Table Of ContentFOREWORD
The present volume of this series should again provide highly interesting articles
written by some of the most eminent organic chemists today. They range from
stereocontrolled synthesis of complex natural products to structural studies on a variety of
different types of natural products. It is hoped that this volume will be received with the
same enthusiasm by the readers as the previous ones of the series.
I wish to express my thanks to Miss Farzana Akhter and Syed Ejaz Ahmed Soofi
for their assistance inthe preparation of the index. I am also grateful to Mr. Wasim Ahmad
and Mr. Ahmed Ullah for the typing work and Mr. Mahmood Alam for secretarial
assistance.
Prof. Atta-ur-Rahman
H.E.J. Research Institute of Chemistry
University of Karachi
Vll
PREFACE
Further developments in organic chemistry, natural products chemistry, and
associated fields continue unabated. This high level of activity lies in sharp contrast to
statements made during the past two decades by some prognosticators who had quite
mistakenly predicted the rapidly approaching obsolescence of these fields of investigation.
These predictions were based upon organic chemistry having reached a very mature level of
development at a time when new areas of scientific inquiry were opening. Nevertheless,
organic chemistry remains as vital and as active as ever in laboratories around the world.
This continued activity may be attributed to many factors, including the development of
new screening procedures for biologically active compounds, improvements in
spectroscopic methods for determination of molecular structure, the availability of new,
highly selective and often asymmetric methods for the synthesis of ever more complex,
highly functionalized structures, and the applications of computer technology to chemistry.
Another driving force for further work in organic chemistry continues to be the search for
more effective pharmaceutical agents to treat many diseases such as cancer and other
maladies that continue to plague humankind. In this same vein, continued searches are
underway for new antibiotics to combat dangerous infectious bacterial strains that have
become resistant to previously developed antibiotics. Organic chemistry has also been
widely adopted as a tool for use in other areas of science, most notably in the biological
realm wherein specially synthesized compounds can, for example, be used to probe the
molecular details of cell function.
In the most recent volume of this well-established series. Professor Atta-ur-Rahman
again brings together the work of several of the world's leading authorities in organic
chemistry. Their contributions demonstrate the rapid, ongoing development of this field by
illustrating many of the latest advances in synthetic methods, total synthesis, structure
determination, biosynthetic pathways, and biological activity. The opening chapter
presents an overview of strategies for the synthesis of several classes of natural products
with an emphasis on complex polycyclic systems. The next several chapters discuss the
synthesis of specific classes of compounds, including morphine, polyketides, acetogenins,
nonactic acid derivatives, complex spirocyclic ethers, 8-lactam and pyridone derivatives,
inositol phosphates, sphingolipids, brassinosteroids, Hernandia lignans, and dimeric
steroidal pyrazine alkaloids. Structure determination and biological function provide
additional themes through many of these chapters. On the other hand, structure is
discussed more exclusively in chapters on liverwort sesquiterpenoids, gymnemic acids,
compounds of the Celastraceae plant family, fungal and protozoan glycolipids, and
coumarins. Finally, the ever stronger links between chemistry and biology are reinforced
by chapters on the origin and function of secondary metabolites, bioactive conformations of
gastrin hormones, and immunochemistry.
Professor Atta-ur-Rahman is to be congratulated for bringing together the present
set of contributions as a continuation of this outstanding series. He has again met the goal
of this series in demonstrating the strength, the vitality, and the diversity of organic
chemistry as a central field of scientific investigation.
Paul Helquist
University of Notre Dame
January 1996
CONTRIBUTORS
G. Adam Department of Natural Products Chemistry, Institute of Plant
Biochemistry, Weinberg 3, P.O. Box 250, D-06018 Halle/S.
N.L. Alvarenga C.P.N.O. Antonio Gonzalez, Universidad de La Laguna, Carretera La
Esperanza 2, La Laguna-Tenerife, Espana.
Masao Arimoto Osaka University of Pharmaceutical Sciences, 10-65 Kawai 2-Chome,
Matsubara 580, Japan
Nancy S. Barta Department of Chemistry, University of Michigan, Ann Arbor, Michigan
48109-1055, U.S.A.
