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Total Synthesis
REVIEWS
At the dawn of the twenty-first century, the state of the art and science of
total synthesis is as healthy and vigorous as ever. The birth of this exhilarating, multifaceted, and boundless science is marked by Whlers synthesis
of urea in 1828. This milestone event
as trivial as it may seem by todays
standardscontributed to a demystification of nature and illuminated the
entrance to a path which subsequently
led to great heights and countless rich
dividends for humankind. Being both a
precise science and a fine art, this
discipline has been driven by the constant flow of beautiful molecular architectures from nature and serves as the
engine that drives the more general
field of organic synthesis forward.
Organic synthesis is considered, to a
large extent, to be responsible for some
1. Prologue
Your Majesty, Your Royal Highnesses, Ladies and Gentlemen.
In our days, the chemistry of natural products attracts a very
lively interest. New substances, more or less complicated,
[*] K. C. Nicolaou, D. Vourloumis, N. Winssinger, P. S. Baran
Department of Chemistry
and The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
Fax: ( 1) 858-784-2469
E-mail: kcn@scripps.edu
[**] A list of abbreviations can be found at the end of the article.
Angew. Chem. Int. Ed. 2000, 39, 44 122
more or less useful, are constantly discovered and investigated. For the determination of the structure, the architecture
of the molecule, we have today very powerful tools, often
borrowed from Physical Chemistry. The organic chemists of
the year 1900 would have been greatly amazed if they had
heard of the methods now at hand. However, one cannot say
that the work is easier; the steadily improving methods make
it possible to attack more and more difficult problems and the
ability of Nature to build up complicated substances has, as it
seems, no limits.
In the course of the investigation of a complicated
substance, the investigator is sooner or later confronted by
the problem of synthesis, of the preparation of the substance
by chemical methods. He can have various motives. Perhaps
he wants to check the correctness of the structure he has
found. Perhaps he wants to improve our knowledge of the
reactions and the chemical properties of the molecule. If the
1433-7851/00/3901-0045 $ 17.50+.50/0
45
REVIEWS
K. C. Nicolaou et al.
K. C. Nicolaou
D. Vourloumis
N. Winssinger
P. S. Baran
K.C. Nicolaou, born in Cyprus and educated in England and the US, is currently Chairman of the Department of Chemistry
at The Scripps Research Institute, La Jolla, California, where he holds the Darlene Shiley Chair in Chemistry and the
Aline W. and L. S. Skaggs Professorship in Chemical Biology as well as Professor of Chemistry at the University of
California, San Diego. His impact on chemistry, biology, and medicine flows from his works in organic synthesis described
in nearly 500 publications and 70 patents as well as his dedication to chemical education, as evidenced by his training of
over 250 graduate students and postdoctoral fellows. His recent book titled Classics in Total Synthesis,[3] which he coauthored with Erik J. Sorensen, is used around the world as a teaching tool and source of inspiration for students and
practitioners of organic synthesis.
Dionisios Vourloumis, born in 1966 in Athens, Greece, received his B.Sc. degree from the University of Athens and his
Ph.D. from West Virginia University under the direction of Professor P. A. Magriotis, in 1994, working on the synthesis of
novel enediyne antibiotics. He joined Professor K. C. Nicolaous group in 1996, and was involved in the total synthesis of
epothilones A and B, eleutherobin, sarcodictyins A and B, and analogues thereof. He joined Glaxo Wellcome in early 1999
and is currently working with the Combichem Technology Team in Research Triangle Park, North Carolina.
Nicolas Winssinger was born in Belgium in 1970. He received his B.Sc. degree in chemistry from Tufts University after
conducting research in the laboratory of Professor M. DAlarcao. Before joining The Scripps Research Institute as a
graduate student in chemistry in 1995, he worked for two years under the direction of Dr. M. P. Pavia at Sphinx
Pharmaceuticals in the area of molecular diversity focusing on combinatorial chemistry. At Scripps, he joined the
laboratory of Professor K. C. Nicolaou, where he has been working on methodologies for solid-phase chemistry and
combinatorial synthesis. His research interests include natural products synthesis, molecular diversity, molecular evolution,
and their application to chemical biology.
Phil S. Baran was born in Denville, New Jersey in 1977. He received his B.Sc. degree in chemistry from New York University
while conducting research under the guidance of Professors D. I. Schuster and S. R. Wilson, exploring new realms in
fullerene science. Upon entering The Scripps Research Institute in 1997 as a graduate student in chemistry, he joined the
laboratory of Professor K. C. Nicolaou where he embarked on the total synthesis of the CP molecules. His primary research
interest involves natural product synthesis as an enabling endeavor for the discovery of new fundamental processes and
concepts in chemistry and their application to chemical biology.
46
REVIEWS
O
NH2
Me
OH
HO
HO
O
OH
OH
urea
acetic acid
glucose
[Whler, 1828][8]
[Kolbe, 1845][9]
[Fischer, 1890][12]
REVIEWS
in medicine, computer science, communication, and transportation have dramatically changed the way we live and the
way we interact with the world around us. An enormous
amount of wealth has been created and opportunities for new
enterprises abound. It is clear that at the heart of this
technological revolution has been science, and one cannot
deny that basic research has provided the foundation for this
to occur.
Chemistry has played a central and decisive role in shaping
the twentieth century. Oil, for example, has reached its
potential only after chemistry allowed its analysis, fractionation, and transformation into myriad of useful products such
as kerosene and other fuels. Synthetic organic chemistry is
perhaps the most expressive branch of the science of
chemistry in view of its creative power and unlimited scope.
To appreciate its impact on modern humanity one only has to
look around and recognize that this science is a pillar behind
pharmaceuticals, high-tech materials, polymers, fertilizers,
pesticides, cosmetics, and clothing.[7] The engine that drives
forward and sharpens our ability to create such molecules
through chemical synthesis (from which we can pick and
choose the most appropriate for each application) is total
synthesis. In its quest to construct the most complex and
challenging of natures products, this endeavorperhaps
more that any otherbecomes the prime driving force for
the advancement of the art and science of organic synthesis.
Thus, its value as a research discipline extends beyond
providing a test for the state-of-the-art. It offers the opportunity to discover and invent new science in chemistry and
related disciplines, as well as to train, in a most rigorous way,
young practitioners whose expertise may feed many peripheral areas of science and technology.[6]
K. C. Nicolaou et al.
REVIEWS
HO
OH
OH
patulin (1950)[23]
H
H
MeO2C H
reserpine (1958)[28]
O
H
OMe
Me
H
O Me
Me
H
H2N
OH
NH2
Me
Me
O H
O P
O
O
H
MeO
NH2
HO
H OH
HO
PGF2 (1973)[31]
H
O
cephalosporin C (1966)[30]
isolongistrobine (1973)[287]
OHC
OMe OMe
illudalic acid
CO2H
(1977)[289]
illudinine
(1977)[289]
HO
H
N
R
O
MeO
Me
Me
Me
OMe
OHC
OAc
OH
HO
NHAc
colchicine (1965)[286]
CO2H
illudacetalic acid
penems
(1977)[289]
HO
S
N
O
H
OH
MeO
Me
OH
CO2H
OH
O
Me
OMe
O
CO2
N
HO
H H H
N
S
H3N
Me O
Me
MeO
OH
HO
Me
HO
O H
NMe2
NH2
OH
chlorophyll a (1960)[29]
O
H
N
6-demethyl-6-deoxytetracycline (1962)[285]
OMe
Me
CN
lanosterol (1954)[25]
NH2
N
OMe
Co
NH
HN
strychnine (1954)[27]
Me MeH
MeO2C
H2N
Me
HO
Mg
MeO
Me
NMe
O
H
H2N
N
N
H
cortisone (1951)[24]
quinine (1944)
Me
[22]
H
N
CO2H
Me
O
Me
MeO
Me
OH
R'
OH
Me
HO
O
OH
Me
Me
O
O
CO2H
(1978)[290]
OMe
NMe2
Me
Me
Me
OH
O
Me
erythromycin A (1981)[33]
REVIEWS
K. C. Nicolaou et al.
50
REVIEWS
REVIEWS
K. C. Nicolaou et al.
a)
Me
N
Mannich reaction
CO2H
CHO
NMe
O
CO2H
H
O
H2NMe
CHO
CHO
Mannich reaction
1: tropinone
b)
H2NMe
Me
- H2 O
Equilenin (1939)
NMe
NMe
+ H2O
CHO
H
2: succin-dialdehyde
OH
7
O
Me
CO2H
CO2H
10
H
CO2
CO2H
O H
Me O
Dieckmann
cyclization
CO2H
CO2H
9
[intramolecular Mannich reaction]
HCl
-2 CO2
O2 C
Me
Me
N
HO
O
H CO2H
H
MeO
HO
1: equilenin
4: Butenandt's ketone
Me
CO2Me
HO
CO2H
CO2Me
HO
Arndt-Eistert reaction
Reformatsky
reaction
a. (CO2Me)2, MeONa
b. 180 C, glass
b)
MeO
Me
CO2Me
(90%)
MeI, MeONa
(92%)
O
MeO
CO2Me
O
MeO
Me
CO2H
H
O
MeO
Cl
MeO
Haemin (1929)
CO2H
Me
Me
H
MeO
CO2Me
CO2Me
a. MeONa
b. HCl, AcOH
CO2Me
MeO
10
CO2H
MeO
3a
(84% overall)
a. CH2N2
b. Ag2O, MeOH [-N2]
[Arndt-Eistert
reaction]
(39% overall)
CO2H
Me O
HO
(92%)
1: equilenin
REVIEWS
Me
Me
Me
Me
Me
Me
Me
Br
Me
Me
1: haemin
HO2C
b)
Me
HO
Me
Me
Me
CO2H
Me
5
CO2H
NH HN
Me
HO2C
H
HO
Me
N
H
4
Br
Me
OHC
N
H
Fe
N
Me
NH HN
CO2Et
N
H
CO2H
6
Me
Me
Me
Me
HBr
Me
N
H
Me
Me
N
H
Me
H
NH HN
Me
Me
Me
a. H2SO4
HCO2H
b.
Me
HCl
CO2Et
N
H
Me
OHC
Me
CO2Et
N
H
11
Me
12
CO2H
Me
piperidine
[Knoevenagel]
CO2Et
N
H
Me
N
H
Me
Me
Me
Me
CO2Et
N
H
Me
CO2Et
N
H
17
16
HO2C
HO2C
Me
HO2C
CO2Et
N
H
NH HN
Me
10
HO2C
HO2C
H2 O
Me
NH HN
Me
HBr,
Br2
Me
15
HO2C
Me
HO
9 Br
Na/Hg
CO2Et
N
H
13
HO2C
Me
HO2C
HO2C
14
Me
Me
NH HN
Me
Me
CO2H
EtO2C
Me
NH HN
Me
Me
H Me
Br
CO2Et
CO2Et
N
H
22
CO2Et
N
H
21
Br
CO2Et
N
H
19
20
CO2Et
N
H
Br
Br
18
O
HO2C
EtO2C
Me
Me
Me
CO2Et
NH HN
Me
HO2C
HO
N
H
CO2Et
N
H
22
CO2Et
H
CO2H
23
H
H
Me
Me
NH HN
- Br Br + Me
Me
Me
CO2H
HO2C
Me
Me
Me
Me
Me
Me
NH HN
Me
Br
Me
NH HN
CO2H
Br
Br
NH HN
Me
27
HO2C
CO2H
26
Me
NH HN
Me Br
CO2H
CO2H
NH HN
Me
CO2H
25
28
29
HO2C
Me
Br
[CO2]
HO2C
NH HN
NH HN
HO2C
24
Br
NH HN
NH HN
Me
Me
Me
HO2C
CO2H
CO2H
CO2H
HO2C
[oxidation]
O
Me
Me
a. Fe3
b. Ac2O, AlCl3
HN
Me
HN
c. H
Me
NH
Me
NH
HO2C
31
30
CO2H
Me
O
KOH,EtOH,
Me
Me
HN
OH
[reduction]
[Friedel-Crafts acylation]
Me
HO
Me
Me
CO2H
Me
NH
O2C
32
a. /H
[dehydration]
Me
Me
CO2
Cl
Me
1: haemin
HO2C
HO2C
N
Fe
b. Fe3
Me
CO2H
Scheme 2. a) Strategic bond disconnections and retrosynthetic analysis of haemin and b) total synthesis (Fisher, 1929).[18]
REVIEWS
confidence that synthetic chemists had in their designed
strategies was soon to decrease as the complexity of newly
discovered natural products increased, thus catalyzing the
development of novel strategies and new chemistry in
subsequent years. In addition, advances in theoretical and
mechanistic organic chemistry as well as new synthetic tools
were to allow much longer sequences to be planned with a
heightened measure of confidence and considerable flexibility
for redesign along the way.
Strychnine (1954)
As the most notorious poison[53] of the Strychnos plant
species, strychnine (1 in Scheme 4) occupied the minds of
K. C. Nicolaou et al.
structural chemists for a rather long time. Its gross structure
was revealed in 1946[54] and was subsequently confirmed by
X-ray crystallographic analysis.[55] In 1952, Sir Robert Robinson commented that strychnine: For its molecular size it is
the most complex substance known.[56] This estimation had
not, apparently, escaped R. B. Woodwards attention who had
already been fully engaged in strychnines total synthesis. In
1948 Woodward put forth the idea that oxidative cleavage of
electron-rich aromatic rings might be relevant in the biogenesis of the strychnos alkaloids.[57] This provocative idea was
implemented in his 1954[27] synthesis of strychnine, which
established Woodward as the undisputed master of the art at
the time. The total synthesis of ()-strychnine by Woodward
(Scheme 4) ushered in a golden era of total synthesis and
Scheme 4. a) Strategic bond disconnections and retrosynthetic analysis of ()-strychnine and b) total synthesis (Woodward et al., 1954).[27]
54
REVIEWS
a)
Ring formation
Amide formation
H
N
PhO
H
S
Me
Me
Me
Me
OH
Me
HClH2N
CO2H
2
Me
NH2
HN
5: valine
4
O
O
Me
(75%)
Me
Ac2O, 60 C
CO2H
Me
(72-80%)
Me
HS
CO2H
ClCH2COCl
CO2H
Me
tBuO2C HN
CO2H
Lactamization
1:penicillin V
b)
PhtN
PhtN
Me
Cl
Me
O
Cl
OAc
SH
Me
Me
[isomerization]
Me
Me
Me
Me
11
Me
O
H
Me
Me
O
O
N
10
Cl
Cl
Me Me
Me O OMe
OMe Me
HS
HS
Me
12
13
Me
Me
HS
O
CHO
Me
HClH2N
tBuO2C
NaOAc
a. N2H4
tBuO2C HN
Me
HClH2N
(82%)
Me
H
N
H
S
PhO
tBuO2C HN
CO2H
16
PhOCH2COCl,
Et3N
(70%) O
b. HCl, H2O
Me
Me
tBuO2C HN
Me
CO2H
H
S
N
O
O
Me
Me
H
N
(100%)
H
S
PhO
HO2C HN
Me
Me
CO2H
CO2K
[potassium salt of 1]
Me
19
a. HCl
b. py, acetone, H2O
H
N
Me
CO2H
18
PhO
CO2H
O
H
3a
Me
S
N
CO2H
4: D-penicillamine
hydrochloride
tBuO2C
17
HCO2H
Ac2O
(74%)
a. brucine
b. resolution
Me
c. HCl, H2O
Me
d. HCl
Me
CO2H
15
Me
HS
Me
S
N
H
CO2Me (100%)
14
Me
Me
b. Me2CO
N
H
Me
a. tBuONa
b. tBuOCHO
a. HCl, H2O
Me
20
REVIEWS
K. C. Nicolaou et al.
a)
MeO
Lactamization
MeO
B
N
H
C-C bond
formation
A
B
N O
H
N
H
H
MeO2C
Imine
formation
N
H
OMe
MeO2C
OMe
OAc
OMe
OMe
1: reserpine
OMe
Esterification
O
H
O
H
Diels-Alder
reaction
O
H
MeO2C
CO2Me
MeO2C
E
OAc
MeO2C
H
OMe
[Meerwein-Pondorff-Verley
reduction]
b)
O
[Diels-Alder
reaction]
O
AcOH
OH
H
HO
13
B
C
N
N
H H
D
OAc
B
N
H
NaBH4
MeO2C
OAc
POCl3
H
OAc
MeO2C
OMe
N
H
OAc
15
OAc
R
HN
MeO
R = CO2Me
17
H
N H
H
O
MeO
HN
O
18
19
tBuCO2H,
[isomerization]
OMe
OMe
A
B
C
N
N
H H
D
H
H
N
NaOMe, MeOH,
H
O
E
OH
21
H
HN
MeO
MeO2C
OMe
20
py
Cl
OMe
OMe
MeO
OMe
B
C
N
N
H H
D
H
H
O
MeO2C
a. MeOH/CHCl3
(+)-CSA
b. resolution
c. 1 N NaOH
OMe
O
OMe
23
OMe
[esterification]
22
OMe
OMe
OMe
a. KOH, MeOH
b. DCC, py
N H
Chlorophyll a (1960)
16
MeO
OMe
MeO
OAc
B
N Cl
H
OMe
OAc
OMe
17
MeO2C
MeO
OMe
B
N
H
MeO
OMe
NH2
OMe
B
O
N
H
MeO2C
14
NaBH4, MeOH
[reductive amination-lactamization]
MeO
OH
OMe
MeO2C
10
OMe
MeO
H2O
MeO
OH
HO2C
H
H H2SO4 H
O
H
MeO2C
NaOMe
MeOH
11
a. CH2N2
b. Ac2O
c. OsO4
d. HIO4
e. CH2N2
Br
OMe
Br
O H
NBS
H2Cr2O7 H
AcOH
HO
H
OH
OMe
12
[elimination-conjugate addition]
Zn
Br
H
H
OH
Zn
Br2
Br
OH
OH
H
5+6 CO2Me
MeO2C
Zn
O Al(OiPr)3,
H
iPrOH
A
B
C
N
N
H H
D
H
H
O
OMe
MeO2C
OMe
1: ()-reserpine
OMe
OMe
56
cleverly coaxing his polycycle into an unfavorable conformation (through intramolecular tethering), which forced an
isomerization to give the desired stereochemistry.
These maneuvers clearly constituted unprecedented sophistication and rational thinking in chemical synthesis
design. While this rational thinking was to be further
advanced and formalized by Coreys concepts on retrosynthetic analysis, the stereocontrol strategies of this era were to
dominate synthetic planning for some time before being
complemented and, to a large degree, eclipsed by acyclic
stereoselection and asymmetric synthesis advances which
emerged towards the end of the century.
Longifolene (1961)
The publication of the total synthesis of longifolene (1 in
Scheme 8) in 1961 by Corey et al.[34] is of historical significance in that in it Corey laid out the foundation of his
systematic approach to retrosynthetic analysis. Our thinking
about synthetic design has been profoundly affected and
shaped by the principles of retrosynthetic analysis ever since,
and the theory is sure to survive for a long time to come.
Coreys longifolene synthesis[34] exemplifies the identification
and mental disconnection of strategic bonds for the purposes
of simplifying the target structure. The process of retrosynthetic analysis unravels a retrosynthetic tree with possible
pathways and intermediates from which the synthetic chemist
can choose the most likely to succeed and/or most elegant
strategies. The total synthesis of longifolene itself, shown in
Scheme 8, involves a Wittig reaction, an osmium tetroxidemediated dihydroxylation of a double bond, a ring expansion,
and an intramolecular Michael-type alkylation to construct
the longifolene skeleton. This synthesis remains a landmark in
the evolution of the art and science of total synthesis.
Angew. Chem. Int. Ed. 2000, 39, 44 122
REVIEWS
Me
OHC
Me
HN
Mg
Me
Me
NH
Me
H
H
Dieckmann cyclization
H
Me
Me
H2N
NC
Me
NH
NH
HN
HBr
NH
Me
NH
Me
HN
AcOH
b. H2S
Me
a. MeO2C
Me b. NaOH
c. CH2N2
HN
Me a. EtNH2,
NaBH4
HN
MeO2C
CO2Me
CO2Me
CN
Me
Me
Me
CO2Et
HN
HN
HCl
Me
CO2Et
formation]
NC
HN
HN
Me
CO2Et [thioaldehyde
MeO2C
Me
Cl
CN
OHC
SHC
MeO2C
NH
Me
Me
NH
Me
Me
Me
4: phytol
CO2Me
H3N
Me
Me
Me
Me
MeO2C
OHC
H2N
Me
CO2Et
1: chlorophyll a
b)
OH
+
Me
Me
Me
Ester
formation
Me
HN
NH
Me
O
CO2Me
Me
Cl
CO2Et
Me
HCl
AcHN
H3N
N
Me
Me
AcHN
Me
NH HN
Me
NH HN
Me
Me a. I2 [oxidation]
Me
Me
NH
Me
Me
NH HN
Me
Me
Me
AcOH,
(50% overall)
Me
Me
NH HN
Me
b. Ac2O, py
NH HN
AcHN
Me
Me
NH
Me
NH HN
Me
Me
CO2Me
CO2Me
CO2Me
10
CO2Me
CO2Me
CO2Me
CO2Me
11
NH
CO2Me
13
12
Me
NH
Me
NH
Me a. resolution
Me
Me
HN
Me
H
H
CHO CO2Me
CO2Me
b. CH2N2 Me
b. NaOH, H2O Me
HN
Me
H
HO2C
19
CO2Me
14
HO
NH
HN
Me
O2, hv
Me
H
O CHO
CO2Me
NH
HN
CO2Me
MeO2C
MeO2C
17
Me
[Hofmann
elimination] Me
Me a. HCl,
MeOH
b. Me2SO4, Me
Me
NaOH
H
[photooxygenation]
MeO2C
MeO2C
18
Me
Me
[highly specific
photochemical
Me
Me cleavage of the
cyclopentadiene ring]
AcOH/
[hydrolysis]
Me
NH
HN
Me
CO2Me
MeO2C
MeO2C
16
Me
15
[cyanohydrin lactone
formation]
HCN, Et3N
Me
NH
a. KOH, MeOH
with quinine
Me
Me
Me
Me
CO2Me
CO2Me
AcHN
Me
Me
CO2Me
CO2Me
CO2Me
NH
[oxidation] Me
Me
O
CO2Me
air
Me
HN
Me
H
H
NC
CO2Me
Me
Me
a. Zn, AcOH
b. CH2N2
c. MeOH, HCl
[reduction]
[methylation]
[methanolysis]
20
Me
Me
NH
HN
H
H
MeO2C
CO2Me
Me
Me
Me
[Dieckmann
cyclization]
Me
b. H ,
Me
HN
Me
H
H
CO2Me
21
NH
NaOH, py
Me
a. NaOH, H2O
4
Me
c. Mg(OEt)2
[ester exchangemagnesium
insertion sequence]
Me
Me
Me
MeO2C
CO2Me
N
Mg
H
O
22
O
CO2Me
Me
1: chlorophyll a
Me
Me
Me
Me
Scheme 7. a) Strategic bond disconnections and retrosynthetic analysis of chlorophyll a and b) total synthesis (Woodward et al., 1960).[29] The locking of 2
and 9 together through formation of a schiff base forces the cyclization to proceed with the desired regioselectivity.
