalized the C-19 position obtaining 2b in
68%. The radical transformation was carried out in solid state yielding better
yields than in solution. The strained cyclobutanol ring was then selectively frag-
mented after exposure of 2b to oxidative reaction conditions using
N-iodosuccinimide (NIS), and 2c was generated in 85% yield. Deprotection
of the A-ring ketal and hydrolysis of the C-19 iodide was achieved in a two-step
protocol TiCl4/AgOAc to afford 2d in 71% creating the new hydroxyl function.
The stereochemistry of the primary hydroxyl achieved in this intermediate 2d
would serve afterward to direct the hydroxyl functions with facial selectivity
at C-1 and C-5 in 2g. As result of epoxidation of enones 2d and later 2e, the
diepoxide 2f was obtained (50% three steps). Exposure of 2f to the amalgam
Al-Hg promoted the epoxide opening, and 2g was obtained in 56% yield.
After several transformations, enone 2j was obtained using Saegusa’s pro-
tocol; remarkably, after extensive survey of conditions, employment of per-
fluorotoluene gave a productive transformation from 2i to 2j in 55% yield,
while suppressing epimerization at C-14.
The last hydroxyl at C-14 (C–D rings junction) was inserted using
Mukaiyama hydration onto enone 2j in 86% yield, and the protected key
intermediate 2k was used to construct a library of ouabagenin analogs by
exchanging the characteristic butenolide framework of the natural product
for other subunits. The last steps comprised the transformation of the ketone
at C-17 into the vinyl iodide and Stille cross-coupling (Fürstner modification)
after which the cross-coupling product 2l was obtained in 42%. Reduction of
the dienoate 2l and isomerization of the resulting olefin (albeit dr ¼ 3:1 was
observed in this step) provide 2m (70% yield two steps). Finally, global
deprotection of 2m procured stereoselectively ouabagenin (2).
Despite the fact that the classical chemistry of steroids has been exten-
sively exploited, this example shows us that the beautiful frameworks of these
compounds designed by nature allow different types of C–H functionalization
reactions. These reactions in final term are crucial in supplying scalable
amounts of material no previously achieved by conventional methods in some
fully elaborated members of the family of steroids.

Gracilioether F
Gracilioether F (3) is an oxygenated polyketide natural product isolated from
the apolar extracts of the marine sponge Plakinastrella mamillaris. The
marine invertebrate was first collected in the Fiji Islands, and this organism
has been a rich source of polyketides showing antimicrobial, antitumor, anti-
fungal, and antiparasitic properties [38,39]. Gracilioether F (3) possesses an
unusual tricylcic core and five contiguous stererocenters which distinguish it
8 Studies in Natural Products Chemistry

from other gracilioethers with fewer rings that have been found in the sponge
Agelas gracilis. Thus a plausible biosynthetic origin of the gracilioether fam-
ily from a common furanylidene motif was postulated by Perkins et al.
[40,41] (Fig. 1.4).
In Brown’s synthetic endeavor, two key steps were employed: (a) a new
[2 +2] cycloaddition between an alkene and monosubstituted ketene catalyzed
by Lewis acid and (b) a late-stage oxidation (C–H functionalization step) to
build the lactone ring [42].
The advanced intermediate cyclobutanone 3c was assembled through a
ketene–alkene [2 + 2] cycloaddition. The methodology developed by the same
authors generated the alkenyl ketene in situ from an unsaturated acid chloride
3a to give 3c in 65% yield and good diastereomeric ratio (20:1) after conden-
sation (Scheme 1.4). Then alkylation was carried out to obtain 3d in high

C–H oxidation
Et O Et H R
H

O R1 R O
O
Et H Et Et H Et
O O
O R
Gracilioether F (3) Gracilioether skeleta

FIG. 1.4 Gracilioether F.