I.L. Bazzocchi C.P.N.O. Antonio Gonzalez, Universidad de La Laguna, Carretera La
Esperanza 2, La Laguna-Tenerife, Espana.
Eliana Barreto Bergter Instituto de Microbiplogia da UFRJ, Centro de Ciencias da Saude-blocol
21.944-970-Cidade ijniversitaria, Rio de Janeiro-RJ
Maria Helena S. Villas Instituto de Microbiologia da UFRJ, Centro de Ciencias da Saude-blocol
Boas 21.944-970-Cidade Universitaria, Rio de Janeiro-RJ
Gabor Butora Virginia Polytechnic Institute and State University, Blacksburg, Virginia
24061
Andre Cav6 Universite Paris-sud, Faculte de Pharmacie de Chatenay-Malabry,
Laboratoire de Pharmacognosie, URA 1843 CNRS (BIOCIS)
Carsten Christophersen Department of General and Organic Chemistry, The H.C. 0rsted
Institute, K0benhavns Universitet, Universitetsparken 5, DK-2100
Copenhagen, Denmark
Helmut Duddeck Institut fur Organische Chemie, Universitat Hannover, Schneiderberg IB,
D-3000 Hannover 1, Germany
Bruno Figadere Universite Paris-sud, Faculte de Pharmacie de Chatenay-Malabry,
Laboratoire de Pharmacognosie, URA 1843 CNRS (BIOCIS)
Ian Fleming Department of Chemistry, University of Cambridge, Lensfield Road,
Cambridge CB2 lEW, U.K.
Stephen P. Feamley Virginia Polytechnic Institute and State University, Blacksburg, Virginia
24061, U.S.A.
A. Ganesan Centre for Natural Products Research, Institute of Molecular and Cell
Biology, National University of Singapore, 10 Kent Ridge Cresent,
Singapore 0511
Manfred Gemeiner Veterinar-Medizinische Universitat, Wien, Austria.
Sunil K. Ghosh Department of Chemistry, University of Cambridge, Lensfield Road,
Cambridge CB2 lEW, U.K.
A.G. Gonzalez C.P.N.O. Antonio Gonzalez, Universidad de La Laguna, Carretera La
Esperanza 2, La Laguna-Tenerife Espana.
Andrew G. Gum Virginia Polytechnic Institute and State University, Blacksburg, Virginia
24061, U.S.A.
Maria Helena Institute de Microbiologia da UFRJ, Centro de Ciencias da Saude-blocol
21.944-970-Cidade Universitaria, Rio de Janeiro-RJ
GerdHiibener Max-Planck-Institut fiir Biochemie, Am Klopferspitz 18a, D-82152
Martinsried, Germany
Tomas Hudlicky Virginia Polytechnic Institute and State University, Blacksburg, Virginia
24061, U.S.A.
Akitami Ichihara Faculty of Agriculture, Hokkaido University, Kitata 9, Nishi 9, KJTA-
KU, Sapporo 060, Japan
Tadao Kamikawa Department of Chemistry, Kinki University, Faculty of Science &
Technology, Kowakae, Higashi, Osaka 577, Japan
Jiirgen Lutz Max-Planck-Institut fiir Biochemie, Am Klopferspitz 18a, D-82152
Martinsried, Germany
Shashi B. Mahato Indian Institute of Chemical Biology, A Unit of C.S.I.R. Govt, of India,
4, Raja S.C. Mullick Road, Jadavpur, Calcutta-700-032, India
B. Mikhova Institut fiir Organische Chemie, Universitat Hannover, Schneiderberg IB,
D-3000 Hannover 1, Germany
Luis Moroder Max-Planck-Institut fiir Biochemie, Am Klopferspitz 18a, D-82152
Martinsried, Germany
Johann Mulzer Institut fur Organische Chemie der Freien Universitat Takustra^e 3, D-
14195, Berlin, Germany
O. Muhoz Universidad de Chile, Facultad de Ciencias Casilla 653 Santiago, Chile
XI
S. Nishibe Osaka University of Pharmaceutical Sciences, 10-65 Kawai 2-Chonie,
Matsubara 580, Japan
Hideaki Oikawa Department of Bioscience and Chemistry, Hokkaido University, Sapporo
060, Japan
Leo A. Paquette Department of Chemistry, The Ohio State University, 120 West 18th
Avenue, Columbus, OH 43210-1173, U.S.A.