Lycopodine (1968)
Lycopodine (1 in Scheme 9), first isolated in 1881, is the
most wildly distributed alkaloid from the genus lycopodium.[71] In addition to the great challenge of synthesizing this
novel polycyclic framework in a stereocontrolled manner, one
must effectively address the challenge posed by the C13
quaternary center, which is common to all four rings. Gilbert
Stork was one of the first to successfully complete the total
synthesis of lycopodine.[72] This masterfully executed synthesis
Angew. Chem. Int. Ed. 2000, 39, 44 122
REVIEWS
a)
K. C. Nicolaou et al.
Alkylation
Me
Me
Michael Me
addition
a)
Me
O
Allylic
Me
H oxidation
Me
OMe
H
O
H
Olefination
Me
1: longifolene
N
N
Me
Me
Cl3C
Lactamization
O
Me
pinacol
rearrangement
Me
1: lycopodine
Me
5: Wieland-Miescher
ketone
OH
OTs
Ozonolysis
CO2Me
Me
Me
N
H
Cationic
cyclization
2
Stork enamine
Me
O
CHO
O
OMe
MeO
OMe
CO2Et
Conjugate
addition
b)
HO
a.
OH
pTsOH,
b. Ph3P=CHMe
Me
a. OsO4, py
b. pTsCl, py
Me
O Me
7
O
[pinacol
(31% overall) rearrangement]
4 H
OTs
LiClO4,
CaCO3
b)
MeO
HO
O
O
OH
O Me
Et3N ,
a.
Me
O
O
HS
Me Me
S
SH
BF3Et2O
b. LiAlH4,
Me
Me
H
Me
Me
a. Na, NH2NH2,
b. CrO3, AcOH
O
H
Me
Me
H
Me
N
H
[Stork
enamine]
Ar
H2N
N
Me
(55%) O
Me
c. KOtBu
d. O
OMe
12
11
Cl
Me
a. LiAlH4
b. Li-NH3
[Birch
reduction]
N
H
OMe
H
H
(49% overall)
Me
10
H3PO4:HCO2H (1:1)
H
Me
a. MeLi,
b. SOCl2, py
N
O
CCl3
13
OMe
Cl3C
O3, MeOH
H
Me
Me
Cephalosporin C (1966)
Cephalosporin C (1 in Scheme 10) was isolated from
Cephalosporium acremonium in the mid-1950s[75] and was
structurally elucidated by X-ray crystallographic analysis in
1961.[76] Reminiscent of the penicillins, the cephalosporins
represent the second subclass of b-lactams, several of which
became legendary antibiotics in the latter part of the
twentieth century. Having missed the opportunity to deliver
penicillin, the Woodward group became at once interested in
the synthesis of cephalosporin C and, by 1965, they completed
the first total synthesis of the molecule.[30]
This total synthesis of cephalosporin C was the sole topic of
Woodwards 1965 Nobel lecture in Stockholm. Indeed, in a
move that broke tradition, R. B. Woodward described on that
occasion for the first time, and in a breathtaking fashion, the
elegant synthesis of cephalosporin C. Highlights of this synthesis, which is summarized in Scheme 10, include the
development of the azodicarboxylate-mediated functionalization of the methylene group adjacent to the sulfur atom of
l-cysteine, the aluminum-mediated closure of the aminoester
to the b-lactam functionality, the brilliant formation of
cephalosporins sulfur-containing ring, and the use of the
b,b,b-trichloroethyloxy moiety to protect the hydroxyl group.
This total synthesis stands as a milestone accomplishment in
the field of natural product synthesis.
Ar
(20-25%
of
desired
isomer)
Me
[cationic
cyclization]
10
H
N
Me
H2N
1: longifolene
58
OH
H
N
Me
OH
H
[conjugate
addition]
(90%)
OMe
Me
a. LiAlH4
b. MeMgBr,
CuCl2
Me
Me 8
OMe
OMe
(36%)
(10-20%)
CH3
b. K2CO3, H2O
[decarboxylation]
O Me
2 N HCl,
[Isomerization;
Michael addition]
a. NaOEt, 7
CO2Et
Me
Me
EtO2C
Me
H
H
O
O
N
O
Cl3C
N
O
16
CO2Me
O
Cl3C
15
CO2Me
Cl3C
H
O
O
N
OH
Me
OH
14
SeO2
N
H2O2
(30%
O
overall)O
CO2Me
Cl3C
CHO
CO2Me
Me
N
H
Me
N
O
H
H
a. LiAlH4
b. CrO3-H2SO4
O
H
17
MeO
H
H
1: lycopodine
18
REVIEWS
CO2H
Conjugate
addition
O
H
NH H
H2N
H
Cyclization
O
CH2OAc
MeO2C
H
H2N
Me
CO2Me
N N
MeO2C
H
Me
tBuOC(O)N
S
Me
N3
H
tBuOC(O)N
Me
MeO2C
Me
MeO2C
H
Me
a. acetone
MeO2C
H
b. tBuOCOCl
N
c.
CH
2
2
SH
tBuOC(O)N
HO2C
H
OAc
H
tBuOC(O)N
6: L-(+)-cysteine
b)
H
Me
HO2C
H
SH
Me
1: cephalosporin C
H2N
CHO
tBuOC(O)N
CO2CH2CCl3
NH
N CO Me
2
S N
Me
Me CO2Me
OAc
CO2Me
MeO2C H
H
S
CO2Me
MeO2C H
H
tBuOC(O)N
Me
tBuOC(O)N
[oxidation]
Me
12
tBuOC(O)N
Me
MeO2C
H
Pd(OAc)4
N
S
Me
13
CO2Me
tBuOC(O)N
CO2Me
Me
tBuOC(O)N
CO2Me
Me
MeO2C
H
NH
Me
11
MeO2C
H
OAc
Me
CO2Me
N
10
Me CO2Me
MeO2C OAc
N
H
N
OAc
NH
S N
tBuOC(O)N
CO2Me
Me
Me
14
CO2Me
Me
15
OAc
[-N2]
MeO2C
H
OAc
H
tBuOC(O)N
Me
MeO2C
H
tBuOC(O)N
Me
Me
5: major product
MeO2C
H
OAc
H
OAc
tBuOC(O)N
S
Me
Me
Me
16
AcO, MeOH
O
MeO2C
OH a. MeSO2Cl
H
H b. NaN3
tBuOC(O)N
S
MeO2C
H
tBuOC(O)N
Me
Me
Me
18
Me
[lactamization]
CHO
H
NHCO2CH2CCl3
H
N H
H
O
CO2CH2CCl3
a.
27
CO2CH2CCl3
O
N
TFA
H
tBuOC(O)N
Me
N H
H
CO2CH2CCl3
py
[equilibration]
Me
CH2OAc
CO2H
O
CH2OAc
N
H
N H
H
O
CO2CH2CCl3
28
23
H
NHCO2CH2CCl3
CHO
CH2OAc
O
CO2CH2CCl3
25
24
b. CCl3CH2OH, DCC
26
NHCO2CH2CCl3 H2N
H
CO2H
CO2H
CO2CH2CCl3
H
22
DCC
Me
CO2CH2CCl3
CO2CH2CCl3
CHO
S
21
CO2CH2CCl3
N
Me
NaO
20
H
S
CCl3
CHO
HO2C H
HO
NH
H
a. Al/Hg/MeOH
tBuOC(O)N
b. iBu3Al
OH
[reduction of azide]
N3
Zn, AcOH
NH2
N H
H
H
CO2H
[reductive removal of
the protecting groups]
1: cephalosporin C
retrosynthetic analysis concepts and demonstrated the utilization of the bicycloheptane system derived from a Diels
Alder reaction as a versatile key intermediate for the synthesis of several of the prostaglandins. A large body of
Angew. Chem. Int. Ed. 2000, 39, 44 122
REVIEWS
K. C. Nicolaou et al.
of Corey, those of A. I. Myers,[86] D. A. Evans,[87] W. Oppolzer,[88] and H. C. Brown[89] as well as many others helped shape
the field.
Finally came the era of catalyst design and here again the
prostaglandins played a major role in providing both a driving
force and a test. In a series of papers, Corey disclosed a set of
chiral aluminum- and boron-based[90, 91] catalysts for the
Diels Alder reaction (and several other reactions) that
facilitated the synthesis of an enantiomerically enriched
intermediate along the route to prostaglandins. And, finally,
the problem of stereoselectivity at C15 was solved by the
introduction of the oxazaborolidine catalyst (CBS) by Corey
in 1987.[92] These catalysts not only refined the industrial
process for the production of prostaglandins, but also found
uses in many other instances both in small scale laboratory
operations and manufacturing processes of drug candidates
and pharmaceuticals. For a more in-depth analysis of the
Corey syntheses of prostaglandins F2a and E2 and other
advances on asymmetric catalysis, the reader is referred to
ref. [4] and other appropriate literature sources.
Progesterone (1971)
Progesterone (1 in Scheme 12), a hormone that prepares
the lining of the uterus for implantation of an ovum, is a
member of the steroid class of compounds that is found
ubiquitously in nature. Its linearly fused polycyclic carbon
framework is characteristic of numerous natural products of
steroidal or triterpenoid structures. A daring approach to
progesterones skeleton by W. S. Johnson[93] was inspired by
the elucidated enzyme-catalyzed conversion[94] of squalene
oxide into lanosterol or to the closely related plant triterpenoid dammaradienol. This biomimetic strategy was also
encouraged by the Stork Eschenmoser hypothesis, which
was proposed in 1955[35] to rationalize the stereochemical
outcome of the biosynthetic transformation of squalene oxide
to steroid. According to this postulate it was predicted that
polyunsaturated molecules with trans CC bonds, such as
squalene oxide, should cyclize in a stereospecific manner, to
furnish polycyclic systems with trans,anti,trans stereochemistry at the ring fusion.
This brilliant proposition was confirmed by W. S. Johnson
and his group through the biomimetic total synthesis of
progesterone (Scheme 12). A tertiary alcohol serves as the
initiator of the polyolefinic ring-closing cascade, in this
instance, but other groups have also been successfully
employed in this regard (for example, acetal, epoxide). The
methylacetylenic group performed well as a terminator of the
cascade in the original work. A number of new terminating
systems have since been successfully employed (for example,
allyl or propargyl silanes, vinyl fluoride). The work of W. S.
Johnson was complemented by that of van Tamelen[95] and
others[3, 4] who also explored such biomimetic cascades.
Tetrodotoxin (1972)
Tetrodotoxin (1 in Scheme 13) is the poisonous compound
of the Japanese puffer fish and its structure was elucidated by
60
REVIEWS
HO
C-N Bond
formation
N O
H
HO
NH2
AcHN
O
O
1: tetrodotoxin
H
CH2OH
HN
H2N
OH
OH
OAc
CH2OAc
AcO H
OH
OAc
trans-Esterification/
epoxide opening
Orthoester
formation
Epoxide opening/
cyclization
HO
AcO
OAc
AcNH
, SnCl4
Me
Me
O
Me
a. MsCl, Et3N
b. H2O,
(61%)
[Beckmann
rearrangement]
AcN O
H
Me
(83%)
HO
O
AcNH
Diels-Alder
reaction
CH2OAc
O
O
b)
Baeyer-Villiger
oxidation
Me
Me
a. SeO2
b. NaBH4
(100%) O
H
OH
O
O AcN
H OAc
9
a. mCPBA
b. Ac2O, py
c. TFA, H2O;
Ac2O, py
O
O
AcO AcN OAc
H
10
O
AcHN
OH
14
OH
HO
H2N
AcHN
O
H
OAc
OAc
CH2OAc
H
O
S
H2N
OH
AcN O
H
O
OAc
a. KOAc, AcOH
b. Ac2O, CSA,
CH2OAc
OAc
N
H
AcO
H O
H
13
a. H5IO6
b. NH4OH
(9% overall)
OAc
15
OH
OAc
OAc
AcO
Me
O
O
O
AcHN
O
(100%)
c. vacuum,
H O
[Baeyer-Villiger O
300 C
AcO
oxidation]
AcO AcN OAc [acetate elimination]
H
H
O
(80%)
11
3
a. OsO4, py
(65%)
b. (MeO)2CMe2, CSA
c. Et3O BF4 , Na2CO3; AcOH
BF4 ;
Ac2O, py
b. acetamide
(50%)
a. BF3, TFA
b. TFA, H2O
HO
c. Al(OiPr)3, iPrOH,
d. Ac2O, py
(86% overall)
mCPBA
H O a. Et O
3
AcO
H
HO
OAc
AcO-
CH2OAc
H
OAc
N
AcHN
OH
HO
8
d. (EtO)3CH, CSA; Ac2O, py [diethylketal formation]
e.
[ethyl enol ether formation]
f. mCPBA, K2CO3
[epoxidation]
g. AcOH
[epoxide opening and acetylation]
(53% overall)
OAc
Me
O AcN
H OAc
a. CrO3, py
b. BF3Et2O,
CH2OAc
H
OAc
CH2OAc
H
OAc
H2N
H O
a. BrCN, NaHCO3 AcO
H
b. H2S
O
(100%)
12
HO
H
H
OH
CH2OH
HN
H2N
N O
H
HO H
H
O
O
OH
1: tetrodotoxin
REVIEWS
K. C. Nicolaou et al.
Scheme 14. a) Strategic bond disconnections and retrosynthetic analysis of ()-vitamin B12 , b) key synthetic methodologies developed in the course of the
total synthesis, c) and final synthetic steps in the Woodward-Eschenmoser total synthesis of vitamin B12 (Woodward Eschenmoser, 1973).[32]
62
REVIEWS
Me
O
Me
Me
Me
Me
O
Me
OBz
O
HO
OH
Me
OH
OTBS
O
OTBS
OBz
Me
Me
Me
Me
1: erythronolide B
Bromolactonization
Me
Br
Me
Bromolactonization
Me
Me
Me
NaOMe
(72%)
Me
10
Me
Me
O
13
a. H2, Raney-Ni
b. BzCl
12
OBz
OBz
a. LDA
Me
b. MeI
(75%
O overall) BzO
Me
Br2, KBr
Me
Me
(91%)
Me
Me
O
Me
11
[bromolactonization]
CO2H
OBz
Me
Me
BzO
Me
Me
O
Br
Me
(93%)
Me
O
Me
nBu3SnH
Me
AIBN
Me
CO2H
(76%)
a. LiOH
Me
b. CrO3, H2SO4
(80%)
OBz
Me
Me
Me
CH3CO3H
BzO
Me
(70%) BzO
Me
Me
CO2H
[Baeyer-Villiger
oxidation]
Me
16
14
5
a. H2O2, Na2WO4
b. resolution
c. ClCO2Et
Me d. NaBH4 OMe
e. POCl3,
(76% overall)
O
Me
18
15
a.
Li
b. Amberlyst IRC-50
c. ArSO2Cl, py
Me d. Me2CuLi
Me
I
O e. TBSCl, imid.
Me
f. LDA; MeI
OMe g. [Cp2ZrHCl]
OTBS
Me h. I2, CCl4
Me
19
Ph3P
17
N
S S
(65%)
OBz
Me
Me
BzO
Me
O O O
S
tBuLi, MgBr2
Me
(90%)
OH
Me
Me
Me
Me
a. AcOH
HO
b. LiOH
OBz
H2O2 Me
Me
BzO
Me
O O O
Me
Me
OH
iPr
Me
Me
OH
tBu
N
N
S S
23
Ph3P;
Me
iPr
PhMe,
(50% )
a. MnO2
(98% )
b. H2O2, NaOH
10
OH
Me
OH
OH
OH
Me
24
Me
1: erythronolide B
Me
Me
O
Me
Me
OH
Me
O
Me
O
Me
O
Me
Me
25
O
O
Me
Me
Me
O
OH
Me
Me
Me
Me
O
Me
22
Me
Me
Me
Me
Me Me
20
tBu
Me
OH
Me
OTBS
Me
Me
Me
HO
OTBS
d. Amberlyst IRC-50
e. KOH
(61% overall)
Me
Me
Me
Me
OH
Me
Me
Me
OMe
Me
Zn(BH4)2
OBz
21 HO
a. KOH
b. CH2N2
c. HBr,
Me
OBz
OH
Me
OH
OBz
OBz
Me
Me
Me
CO2H
HO2C
5
O
(96%)
Me
HO
O [bromolactonization]
Br
Me
Br2, KBr Me
Me
Br
Me Al/Hg
BzO
Me
a. BH3THF;
Me
H2O2, NaOH
b. CrO3, H2SO4
Me
Me
Me
Me
Me
OH
OBz
Br
Me
Me 7
S
Me
Me
O O O
Baeyer-Villiger
oxidation
8 Me
b)
Me
Alkylation
Me
Me
Me
BzO
Me
Lactonization
OH
Me
Me
OH Functionalization
Me
Me
Me
OH
Me
OBz
REVIEWS
K. C. Nicolaou et al.
a) Aldol condensation
Spiroketalization
O
HO
Me
Me
Me
O
Me
Me H
Me
CO2H
a.
OMe
Me
Me
Ph3P
Me
H Me
CO2Me
HO O
MeO
Me
H
BH3;
KOH, H2O2
(85%)
Me
OH
Me
BH3
O
Me
Me
[8:1 mixture]
MeO
a. O
(MeO)2P
a. KH, MeI
b. H2, 10% Pd/C
c. resolution
d. PCC
(77% overall)
OBn
H Me
HO O
OBn
b. LiAlH4
c. BnBr, KH
(66% overall)
CO2Et
Me
Me
Et
MeO
Me
H Me
1: monensin HO
b)
a. nBuLi, MeI
CN
b. KOH
c. LiAlH4
5
d. PCC
Me
Et
Me
O OH
OBn
H
HO O
OMe
Me
Et
OMe O
Me
CO2Me
OMe
Me
Me
O
Me
b. LiAlH4
(73%)
Me
O
Me
Me
(80%)
Me a. mCPBA
Me
Me
Me
b. KOH aq.
c. resolution
CO2H
OH
(35% overall)
PPh3
14
13
15
a. PhCHO, CSA
b. LiAlH4-AlCl3 (1:4)
OH c. resolution
HO
HO
CH3C(OEt)3
CH3CH2CO2H,
Et
H
(93%)
OBn
a. PCC
b.