AlMe3
O Et
O (a) AlMe3 (2.5 equiv) H O
i-Pr2NEt (1.1 equiv) Me C 3b
Ph
Cl
Ph H
Me [2 + 2] H
3a CH2Cl2, –78 to –45°C Et
Cycloaddition Me
+ Generation of Ph
Et 65% yield, 20:1 d.r. 3c
ketenes in situ
2 equiv

3b Et
(d) O3, CH2Cl2, –78°C then
Et H (e) NaClO2, NaH2PO4, t-BuOH,
O Et H O Et H O
(c) H2O2, NaOH isobutylene
(b) KHMDS Et MeOH, 22°C 22°C
O O
THF, –78 °C, H 61% yield Et 83% yield Et
Et H H
EtI, –78 to 22°C Me Et Me Et
Ph HO O
91% yield, 20:1 d.r. 3d 3e
Ph 3f
Gram scale

Et H Et H O
O (f) Cu(OAc)2 (1 equiv), H2O2,
H MeCN, 0°C
4 O
Et O
Et Et Et
10%, 88% brsm H
H O
HO O O
3f Gracilioether F (3)

SCHEME 1.4 Synthetic sequence.

 Recent Accomplishments in the Total Synthesis Chapter 1 9

diastereoselectivity, and the alkylated product was submitted to Baeyer–

Villiger conditions, providing the lactone 3e in 61% yield over two steps.
Compound 3f, crucial for the success of the synthesis through application of
the late stage C–H oxidation, was prepared after performing a one-pot ozono-
lysis and quenching under Pinnick oxidation conditions in 83% yield.
Finally, attempts were made to oxidize the C–H bond at C-4 exploring a
range of conditions (RuO4, TFDO, Fe(OAc)2, etc.) and bearing in mind the
privileged stereoelectronic position of this bond. However, gracilioether (3)
was only achieved when the oxidation was carried out with the combination
of Cu(OAc)2 and H2O at 0°C in a 10% (88% recovered starting material)
using as starting material the carboxylic acid 3f.

METAL-CATALYZED C–H FUNCTIONALIZATION

Podophyllotoxin
Podophyllotoxin (4) is a lignan natural product originated from the shikimate
pathway. In this biosynthetic route, coniferyl alcohol is generated and used as
the basic unit of construction to elaborate more complex lignans through fur-
ther cyclizations and enzymatic modifications [43]. Podophyllotoxin (4) can
be found in the rhizome and roots of Podophyllum hexandrum (P. emodi) or
P. peltatum (Berberidaceae). This family of compounds displays important
bioactivities, for example, etoposide and teniposide, derived from 4 by
anchoring glucosides to the oxygen placed in C-4, which have found clinical
application in cancer theraphy [44] (Fig. 1.5).
The brevity of the synthesis of 4 in five steps reported by Maimone and
coworkers stems from the successful application of a diastereoselective Pd
catalyzed C (sp3)–H arylation reaction enabled by a conformational biasing
element. The method used highlights the importance of C–H activation in pre-
paring a family of different analogs by modifying the arene coupling
counterpart [45].

OH
H R
O 4 H
O O
O Ar1 O
H O O
H O
C–H arylation
Ar2
MeO OMe
OMe
Podophyllum lignans
Podophyllotoxin (4)

FIG. 1.5 Podophyllotoxin.

10 Studies in Natural Products Chemistry

Structurally, podophyllotoxin (4) has four contiguous stereocenters in a

1,2-cis- 2,3-trans-configuration which are crucial to reveal biological activity
and hitherto the ease with which isomerization forms the cis lactone and leads
to a loss of bioactivity that has limited synthetic approaches to some extent.
From the synthetic point of view, one of the key achievements in the new
route was the preparation of the intermediate 4d bearing the pendant directing
group to drive the C–H activation event. To make 4d in 41% yield (three
steps), cycloaddition of the o-quinodimethane generated after deprotonation
of 4b with the amide 4c was carried out, then the resulting condensation prod-
uct 4c was reduced and the diol treated with 2,2 dimethoxypropane under
acidic conditions (Scheme 1.5).
The intermediate 4d was protected as an acetal form since previous inves-
tigations with other protecting groups over the same carbocyclic substrate
afforded mainly the b-lactam (competitive reductive elimination product in
the C–H activation event). The authors proposed the higher reactivitiy of 4d
in terms of conformational locking of the PdIV intermediate; thus, the cyclo-
hexyl ring is fixed into a half-chair-like conformation releasing the steric
crowd around the palladium center and facilitating the productive aryl transfer
through the achievement of the correct organometallic geometry.
Among the parameters under study in the cross-coupling event, the direct-
ing group (2-thiomethylaniline), bases, solvents, etc. were evaluated, proving
the importance of the addition of dibenzyl phosphate that was turned into a
58% for the diastereoselective installation of the aryl moiety. Finally, removal
of the directing group under acidic conditions resulted in 43% of podophyllo-
toxin (4) together with C-4-epi-4 in 33% yield. The latter has the same config-
uration as etoposide.