A. Penaloza Universidad de Chile, Facultad de Ciencias Casilla 653-Santiago, Chile
A. Porzel Department of Natural Products Chemistry, Institute of Plant
Biochemistry, Weinberg 3, P.O. Box 250, D-06018 Halle/S.
A.G. Ravelo C.P.N.O. Antonio Gonzalez, Universidad de La Laguna, Carretera La
Esperanza 2, La Laguna-Tenerife Espana.
J. Schmidt Department of Natural Products Chemistry, Institute of Plant
Biochemistry, Weinberg 3, P.O. Box 250, D-06018 Halle/S.
B. Schneider Department of Natural Products Chemistry, Institute of Plant
Biochemistry, Weinberg 3, P.O. Box 250, D-06018 Halle/S.
Michele R. StabiV. Virginia Polytechnic Institute and State University, Blacksburg, Virginia
24062, U.S.A.
John R. Stille Chemical Process Research and Development Eli Lilly and Company,
Indianapolis, Indiana 46285-4813, U.S.A.
Motoo Tori Faculty of Pharmaceutical Sciences, Tokushima Bunri University,
Yamashiro-cho, Tokushima 770, Japan
H. Toshima Faculty of Agriculture, Hokkaido University, Kita 9, Nishi 9, KTTA-KU,
Sapporo 060, Japan
B. Voigt Department of Natural Products Chemistry, Institute of Plant
Biochemistry, Weinberg 3, P.O. Box 250, D-06018 Halle/S.
Yutaka Watanabe Faculty of Engineering, EHIME University, 3, Bunkyo-cho, Matsuyama
790, Japan
H. Yamaguchi Osaka University of Pharmaceutical Sciences, 10-65 Kawai 2-Chome,
Matsubara 580, Japan
Atta-ur-Rahman (Ed.) Studies in Natural Products Chemistry, Vol. 18
© 1996 Elsevier Science B.V. All rights reserved.
Strategies for the Stereocontrolled De Novo Synthesis of
Natural Products
Leo A. Paquette
LEO A. PAQUETTE
In no area of chemistry is stereoselectivity more often a necessary
consideration than in the synthesis of structurally complex natural products. A
practitioner in this field must be knowledgeable not only of many useful
transformations and the mechanistic principles underlying their ability to bring
about controlled chemical change, but also be capable of deploying the vast array
of available reagents in that chemoselective, regioselective, and stereoselective
manner appropriate to the target molecule under consideration. Although the
achievements of the last three decades have in the minds of many caused these
very important prerequisites to become highly developed, the demands placed on
synthetic chemists are hardly exhausted. A recently pubhshed treatise entitled
"Stereocontrolled Organic Synthesis" addresses many of the relevant issues from
the viewpoint of how the field can expect to develop well into the 21st century [1].
There exists no doubt that the pace of progress has been breathtaking.
Certainly, the fantastic advances in NMR spectroscopy and X-ray crystallography
have greatly reduced the time needed to determine the structures of newly
synthesized compounds. Notwithstanding, effective strategies remain the
province of synthetic organic chemists, and it is in this arena where
stereochemical elements are deployed with remarkable sophistication. In this
chapter, we welcome the opportunity to provide an overview of some of the
stereocontrolled syntheses successfully brought to completion in this laboratory in
recent years.