Et
HO
[Johnson
orthoester Claisen
rearrangement]
16
Me
Me
Me
Ar
O
Et H
[bromoetherification]
26
KO2,
[18]crown-6
DMSO
Me
Ar
H
Et H
H H
OH
27
Me
Me
MeO OH
OH
Ar
OH
H
Et H
Me
OH
Me
11
[12:1 mixture]
Et
21 OH
O
Et
Et
Ar
mCPBA
OH
(36%)
[7:2 mixture]
24
(78%)
OH
[hydroxyl-directed
epoxidation]
22
23
a. NaOMe, MeOH
b. (CH3O)3CH
MeOH, CSA
Me
Me
Me
a. Cl3CCOCl, py
Me
b. OsO4, py
Ar
OBz
O
c. BzCl, py
O
O
H
Et H
H HO
d. CrO3, H2SO4
CCl3
28
O
Me
H
Me
PPh3
[Wittig reaction]
25
20
a. pTsCl
O
b. LiAlH4
c. CSA
Ar
d. OsO4, NaIO4
Me
a. LiAlH4
Ar
b. PCC
OBn c. MeOC H MgBr
6 4
H
d. CrO3, H2SO4
e. BCl3
(31% overall)
EtO2C
OBn
OMe OH
(47%)
Me
15
Me
Me
NBS Ar
O
OH
(57%)
H
Et H
Br
Me
19
Me
Me
Me
18
17
EtO
BH3; H2O2
Et
Et
OBn
MgBr
a. MOMBr,
OMe OBn O
OMe OBn OMOM
a. CH2N2
PhNMe2
MeO2C
HO2C
H
b. BnBr, KH O
b. HCl
c. O3 , MeOH
Me Me Me
Me Me Me
c. PCC
12
2
(33% from 11)
Me
Me
12 steps
OH
10
Me
(53% overall)
Me
Me
Me
MeMgBr
O
Et H
H H
OMe
(22% from 4)
OHC
MeO O
Me
Et H
H H
Li, EtOH
NH3 (l)
OH
OMe
[Birch reduction]
Me
OH
Me
MeO
H O Et H O H H O OMe
31
OH
30
a. (CH3O)3CH
MeOH, CSA
b. O3 , MeOH
c. MgBr2
Me
Me
Me
MeO
H
Et H
H H
OH
OMe
29
a. O3 , MeOH
b. HCl, MeOH
c. MeLi
OH
H
Me
Me
O OH
Et
O
HO
Me
iPrNMgBr, 2
H Me
OBn
Me
OMe
Me
HO O
Et
Me
Me
Me
OH
O H
O
a. H2 , 10% Pd/C
b. CSA, H2O
Me
c. NaOH-MeOH (1:5)
Me
H Me
Me
[8:1 mixture]
MeO
32
Et
O
Me H
H
OMe
Me
HO O
CO2Me
MeO
HO
Me
H Me
H
HO
CO2Na
HO
Me
Me
Scheme 16. a) Strategic bond disconnections and retrosynthetic analysis of monensin and b) total synthesis (Kishi et al., 1979).[108]
REVIEWS
Scheme 17. a) Strategic bond disconnections and retrosynthetic analysis of monensin and b) total synthesis (Still et al., 1980).[110]
thesis of efrotomycin, accomplished in 1985 in our laboratories,[115] addressed both problems by devising new methodologies for the stereoselective construction of glycosides and
tetrahydrofurans. Scheme 20 summarizes this total synthesis
in which the two-stage activation procedure for the synthesis
of oligosaccharides utilizing thioglycosides and glycosyl
65
REVIEWS
K. C. Nicolaou et al.
CO2R
CO2R
Ph
Ph
a CO2R
CO2R
Ph
Ph
CO2R
RO2C
CO2R
Ph Ph
H
H
HO2C
endiandric acid D
Ph
Ph
endiandric acid E
Ph
H
H
CO2H
HO2C
endiandric acid F
Diels-Alder
Ph
endiandric acid G
Diels-Alder
H
HO2C
H
H
endiandric acid A
H
H
CO2H
Ph
Diels-Alder
Ph
H
H
H
H CO H
2
Ph
Ph
RO2C
H
H
endiandric acid B
CO2H
H
H
Ph
endiandric acid C
Scheme 18. The endiandric acid cascade (Black et al., R Me, H). a) Conrotatory 8-p-electron cyclization; b) disrotatory 6-p-electron cyclization.[111]
Scheme 19. a) Strategic bond disconnections and retrosynthetic analysis of endiandric acids A C, b, c) total synthesis, and d) biomimetic synthesis of
endiandric acid methyl esters A C (Nicolaou et al., 1982).[112]
66
REVIEWS
OMe
Glycosidation
H
O
Me
O
Me
Wittig
olefination
OH
Me
OMe H
H
N
Me
O
Me
OH
OMe
OTBS
Me
OMe H
H
N
Me
Me
O
Me
OMe
OH
Me
Me
Me
Me
Me
Ph3P
OH
1: efrotomycin
Me
OH
TBSO
OH
Me
Me
O
O
Me
N
PhS
Me
HO OH
Me
Amide
formation
CCl3
OMe Me
OMe
OH
OMe
HO
Glycosidation
Me
Br
OBn
b)
a. LiCuMe2; TMSCl
b. O3; Me2S
c.
OMe
a. KCH2S(O)CH3
b. TBSCl, imid.
MeO2C
OMe H
OTBS
CuLi
MeO2C
O
7
Me
Me
OH Me
OMe
OH
a. nBu2SnO,
b. BnBr
c. KH, MeI
O
Me
OMe
OBn
Me
(55%)
OMe Me
d. NBS, DAST
12
MeO
Me
a. H2, 5% Pd/C
b. TBSCl, imid.
c. PhSTMS, ZnI2
OMe Me
OTBS
Me
Me
5, 6
Me
TMSO
10
Me
OTMS
OMe
OMe
OTBS
a. AgClO4, SnCl2
b. NBS, DAST
O
O
O
HO
NBS, AIBN
Ph
(100%)
c. PhSTMS, ZnI2;
K2CO3, MeOH
(70%)
14
a. Swern [O]
b. tBuOK,
Me
O
a. [Rh], H2
b. LiAlH4
c. CSA, acetone
Me
O
Me
15
OH
Me Me
(70%)
17
18
OMe
O
(80%)
OH
AcO
16
Me
a. (-)-DET, Ti(iPrO)4
tBuOOH
b. BnOC(O)Cl, py
c. AlCl3; H2O
(65%)
HO
O
O
c. DIBAL-H
(85%)
Me
a. AcOH, H2O
b. NaOH/EtOH
Me Me
19
Me
O
Me
Me
(85%)
O
H
OMe
Me
(85%)
Me
OH
O
O
a. (MeO)2CMe2,
CSA
b. K2CO3, MeOH;
CSA
c. RuO2, NaIO4
O
Me Me O
20
a. AcOH, H2O
b. PCC
c.
Me
22
Me
Me
O
Me
a. AlMe3, 10
b. HFpy
c. DDQ, MeOH
OH
24
Me
OMe H
H
N
O
Me
OH
OMe
OH
Me
Me
(26% overall)
21
Me
HO
O
Me Me
Me
OMe
O
Me
P(O)Ph2
(59%)
OMe
Me
Me
CO2H
O
O
Me
OMe
OH
(86%)
Me
Me
, nBuLi
Me
Me
Me
OH
Me
Me
Me
O
O
HO
O
CH3CH2CH2CO2Et,
LDA
Me
O
Me
OEt
O
23
c. 16, AgClO4, SnCl2
d. K2CO3, MeOH
OMe
(86%)
Me
Me
OH
OH
OMe
OAc
Me
Me
Me
Me
OMe
OH
Me
CO2Me
F
Me
TBSO
Me
MeO3P(O)
SPh
OPMB
TBSO
(63%)
a. nBu3SnH, AIBN
b. TBSCl, imid.
Br
OBz
HO
13
Me
OMe
OMe
OTBS
OMe
OMe
OMe
Me
a. TBAF
b. Ac2O, 4-DMAP
OMe
Me
OMe
(66%)
Me
O
H2N
d. KH, MeI
e. AcOH, H2O
(90%)
11
MeO
Me
Me
OMe H
1: efrotomycin
Me
Me
HO OH
Me
OH
Scheme 20. a) Strategic bond disconnections and retrosynthetic analysis of efrotomycin and b) total synthesis (Nicolaou et al., 1985).[115]
okadaic acid exhibits potent inhibition of certain phosphatases and is a strong tumor promotor. With its three spiroketal
moieties and seventeen stereogenic centers, the molecules
polycyclic structure presented a serious challenge to synthetic
chemistry. The first total synthesis of okadaic acid was
achieved in 1984 by the Isobe group in Japan[119] and was
followed by those of Forsyth[120] and Ley.[121] The Isobe
synthesis of okadaic acid, summarized in Scheme 21, highlights the use of sulfonyl-stabilized carbanions in synthesis, the
67
REVIEWS
K. C. Nicolaou et al.
Scheme 21. a) Strategic bond disconnections and retrosynthetic analysis of okadaic acid and b) total synthesis (Isobe et al., 1986).[119]
amphotericin B[122] (1 in Scheme 22), isolated from Streptomyces nodosus, occupies a high position as a consequence of
its complexity and medical importance as a widely used
antifungal agent. Its total synthesis[123] in 1987 by our group
represented the first breakthrough within this class of complex molecules. This total synthesis featured the recognition
of subtle symmetry elements within the target molecule that
allowed the utilization of the same starting material to
construct two, seemingly unrelated, intermediates and the
Angew. Chem. Int. Ed. 2000, 39, 44 122
REVIEWS
HO
Me
OH
OH
OH
OH
Me
OH
OTHP
TBSO
O
H
O
Me
OH
OTBS
Ph
TBSO
CO2Et
(EtO)2P
O
NH
TBSO
Cl3C
Ketophosphonate-aldehyde
macrocyclization
1: amphotericin B
4
O
NH2
OH
O
O
Me
Glycosidation
Phosphonate-aldehyde
condensation
Me
O
CO2H
Me
OBn O
(MeO)2P
MeO
Me
Phosphonate-aldehyde
condensation;
ring closure
OAc
Me
OTBS
N3
b)
HO
TPSO
O
OH
OH
(+)-8: (+)-xylose
OH
O
HO
HO
OH
7 steps
a. acetonide
formation
b. TPSCl, imid.
c. PhOC(S)Cl, py
d. nBu3SnH, AIBN
OBn O
(38% overall)
9a
BnO
(32% overall)
O
HO
(MeO)2P
OTBS
9b
()-9: ()-xylose
OH
OR1
a. PPTS [cyclization]
OMe
a. H2, Pd/C
O
Ph b. NBS, MeOH
(63%)
b. imid.
BnO
O
O
AcO
O
O
OR2 OR3 O
O
c. TBSOTf
c. 5 steps (53%)
d. LiOH
MeO
12
13
e. CH2N2
O
f. PDC
g. CH2N2
mixture of R1, R2 = acetonide, R3 = TBS and R1 = TBS, R2, R3 = acetonide
h. K2CO3,
OR1
MeOH
OMe
a. Et2AlC CH2OTPS
OTBS
HO
i. PDC
b. NaH, BnBr
2 OR3
j. (MeO)2P(O)CH2Li
O
O
O
OR
O
c. TBAF
CO2Me
(16% overall)
14
HO
OTPS
PCl5
BnO
(86%)
BnO
Cl
11
(67% overall)
OH
BnO
a. KSAE
b. Red-Al
c. TBSCl, imid.
d. H2, Pd(OH)2/C
Ph
O
O
16
17
LiCuMe2
BnO
e. PhCH(OMe)2, CSA
f. SO3py
TBSO
(47% overall)
a. H2, 10% Pd/C
b. Me2C(OMe)2, CSA
OBn c. CSA, MeOH
d. PCC
OH
BnO
OBn
Me
18
20
B(nBu)2
O
O
O
O
OTHP
Me
Me
O 21
Me
a. LDA, 6
b. DIBAL-H
c. MnO2
OTHP
TBSO
Me
Me
(86% overall)
Me
TBSO
26
Me
Me
(69%)
(60%)
22
TBSO
Me
OH
TBSO
Me
14
O
Me
O
HO
Me
OR2
Me
OR3
O
N
Me
23 Ph
OTBS
a. K2CO3, [18]crown-6
b. NaBH4
CO2Me
(MeO)2P
28
(70%)
Me
OMe
DCC, 4-DMAP
27
24
25
Ph
(72%)
Me
OCO2tBu
OR1
Me
a. LiBH4
b. tBuCOCl, py
c. TBSOTf, lut.
d. AcOH, THF, H2O
e. PhSSPh, nBu3P
OH
Me
(48% overall)
TBSO
SPh
a. Raney Ni
b. DHP, CSA
c. DIBAL-H
d. PCC, NaOAc
Me
[Evans' aldol]
a. LDA, 6
b. MeOH, PPTS
c. DIBAL-H
d. MnO2
Ph
TBSO
19
(88%)
P(OMe)2
HO
K2CO3 ,
OCHO MeOH
OEt
O
OTBS
H
O
(65% overall)
a. LDA; MeSSMe
Ph b. LDA; 5
c. TBAF
SMe
d. Red-Al
(MeO)2P
a. (EtO)3CH, AcOH
EtO2C
OH
b. LiAlH4
BnO
c. BnBr, NaH
BnO
OH
EtO2C
(87%)
15: (+)-diethyl-L-tartrate
a. H2, Pd/C
b. L-Selectride
(75% overall)
c. TPSCl, imid.
d. TBAF
BnO
O
e. MsCl, Et3N
f. NaI, acetone
g. (MeO)2P(O)H, NaH
10 steps
(68% overall)
10
OTPS
O
NaH, DME
(67% overall)
O
OH
Me
HO
Me
OH
OH
OH
MeO
OH
OH
O
H
CO2H
Me
1: amphotericin B
O
OH
Me
OH
NH2
Me
a. HFpy
b. HS(CH2)3SHEt3N
[azide reduction]
c. MeOH, CSA
d. LiOH, THF, H2O
(54% overall)
7
PPTS (cat.)
[glycosidation]
(40% overall)
TBSO
OMe
O
Me
O TBSO
OTBS
O
H
CO2Me
Me
29
OH
Scheme 22. a) Strategic bond disconnections and retrosynthetic analysis of amphotericin B and b) total synthesis (Nicolaou et al., 1987).[123]
69
REVIEWS
employment of the then newly discovered Sharpless asymmetric epoxidation reaction[124] to stereoselectively construct
the 1,3-diol systems.
The Horner-Wadsworth-Emmons process[125] emerged as
the most valuable reaction of the synthesis, having been
utilized five times to construct carbon carbon double bonds.
Particularly striking was the application of an intramolecular
ketophosphonate aldehyde condensation to construct the
38-membered ring of amphotericin B. A further, notable
feature within this total synthesis is the strategy through which
the carbohydrate moiety was installed stereoselectively on a
derivative of amphoteronolide B to construct the challenging
b-1,2-cis-glycoside bond of the target molecule. Important in
this field is also Masamunes elegant synthesis of 19-dehydroamphoteronolide B.[126]
K. C. Nicolaou et al.
a)
Epoxidation
Epoxide opening
and lactonization
O
HO
HO
HO
Aldol
reaction
C-C bond
formation
Ring closure
MeO
Baeyer-Villiger
oxidation
O
OMe
O
OMe
tBu
H
Tandem vicinal
di-functionalization
tBu
OH
4 O
Intramolecular ketene-olefin
[2+2] cycloaddition
a.
b)
OMe
Ginkgolide B (1988)
OMe
OMe
OMe
a. [tBu2Cu(CN)Li2]
b. TMSCl, Et3N
OMe
b. 6N HCl
(75%)
OMe
a. Cy2BH
b. AcOH; H2O2
c. 1N HCl
d. pH 11; pH 3
MeO
tBu
O
12
(65%)
b. LDA; PhNTf2
(86%)
tBu
a. TiCl4, O
MeO
tBu
TMSO
11
MeO
10
tBu
TfO
CO2H
a. (COCl)2
(80%) b. nBu N,
3
MeO
[ketene-olefin
[2 + 2]
cycloaddition]
[Baeyer-Villiger
oxidation]
(86%)
Ph3COOH, NaOH
tBu
tBu
13
O 4
tBu
OH
14
a. HS(CH2)3SH, TiCl4
(75%)
b. PDC, AcOH
H OMe
a. LiNEt2
b.
N
PhO2S O
H
tBu
MeO
then (MeO)3P
(72%)
OH
18
(68%)
H
tBu
LDA, HMPA
O
OH
tBuO
tBuO
15
O O
O
O
Me
HO
Me
tBu
OH
Ph3COOH,
(80%)
OH
H
tBu BnMe3N-OiPr; O
tBu
OMe
16
17
a. NBS, hv
(40%) b. AgNO3
c. PPTS, py
Ph
c. CSA
(75%)
OH
70
OMe
OH
Hydroxylation
1: ginkgolide B
H
tBu
O
O
OH
Oxidation
H
tBu
Me
H
tBu
OH
19
20
CSA (92%)
[lactol oxidation]
O
O
HO
HO
Me H
HO
O
O
H
tBu
OH
1: ()-ginkgolide B
a. I2, CaCO3
O
b. BF3Et2O
(89%)
HO
TBSO
H
O
Me H
HO
O
O
22
OH
OH
O
H
tBu
a.TBSOTf
O
b. OsO4, py
(65%)
HO
Me H
HO
O
O
H
tBu
OH
21
REVIEWS
84
a)
O
O
OH
O
HO
85
98
OH
HO
d
e
N
H
N
H
OH
OH
HO
HO
OH
OH
OH
OH
OH
23
Me
THPO
Me
37
Me
OPMB
Me O
TBS
Me
PPh3
11
AcO
a. CrCl2, NiCl2, 11
b. Ac2O
c. PPTS, MeOH
d. [RuCl2(PPh3)3]
OMe
OPMB
OPMB
PMBO
OPMB
22
Me
OPMB
OMe
O
38
115
OBz
HO
N
H
NH2
SePh
12
j. camphor sulfonyl
oxaziridine
[cis-trans isomerization] k. hv
[Suzuki coupling]
OTBS
Me
OTBS
OTBS TBSO
TBSO
77
HO B
(7.5% overall)
a. [Pd(PPh3)4], 2
b. LiCH2P(O)(OMe)2
84
OH
OTBS
(72% overall)
51
O
OBz
BzO
BzO
OTBS
TEOCNH
Me
37
OTBS
85
a. Ketophosponate 10,
NaH; then 3
b. LiBH4
c. Ac2O
d. DDQ, Ac2O
e. HClO4
f. LiOH
g.TBAF
h. AcOH
O
i. py,
23
51
OBz
Me
OH
OBz
BzO
BzO
Me
Me
37
OPMB
OPMB
OPMB
OMe
O
Me
(64-46% overall)
51
O
OBz
38
PMBO
PMBO
PMBO
Me
99
98
TBSO
TBSO
OPMB
22
84
O
O
PMBO
37
Me
Me
OPMB
O
OAc
23
BzO
BzO
OPMB
OPMB
OPMB
OPMB
OPMB
PMBO
TBS
Me PMBO
PMBO
MeO
OBz
22
OTBS
H
OTBS
MeO
53
Me
PMBO
Me
OTBS
O
TBSO
OPMB
38
23
TBSO
51
OBz
AcO
OPMB
Me
Me
OH
OBz
BzO
BzO
Wittig reactions;
hydrogenation
OPMB
OMe
O
Me
OPMB
OTBS
OTBS
37
MeO
OPMB
22
OPMB
22
THPO
OTBS
OPMB
PMBO
PMBO
O
OTBS
PMBO
PMBO
PMBO
OPMB
PPh3
O
OAc
OTBS
PMBO
PMBO
PMBO
28
Me
Horner-WadsworthEmmons reaction
1: palytoxin
75
OPMB
23
OH
OH
Me
Me
H
OH
53
51
b)
O
OAc
OH
52
37
HO
HO
NiCl2 /CrCl2
coupling
HO
Me
OH
38
PMBO
TBS
Me PMBO
PMBO
MeO
AcO
HO
Me
OPMB
OH
23
Me
OH
OH
22
Me
HO
Me
OH
OH
OH
77
HO B
OH
HO
Me HO
Me HO
OTBS
Suzuki coupling
HO
Me
OTBS
TEOCNH
76
75
OH
H2N
Amide bond
formation
f
HO
OH
Me
OH
HO
TBSO
OTBS
97 93
OTBS TBSO
77
OTBS
Wittig 98
reaction
O
115
O
115
OH
OTBS
85
99
OH
HO
OH
99
84
TBSO
TBSO
99
98
a. CrCl2, NiCl2
b. PDC
c. Ph3P=CH2
d. PPTS
e. Swern [O]
f. LiCH[B(OCH2CH2CH2O)]2;
then EtOAc, brine/1N HCl
O
115
TEOCNH
TBSO
TBSO
OTBS
85
TBSO
OTBS
97 93
1: palytoxin
OTBS
O
77
Me
OTBS
OTBS TBSO
OAc
OTBS
OTBS
OTBS
O
OTBS
OTBS
O
O
99
98
TBSO
TBSO
OTBS
Me
OTBS
OTBS
13
TBSO
OTBS
OTBS
O
OTBS TBSO
TEOCNH
85
OTBS
O
115
84
TBSO
TBSO
77
OTBS
OCPh2(C6H4-p-OMe)
MeO
14
MeO
H
OTBS
P
O
10
Scheme 24. a) Strategic bond disconnections and retrosynthetic analysis of palytoxin and b) highlights of the total synthesis (Kishi et al. 1989, 1994).[133, 134]
71
REVIEWS
Cytovaricin (1990)
Cytovaricin (1 in Scheme 25) is a 22-membered macrolide,
isolated from Streptomyces diastatochromogenes in 1981,[135]
K. C. Nicolaou et al.
which is endowed with impressive antineoplastic activity and
complex molecular architecture. Possessing seventeen stereogenic centers on its main framework, a spiroketal, and a
glycoside moiety with four additional stereocenters, cytovar-
Scheme 25. a) Strategic bond disconnections and retrosynthetic analysis of cytovaricin, b) key asymmetric alkylation and aldol reactions, and c) outline of
the total synthesis (Evans et al., 1990).[137]
72
REVIEWS
Calicheamicin g I1 (1992)
The arrival of calicheamicin g I1 [139] (1 in Scheme 26) and its
relatives, collectively known as the enediyne anticancer
antibiotics,[140] on the scene in the 1980s presented an entirely
new challenge to synthetic organic chemistry. Isolated from
Micromonespora echinospora ssp calichensis, this fascinating
natural product provided a unique opportunity for discovery
and invention in the areas of chemistry, biology, and medicine.
Its novel molecular structure is responsible for its powerful
biological properties, which include strong binding to duplex
DNA, double-strand cleavage of the genetic material by
formation of a benzenoid diradical, andas a consequence
potent antitumor and antibiotic activity.
The structure of calicheamicin g I1 is comprised of a carbohydrate domain and an enediyne core carrying a trisulfide
moiety that acts as a triggering device for the cascade of
events which leads, via a Bergman cycloaromatization,[141] to
the diradical species and DNA rupture. The oligosaccharide
domain of calicheamicin g I1 is endowed with high affinity for
certain DNA sequences, and acts as the delivery system of the
molecule to its biological target. The highly strained 10membered enediyne system, the novel oligosaccharide fragment, and the trisulfide unit are but some of the unusual and
challenging features of calicheamicin g I1 . Even more challenging, of course, was the chartering of the proper sequence for
assembling all these functionalities into the final structure.