Dictyodendrin A and Dictyodendrin B

The search for natural products in marine and terrestrial environments has led
to the discovery of a number of biologically active indole alkaloids which
includes the family of dictyodendrins, isolated from a Japanese marine
sponge, Dictyodendrilla verongiformis in 2003 [46] (Fig. 1.6).
Among the biologically active properties that have been found are the first
telomerase inhibitory natural products (showing 100% inhibition at 50 mg/mL)
of marine origin as well as promising anticancer compounds. It is also
important to underline that in March 2012, chemical analysis of a southern
Australian marine sponge, an Ianthella sp., yielded dictyodendrins F–J as
new examples of these rare types of marine alkaloids [47]. Dictyodendrins
F and H–J exhibited significant protease b-secretase (BACE) inhibitory activity
(IC50 1–2 mM), with the differential cytotoxicity displayed by F–I against two
human colon cancer cell lines (IC50 2–16 mM) marking them as both
cytotoxins and probable substrates for the multidrug resistance efflux pump
P-glycoprotein.
 (c) KHMDS OK
S −78 to 1°C
CHO (a) I OH O CO2Me
O O

O O
O Br DCM/ NaOH O
MeO2C
BnNEt Cl SMe HN
3 H
4a 2 steps N
(b) n-BuLi, MgBr2
1 recrystallization
MeS
4b O
4c

(f) 15% mol Pd(OAc)2, K2CO3 (1.5 equiv),

OH
5-Iodo-1,2,3-trimethoxybenzene (2 equiv), H
O 40% (BnO)2PO2H O 4
(d) LiEt3BH O O
H t-AmOH (0.1 M), 50 h, 110°C
–78°C H O
58% yield
H H O
HN O
MeO OMe
(e) MeS
(g) TFA/ H2O
MeO OMe
TsOH, THF THF
OMe
(41% yield, overall 3 steps) 25 °C
4d 4
Pd catalyzed C–H activation 43% + 33% 4-epi
SCHEME 1.5 Synthetic sequence.
 Recent Accomplishments in the Total Synthesis Chapter 1 23

(+)-Hongoquercin A
Professors Baran and Yu envisioned the synthesis of (+)-hongoquercin (9)
by taking advantage of the invention of a number of C–H functionalizations
of benzoic acids derivatives developed in the laboratories of Professor Yu
[73–77]. Apart from hongoquercin, the authors showed how C–H functionali-
zations proved to be a valid strategy to “the divergent functionalization of nat-
ural product cores” [78]. Thus, a number of hongoquercin derivatives were
prepared using this approach (Fig. 1.10).
(+)-Hongoquercin A (9) was isolated from the extracts of an unidentified
fungus in 1998. This substance exhibits activity against methicillin-resistant
Staphylococcus aureus and vancomycin-resistant Enterococcus faecium [79].
The synthetic route toward hongoquercin commenced with (+)-chromazonarol
(9a), a compound available from commercial (+)-sclareolide [80]. Hydroxycar-
bonylation of the corresponding triflate of 9a afforded the required benzoic
acid derivative 9b. Pd-mediated C–H methylation required extensive research
to optimize of reaction conditions, a study carried out with m-toluic acid
as model. It was found that the presence of both Boc-Phe-OH as ligand and
1,4-benzoquinone was essential for the success of the transformation. Under
the optimized conditions shown in Scheme 1.16, monoalkylated derivative 9c
was produced in 60% yield. At this point, only a C–H hydroxylation was needed
to reach the target (+)-hongoquercin (9). However, when 9c was subjected to
the previously reported protocol for the Pd(II)-catalyzed hydroxylation of
arenes [77], no (+)-hongoquercin (9) was detected, and only a 10–15% yield
of this compound was detected when the pressure of O2 was raised to 10 atm.
The authors then considered previous studies by Professor Yu showing that
electron-deficient aryl amides can enable C–H activation where other directing
groups failed [81]. In the event, once the corresponding amide 9d formed, C–H
methylation took place in reasonable yield. At this point, and after extensive

C–H oxidation
CO2H OH
HO Me

O C–H methylation O
H H

(+)-Hongoquercin (9) meroterpene skeleton

FIG. 1.10 Hongoquercin A.

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