Two groups rose to the challenge, ours (1992)[142] and that of
S. J. Danishefsky (1994).[143]
Notable features of our total synthesis of calicheamicin g I1
(Scheme 26) are the installment of the sulfur atom in the
carbohydrate domain through a stereospecific [3,3]-sigmatropic rearrangement and the [32] olefin nitrile oxide
cycloaddition reaction employed in the construction of the
enediyne core. That a molecule of such complexity could be
assembled in the laboratory in less than five years after its
structural elucidation in 1987 is an accurate reflection of the
high level of the state-of-the-art in the early 1990s. Just as
impressive is Danishefskys synthesis of calicheamicin, which
can be found in the original literature.[143]
Angew. Chem. Int. Ed. 2000, 39, 44 122
Strychnine (1993)
Although ()-strychnine had succumbed to the ingenuity
of Woodward in 1954 (see Scheme 4) it can still be considered
a target of choice to demonstrate the application of new
reactions and novel strategies by virtue of its abundant
stereochemical features densely packed in a heptacyclic
framework. Almost 40 years after Woodwards seminal
synthesis, Overmans synthesis of strychnine[58] (Scheme 27;
see p. 76) stands as a testimony to the evolution of organic
synthesis. Indeed, powerful palladium-mediated reactions
were used to expedite the assembly of the crucial intermediate
13 (Scheme 27) in a stereospecific fashion, thereby setting the
stage for the key tandem aza-Cope rearrangement and
Mannich reaction. This tandem reaction proved to be
particularly efficient and well-suited to afford an advanced
tricyclic system with concomitant formation of the quaternary
center stereospecifically, under mild conditions, and in nearly
quantitative yield. The sophisticated sequence of reactions
which ultimately led to Overmans ()-strychnine synthesis
deserves special mention for its elegance.
Rapamycin (1993)
Rapamycin (1 in Scheme 28; see p. 77) is an important
molecule within the field of immunosuppression that was first
isolated in 1975[144] from Streptomyces hygroscopicus, a
bacterial strain found in soil collected in Rapa Nui (Easter
Island), and structurally elucidated in 1978.[145] Its potent
immunosuppressive properties are reminiscent of those of
cyclosporin and FK506, whose biological and medical importance, particularly in the field of organ transplants, became
evident in the 1980s.[146] Although the structures of rapamycin
and FK506 possess striking similarities, the former is considerably more complex and attracted serious attention from the
synthetic chemists in the late 1980s and early 1990s. By 1995
there were four total syntheses of rapamycin,[147150] the first
being reported from this group in 1993 (Scheme 28).[147] This
asymmetric synthesis of rapamycin is an example of high
convergency and acyclic stereoselection, and is perhaps
known best for the way in which the macrocyclic ring was
formed. A palladium-catalyzed reaction based on Stilles
chemistry allowed a stitching cyclization process to proceed, to furnish the required conjugated triene system
concurrently as it formed the 29-membered ring of the target
molecule.[151]
Taxol (1994)
Taxol (1 in Scheme 29; see p. 78), one of the most
celebrated natural products, was isolated from the Pacific
yew tree and its structure was reported in 1971.[152] Its arduous
journey to the clinic took more than 20 years, being approved
by the Food and Drug Administration (FDA) in 1992 for the
treatment of ovarian cancer.[153] Synthetic chemists were
challenged for more than two decades as taxols complex
molecular architecture resisted multiple strategies toward its
construction in the laboratory. Finally, in 1994, two essentially
simultaneous reports[154, 155] described two distinctly different
73
REVIEWS
K. C. Nicolaou et al.
Swinholide A (1994)
Swinholide A (1 in Scheme 31; see p. 80), a marine natural
product with antifungal and antineoplastic activity, was
originally isolated from the Red Sea sponge Theonella
swinhoei.[169a] Its structure was fully established in the late
1980s by X-ray cystallographic analysis.[169b] The structure of
swinholide A has C2 symmetry and is distinguished by two
conjugated diene systems, two trisubstituted tetrahydropyran
systems and two disubstituted dihydropyran systems, a 44membered diolide ring, and thirty stereogenic centers. Its
challenging molecular architecture coupled with its scarcity
74
REVIEWS
75
REVIEWS
K. C. Nicolaou et al.
elucidated (1981).[177] The beauty of brevetoxins molecular
architecture, which accommodates eleven rings and twentythree stereogenic centers, attracted immediate attention from
the synthetic community. This neurotoxin, whose mechanism
of action involves the opening of sodium channels, shows
remarkable regularity in its structure. Thus, all rings are transfused and each contains an oxygen atom. All ring oxygens are
separated by a CC bond and each is flanked by two synarranged hydrogen or methyl substituentsexcept for the
first which carries a carbonyl to its left and the last which is
flanked by two anti-oriented hydrogens. With its imposing
structure, brevetoxin B presented a formidable and daunting
problem to synthetic organic chemistry. Not only did new
methods need to be developed for the construction of the
various cyclic ether moieties residing within its structure, but,
most importantly, the right strategy had to be devised for
the global assembly of the molecule.
After several abortive attempts, brevetoxin B was finally
conquered, and the total synthesis was reported in 1995 from
these laboratories (Scheme 33).[178] Along with the accomplishment of the total synthesis, this twelve-year odyssey[179]
yielded a plethora of new synthetic technologies for the
construction of cyclic ethers of various sizes. Prominent
among them are (see Scheme 33 b): a) the regio- and stereoselective routes to tetrahydrofuran, tetrahydropyran, and
H
N
1: ()-strychnine
b)
OH
OtBu
EtO2C
N
H H
HO
N
H
O
OtBu
(89%)
tBuO
HO
15
R2N
[Mannich
reaction]
(98%)
R 2N
O 4
a. LDA, NCCO2Me
b. 5% HCl-MeOH,
[carboxymethylation;
imine formation;
tautomerization]
OtBu
(70%)
N
H
H
HO
1: ()-strychnine
[epoxide opening]
a. NaH,
b. KOH, H2O
(62%)
CO2Me
OtBu
TIPSO
[Pd2(dba)3], Ph3As, CO
O
MeN
7
OtBu
NMe
(80%)
11
R 2N
OtBu
a. tBuOOH,
Triton-B
HO b. Ph P=CH
3
2
c. TBAF
(84%)
a. MsCl, iPr2NEt
b. LiCl, DMF
R2N
OtBu c. NH COCF , NaH
2
3
(83%)
N
H
Zn:
N
H H
OtBu
12
N
H
N
H
N
H H
O
OH
OMe
16
ZnO
OMe
OH
17 OH
H
CH2(CO2H)2
Ac2O,
(65%)
HO
20
TIPSO
R2N
Zn
10% H2SO4,
MeOH,
N
H
H
H
[isomerizations]
HO2C
OtBu
13
H
N
H H
[lactamization]
H
Me3Sn
OtBu
F3COCHN
R2N
R2N
MeN
NMe
MeN
14
10
(CH2O)n,
Na2SO4,
HO
HO
TIPSO
I
a. CrO3,
H2SO4
b. L-Selectride;
then PhNTf2 Me3Sn
c. Me6Sn2, [Pd(Ph3P)4]
OtBu
(78%)
tBuO
NMe
tBuO
[3,3]
[aza-Cope
rearrangement]
MeN
N
NMe
3 OH
a. NaCNBH3,
TiCl4
HO
b. DCC, CuCl
H2O
c. DIBAL-H
d. TIPSCl
(57%)
CO2Me
H CO2Et
AcO
O
F3COCHN
O
a. MeOCOCl, py
b. NaH, [Pd2(dba)3],
O
AcO
lactone
formation; 2: Wieland- Carboxymethylation;
imine formation;
reduction Gumlich
tautomerization
aldehyde
HO
Tandem Mannichaza-Cope
N rearrangement
Epoxide
opening
19 CO2H
OH
a. NaOMe, MeOH
b. DIBAL-H
H
N
H H
HO
(65%)
H
N
H H
CO2Me
18
OH
Scheme 27. a) Strategic bond disconnections and retrosynthetic analysis of ()-strychnine and b) total synthesis (Overman et al., 1993).[58]
76
REVIEWS
Epoxide
opening
Me
Me
OMe O
Me
N
H
SnnBu3
H
Me
O
Me
nBu3Sn
OMe
OH
MeMeO
OH
OMe O
OH
I
I
Me
b)
Me
a. nBu3SnH, cat.
Me
TMS
b. I2
OH
Me
(81%)
Me
Me
Me
TMS
O
(80%)
OMe O
Me
,LDA
c. K2CO3, MeOH
(65%)
Li
10
OMe
Me
Me
Me
a. DDQ
OMe OTIPS
(68%)
11
PmBO
b. LiOH
Me
TMS
(88%)
[2-thienylCu(CN)Li]
OTBDPS
NiII/CrII coupling
OMe
a. HO
OMe
Me
(70%)
OH
OH
Esterification
H
a. CSA, MeOH
b. CF3SO2Cl, Et3N
Me
a. LiI, LiAlH4
O b. NaH, MeI
OH
OMe OTIPS
7
O
cat. = [Mo(allyl)Br(CO)2(CH3CN)2]
Me
TMS
MeO
OMe Me
tBuLi;
O
O
Me
OTES
Me
HN
3
Takai reaction
OTES OTIPS
1: rapamycin
TMS
Aldol reaction
HO
OTIPS
OH
Stille couplings
"stitching macrocyclization"
Me
Me
b. Swern [O]
(92%)
14
Me
Me
a. TIPSOTf TMS
b. NIS
I
OMe OTIPS PMBO
OMe OH
(95%)
13
Me
PMBO
12
Me
OH
nBuLi, tBuOK;
Me
(+)-Ipc2B
(+)-Ipc2BOMe,
BF3Et2O
15
OTBS
(75%)
16
b. O3; Me2S
17
Me
HO
PmBO
OTBS
CrCl2, NiCl2,
Me
Me
(93%)
Me
OMe Me
Me
PMBO
OMe
OPMB
CHO
Me
Me
OMe Me
Me
Ph
26
Me
Me
20
PMBO
OTIPS
PMB
OH
a. LiBH4
b. pTsCl, Et3N, 4-DMAP
OMe
OMe Me
OTBDPS
O
O
Ph
Me
Me
Me
Me
Me
OTBDPS
O
O
OMe Me
OMe
OH
Me
Me
31
OMe
PMBO
O
Me
Me
(60%)
OMe
OTIPS
I
OMe Me
Me
Me
OTBDPS
PMB
29
Me
Me
Me
O
OH
OMe O
SnnBu3
Me
O
Me
OMe Me
Me
O
OH
N
H
O
OH
OH
OMe O
O
O
Me
(27%)
H
CO2H
DIC, iPr2NEt
b. OsO4, NMO
c. Pb(OAc)4
d. CHI3, CrCl2
N
O
(87%)
2
[PdCl2(CH3CN)2], iPr2NEt
OTBDPS
nBu3Sn
a.
SnnBu3
OMe Me
OMe Me
a. DDQ
b. TESOTf
c. 3, DIC, HOBt
Me
O
Me
Me
30
PMB
OH
Boc
OMe
Me
OH
OMe O
24
Boc
OTES OTIPS
Me
OTIPS
(81%)
Me
OTES
OTBS
iPr2NEt, LiCl
(96%)
OTBS
OH
HO
OTIPS
OMe O
Me
OMe
Me
Me
Me
28
(70%)
Ph
25
27
Me
d. Swern [O]
e. HFpy
f. Swern [O]
g. HF, CH3CN
Me
O
N
P(O)(OEt)2
OMe
Ph
PMBO
c. LiEt3BH
Me
nBu2BOTf, Et3N,
(86%)
Me
c. TBDPSCI, imid.
(75%)
OTBDPS
Me
23
Me
a. [RhCl(Ph3P)3], Et3SiH
b. aq. HF
OMe
Cp2ZrHCl; I2
(85%)
OTBS
OTIPS
PMBO
OTBS
Me 19
[Nozaki-Takai-Hiyama-Kishi reaction]
(83%)
22
PMBO
b. nBuLi; MeI
(98%)
21
a. TIPSOTf
b. HFpy
c. Swern [O]
Me
a. CBr4, Ph3P, Zn
18
Me
Me
OTBS
(72%)
PMBO
PMBO
PMBO
a. NaHMDS, PMBBr
OTBS
Me
Me
32
O
OMe
Me
OH
O
Me
OH
OMe Me
Me
OMe
OH
Me
1: rapamycin
Scheme 28. a) Strategic bond disconnections and retrosynthetic analysis of rapamycin and b) highlights of the total synthesis (Nicolaou et al., 1993).[147]
Angew. Chem. Int. Ed. 2000, 39, 44 122
77
REVIEWS
K. C. Nicolaou et al.
a)
AcO
Ph
O
Ph
N
H
McMurry coupling
Esterification
O
OH
Me
Me
O
Oxetane formation
OH
O
H
OBz OAc
HO
Oxygenation
Shapiro coupling
1: Taxol
TPSO
TESO
Me
Ph
Diels-Alder reaction
b)
OAc
Me
5
Cl
(85%)
CN
[Diels-Alder
reaction]
OAc
Me
(65%)
O
NNHSO2Ar
Me
OH
12
HO
10
PhB(OH)2
Me
OH
EtO2C
OB
[Diels-Alder
reaction]
OTBS
EtO2C
OEt
Me
a. TBSCl,
imid.
b. H2NNHSO2Ar
(68%)
CN
Cl
OH
OH
KOH, tBuOH
O
Me
Diels-Alder reaction
4
Me
Dynemicin A (1995)
NNHSO2Ar
OBn
Ph
Me
OTBS
[boronate
cleavage]
Ph
HO
OH
11
13
[lactone migration]
Me
TBDPSO
a. LiAlH4
b. CSA, MeO
OBn
OMe
Me
c. TPAP, NMO
TBDPSO
(63% overall)
O
O
15
Me
OTBS
nBuLi
(82%)
16
[Shapiro reaction]
Li
a. [V(O)(acac)2],
TBSO
OTBDPS
tBuOOH
OBn
Me
Me
b. LiAlH4
c. KH, COCl2
(50%)
TBSO
Me
a. TBSOTf
O
OH
b. LiAlH4
Me
c. CSA, MeOH
EtO
H
d. TBDPSCl, imid.
OH
OTBS e. KH, nBu4NI, BnBr
O
(46% overall)
O
O
14
OBn
H
OH
Me
O
O
17
OTBDPS
a. TBAF
HO
b. TPAP, NMO
Me
c. TiCl3(DME)15
Zn/Cu
(17%)
O
[McMurry
O
coupling]
O
18
OH
OBn
Me
OBn
H
O
19
a. Ac2O, 4-DMAP
b. TPAP, NMO
c. BH3THF; H2O2
AcO
OTES
Me
Me
O
O
O 21
OMs
OH
OAc
AcO
a. HCl, MeOH
b. Ac2O, 4-DMAP
c. H2, Pd(OH)2/C
d. TESCl, py
e. MsCl, 4-DMAP
(46% overall)
(48%)
OBn
Me
Me
OH
O
O
O
20
AcO
OTES
Me
Ph
HO
HO
22
O
H
OBz OAc
Ph
a. NaHMDS, 2
b. HFpy
N
H
Me
OH
Me
O
OH
HO
1: Taxol
O
H
OBz OAc
REVIEWS
Scheme 30. a) Strategic bond disconnections and retrosynthetic analysis of zaragozic acid A and b) total synthesis (Nicolaou et al., 1994).[164]
REVIEWS
K. C. Nicolaou et al.
a)
OMe
OMe
Me
OH
Me
Me
OH
Me
Me
Yamaguchi
esterification
OH
O
Ar
OH
Me
Me
Me
Dimerization
Me
HO
OTBS
tBu
Me
Me
tBu
CO2Me
OH
Me
Vinylogous Mukaiyama
aldol reaction
Me
Brown's
syn-crotylboration
Mukaiyama coupling
Me
O
HO
Me
Yamaguchi
macrolactonization
TBSO
Me
MeO
O
OH
Me
HO2C
OH
OMe
Me
OH
Me
O
OMe
O
Me
O
Si
MeO
Me
O
Me
Me
O
Ar
Me
3
OMe
OMe
1: swinholide A
b)
[catalytic asymmetric
epoxidation]
a. (+)-DIPT, Ti(OiPr)4,
Me
Me
OMe
Me
[hydroxy-directed
reductive opening of epoxide]
OH
OMe
H2C=CHCH2TMS
TMSOTf
(96%)
(79%)
b. Red-Al
(34%)
OH
Me
OH
tBuOOH
OMe
OMe
7
Me
Me
Me
tBu
OMe
[hydroboration-oxidation]
a. thexylborane;
OBn
H2O2, NaOH Me
b. (imid)2C=S
c. nBu3SnH
[deoxygenation]
(70%)
Me
Si
tBu
13
(93%)
Me
Me
Me
Me
Me
tBu
OMe
Si
TBSO
25
MeO
Me
11
Me
]2B
TBSO
HO
Me
TBSO
; H2O2
[Brown's syn
-crotylboration]
24
23
O
Me
(80%)
TMSO
TiCl2(OiPr)2
20
OTBS
BzO
TBSO
a. CH2N2
b. HFpy, py Me
10
B(cC6H11)2
Me
OMe
(97%)
MeO
Me
BzO
(83%)
20
HO2C
Si
OBn
MeO2C
tBu
Me
OBn
OH
12
Me
tBu
tBu
Me
b. tBu2Si(OTf)2
(78%)
Me
Me
OBn a. Me4NBH(OAc)3 Me
Me
a. MeOTf
b. PdCl2, MeO2C
CuCl, O2
(74%)
[Wacker oxidation]
MeO2C
14 tBu Si tBu
Me
O
Me
OMe
(cC6H11)2BCl, Me
Et3N
Me
OBn
CHO
(82%)
Me
21
[Luche reduction]
a. NaBH4, CeCl37H2O
b. Ac2O, iPr2NEt
Me
OH
BF3OEt2
[vinylogous Mukaiyama
aldol reaction]
(85%)
BzO
22
]2BCl
Me
Me
O
Ar
Me
TMSOTf,
HO
iPr2NEt
(61%) BzO
O
BzO
(94%)
Cl
19
a.
b.
18
OMe
, iPr2NEt
16
Cl
O
Me
CHO
BzO
17
(56%)
[asymmetric aldol reaction]
15
OMe
(65%)
OMe
OMe
Me
Ar
O
OH
Me
OH
OMe
O
Me
Me
Me
O
Ar
2,4,6-Cl3C6H2COCl, Et3N, 3;
4-DMAP, 2
Me
OTBS
Me
OH
O
Me
[Yamaguchi
esterification]
(54%)
Me
OTBS
Me
Me
CO2Me
O
Me
tBu
O
tBu Si
O
Me
2
OTBS
Me
Me
Me
OH
OH
O
OH
Ar
OH
O
Me
Me
Me
O
MeO
Me
O
Me
O
HO
OH
Me
Me
Me
Me
d. 2,4,6-Cl3C6H2COCl, Me
Et3N; 4-DMAP
O
OMe
e. HF/H2O/MeCN
MeO
(27%)
O
[Yamaguchi
Me macrolactonization]
O
OMe
a. TBSCl, Et3N
b. HFpy, py
c. Ba(OH)28H2O,
MeOH
Me
OH
OH
Me
Me
26
O
OMe
OMe
OMe
1: swinholide A
Scheme 31. a) Strategic bond disconnections and retrosynthetic analysis of swinholide A and b) total synthesis (Paterson et al., 1994).[170]
80
REVIEWS
OMe
OMe
Enders alkylation
Me
OH
Me
Me
Yamaguchi
esterification
OH
O
OH
Me
Ar
Me
Me
Me
Me
Yamaguchi
macrolactonization
TBSO
OTBS
HO
CO2Me
TMSO
Me
OH
Me
Me
MeO
Me
Me
O
HO
OH
HO2C
Me
OMe
MeO
Ghosez
lactonization
Me
OH
Dimerization
Mukaiyama aldol
Me
OTBS
Me
Me
O
Me
O
O
OMe
Me
Dithiane-cyclic
sulfate coupling
OH
TBSO
Me
2
Me
Me
O
Ar
Me
3
OMe
OMe
1: swinholide A
b)
a. Ac2O, Et3N,
Me
Me
4-DMAP
OH
Me
Me
HO
OH
BF3OEt2, TMSOTf HO
c. NaOMe, MeOH
(74%)
5: L-rhamnose
OH
OH
Me
Me
Me
Me
O
TBSO
b. CH2=CHCH2TMS,
OBz O
12
TBSO
a. TiCl2(OiPr)2,
20 OTMS
b. TBSOTf
c. K2CO3, MeOH
Me
d. Swern [O]
BzO
OMe
Me
Me
Me
H
OMe
(68%)
OMe
d. O3 8
[Enders alkylation]
(67%)
Me
Me
Me
OBz OBn
11
OMe
Me
Me
O
OMe
OMe
OTBS e. TiCl , SH SH
4
f. DIBAL-H
g. TBSOTf
(50%)
21
a. tBuLi, HMPA;
b. H2SO4
a. DIBAL-H
b. BF3OEt2,
c. BzCl, Et3N
d. OsO4, NMO;
Pb(OAc)4
(60%)
Me
a. PhCHO, SmI2
b. TBSOTf
[1,3 anti-reduction;
Evans-Hoveyda modification
of the Tishchenko reduction]
(77%)
Me
Me
Me
Me
O
S
OBz OH
TBSO
OMe
(68% overall)
[selective desilylation]
Me
Me
Me
OH
OMe
Me
Me
OMe
Me
Me
Me
OMe
OTBS
a. NaOH, MeOH/THF/H2O
b. TMSOTf, iPr2NEt
Me
Me
Me
O
TBSO
OTMS O
O
Ar
(84%)
[Ghosez lactonization]
OMe
18
HO
a. PMBCO(NH)CCl3,
CSA
O
b. DIBAL-H
OMe c. (+)-Ipc B(allyl);
PMBO
2
Me
NaOH, H2O2
13
(74%)
OMe
Me
16
O
OH
nBuLi;
CO
2
Me
Me
;
I
14
PMBO
I
15
OMe
[Yamaguchi esterification]
a. 2,4,6-Cl3C6H2COCl, Et3N, 2,
4-DMAP
b. PPTS, MeOH
c. Ba(OH)28H2O
d. 2,4,6-Cl3C6H2COCl, Et3N;
4-DMAP
e. HF/H2O/MeCN
[Yamaguchi
macrolactonization]
Me
OMe
CO2Me
Ar
(82%)
PMBO
OH
Me
OH
OTBS
O
OH
10
OMe
Me
O
TBSO
OBn
a. MnO2
b. (MeO)2P(O)CH2CO2Me, nBuLi
(92% overall)
Me
23
Ar
OH
Me
O
OMe
Me
OTBS
Me
O
TBSO
OBn
O
a. NBS, AgClO4
b. nBu3B; NaBH4; H2O2, NaOH
c. p-MeO-C6H4CH(OMe)2, CSA
d. DIBAL-H
e. HFpy, py
Me
OTBS
22
OMe
Me
K2CO3, MeOH
(52% overall)
Me
Me
PMBO
Me
TMS
19
(72%)
Me
OBn
Me
OBn
TBSO
OBn
O
4
[aldol condensation]
OMe
TiCl4, Et3N
Me
O
OMe
Me
a. O3; NaBH4
b. I2, Ph3P, imid.
c. LDA,
(7% overall)
CO2H
OH
Me
Me
OH
O
OH
Me
OH
O
Me
OMe
O
Me
Me
O
Me
MeO
O
O
HO
OH
Me
Me
OH
OH
Me
Me
OTBS
OMe 1: swinholide A
Scheme 32. a) Strategic bond disconnections and retrosynthetic analysis of swinholide A and b) total synthesis (Nicolaou et al., 1995).[171]
Angew. Chem. Int. Ed. 2000, 39, 44 122
81
REVIEWS
K. C. Nicolaou et al.
Eleutherobin (1997)
A marine natural product of some note, eleutherobin (1 in
Scheme 40; see p. 88) includes in its structure a number of
unique features. Isolated from an Eleutherobia species of soft
corals and reported in 1995,[198] this scarce natural product
elicited immediate attention from the synthetic community as
a result of its novel molecular architecture and tubulin binding
properties. Among the challenges posed by the molecule of
eleutherobin are its oxygen-bridged 10-membered ring and its
glycoside bond. Solutions to these problems were found in our
1997 total synthesis[199] as well as in Danishefskys total
synthesis,[200] which followed shortly thereafter. Scheme 40
summarizes our strategy to eleutherobin from ()-carvone.
Highlights include the intramolecular acetylide aldehyde
condensation to give the desired 10-membered ring and the
spontaneous intramolecular collapse of an in situ generated
hydroxycyclodecenone to form eleutherobins bicyclic framework. This total synthesis exemplified the power of chemical
synthesis in delivering scarce natural substances for biological
investigations.
Sarcodictyin A (1997)
Sarcodictyins A and B (1 and 2 in Scheme 41; see p. 88) are
two marine natural products discovered in 1987 in the
Mediterranean stoloniferan coral Sarcodictyon roseum.[201]
82
REVIEWS
Me
Me
a. Ac2O, py
O
OH b. BF Et O, TMSOTf,
3
2
O
OH
HO
[Barton-McCombie
deoxygenation reaction]
a. Im2C=S
OH
b. nBu3SnH, AIBN HO
TMS
HO
c. NaOMe, MeOH
OH d. TBDPSCl, imid.;
CSA, OMe
4: D-mannose
c. Amberlyst-15
d. nBu2SnO; BnBr
(35%)
O
H
TBDPSO
a. Swern [O]
OBn
b. AlMe3,
Me
MgBr2Et2O HO
K
(61%)
O
OBn
O
H
TBDPSO
H
TBDPSO
a. NaH
[Intramolecular
conjugate addition]
b. DIBAL-H;
Ph3P=CHCO2Me
(62%)
SEt H
EtS
OTBS
Me
a. EtSH, Zn(OTf)2
b. CSA, MeOH
K
H
(69%)
c. SO3py, Et3N,
DMSO
(68%)
TBDPSO
Me
HO
HO
OH 10 steps
(49%)
H
O
H
H
TBDPSO
12
PPTS
TfO
Ph
b. LiHMDS, HMPA;
PhNTf2
(58%)
OBn
Me
20
J
HO
Me
a. DIBAL-H
b. mCPBA
c. Swern [O]
OBn
Me
Me
O
OH
Me
(58%)
Me
TBSO
OBn
OBn
Me
18
(83%)
(85%)
7 steps
e. NaClO2, NaH2PO4
f. TBAF
19
17
a. TBSO
PPh3
b. H2, Pd/C
c. CSA, MeOH
d. Swern [O]
OBn
Me
Ph
e. TBAF
f. PPTS
(65%)
G
H
Me
O
CO2Et d. CH2PPh3
16
Me
O
H
H
TBDPS TBDPSO
a. DIBAL-H
b. mCPBA
c. SO3py
O
H Me
TBS
(58%)
Me
OBn
Me
MeO2C
O
H
d. Ph3P=CHCO2Me
TBDPSO
F
O
e. TBAF
HO
OH H
OBn
Me
10
Me
a. 2,4,6-Cl3C6H2COCl,
Et3N; 4-DMAP
OBn
MeO2C
c. Swern [O]
Ph
d. Ph3P=C(Me)CO2Et
(77%)
OH
a. TBSCl, imid.
b. 9-BBN;
H2O2, NaOH
Me
15
11 TBDPSO
Me Me
O
[(2-thienyl)(CN)CuLi]
[Murai coupling]
H
MeO2C
Me
OH
Me
14
Li
21
OTBS
Me
(89%)
13: 2-deoxy-D-ribose
Me
TBSO
Me
Ph
[6-endo hydroxy
epoxide
OBn
H
H
Me
cyclization]
HO
O
O
12 steps
CSA
K
I
J
(71%)
(55%)
E
R
R=
O
O
TBS
O
C
H
H
O
Me
O
H
Me
CHO
23
PivO
OBn
Me
HO
Me
TBSO
H
O
O
H H
Me
PivO
(64%)
Me
Me
22
Me
OBn
OBn
G
H
Me Me
O
H
O
O
H H
Me
a. DIBAL-H
b. Ph3P=CHCO2Et
c. DIBAL-H
d. (+)-DET, Ti(OiPr)4
Me H H
O
TBSO
tBuOOH
D
C
e. SO py
OBn
G
O
Me
a. TBAF
b. PPTS
c. TBSOTf
d. O3; Ph3P
e. MeMgCl
f. DMP
Me
O
C
H
Me
TBSO
(72%)
Me
H
O
H
H
CO2Me
OBn f. CH2=PPh3
27
H
O
O
H H
Me
Me
(69%)
OBn
Me
O
H H
Me
OBn
G
O
Me
OBn
26
A
O
PivO TESO
Me
H
O
Me
H O
H
EtS
OH
G
O
H
AgClO4,
NaHCO3,
SiO2, 4 MS
I
O
Me
Me
H
O
Me
G
H
A
O
H O
O
H
Me
H
O
Me
OBn
O
H H
Me
Me
OBn
G
O
Me
a. DIBAL-H
b. BF3Et2O, Et3SiH
c. Li, (l) NH3
d. pTsCl, py
e. NaI
f. TMS-imid.
g. Ph3P
OBn
29
Me
a. nBuLi, HMPA, 3
b. PPTS, MeOH
Me
H
(75%)
Me
H
O
D
H
Me
OTMS
O
H H
Me
Me
PPh3I
2
30
O
E
O
H
H
Me
H
HO
Me
H
O
H
H O
[methylenation]
Me
a. CH2=NMe2 I
b. HFpy
Me
38
(76%)
O
H
HO
Me
Me
H
O
OBn
Me
TBSO
OH
EtS
O
H H
Me
O
H
H
Me
O
H
[hydroxy dithioketal
cyclization]
31
Me
Me
EtS
Me
OTBDPS
TBSO
25
Me
H
Me
H
O
d. CSA, MeOH
e. KH
(74%)
Me
[intramolecular
Horner-Wadsworth-Emmons
olefination]
OBn
28
Me
a. TBAF
b. BrCH2COCl, py
c. (MeO)3P
d. iPr2NEt, LiCl
OBn
G
H
Me
a. DIBAL-H
b. DMP
c. (MeO)2P(O)CH2CO2Me,
NaHMDS, [18]crown-6 TBSO Me
(65%)
Me
Me
24
Me
Me
d. 2,4,6-Cl3C6H2COCl,
Et3N; 4-DMAP
OBn
(62%)
Me
21
Me
a. PPTS, H2O
b. BH3THF; H2O2, NaOH
c. LiOH, MeOH, H2O
O
OBn
G
H
Me
Me
Me
O
O
H
O
H
Me
O
H
H
Me
Me
HO
K
O
I
O
O
H
Me
1: brevetoxin B
83
REVIEWS
K. C. Nicolaou et al.
a)
CO2Me
O
H
O
N
Me
H
HN
OMe O
OMe
CO2Me
O
OCH3
Diastereoselective
OMe
epoxidation
Friedel-Crafts
1: tri-O-methyl dynemicin A
HO2C
methyl ester
OMe O
OMe
H
Br
OMe
CO2Me
Me
Allylic
3 OMe diazene
rearrangement
OBz
Pd-catalyzed
coupling
Me
O
N
MeO
MeO
O
H
Br
H
N
Stereoselective
imine attack
OH
MeO
Me
Pd-catalyzed
coupling
OMe
Tandem
macrolactonizationDiels-Alder
b)
a. ClCO2Me,
N
[Pd(PPh3)4]
MeO
TBSO
BrMg
MeO
Me
SiR3
OTBS b. TBAF
SnnBu3
Br
[Stille coupling]
(85%)
c. BrCH=CHCO2Me, (12%)
[Pd(PPh3)4]
[Sonogashira coupling]
Me
MeO2C
OBz
Me
H
O
H
N
9
H
a. LiOH
b. 4-DMAP,
H
N
Me
a. KOH
O b. py, MeO
Cl
OBz
(82%)
OMe 4
OMe
Cl
O
S NHNH2
O
H N
NH N
Me
O
O
OMe
O
H
N
[-N2]
H
HH
O
11
(57%)
OMe
a. AgOTf
b. K2CO3,
Me2SO4
[Friedel-Crafts]
H
OMe
OMe
O
OMe
a. MeAlCl2,
Et3SiH
b. SOCl2
CO2Me
O
H
N
O
CO2Me
OH
Br
Me
O
H
N
O
OMe O
Me
CO2Me
OMe
CO2Me
a. TMSOTf
b. DDQ
[Friedel-Crafts]
(51%)
OMe
H
OMe OH
OMe
13
OMe
H
HN
Me
MeO2C
Me
CO2Me
O
OMe
H
OMe O
OMe
OMe O
O O
11 O
a. DMP
b. NaClO2
(ca. 20%) c. LiOH
d. CH2N2
e. NaIO4
CO2Me
O
H
OMe O
N
COCl
OMe 12
OH
OMe
OMe
(82%)
Me
H
(ca. 50%)
10
(ca. 80%)
CO2Me
O
H
Me
Me
O
MeO
O
a. KHMDS,
H
MoOPh O
N
b. NaBH4
O
c. NaOMe
O d. (Cl3CO)2CO
OMe
9
[allylic diazene rearrangement]
CO2Me
O
H
O
N
OH
HO
BzO
O
Me
H
MeO
(33%)
[tandem Yamaguchi
macrolactonizationDiels-Alder]
O(CH2)3OBz
O
N
COCl
Cl
MeO
Cl
[oxidation at a and
deprotection at b]
a. CAN
b. Cs2CO3, MeI
[reprotection of b]
OMe
(50%)
a. mCPBA
b. DBU, MeOH
Me
OMe O
H
HN
CO2Me
O
OMe
a
3
OMe OH
OMe
14
84
REVIEWS
Ring stitching
Carbonylation
Me
H
HN
OH
Me
MOMO
CO2H
O
OMe
OH
MOMO
1: dynemicin
CO2MOM
O
H
OH
H
N
OMe
H
Oxidation
Diels-Alder
Stereoselective I Me3Sn
imine attack
+
Diels-Alder
Imine formation
OH
Me
TMS
O
Me
O O
SnMe3
Me I
OH
[O]
OH
H
6
O
OTBS
4
TBSO Diastereoselective
OTBS
epoxidation
b)
a. K2CO3,
Br
OH
b. NaH,
CHO
EtO
ZnCl2
CHO
O
CO2Et
P
OEt
c. DIBAL-H
d. Swern [O]
(82%)
OMe
OH
(60%)
Me
Me
Me
Ph a. OsO4, NMO
Ph
BrMg
OTBS
O
Ph
Ph
10
Me
OMe
(90%)
[Diels-Alder]
OMe
O O
CAN
CHO
TIPS
Me
Cl
b. Ph2C(OMe)2;
TBSCl, imid.
(80%)
OTBS
OTBS
12
TBSO
OTBS 5
11
Resiniferatoxin (1997)
(80%)
TIPS
TIPS
Me
H
R
a. HCl
O
Me
H
R
Ph b. Swern [O]
c. Ph3P, CBr4
O Ph d. nBuLi
[Corey-Fuchs
OTBS
homologation]
13
(54%)
OTBS
Ph b. HCl
OAc
Ph c. NaH, TBSCl
d. Ac2O, Et3N
(60%)
OAc
14
OTBS
TMS
TMS
O
R=
Me
OH
5
OH
O
R
a. AgNO3, NIS
16
CO2MOM
O
+
O
OMe
H
MOMO
18
OH
O
b. [Pd(PPh3)4],
OH
H
SnMe3
(74%)
OTBS
Me
[Tamura
homophthalic
O anhydride
protocol]
MOMO
Me
Me3Sn
(78%)
Cl
c. NH3, MeOH
d. mCPBA
LiHMDS
H
N
15
OTBS
a. [Pd(PPh3)4],
morpholine
O
b. NaH,
Me
Me
a. TBAF
R=
H
HN
MOMO
CO2H
O
OMe
H
-[CO2]
MOMO
OH
19
a. PhI(OCOCF3)2, THF
b. air, daylight
O
Me
OH
H
HN
O
H
Me
CO2H
OMe
OH
MOMO
MgBr2, Et2O
H
HN
CO2H
O
OMe
(15%)
OH 1: dynemicin
H
MOMO
OH
20
Brevetoxin A (1998)
Within the polluted red tide waters often resides a more
powerful neurotoxin, and that is brevetoxin A (1 in
Scheme 42; see p. 90). Isolated from the dinoflagellate species
Ptychodiscus brevis Davis (Gymnodium breve Davis), breve85
REVIEWS
K. C. Nicolaou et al.
a)
HO
NH
MeO
Esterification
Spiro tetrahydroisoquinoline
formation
OMe
O
AcO
Me
HO
S H
H
Mannich bisannulation
Me
OH
Curtius rearrangement
1: ecteinascidin 743
Fl =
TBSO
O
OAllyl
O H
HN
Me
N
H
TBSO
Fl
H
NH
NHCO2All
CN
19
MOMO
OH
(87%)
OMOM
a. nBuLi
b. DMF Me
a. CH3SO3H
CHO b. NaH, Me
BnBr
OMOM
(64%)
(86%)
BOPCl;
OH
CO2All
OMe
HO
10
O
CO2All
OMe
11
12
a. piperidine
Me
AcOH, 9
OMe
b. [Pd(PPh3)4]
OMe
Et3N/HCO2H O
(93%)
Me
O
N
15
OMe
OMe
[Curtius
rearrangement]
[-N2]
O
HN
O
O
OBn
16
[Rh(cod)-(R,R)-dipamp}] BF4
Me
H2
[asymmetric
hydrogenation]
(97%, 96% ee)
OH
Me
23
Me
CN
Fl
NHCO2All
OBn
O
AcO
OMe
O
HN
OMe
O
O
Me
S H
O H
Me
H
H
a. 5
b. CF3CO2H
c. AgNO3 - H2O
(high yield)
Me
Me
N
H
O
OH
O
AcO
Me
24
CN
MOM OMe
O
Me
S H
O H
N
Me
N
O
H
O
1: ecteinascidin 743
17
O
S H
H
N
O
OBn
O
AcO
Me
NH MOM OMe
OMe
HO
CN
21
a. nBu3SnH, [PdCl2(Ph3P)2]
(70%)
O , DBU
b.
25
NH
CO2All
H
CO2All
N
MeO
N
N
HO
OH
Me N
OMe
(79%)
[tandem quinodimethane formation,O
deprotection and cyclization]
HO
OMe
OMe
OMe
20
Me
Me
(PhO)2P(O)N3,
Et3N
OBn
14
Me
O
OMe
OH
MOMO
OMe
13
(93%) BnOH
OBn
CN
HO
OMe
O
CN
Me
H
22
[position-selective
angular hydroxylation]
a. (PhSeO)2O
(68%)
b. TBAF
c. EDCHCl, 4-DMAP, 2
CHO
O
OBn
O
TBDPSO
OBn
[-N2]
OBn
OMe
Me
a. nBuLi,
TMEDA Me
b. MeI
CO2All
H
OMe
NH2
MeO
N
OMOM
N
N
HO
Me
b)
a. DIBAL-H
b. KF2H2O, MeOH
c. CH3SO3H
[Mannich bisannulation]
(55%)
OH
Me
CO2All
OTBS
H
N
AllO
AllylO
OH
Me
HO
OTBS
OMe
OH
OMe
OMe
a. 4 , AcOH, KCN
b. Cs2CO3, allylbromide
(53%)
Me
CN
26
BF3Et2O, H2O
O
OH
O
Me
H
NH
O
O
OBn
a. BF3Et2O, 4 MS
b. H2, Pd/C
(73%)
Me
H
NCO2Bn
O
O
18
Scheme 37. a) Strategic bond disconnections and retrosynthetic analysis of ecteinascidin 743 and b) total synthesis (Corey et al., 1996).[186]
REVIEWS
a)
S
HO
O
Me
O
OH
HO
Me
BnO
O
TBSO
Me
OH
O
a. DHP. PPTS
b. TMS Li
BF3Et2O
c. MOMCl, iPr2NEt
d. PPTS, MeOH
e. Swern [O]
f. MeMgBr
g. TPAP, NMO
(36%)
TMS
a. nBuLi,
Ph2(O)P
Me
O
OMOM
a. TiCl4, MeO
Me
b. CSA
Me
OH
6 O
Br
Me
Me
TPSO
(78%)
H
O
a. LiAlH4
b. Et2Zn, CH2I2
Me
Me
(85%)
Me
a. Ph3P=CHOMe
(59%) b. pTsOH
c. Ph3P=CH2
d. PhI(OCOCF3)2, MeOH
(88%)
EtO2C
HO
O
O
OH
CO2H
O
HO
Me
(61% overall)
(+)-Ipc2B(All)
(96%)
NaHMDS; 10
16
17
Me
OTBS
Me
OH
13
O
I PPh3 (>70%)
Me
Me
OH
15
Me
OTBS
14
BnO
CO2H
O
12
a. HFpy
(ca. 95%)
b. Swern [O]
OTBS
LDA
ZnCl2
HO
S
Me
TBSO
N
O
Me
Me
Me
(84%)
OTBS
a. 1,4-butanediol, NaH
b. Ph3P, I2, imid.
c. Ph3P
(>90%)
Cl
a. nBu3SnH, AIBN
b. TPSCl, imid.
MeO
c. HS(CH2)3SH, TiCl4
[Suzuki coupling]
TPSO
O
O
15
(64%)
[Aldol macrocylization] a. KHMDS
(47%)
b. HFpy, py
c. TBSOTf
a. Dess-Martin [O]
S
S
b. HFpy
c. O O
TBSO
13
11
BnO
OMe
OMe
O
3 TPS
a. O3; Ph3P
b. NaClO2
Me
10
TBSO
OH
a. 9-BBN, 4; [PdCl2(dppf)],
Cs2CO3, Ph3As
b. pTsOH
Me
b. O3 ; Me2S
(85%)
Me
a. (+)-Ipc2B(All)
b. TBSOTf
(73%)
Me
Me
a. DIBAL-H
b. Ph3P=C(Me)CHO
Me
MgBr
TBSO
12
BnO
TPSO
14
TBSO
a. TBSCl, imid.
b. NaI, acetone
(98%)
11
Esterification
OTBSO
Me
O
Me
OTMS
OTBS O
NIS, MeOH
Me
Aldol reaction
a. Li2CuCl4 ,
HO
Me
N
O
b)
(34%)
BnO
a. TBSOTf
b. DDQ
c. Swern [O]
TBSO
OH
10
(87%)
[hetero Diels-Alder
reaction]
S
HO
BnO
Me
8
b. NIS, AgNO3
c. Cy2BH, AcOH
I
d. PhSH, BF3Et2O
e. Ac2O, py
3
S
OH
Emmons-type
homologation
OMe
O
TPS
b)
Me
OMe
Me
Me
Me
OH
1: epothilone A
Aldol reaction
Me
O
1: epothilone A
HO
Me
O TBSO
Me
Epoxidation
S
TBSO
Olefin
metathesis/
cyclorelease
a)
Epoxidation
(41%)
1: epothilone A
CO2H
18 O
OH
O
O
TBS
HO
N
O
Me
Cl
PCy3
Ru
PCy3 Ph
HO
[olefin metathesis
reaction]
(52%)
O
O
TBS
Me
O
O
O
TBS
19
TFA
CH2Cl2
(91%)
O
S
HO
Cl
Me
O
OTBS
Me
(ca. 90%)
(two diastereoisomers)
[Aldol reaction]
N
O
Me
O
OH
O O
Me
CF3
(85%)
HO
N
O
Me
[5:1 mixture of
diastereoisomers]
1: epothilone A
OH
REVIEWS
K. C. Nicolaou et al.
Martin et al. in 1999 (Scheme 46; see p. 94)[218] on the other
hand involved an intramolecular Diels Alder reaction and
two olefin metathesis ring closures to construct the pentacyclic framework of the target molecule. All three approaches
a)
R'
O
Me
R'
Me
Me trans-Ketalization
O
Me
Cleavage
O
O
H
Me
OH
R''
Me
OH
H
OH
Me
OTIPS
Me
Resin
Me
Me
OTIPS
7
a. TIPSOTf
b. LiHMDS
c. Dess-Martin [O]
d. Et3N3 HF
OTES
Me
OTES
CHO
H
Me
OH
Me
Me
OH
(65%)
H
OH
Me
Me Loading
b)
H
R'
O
6
+
Me
R'''
Ester or carbonate
formation
Linker
Me
H
Me
Me
Functional group
3
manipulations
Me
R'''
Me
Me
Me
9
(>80%)
H2, [Rh(nbd)(dppb)]BF4
OAc
Me
a. Ac2O, py
b. PPTS, HO
11
Me
H
O
H
Me
Me
I PPh3
14
Me
Me
OAc
Me
Me
OTIPS
15
OH
OTIPS
O
O
Me
H
Me
10
O
H
Me
H
O
a. 1,4-butanediol,
NaH
Cl
13
b. Ph3P, I2,
imid.
Me
c. Ph3P
H
(>90%)
OAc
H
OH
Me
O
NaHMDS
(>95%)
OH
Me
c. Dess-Martin [O]
(85%)
OTIPS
12
Me
OTIPS
OTIPS
15
a. NaOMe
b. LG
c. TBAF
Me
(>81%)
R1
16
O
Me
R1
R1
Me
a. LG
R3
HO
Me
20
R3
19
Me
O
Me
21
R4
R1
d. CSA,
HO
Me
OH
(49-73%)
c. LG
25
or
DCC, 4-DMAP,
H2N
Me
17
a. (PhO)2P(O)N3,
DEAD, Ph3P
b. Ph3P, H2O
a. Dess-Martin [O]
b. NaClO2
c. DEAD, Ph3P,
HO
(42-86%)
R2
Me
18
b. PPTS,
O
H
Me
Me
R2
R5
d. PPTS, HO
R4
R1
22
R3
R3
26
O
Me
23
Me
(46-70%)
O
Me O
24: X = O, N
ed
evidence for their hypothesis through synthetic studies
culminating in the synthesis, albeit in low yield, of keramaphidin B (Scheme 45; see p. 93). The synthesis reported by
[219]
88
H
Me
R4
R3
H
Me
Me
27
R3
HN
R5
REVIEWS
REVIEWS
a)
K. C. Nicolaou et al.
Me
H
O
Me
O H
Lactonization
Me
H
OH
Lactonization H O
H
H
O Me
F
HO
H
H
TPSO
OH
HO
OH
TBDPSO
4: D-mannose
Ph
EtS
OBn
Ph
PPh3I
11
SEt
12
TBDPSO
H
H
(74%)
Ph
H
O Me
[acting as
Lewis acid and
nucleophile]
O
O
AlMe3
TBDPSO
Me
OH
HO
12 steps
OH
BnO
(18%)
Me
C
OH
HO
D
O
e. Ac2O, 4-DMAP
f. TFA
(91%)
O
H
22
Me
e. (+)-DET, Ti(iPrO)4
tBuOOH
f. SO3py
g. CH2=PPh3
OBn
I
TBSO
a. TBAF
b. PPTS
c. O3; NaBH4
d. PPTS,
Me2C(OMe)2
e. TBAF
(76%)
TBDPSO
a. SO3py, DMSO
b. MeO2C PPh3
Me
f. K2CO3, MeOH
g. TPAP, NMO
h. EtSH, Zn(OTf)2;
d. H2, Pd(OH)2/C
e. TBSOTf
PPTS
i. SO3py, DMSO
Me
a. Zn(OTf)2, EtSH
b. TBSCl
c. Ac2O
MeO2C
BnO
17
EtS
Me
H
TBDPSO
Me
Me
B
(65%)
Me
Me
B
OH
PivO
Me
H
OAc
D
H
23
Me
H H
O
OH
H
a. TPAP, NMO
b. Ph3P=(CH2)3CO2Me
O
H
Me
H
c. [{Ph3PCuH}6] TBDPSO
(65% overall)
H
TBDPSO
B
OH
H
TrO
Me
H H
O
D
H
OH
OH
H
Me
a. CH2=C(OMe)CH3, POCl3
b. Al2O3
H
TBDPSO
c. MsCl
d. Ph2PLi; H2O2
TrO
(78%)
Me
Me
Me
OH
D
H
Me
H
O
Me
O H
O
H
H O
H
OH
H
a. (PhO)2P(O)Cl,
KHMDS
b. nBu3SnCH=CH2
c. O2, hv
Me
Me
H
[reductive TBDPSO
cleavage of
endoperoxide]
OH
H
OH
H
PivO
a. nBuLi, 3
PPh2
Me
H
O
O
O
H
O
H
25
OMe
(49%)
Me
O H
B
O
H
H
TrO
H O
H
Me
H
OH
F
HO
H
1: brevetoxin A
H
O Me
G
H
I
H
H
TBDPSO
O
MeO
O
H
H O
H
Me
H
OH
D
E
F
HO
H
30
OH
EtS
29
Me
O H
OH
J
H
EtS
Me
c. CH2=N(Me)2I
[Eschenmoser's salt]
(52%)
Me
H
OH
24
D
O
19
Me
H
TBDPSO
OH
(69%)
SnMe3
26
Me
H H
O
a. HFpy
b. Dess-Martin [O]
(94%)
Me
a. KHMDS, (PhO)2P(O)Cl
b. Me3SnSnMe3, [Pd(Ph3P)4]
a. H2, [RhCl(Ph3P)3]
b. H2, 10% Pd/C
18
Al(Hg)
O
Me
28
OH
Me
H
O
PivO
Me
O
OTBS
Me
O
H
OH
H
TBSO
H
HO
Me
D
H
20
Me
a. TBSCl, imid.
b. TPAP, NMO
27
PivO
G
H
Me
c. LiOH
OH d. 2,4,6-Cl C H COCl
3 6 2
PivO
[Yamaguchi lactonization]
Me
Me3Sn
H
TBDPSO
OH
(70%)
Me
(70%)
OBn
TBSO
Me
Me
(70%)
a. DIBAL-H
b. TrCl4-DMAP
c. TPAP, NMO;
DIBAL-H
OHC
H
EtS
O Me
c. 2,4,6-Cl3C6H2COCl
d. HFpy
e. [PhC(CF3)2O]2SPh2
OBn CO2Me
nBuLi; Cu-CCnPr
TfOCH2CH2OBn
OBn
a. LiOH
b. Li, NH3 (l)
OTBS
D
H
TBDPSO
21
a. PivCl, 4-DMAP
c. CSA, MeOH
d. TrCl4-DMAP
Me
H
O
(48%)
Me
Me
C
OH
BnO
Me
Me
OTBDPS
TBDPSO
c. IZn(CH2)2CO2Me,
[Pd(PPh3)4]
(68%)
Me
14
(65%)
OTBS
OBn
a. Hg(OAc)2;
Li2[PdCl4], CuCl2,O2
OTBS
16
a. hexylborane;
H2O2, NaOH
b. TBDPSCl, imid.
c. H2, Pd/C
OMe
d. PPTS,
OMe
Me
15: D-glucose
H
TBDPSO
(94%)
OH
Epoxide opening
TBDPSO
13
TBDPSO
O 2
OBn
H
O SEt H O H
a. PPTS, MeOH
OBn
b. TBSCl, imid.
Me H
H
H
O
O
c. TPAP, NMO
Me
I
H
J
d. EtSH, BF3Et2O
O
O
O
e. SO3py, DMSO
H
H
H
(73%)
9
OBn
10
a. TBAF
Ph
b. AgClO4, NaHCO3
c. mCPBA
[hydroxy dithioketal
cyclization]
EtS
EtS
(55%)
TBDPSO
HO
EtS
nBuLi
(88%)
OMe
H
Me
O
a. 9-BBN; H2O2
b. SO3py, DMSO
c. MeO C PPh
2
3
d. DIBAL-H
OTBS
TBS
SEt
TBSO
(86%)
H
O
OHC
OBn
[6-endo hydroxy
epoxide cyclization]
(17%)
OH
Epoxide opening
PPh2
bis-Lactonization
OBn
TESO
15 steps
OH
OH
Me
H
O
1: brevetoxin A
b)
Me
TrO
Me
Horner-Wittig coupling
Dithioketal cyclization
HO
Dithioketal cyclization
Conjugate addition
H
O Me
G
H
I
H
OTBS
H
O Me
a. AgClO4, NaHCO3
b. mCPBA
c. BF3Et2O, Et3SiH
d. Dess-Martin [O]
e. NaClO2
f. CH2N2
OTBS
H
H
OTBDPS
TBDPSO
(48%)
Scheme 42. a) Strategic bond disconnections and retrosynthetic analysis of brevetoxin A, b) total synthesis (Nicolaou et al., 1998),[212] and c) key synthetic
methodologies developed in the course of the total synthesis (Nicolaou et al., 1998).[212]
90
REVIEWS
Ph
H
O
O
H
Ph
H
O
O
H
(75%)
H
O
O
H
P(OPh)2
O
SnMe3
H
O
tri-n-butyl(2-ethoxyvinyl)tin
[Pd(PPh3)4], LiCl
(81%)
tri-n-butyl(1-ethoxyvinyl)tin
[Pd(PPh3)4], LiCl
(84%)
Ph O
H OEt
O
O
H
Ph
nBu3Sn
Ph O
[Pd(PPh3)4], LiCl
O
H
(96%)
Ph
hexamethylditin
[Pd(PPh3)4], LiCl
O
OTBS
(90%)
Ph
Ph
KHMDS
(PhO)2POCl
H
O
O
H
Me3Sn
O
OTBS
Ph
H
O
O
H
OEt
O
Ph
O a. KHMDS,
(PhO)2P(O)Cl
O
H
Ph
H
O
O
Ph
b. nBu3SnCH=CH2,
[Pd(PPh3)4]
H
OH
O
H
b. H2,
Lindlar's
cat.
O
O
H
H
OH
a.
H
OH
F
HO
H
G
H
OH
H
O
O
a. O2, TPP Ph
O
H
H
HO
AgClO4
Ph
H
O
H H
O
b. Ph3SnH, AIBN
O
H
H EtS
OH
EtS
S
O
1,4-diiodobutane
THF,
S O
O
O
O
Li
O
H
H
O
O
H
N
Boc
N
Boc
a. Me3SiCH2MgCl
Ni0
h. PhZnBr
0
Pd
g. Et3Al, Pd0
N H
Boc
f. nBu3Sn
Pd0
N
Boc
N
R
SiMe3
N CO Me
2
CO2Ph
Pd0
b. CO,
MeOH
O
O P(OPh)2
Pd0
N
Boc
d. Me3SnSnMe3
Pd0
e. Me3Si
CuI, Pd0
N SnMe
3
Boc
N
Boc
SiMe3
c. nBu3Sn
O
H
91
REVIEWS
K. C. Nicolaou et al.
Scheme 43. a) Strategic bond disconnections and retrosynthetic analysis of resiniferatoxin and b) total synthesis (Wender et al., 1997).[210]
one-carbon
homologation
of
hindered
aldehydes
(Scheme 49 d, bottom);[235] and 6) the daring and counterintuitive conversion of the structurally robust CP molecule 1
into its hydrated CP derivative 2 passing through a multiplycharged intermediate in yet another cascade sequence.[230] The
total synthesis of the CP molecules stands as an instructive
example of how total synthesis can act as a driving force for
the discovery and development of new concepts and methods
in chemistry.
Aspidophytine (1999)
For over 25 years aspidophytine (1 in Scheme 51; see p. 101)
has remained an unanswered challenge for organic synthesis.
Best known for its use as an anticockroach/insecticidal
92
REVIEWS
a)
Pictet-Spengler cyclization
NH
N
Photoaddition
SN2 Displacement
CHO
N
H
H
OH
Mannich closure
H
1: manzamine A
N
H
H
redox exchange
CHO
H
N
N
HN
HN
N
OH
H H
N
N
Boc
N
H
b)
H H
N
1: manzamin B
NH2
(99%)
BocN
[Michael addition]
N
Boc
N
HO
OH
NH3
HO
HO
BocN
HO
b)
a. pTsOH,
I
Ph3P
b. KHMDS,
CO2Me
BocN
(20% overall)
a. TBSCl
b. LHMDS,
MeOCOCN
c. NaBH4
d. MsCl
e. DBU, C6H6
(62%)
H
HO
10
CO2Me
CO2Me
OH
14
a. TBAF
b. pTsCl
H
BocN
c. TFA
d. iPr2NEt
H
e. Lindlar's cat.
(76%)
OH
BocN
CO2Me
BocN
N
H
N
H
OH
TFA, 4
N
OH
DDQ
(50%)
[Pictet-Spengler]
(58%)
H
15
OH
16
1: manzamine A
H
(0.2-0.3%)
N
N
H
H
a. DIBAL-H
b. Dess-Martin [O] (75%)
[Diels-Alder]
12
TBSO
HN
12
13
CHO
MeOH/
pH 7.3
DBU,
C 6H 6
b. Tf2O
(98%)
6
11
a. mCPBA
b. NaOMe
(69%)
(50%)
a. mCPBA
N
TBSO
TBSO
a. HCl
b. pTsCl
c. NaI
d. NaBH4
10
(77%)
BocN
N
11
CHO
N
OTHP
OH
py, AcOH
HO
O NH3
BocN
BocN
4: keramaphidin B
4: keramaphidin B
REVIEWS
K. C. Nicolaou et al.
Everninomicin 13,384-1 (1999)
a)
PictetSpengler
cyclization
N
H
N
N
Ring-closing
olefin metathesis
CO2Me
Tandem Stille/
Diels-Alder
reaction
OH
NBoc
Organolithium
addition
NH2
Wittig
2
1: manzamine A
N
H
Br
CO2Me
CO2Me
Br
O
NBoc
NBoc
NH
OTBDPS
OTPS
OTBDPS
OTBDPS
b)
NBoc
OTBDPS
Br
CO2 Na
a. LHMDS, CO2
(COCl)2;
O b. NaBH4
c. Na2CO3
(95%) TBDPSO
OH
N
Boc
CO2Me
N
CO2Me
NBoc
Br
5
+ Et3N
TBDPSO
OTBDPS
(79%)
SnnBu3
(68%) [Pd(Ph3P)4],
toluene,
MeO
OMe
H
H
O
N
a. DIBAL-H
b. Dess-Martin [O]
c. HC(OMe)3,H+ N
d.
Li
[stereocontrolled
alkyl lithium addition]
(26%)
[tandem StilleDiels-Alder]
a. CrO3
b. HCl
H
c. Swern [O]
O
d. PPh3=CH2
NBoc
[double Wittig]
(30%)
2
Cl
Ru
PCy3 Ph
MeO
[olefin metathesis
reaction]
NBoc
OTBDPS
OTBDPS
8
(67%)
MeO
OMe
OMe
[olefin metathesis
reaction]
a.
Cl
a. KOH, MeOH
b. Et3N,
10
OH
O
Cl
CO2Me
H
PCy3
Cl
OTBDPS
NH
(75%)
11
Cl
N
H
PCy3
Ru
PCy3 Ph
b. HCl
c. DIBAL-H
d. Dess-Martin [O] H
e. TFA,H
OH
NH2
1: manzamine A
f. DDQ
(ca. 5% overall)
REVIEWS
OH
HO
OH
H
N
O
O
H
N
H
NH
NHMe
N
H
HO
MeO
OAll
OH
HO
O
Cl
H
N
H
N
NH2
H
N
HO
Addition of oxygen
MeO
Atropisomerization
NO2
F
HO
NH
OMs
Cl
H
N
O
O
NO2
OAll
HO
NHBoc
O
N
H
21
OPiv
OMs b. MeOH, 55 C
[atropisomerization and
transoid to cisoid
isomerization]
[>95:5 ratio of
NHTfa
atropisomers]
Cl
H
N
O
N
H
O
NH
(P)-23
NO2
N
Br
Bn
NO2
a. nBu2BOTf, Et3N
HO
O
HO
KHMDS;
then TsN3
N3
Bn
MeO
OMe
MeO
13
N
NCS
NO2
Sn(OTf)2
MeO
F
NO2
Bn
14
25
OAll
HO
HOAt, EDC
(86%)
NH2
TMSEO
O
O
HO
O
NHDdm
16
a. EDC,
HOBt
b. Ph3P-H2O
Boc
15 O
(53%)
NO2
N
H
OBn
OBn
Boc
N
Me
O
O
O
H
H
NH
N
H
NHDdm
OH
OBn
11
TFA
Cl
a. EDC,
HOBt
b. Li2CO3
c. TFA
15
a. N2O4
HO
b. LiOOH
H
c. [Pd(PPh3)4], morpholine
N
d. Pd/C, 1,4-cyclohexadiene
e. TFA
O
H
OH
O
OMe
18
d. EDC,HOBt
e. TFA; then
TFAA
(54%, 6 steps)
MeHN
O
NH
N
H
NHTfa
OBn
NH
OMe
Cl
OH
Cl
O
H
H
N
O
N
H
H
N
O
N
H
NHMe
(24%)
HO
HO
MeO
27
NO2
NMe
N
H
OBn
OBn
BnO
(62%)
Boc
H
N
NHDdm
NHBoc
26
OH
O
H
N
MeHN
3
HO2C
Boc
NMe
Cl
Cl
H
N
O
N
H
NHDdm
OAll
HO
OH
O
H
N
HO
a. HOBt, EDC
b. TBAF
(72%)
N
H
H
N
BnO
17
H
NH
O
N
NMe
OH
O
H
N
MeHN
(46%)
Boc
HO
NO2
F
Cl
O
H
N
c)
OH
HN
12
OBn
OBn
NO2
Cl
a. Boc2O; then
HCO2H, H2O2
b. LiOOH
Bn
OMe
F
Cl
c. AllBr, Cs2CO3
d. LDA
e. LiOH
11
NH2
(65%)
BnO
10
Cl
H
N
MeHN
NHBoc
MeHN
(91%)
OMe
a. H2, Pd/C;
then Boc2O
b. LiOH
c. MeNH2,
EDC, HOBt
OH
OH
HO
O HN
MeHN
Cl
N3
H
N
OH
NHTfa
O
O HN
OH
OMs
H
N
OAll
O
OPiv
Cl
H
N
OMe
OMe
MeO
(54%)
O
HO
OMe
OMe
MeO
OMe
b)
O
OH
5
OMe
NHBoc
N
H
MeHN
a. Zn, HOAc
b. NaNO2, H3PO4,Cu2O
c. [PdCl2(dppf)]CH2Cl2,
Et3N, HCO2H
HO
d. PivCl
e. TFA; then TFAA O
(68%)
OAllyl
OMs
HO
Cl
H
N
O
NH
OTf
OBn
HO
OMe
OMe
22
Na2CO3;
then PhNTf2
MeHN
MeO
OMe
OMe
NHTfa
N
H
NH
4
MeO
MeHN
OH
MeHN
OH
O
Cl
H N
H
Cl
MeHN
NO2
OMs
H
N
(55%)
OAll
NO2
O
NH
BnO
NHBoc
O
O
OMe
OMe
19
a. NaHCO3
b. 20, HOAt, HATU, collidine
c. HFpy
HO
O
NHDdm
20
Boc
N
Me
N
H
O HN
MeHN
OH
O
OH
MeHN
MeO
NHTfa
N
H
NH
OMs
HO2C
O
O
OMe
OMe
NO2
OH
Cl
[95:5 ratio of
atropisomers]
(65%)
OBn
OAllyl
TBSO
SNAr-driven
ring closure
NHTfa
N
H
NH
MeHN
HO
VOF3, BF3Et2O,
AgBF4, TFA;
then NaHB(OAc)3
OH
O
Cl
H
N
N
H
Cl
O
NO2
NO2
Cl
NH2
OH
1: vancomycin aglycon
OH
OMe
Scheme 47. a) Strategic bond disconnections and retrosynthetic analysis of vancomycin aglycon, b) key methodology for unnatural amino acid synthesis, and
c) total synthesis (Evans et al., 1998).[223]
95
REVIEWS
K. C. Nicolaou et al.
a)
HO
HO
HO
H2N
MeO
Glycosidation
Triazene
H
NH
N
H
Cl
TBSO
O
EtO2C
NHBoc
OC(NH)CCl3
BnO
BnO
Cl
TBSO
Macrolactamization
NH
H
N
OMe
N
H
HO
OMe
OMe
HO2C
OH
nBuLi,
B(OMe)3;
then HCl
7
NHBoc
a. TMSCl, MeOH
a. MeI, K2CO3
b. Boc2O, K2CO3
b. I2, CF3CO2Ag
(84%)
NHCbz
EtO2C
NH2
Br
Br
N
Br
Br
NHDdm
Br
18
NHDdm
OMe
OMe
(53%)
19
OH
21
Boc
NMe
a. EDC,
HOBt
b. LiOH
(92%)
NH2
EtO
Cl
HO
HO
O
O
c. EDC, HOAt
HO
O
DdmHN
H
N
N
O
Boc
OH
O
Cl
H
N
O
O
TBS
23
d. TBSOTf
e. H2, Pd(OH)2/C
f. SO2Cl2
g. LiOH
(46%)
NH2
O 21
NHDdm
Cl
O
ONos
O
MeO
O
OH
OH
O 20
c.
[atropisomerization]
BnO
a. NaN3
b. SnCl2
(81%)
EtO
CO2Et
a. AD (95% ee)
b. TBSCl, imid.
c. DPPA, DEAD,
Ph3P
(66%)
Boc
NMe
N
H
BnO
MeO
N3
N
H
OTBS
O
H
N
16
Br
17
BnO
BnO
H
N
TBSO
NHBoc
HO2C
R1
O
Cl
O
H
NH
R2
O
TBSO
N
Br
NMe
N
H
OMe
30
OMe
MeO
N
Br
(52%)
22
H
N
a. Ph3P, H2O
b. Boc2O, Et3N
c. TBAF
d. TEMPO, NaOCl
H
N
24
EDC, HOAt
(86%)
Boc
15
N
HO
HO
14
OTBS
O
N
H
EtO2C 13
(61%)
OMe
OMe
OMe
29
Cl
NH2
a. NaNO2, HCl;
pyrrolidine, KOH
b. PCC
c. PPh3=CH2
(93%)
O
OH
TBSO
12
NH2
a. Br2, AcOH
b. LiAlH4
c. SO2Cl2
(76%)
HO
NH2
O
Br HO
H
N
10
Cl
a. TBSOTf
b. H2, Pd(OH)2/C
11
H
NH
BnO
OMe
, KOH
H
NH
OBn
c. AA
(41%, 87% ee)
H
N
O
9
a. BnBr, K2CO3
O
O
b.
Cl
NHBoc
OH
OH
OEt
TBSO
MeO
H
N
MeO
OMe
O
(93%)
OMe
N
MeO
OMe
MeO
BnO
MeO
B(OH)
(EtO)2
H
N
OMe
BnO
OH
a. FDPP
b. TBSOTf
c. TMSOTf
(70%)
NHBoc
Cl
(M,P)-28
NH2
(55%)
MeO
NH2
TBSO
N
Br
Br
BnO
HO
H
N
N
H
26
N
N
Cl
O
NHDdm
(75%)
(68%)
O
a. PPh3=CH2
b. AD- (96% ee) BnO
c. nBu2SnO;
then BnBr
MeO
Boc
NMe
MeO
b. TBAF
c. Et3P-H2O
d. LiOH
[1:1 mixture of
atropisomers]
(67%)
MeO
H
N
N
H
BnO
OTBS
O
Cl
H
N
b)
a. CuBrSMe2,
py, K2CO3
27
MeO
OMe
OMe
OMe
OMe
NH2
N
H
OH
N3
AllocO
EtO2C
(85%)
AcO
AcO
NHCbz
18 , EDC, HOAt
H
N
N
H
AcO
OH
Br
TBSO
OTBS
(78%)
Cl
OH
Br
13
a. EDC, HOAt
b. TMSOTf
10
NH2
OH
1: vancomycin
OH
HO
NH2
(P)-25
OMe
HO
EtO2C
OMe
OMe
I
NHMe
N
H
N3
b. (PhO)2P(O)N3,
DEAD, Ph3P (95%)
MeO
c. LiOH (99%)
OH
O
H
N
OH
TBSO
BnO
Cl
H
N
MeO
Cl
O
HO
NHBoc
Cl
NHBoc
HO
a. [Pd(Ph3P)4],
Na2CO3
(56% plus 28%
(M)-atropisomer)
OMe
O 7
O
O
O
B(OH)
OH
O
H
N
BnO
H
NH
O
H
HO
H
N
O
N
H
NHMe
HO
NMe
H
N
OH
OH
NH2
24
Scheme 48. a) Strategic bond disconnections and retrosynthetic analysis of vancomycin aglycon, b) key methodology for unnatural amino acid synthesis, and
c) total synthesis of vancomycin (1) (Nicolaou et al., 1999).[224226]
96
REVIEWS
OH
HO
O
H
N
O
O
Cl
H
N
H
NH
Cl
N
H
NH2
OH
26: vancomycin aglycon
OH
HO
c. CbzCl
(36%)
d. Al2O3KF
a. TBSOTf
b. CH2N2
OH
TBSO
Cl
OTBS
Cl
H
N
O
H
H
NH
H
N
N
H
MeO
Cbz
NMe
N
H
NH2
OTBS 27
OTBS
a. BF3Et2O
TBSO
b. nBu3SnH, [Pd(PPh3)4]
AcO
AcO
(70%)
AllocO
H
N
TBSO
O
NHMe
N
H
HO
O
O
OH
O
H
N
OC(NH)CCl3
AcO
AcO
OTBS
HO
O
O
O
O
TBSO
OTBS
Cl
H
N
O
O
O
H
H
NH
H
N
H
N
N
H
Cbz
NMe
N
H
MeO
F
Cl
NH2
OTBS 28
OTBS
TBSO
(84%)
BF3Et2O
O
NHCbz
AcO
AcO
AcO
AcO
CbzHN
OTBS
O
O
O
O
O
TBSO
OTBS
Cl
H
N
O
O
Cl
O
H
H
NH
H
N
N
H
H
N
O
N
H
Cbz
NMe
MeO
OTBS
OTBS
TBSO
NH2
29
a. HFpy c. Raney N:
b. K2CO3 d. LiOH
(65%)
HO
HO
HO
H2N
OH
O
O
O
O
HO
H
N
O
O
H
NH
HO
HO
Cl
H
N
N
H
Cl
O
NH2
OH
1: vancomycin
OH
OH
O
H
N
O
N
H
NHMe
REVIEWS
K. C. Nicolaou et al.
Scheme 49. a) Strategic bond disconnections and retrosynthetic analysis of the CP molecules (1 and 2) and b) total synthesis (Nicolaou et al., 1999).[230]
c) New cascade reactions: the anhydride cascade, which features the first use of a highly unstable 2-aminofuran in the synthesis. The g-hydroxylactonal
cascade was developed as a mild method to construct the precursor to the fused g-hydroxylactone moiety, the g-hydroxylactonal. The pyran rupture cascade
traverses through a sequence of intermediates, including the tetraanion C. d) New synthetic technologies. (For further information see the text.)
98
REVIEWS
REVIEWS
K. C. Nicolaou et al.
a)
OH
HO
O
O
O
H
N
H
NH
TBSO
OH
O
Cl
O
H
N
N
H
NHMe
N
H
MeO2C
HO
O
H
N
O
H
NH
Macrolactamization
16
OMe
OMe
MEMO
TBSO
NO2
O
NHBoc
H
N
N
H
NMe
MeO
MeO
MeO
BnO
OMe
a. Dess-Martin [O]
b. NaClO2
(76%)
HO
NHCbz
HO2C
H
NH
MeO
OMe
NO2
N
MeO
HO
OH
O
H
N
NHBoc
HO
Boc
NMe
N
H
NC
MEMO
OMe
a.
NHCbz
OMe
OMe
ZrClCp2
NO2
NO2
OH
Cl
H
N
H
N
OBn
(M,M)-16
(50%)
HO
OMe
OBn
AD, BocCl
NHCbz
H
OMEM
OMe
(M,P)-16
a. nBu4NF-HOAc
b. LiOH
c. H2, Pd/C
d. EDC, HOBt
NHBoc
O
OMe
OMe
OMe
BnO
H
N
N
H
OBn
MeO2C
NHBoc
NHCbz
b)
OMe
Cl
O
MEMO
BnO
TBSO
3:1
O
OMe
OMe
MeO
H
N
OH
120 C
Boc
N
H
HO
NC
MeO2C
OH
O
OMe
OH
Cl
O
OMe
Br
OH
Cl
H
N
(88%)
MeO
(M)-15
OMe
O
[Pd2(dba)3], (o-tolyl)3P
Na2CO3, toluene
NHBoc
B(OH)2
+
O
OH
1: vancomycin aglycon
OH
HO
NHCbz
MEMO
H
N
N
H
HO
OH
Cl
H
N
OMe
Cl
17
a. HCO2H
b. EDC, HOBt
(58%)
OH
F
TBSO
9
b. TBSOTf
O
MeO2C
(45%)
8
O
10
HO2C
NH2
NH2
HO
OH F
NHBoc
HO
Cl
H
N
a. Boc2O
b. Br2-pyHBr
c. NaH, MeI
NO2
OMe
O
NHBoc
HO
H
N
H
NH
N
H
MEMO
Br
OH
11
MeO
12
CsF, DMSO
c)
NO2
NO2
OH
HO
TBSO
OMe
OMe
F
TBSO
10
a. EDC,
HOBt
HO
O
b. TBSOTf
(79%)
NHBoc
HO
EDC,
HOBt
(91%)
MeO2C
H
N
N
H
H
N
NHBoc
O
O
Br
O
MeO2C
N
H
OMe
NO2
OH
OH
140 C
TBSO
B Br
1:1.1
NHBoc
MeO2C
N
H
Boc2O
NHBoc
Br
(M)-14 R = NO2
(M)-15 R = Cl
a. H2, Raney Ni
b. tBuONO
(87%)
c. CuCl-CuCl2
N
H
Boc
NMe
d. Dess-Martin [O]
e. NaClO2
f. TMSCHN2
(9-11%)
g. H2O2, K2CO3
h. nBu4NF-HOAc
i. AlCl3, EtSH
OH
H
N
O
Br
N
H
OH
O
H
N
OMe
19
OMe
(50-60%)
O
NC
MeO
OMe
R
H
N
Cl
H
N
NO2
MEMO
K2CO3, CaCO3
TBSO
OMe
OMe
H
NH
13
Br
12
Boc
NMe
18
OMe
OMe
OMe
NH2
N
H
NC
(43%)
MeO2C
OH
O
H
N
HO
OMe
H
N
(P)-14
O
O
H
NH
HO
HO
O
H
Cl
H
N
N
H
Cl
OH
O
H
N
O
N
H
NHMe
O
NH2
OH
OH 1: vancomycin aglycon
Scheme 50. a) Strategic bond disconnections and retrosynthetic analysis of vancomycin aglycon, b) key methodology for unnatural amino acid synthesis, and
c) total synthesis (Boger et al., 1999).[227]
100
REVIEWS
Oxidation
Cationic
cascade
reaction
NH2
CHO
OHC
O
N H
Me
MeO
OMe
+
N
MeO
Me
OMe
1: aspidophytine
b)
O
CeCl3,
THF
Br
TMS
OAc
a. R-CBS reduction
b. Na(Hg), MeOH
Br
TMS
MgBr
(82%)
OHC
b. NaIO4
Me 2
OMe
OiPr
OiPr
MeO
TMS
Me
7 OiPr
N
OiPr
OMe
TMS
(56%)
N:
a. OsO4, NMO
+
N
MeO
a. LDA, TBSCl,
-78oC, then
b. iPrOH, EDC
(57%)
CHO
NH2
MeO
TMS
MeO
Br
N H
Me
MeO
TMS
Me
OMe
OMe
H+
N
OiPr
NaOH
OH
BH3CN
OiPr
(66%)
N
MeO
OMe
Me
N H
OMe Me
MeO
MeO
OMe
N H
Me
K3[Fe(CN)6], NaHCO3
OH
O
(81%)
6. Future Perspectives
a. OsO4
b. Pb(OAc)4
O
O
(71%)
MeO
N H
OMe Me
MeO
10
N H
OMe Me
11
N
O
MeO
OMe
H
Me
12
a. KHMDS,
PhNTf2
b. [Pd(PPh3)4],
nBu3SnH
(47%)
MeO
N H
OMe Me
1: aspidophytine
REVIEWS
K. C. Nicolaou et al.
Scheme 52. a) Strategic bond disconnections and retrosynthetic analysis of everninomicin 13,384-1 and b, c)important synthetic methods; b) orthoester
formation by 1,2-migration of the phenylselanyl group followed by glycosylation (I !II !III !IV), and ring closure after syn-elimination
(V !VI !VII !VIII); c) stereoselective construction of 1,1'-disaccharides; d) synthesis of the building blocks and completion of the total synthesis of
everninomicin 13,384-1 (Nicolaou et al., 1999).[245]
102
REVIEWS
NH
a. TMSOTf
b. MeI, NaH
c. NaOH, MeOH
d. BnBr, NaH
(55%)
OMe
O
OBn
OAll
F
OBn
PhSe
OH
O
OMe
TIPSO
OCA
Me
Me
OMe
OH
MeO
O
PMBO
HO
OPMB
41
OMe
OR
O
OMe
HO
HO
MeO
O
Me
O
F
O
OMe
TBSO
OBn
OPMB
a. CH2Br2, NaOH
(66%) b. DDQ
c. NaH, ArC(O)F
d. nBu4NF, THF
OBn
O
F
MeO
O
CAO
O
OMe
TBSO
H
O
HO
OPMB
Me
Me
SPh
D
O
Me
OPMB
MeO
O
O
D
HO
O
OTBS
Me
Me
Me
Me
Me
PMBO
D
HO
Me
MeO
O
O
OTBS
OTIPS
Me
OTIPS
BnO
OTBS
D
Me
A2
OTBS
Me
O
OMe
A2
O O
TBSO
OTBS
OTBS
Me
O A
Me
O
O
Me
A2
O O
TBSO
OTBS
OTBS
O
F
OTBS
OTBS
OTBS
O
O
OMe
Me
O
O
A2
O O
TBSO
OTBS
OTBS
Me
MeO
O
O
D
C
HO
55
O
OMe
OMe
O
O
Me
(75%)
Me
O
O
O
a. NaIO4, MeOH
b.
OMe
Me
NO2
O
OAc
HN
Me
Me
OMe O
MeO
O
Cl
BnO
Me
Me
O O
OTBS
O
OTBS
(65%)
OMe
54
Me
O A
HO
O
OAc
OTBS
O
Me
Me
Me
A1
HO
Me
TBSO
OTBS
OTBS
OMe
Cl
OTBS
Me
MeO
O
O
O
H
O O
NO2
Me
Cl
PMBO
D
HO
SePh
Me
O
A1
46
a. LiI, DMF
b. nBu3SnH (53%)
c. nBu2SnO;
PMBCl
Me
O
OMe
MeO
O
BnO
OMe O
Cl
OTBS
47
a. nBu4NF
b. Ac2O
(69%)
c. nBuNH2
d. CCl3CN
OMe
Me
Me
O
Cl
O
OTBS
BnO
Me
D
OH
OTBS
MeO
O
F HO
OTBS
HO
OTBS
45
MeO
O
HO
OTBS
Me
Me
HO
A2
O O
OMe
Me
OMe O
OTIPS
pTs O
NO2
O A
a. TPAP, NMO
(74%) b. MeLi, Et2O
c. H2, 10% Pd/C
d. pTsCl, py
Me
a. TBSOTf
b. K2CO3, MeOH
Cl
a.Tf2O,
2,6-tBuPy
b. DDQ
(70%) SnCl , Et O
2
2
OH
(67%)
OTBS
SePh HO
BnO
Me
OTBS
26
Me
O
OMe
OMe
Me
O
C
Me
BnO
A1
O
O
O
OH
Me
O
OTIPS
MeO
23
Ph
OH
Me
OTBS
OBn
A1
44
Ph
OH
HO
Cl
A2
DDQ
(CA)2O, Et3N
OH
MeO
O
HO
O A
Me
BnO
D
H
OBn
OH
OMe O
OBn
O
O
H
O O
OMe
(55%)
A2
BnO
O
OMe
(78%)
Me
O
O
53
OBn
OBn
K2CO3, MeOH
OBn
Cl
O
OMe
HO
Me
Me
O
BnO
OBn
OBn
Me
OBn
A2
O O
OBn
OPMB
42
OMe
Me
43
OMe
Me
O
OMe
a. Dess-Martin [O]
b. Li(tBuO)3AlH
c. NaOH, MeOH
O
O
50: R = PMB
51: R = H
52: R = CA
OBz
OMe
(73%)
OBn
OBn
HO
A2
BnO
OBn
(90%)
HO
OBn
OMe
OR
OBn
O
a. TBSCl, NaH
(54%) b. OsO , NMO
4
c. nBu2SnO; BzCl
OBn
O
Me
a. nBu4NF, THF
b. Martin
sulfurane
c. K2CO3, MeOH
Me
48: R = Ac
49: R = H
40
OTBS
OBn
39
a. 34, SnCl2,
Et2O
b. K2CO3,
MeOH
O
O
(55%) BF3Et2O
Me
O
OMe
NH
RO
OBn
OBn
OPMB
O
OMe
O
OMe
HO
OAc
Cl3C
BzO
OTBS
OAc
O
Me
OBn
O
OBn
OMe
OBn
OBn
O
OMe
O
31
(69%)
a. NaIO4, MeOH
b.
TIPSO
c. nBu4NF
d. BzCl, E3N
(75%)
OBz
Me
MeO
O
PMBO
OAll
a. DDQ
b. TIPSOTf
c.[RhCl(Ph3P)3]; OsO4
d. nBu2SnO; CACl
Me
CCl3
HO
AllO
28
OMe
nBu
OBn
38
OMe
Sn
PMBO
OAll
O
OMe
PMBO
nBu
OBn
O
MeO
Me
OH
OMe
OH
O
F
O
O
OH
O
O
OMe
Me
O
H
O O
HO
A2
OH
OH
NO2
Me
OMe
1: everninomicin 13,384-1
CCl3
103
REVIEWS
K. C. Nicolaou et al.
Scheme 53. a) Strategic bond disconnections and retrosynthetic analysis of sanglifehrin A and b) total synthesis (Nicolaou et al., 1999).[240]
REVIEWS
O
Me
O
H
Me
HO
quinine
[Woodward, 1944]
[Gates, 1970]
[Uskokovic, 1970]
[Taylor, 1972]
[Hanaoka, 1982]
HN
Me
NH
[Gates, 1952]
[Ginsburg, 1954]
[Morrison, 1967]
[Kametani, 1969]
[Schwartz, 1975]
[Rice, 1980]
[Evans, 1982]
[Fuchs, 1987]
[Parker, 1992]
[Overman, 1993]
[Mulzer, 1996]
MeO2C
[Woodward, 1954]
[Julia, 1969]
[Ramage, 1976]
[Oppolzer, 1981]
[Rebek, 1984]
[Ninomyia, 1985]
OMe
HO
MeO
OH
estrone[358]
colchicine
H
Me
H Me
H
lupeol[360]
O
O
[Stork, 1971]
N
N
H
MeO2C
H 2N
O
HN
OH
N
MeO
R = Me: vinblastine[375]
R = CHO: vincristine[375]
H H
N
OAc
NH
HN
CO2Me
NH
OH
OH
Me
HO
HO
O
NH2
H
OMe
N
Me
cytochalasin B
[Stork, 1978]
Cl
MeO
Me
Me
Me
Me
MeO
N
HO H
Me
H
Me
O
N-methylmaysenine[373]
[Corey, 1978]
[Meyers, 1979]
[Isobe, 1984]
HO
Me
Me
Me
Me
OH
fumagillol
illudol[368]
[Matsumoto, 1971]
[Semmelhack, 1980]
[Vollhardt, 1991]
[Malacria, 1997]
OH
OMe O
OH
O
OH
OH
[361]
MeO
N
Me
OAc
CO2Me
vindoline[363]
Me
OH
daunomycinone[362]
[Bchi, 1975]
[Kutney, 1978]
[Ban, 1978]
[Danieli, 1984]
[Langlois, 1985]
[Rapoport, 1987]
[Kuehne, 1987]
[Wong, 1973]
[Hauser, 1981]
[Kende, 1976]
[Kimball, 1982]
[Swenton, 1978]
[Reddy, 1983]
[Kelly, 1980]
[Vogel, 1984]
[Kallmerten, 1980] [Rodrigo, 1984]
[Braun, 1980]
[Garland, 1988]
NH2
H Me
Me
thienamycin[371]
Me
HO
H
quassin[380]
[Grieco, 1980]
[Watt, 1990]
[Valenta, 1991]
[Shing, 1998]
H
MeO
aphidicolin[377]
[Trost, 1979]
[McMurry, 1979]
[Corey, 1980]
[Ireland, 1981]
[van Tamelen, 1983]
[Bettolo & Lupi, 1983]
[Tanis, 1985]
[Holton, 1987]
[Fukumoto, 1994]
[Iwata, 1995]
hirsutene[374]
OMe
MeO
Me
CO2H
ryanodol[376]
[372]
[Kishi, 1977]
[Fukuyama, 1987]
OH
H
OH
OH
OH
NH
Me
NH
Me
[Barton, 1962]
[Kametani, 1969]
[Koga, 1977]
[Corey, 1970]
[Mander, 1980]
[Yamada, 1989]
[Corey, 1972]
[Kim, 1997]
[Sorensen, 1999]
[Taber, 1999]
OH
galanthamine[357]
N
OMe O
CO2H
OH OH
HO HO
MeO
gibberellic acid[366]
OH
H H
[Kishi, 1977]
[Jocobi, 1984]
OH
Me
Me
OH
saxitoxin[370]
[Potier, 1976]
[Yamada, 1972]
[Inubushi, 1974]
[Kende, 1974]
[Roush, 1978]
[Martin, 1991]
[Williams, 1992]
[Uesaka, 1994]
[Sha, 1997]
OH
O
Me
Me
Me
dendrobine[367]
[Woodward, 1962]
[Muxfeldt, 1965]
Me
HO
[Harley-Mason, 1968]
[Saxton, 1969]
[Schlessinger, 1976]
[Winterfeldt, 1979]
[Takano, 1985]
[Fuji, 1987]
Me
H
Me Me
OC
eburnamine[382]
HO
OH
OH
O
HO
[Inubushi, 1969]
[Kametani, 1972]
[Wallace, 1979]
[Schultz, 1998]
Me
cepharamine[359]
H
Me
MeN
biotin
[Review[364]]
[Quinkert, 1980]
[Torgov, 1963]
[Bryson, 1980]
[Smith, 1963]
[Saegusa, 1981]
[Johnson, 1973]
[Ziegler, 1982]
[Cohen, 1975]
[Jung, 1984]
[Danishefsky, 1976]
[Money, 1985]
[Kametani, 1977]
[Posner,
1986]
[Oppolzer, 1980]
[Rao, 1991]
[Vollhardt, 1980]
[Oyasawara, 1992]
[Grieco, 1980]
[355]
[Echenmoser, 1961]
[van Tamelen, 1961]
[Nakamura, 1962]
[Scott, 1965]
[Woodward, 1965]
[Martel, 1965]
[Kaneko, 1968]
[Tobinaga, 1974]
[Kato, 1974]
[Evans, 1981]
[Boger, 1986]
[Magnus, 1987]
[Banwell, 1992]
[Cha, 1998]
MeO
CO2H
OH
6-demethyl-6
-deoxytetracycline[356]
NHAc
yohimbine[354]
H
S
OH
NH2
OH
lysergic acid[353]
NMe2
MeO
HO
H
H
morphine[352]
NH
OMe
MeO
HO
Me O
H
Me
N
H H
[Woodward, 1951]
[Sarett, 1952]
[Kuwajima, 1986]
[Fukumoto, 1990]
[350]
HO2C
cortisone[351]
HO
H
H
MeO
OH
OH
OH
HO
[Hua, 1985]
[Tatsuta, 1979]
[Cossy, 1987]
[Hudlicky, 1980]
[Lacroix, 1989]
[D. R. Little, 1981]
[Sternbach, 1990]
[Mehta, 1981]
[Greene, 1990]
[Magnus, 1981]
[Rao, 1990]
[Wender, 1982]
[Paquette, 1990]
[Ley, 1982]
[Cohen,
1992]
[R.D. Little, 1983]
[Fukumoto, 1993]
[Curran, 1983]
[Oppolzer, 1994]
Me
CHO
OMe
HO
N Me
Me
O
MeO H
O
OMe
delphinine[378]
[Wiesner, 1979]
HO
O
OAc
NMe2
O
Me
OH
O
carbomycin B[383]
Me
O
Me
[Nicolaou, 1979]
[Tatsuta, 1980]
of this art and science, and of its potential for further advances
and contributions. For one, nature has not yet finished
revealing its secrets to us, and many more novel, and presently
unimaginable, structures are destined to dazzle our eyes,
boggle our minds, and challenge our creativity. Furthermore,
the state of the art is comparatively only in its early stages of
development in light of natures seemingly magical and
powerful biosynthetic schemes. To be sure, the competitive
nature of the pharmaceutical and biotechnology industries
and their drive to discover and produce new cures for disease
Angew. Chem. Int. Ed. 2000, 39, 44 122
REVIEWS
K. C. Nicolaou et al.
Me
OH
Me
Me
Me
Me
Me H
OH
coriolin[379]
MeO
Me
Me
Me
O
O
O
Me HO
N
H
N
NH
rifamycin S[387]
N
H
O
OH
O
[385]
Me
NH2
OH
HO
HO
[Kishi, 1985]
[Stork, 1990]
[Holmes, 1999]
N
H
cyanocycline
Me
daphnilactone A[399]
[Heathcock, 1989]
Me
O
HO
[Kishi, 1989]
Me
H
H
Me
Me
O
O
Me
OH
[Smith, 1989]
N
O
NH
Me
N
FK506[401]
[Merck, 1989]
[Schreiber,
1990]
[Danishefsky,
1990]
[Sih, 1990]
[Smith, 1994]
[Ireland, 1996]
CC-1065[396]
[Kelly, 1987]
[Boger, 1988]
H
N
H H
NH2
Me
O
H
H
Me
H H
huperzine[400]
NH
ikarugamycin[397] O
[Kozikowski, 1989]
Me
OMe
OMe
Me
Me
OH
O
OMe
OH
N
H
OH
O
H
O
NH
Me
echinosporin[388]
O
O
OMe
Me
CONH2
O
Me
OH
OH
MeO
Me
[Inoue, 1986]
ophiobolin C[392]
HO
H2N
Et
MeO
OH
O
Me
neosurugatoxin[390]
O
HO
Me
[Corey, 1982]
[White, 1986]
[Nakata & Oishi, 1986]
[Matsumoto, 1987]
NH
fredericamycin A[393]
Me
H
Me
H
N
OH
OH
O
O
H
N
OMe
H
OHC
H
O
aplasmomycin[384]
OH
A[386]
Me
[Hanessian, 1986]
[Ley, 1990]
Me
[White, 1995]
HN
[Evans, 1986]
[Fukuyama, 1987]
OH
Br
HO
Me
O
Me
Me
O
Me
Me
O
B
MeO
HO
Me
OH HO
O
HO
histrionicotoxin[402]
[Ohno,1982]
[Hecht, 1982]
[Boger, 1994]
[Danishefsky, 1987]
HN
bleomycin A2
OH
CN
H
Me
Me
O
[Gibbons, 1982]
[Boeckman, 1989]
[Fukuyama, 1990]
[Myers,1998]
[Corey, 1999]
ClSMe2+
HO
O
MeO
pleuromutilin[391]
N
H
OH
OH
OH
Me
Me O
[381]
Me
[Sih, 1981]
[Hirama, 1982]
[Girotra, 1983]
[Grieco, 1983]
[Heathcock, 1985]
[Keck, 1986]
[Kozikowski, 1987]
[Clive, 1988]
[Danishefsky, 1989]
[Burke, 1991]
[Hagiwara, 1995]
[Kishi, 1980]
[Hanessian, 1982]
NH
Me
Me
compactin[389]
Me
H H
N
NH
N
H
HO
O
Me
OMe
Me HN
H
Me
Me
R = CN: saframycin A
OH
Me
NH2
OH
R = H: saframycin B[381]
NH2
H2 N
HO
[Fukuyama, 1982]
[Kubo,1987]
H
N
Me
OH
Me
Me
[Isoe, 1984]
[Iwata, 1985]
[Wender, 1985]
[Piers, 1985]
[Funk, 1986]
[Magnus, 1987]
[Liu, 1988]
[Little, 1990]
NHCOCOMe
R
Me
H
N
HO
OH
OH
[Danishefsky, 1980]
[Helquist, 1981]
[Burke, 1982]
[Kende, 1982]
[Schlessinger, 1983]
[Vandewalle, 1983]
[Yoshii, 1983]
[Smith, 1984]
OH
quadrone[365]
[Danishefsky, 1980]
[Ikegami, 1980]
[Tatsuta, 1980]
[Trost, 1981]
[Mehta, 1982]
[Matsumoto, 1982]
[Magnus, 1983]
[Koreeda, 1983]
[Wender, 1983]
[Schuda, 1984]
[Funk, 1985]
[Little, 1985]
[Demuth, 1986]
[Curran, 1988]
[Weinges, 1993]
[Kuwajima, 1997]
NH2
Me
H
O
Me
MeO
Me
AcO
[Boeckman, 1989]
[Paquette, 1989]
O
O
H
N
H
koumine[398]
[Magnus, 1989]
and forthcoming. Indeed, automation technologies are already entering the realm of chemical synthesis laboratories.[281] Finally, a goal of paramount importance for the
ensuing century will undoubtedly involve the development of
synthetic strategies for the rapid construction of complex
natural products that rival or even surpass the efficiency of
nature.
In addition to natural products and their analogues,
synthetic chemists are also beginning to target complex and
exotic natural productlike structures for the purpose of
biological screening.[282] Such endeavors are clearly related
to total synthesis and are both inspired and facilitated by
advances in the latter field. Particularly enabling are those
contributions that include both new synthetic technologies
and novel molecular architectures. Examples of such endeavors include those from the Schreiber group,[283a] Sharpless
group,[283b] and our own[283c] (Figure 9; see p. 108).
In closing, in surveying the art and science of total synthesis
of the twentieth century, one is left with awe at its accomplishAngew. Chem. Int. Ed. 2000, 39, 44 122
REVIEWS
N
H
OH
OH
O
OH
HO
O
paspalinine[403]
OH
H2N
Me
H2N
O
OMe OH
[Smith, 1990]
isorobustin[405]
N
O
O H OH
O
H
OH
OH
OH
Me
Me
N
H H
Me
HO
H
OH
ambruticin[408]
O Me
Et
[Kende, 1990]
isorauniticine
halichondrin
Me
O
H
H
B[413] O
Me
Me
Br
OH
N
H
Me
MeO
Me
OH
N
Me
thebainone A[424]
HO
OH
Me
OCONH2
[Tius, 1992]
O
H
N
Me
NMe2
Me
OH
Me
Me
O
discodermolide[416]
lepicidin A[417]
[Evans, 1993]
OMe
Me
HO
OMe
OMe
H
OH
chlorothricolide
magellanine[431]
Cl
O
HN
HN
O
N
H
H
O
Me
H 2N
epoxydictimene[437]
H2N
[Schreiber, 1994]
(CH2)14
ptilomycalin[445]
[Overman, 1995]
[Overman, 1993]
[Ziegler, 1995]
Me
NHMe
[Danishefsky, 1995]
[Wood, 1997]
nPent
OH
Me
H
H
H
H
Me
staurosporine[435]
OH
O
O
Me
[Barrett, 1994]
[Weinreb, 1994]
MeO
OH HO
[Heathcock, 1994]
Me
Me
H
Me
HH
HO
H
Me
H
petrosin[421]
papuamine[420]
H
N
[Terashima, 1994]
[Boger, 1996]
stenine[418]
[Hart, 1993]
[Wipf, 1995]
H
OBz
O
duocarmycin A[427]
O
Me
HO
H H
N
[Roush, 1994]
O
N
H
N
H
HO2C
H H
N
[423]
NH
H
H
Me
OMe
O
MeO2C
OH
[Coleman, 1994]
calphostin A[429]
H
Me
Me
HH
OMe
OH
[Overman, 1993]
Me
OCOPh
Me
H
H
Me
[Williams, 1993]
Me
OCOPh
MeO
Me
[Armstrong, 1998]
MeO
[Nicolaou, 1992]
[Yamamoto, 1995]
[Nakata, 1996]
[Mori, 1997]
OMe
member of the
clavularanes[434]
OH
Me
HO
H
O
OH
O
H
H
hemibrevetoxin B[414]
OH
[Evans, 1992]
[Shioiri, 1996]
[Masamune, 1994] [Smith, 1998]
Me
Me
OMe
OMe
R = H: calyculin A (ent)[415]
OH
CO2H
HO
Me
OH
CO2Me
Me
H
O MeO
isochrysohermidin[426]
H
H
HO P
O
MeHO
Me
OH
Me
O
Me
Me
Me
MeO2C
Me
Me
[Schreiber, 1993]
[Smith, 1995]
[Myles, 1997]
[Marshall, 1998]
OMe O
HO
Et
OH
CN
Me
[Kita, 1992]
Me
O
myrocin C[412]
[Danishefsky, 1992]
Me
O
OH
HO
discorhabdin C[425]
H
O
Me
H
N
H
NMe2 OH
N
H
Me
[Smith, 1991]
Me
OH
breynolide[422]
Br
OO
[Kishi, 1992]
Me
HO
Me
OAc
[Dauben, 1991]
rocaglamide[409]
O
HH
HO
kempene-2[411]
O
O
Me
HO
HO
H
O
CON(Me)2
OMe
O
HO
OH
Ph
HO
Me
Me
[Oppolzer, 1991]
Me
HO
Me
[410]
OH
[Trost, 1990]
[404]
[Danishefsky, 1990]
MeO2C
OMe
MeO
O
[Grieco, 1990]
indolizomycin
Me
Me
H
O
Me
[Schreiber, 1990]
H
Me
chaparrinone[407]
Me
hikizimycin[406]
CO2Me
OMe
OH
OH
N
H
OH
NH2
HO
[Barton, 1990]
HO
OH
Me
HO
O
AcO
7-deacetoxyalcyonin
acetate[438]
[Overman, 1995]
O
O
N
H
HN
OH
balanol[419]
[Nicolaou, 1994]
[Hu, 1994]
[Adams, 1994]
[Stadlwieser, 1996]
[Tanner, 1997]
[Naito, 1997]
OCONH2
OH
OH
syringolide 1[439]
[Wood, 1995]
[Kuwahara, 1995]
[Murai, 1996]
[Sims, 1997]
[Yoda, 1997]
[Wong, 1998]
OHC
NH
FR-900482[441]
[Fukuyama,1992]
[Danishefsky, 1995]
Abbreviations
AA
Ac
acac
AD
AIBN
All
Alloc
9-BBN
asymmetric aminohydroxylation
acetyl
acetylacetonyl
asymmetric dihydroxylation
2,2'-azobisisobutyronitrile
allyl
allyloxycarbonyl
9-borabicyclo[3.3.1]nonane
107
REVIEWS
K. C. Nicolaou et al.
Me
Me
O
O
OH
OH
FR-90848
[Barrett, 1996]
[Falck, 1996]
O
H
N
H
Me
Me
Me
Me
HO
HO H
rubifolide
[456]
[Corey, 1997]
[Robichaud, 1998]
[Danishefsky, 1998]
[Yamada, 1999]
AcO
H
Me
Me
OH
Me
AcO
Me
Me
OH
HO
Me
O
OH
Me
O HO
O
X = Cl: spongistatin 1
[453]
X = H: spongistatin 2
[454]
OH
H H
N
O O
MeO
[Boger, 1999]
preussomerin I[446]
HO
[Heathcock, 1999]
[Roush, 1999]
OH
Me
N
Me
N
H
O
O
Me AcO
N
H
O
N
OH
[Taylor, 1999]
Me
Me
N
OH
N
O
luzopeptin B[452]
O
manumycin B[448]
OAc
H
N
OH
olivomycin A[450]
AcO
Me
MeO
Me
[Evans, 1998]
NH
O
H
O
OH
OMe
Me
HO
OH
O
[Kishi, 1998]
OH
H
O
OMe OH
Me
O
OH H
Me
phorboxazole A[449]
Me
iPrO2C
HO
OH
HO
H
Me
[Forsyth, 1998]
Me
OH
nBu
O
Me
[Romo, 1998]
Me
H
OH
Me
HO
OH
pateamine[444]
Me
H
N
Me
OH
Br
[Kishi, 1998]
Me
7[455]
OMe
Me
H2N
OMe
batrachotoxinin A[439]
Me
[Fuchs,1999]
Me
NMe2
cephalostatin
OAc
[Myers, 1998]
O
O
HO
OH
Me
[Kishi,1998]
[432]
OH
neocarzinostatin
chromophore[447]
Me
HO
[458]
[Paquette, 1997]
O
O
HO
MeO
Me
HO
pinnatoxin A (ent)
H
Me
HO
O
Me
Me
HO
Me
Me
N
OH
Me
salsolene oxide
Me
Me
Me
CO2
Me
Me
OH
OH
OH
Me
[Marshall, 1997]
dysidiolide[451]
MeO
Me
O
O
Me
O
HO
HN
Me
Me
[Danishefsky, 1997]
[Overman, 1998]
Me
HO
NMe2
hispidospermidin[443]
Me
Me
N
HN
Me
O
Me
Me
OH
lubiminol[442]
[Crimmins, 1996]
Me
OH
[Baldwin, 1996]
H
N
[Martin, 1996]
Me
CH2OH
O
N
trichoviridin[428]
croomine[433]
Me
NC
H O
O
HN
[436]
OH
N
H H
HO
O
OMe
OH
diepoxin [457]
[Wipf, 1999]
X1
R1
NH
R2
N
O H
N
R4
R1
R
R2
R5
R2
R3
R1
R4
R
X1 = O, S; X2 = CR2, O, NR
2X
R5
BOP
X1
X2
7-8 steps
2 steps
Schreiber (1998)
Nicolaou (1999)
R2
O
R3
R3
O
R2
R1
R2
R5 X
R4
R2
Ar
O
R1
N N
NH
Ar1
R3
R1
4 steps
Ar1
O
R1
R1
4 steps
Sharpless (1999)
BINAP
Bn
Boc
108
2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl
benzyl
tert-butyloxycarbonyl
Bz
CA
CAN
Cbz
Cod
Cp
CSA
Cy
DABCO
DAST
dba
DBN
DBU
DCB
DCC
Ddm
DDQ
DEAD
DEIPS
DET
benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluoride
benzoyl
chloroacetyl
cerium ammonium nitrate
benzyloxycarbonyl
cyclooctadiene
cyclopentadienyl
10-camphorsulfonic acid
cyclohexyl
1,4-diazabicyclo[2.2.2]octane
(diethylamino)sulfur trifluoride
trans,trans-dibenzylideneacetone
1,5-diazabicyclo[5.4.0]non-5-ene
1,8-diazabicyclo[5.4.0]undec-7-ene
3,4-dichlorobenzyl
N,N'-dicyclohexylcarbodiimide
4,4'-dimethoxydiphenylmethyl
2,3-dichloro-5,6-dicyano-1,4-benzoquinone
diethyl azodicarboxylate
diethylisopropylsilyl
diethyl trtrate
Angew. Chem. Int. Ed. 2000, 39, 44 122
REVIEWS
3,4-dihydro-2H-pyran
diisopropylazodicarboxylate
diisobutylaluminum hydride
5-(3,3-dimethyl-1-triazenyl)-1H-imidazole-4carboximide
DIPT
diisopropyl tartrate
DMA
N,N-dimethylacetamide
4-DMAP 4-dimethylaminopyridine
DMF
N,N-dimethylformamide
DMP
Dess-Martin-periodinane
DMPU
N,N-dimethylpropyleneurea
DMSO
dimethylsulfoxide
Dopa
3-(3,4-dihydroxyphenyl)alanine
DPPA
diphenyl phosphoryl azide
dppb
1,4-bis(diphenylphosphinyl)butane
dppf
1,1'-bis(diphenylphosphanyl)ferrocene
DTBMS di-tert-butylmethylsilyl
EDC
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
FDPP
pentafluorophenyl diphenylphosphinate
Fmoc
9-fluorenylmethoxycarbonyl
HATU
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
HBTU
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate
HMDS
bis(trimethylsilyl)amide
HMPA
hexamethylphosphoramide
HOAt
1-hydroxy-7-azabenzotriazole
HOBt
1-hydroxybenzotriazole
IBX
o-iodoxybenzoic acid
imid.
imidazole
Ipc
isopinocamphenyl
KSAE
Katsuki Sharpless asymmetric epoxidation
LDA
lithium diisopropylamide
lut.
2,6-lutidine
mCPBA 3-chloroperoxybenzoic acid
MOM
methoxymethyl
Ms
methanesulfonyl
MSTFA N-methyl-N-(trimethylsilyl) trifluoroacetamide
nbd
norbaranadine (bicyclo[2.2.1]hepta-2,5-diene)
NBS
N-bromosuccinimide
NIS
N-iodosuccinimide
NMO
4-methylmorpholine-N-oxide
Nos
4-nitrobenzolsulfonyl
OTf
trifluoromethanesulfonate
PCC
pyridinium chlorochromate
PDC
pyridinium dichromate
PG
protecting group
Pht
phthalimidyl
Piv
pivaloyl
PMB
p-methoxybenzyl
PPTS
pyridinium 4-toluenesulfonate
pTs
4-toluenesulfonyl
py
pyridine
Red-Al
sodium bis(2-methoxyethoxy)aluminum hydride
SEM
2-(trimethylsilyl)ethoxymethyl
TBAF
tetra-n-butylammonium fluoride
TBAI
tetra-n-butylammonium iodide
TBDPS
tert-butyldiphenylsilyl
TBS
tert-butyldimethylsilyl
Angew. Chem. Int. Ed. 2000, 39, 44 122
TEMPO
TEOC
TES
Tfa
TFA
TFAA
THF
THP
TIPS
TMGA
TMS
TPAP
TPS
Tr
2,2,6,6-tetramethyl-1-piperidinyloxy
trimethylsilylethylcarbonyl
triethylsilyl
trifluoroacetyl
trifluoroacetic acid
trifluoroacetic anhydride
tetrahydrofuran
tetrahydropyranyl
triisopropylsilyl
tetramethylguanidinium azide
trimethylsilyl
tetra-n-propylammonium perruthenate
triphenylsilyl
trityl
109
REVIEWS
[19] S. A. Harris, K. Folkers, J. Am. Chem. Soc. 1939, 61, 1242 1244; S. A.
Harris, K. Folkers, J. Am. Chem. Soc. 1939, 61, 1245 1247.
[20] S. A. Harris, K. Folkers, J. Am. Chem. Soc. 1939, 61, 3307 3310.
[21] W. E. Bachmann, W. Cole, A. L. Wilds, J. Am. Chem. Soc. 1939, 61,
974 975.
[22] R. B. Woodward, W. E. Doering, J. Am. Chem. Soc. 1944, 66, 849
850.
[23] R. B. Woodward, G. Singh, J. Am. Chem. Soc. 1950, 72, 1428.
[24] R. B. Woodward, F. Sondheimer, D. Taub, K. Heusler, W. M.
McLamore, J. Am. Chem. Soc. 1952, 74, 4223 4251.
[25] R. B. Woodward, A. A. Patchett, D. H. R. Barton, D. A. H. Ives,
R. B. Kelly, J. Am. Chem. Soc. 1954, 76, 2852 2853.
[26] E. C. Kornfield, E. J. Fornefeld, G. B. Kline, M. H. Mann, R. G.
Jones, R. B. Woodward, J. Am. Chem. Soc. 1954, 76, 5256 5257.
[27] a) R. B Woodward, M. P. Cava, W. D. Ollis, A. Hunger, H. U.
Daeniker, K. Schenker, J. Am. Chem. Soc. 1954, 76, 4749 4751;
b) R. B. Woodward, M. P. Cava, W. D. Ollis, A. Hunger, H. U.
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1999, 121, 2071 2084.
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4313 4320.
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