A. THE LYCOPODIUM ALKALOIDS MAGELLANINE AND
MAGELLANINONE
In a series of insightful papers, Castillo and MacLean established that the
club mosses Lycopodium magellanicum and Lycopodium paniculatum produce
alkaloids possessing structural features distinctively different from other
metabolites known to arise from these and related sources. The three members of
this small and unique subset were identified to share in common a central bicyclo-
[3.3.0]octane unit to which a functionalized cyclohexane and an N-
methylpiperidine ring were laterally fused. The occurrence of magcllaninc (1) [2],
magellaninone (2) [3], and paniculatine (3) [4] in nature has attracted significant
attention [5-7], since all three represent challenging objectives for total synthesis.
HgC-N H3C-N.
Our successful acquisition of both 1 and 2 gave particular attention to the
requirement for strict stereochemical control at six of the eight carbons of the
diquinane substructure by retrosynthetic disassembly of the two six-membered
rings. The broadly defined goals were therefore to realize proper cyclo-
hexannulation of enone 4 [8] in advance of a tandem vicinal difunctionalization
process that would establish the heterocyclic ring. Disconnection of strategic
bonds in this manner provided long term for the development of a new Michael-
Michael ring-forming sequence as well as a novel means for incorporating the
piperidine ring [9].
The most expedient means for incorporating ring A involved the K2CO3-
promoted condensation of 4 with ethyl 5-ethoxy-3-oxo-4-pentenoate in
tetrahydrofuran and ethanol containing alumina as a surface catalyst at room
temperature. As a consequence of the somewhat folded conformation of 4, the
face selectivity of the first conjugate addition proceeds syn to the angular
hydrogen as in 5 for obvious steric reasons (Scheme I). Stereocontrol is not
sacrificed in proceeding from 5 to 6 because the acceptor side chain is already
positioned on the p surface and the diquinane segment possesses a latent
thermodynamic preference for becoming cis- and not trans-fused. As a
consequence, 7 is obtained in good yield.
Following acid-catalyzed elimination of ethanol in 7, it proved possible to
reduce the cyclopentanone carbonyl in 8 chemoselectively as expected.
Noteworthy at this stage is the fact that borohydride attack occurs
stereoselectively from the p face. Silyl protection of the resulting a alcohol
afforded 9 and set the stage for unmasking of the second five-membered ring
carbonyl. Recourse to thallium nitrate as the means for removing the dithiane
moiety gave 10. The advantage of this strategy was that both ketone functional
groups in 10 could be simultaneously modified now and at a later stage.
Although the reduction of 10 with diisobutylaluminum hydride was not
100% stereocontroUed at -78 °C, the unwanted minor diastereomers could be
separated chromatographically and reconverted quantitatively to 10 for recycling
O
o
EtO COOEt Qv >r^ Z^^^COOEt COOEt
o
KgCOa.AlgOa,
THF. EtOH lb
25 «C
OH
1. NaBH^,
EtO, COOEt EtOH, CH2CI2, TBSO
(TsOH) QOC
^
2. TBSOTf.
imid,
CH2CI2, n
OH
1. MOMCI.
(/-Bu)2AIH.
TBSO (/-POgNEt.
TI(N03)3 CH2CI2. -78 °C» CH2CI2
^ 4
MeOH, THF PCC/A^Oa, 2. BL^N^F"
CHgCI^ rt HMPA. 3A MS
OH rt
11
OMOM OMOM OMOM
1. LiN(SiMe3)2,
THF; PhSeCI
CH2CI2 2. H202.py
OMOM OMOM OMOM
12 13 14
Scheme I
purposes. This simple tactic raised the efficiency with which 11 was produced to
the 76% level and permitted its ready conversion via 12 to 13. It is significant in
the context of what is to follow that hydride delivery to both carbonyl groups in 10
once again operates with a dominant p-face kinetic preference. Once 13 was in
hand, enone 14 was generated through adaptation of conventional organoselenium
technology for the purpose of incorporating the piperidine ring properly.
The recognized propensity of the anion of (trimethylsilyl)acetonitrile to
exhibit 1,4-addition to conjugated enones [10] was applied to 14. To our
satisfaction, the diastereofacial guidance available to this reagent was identical to
that provided to the reducing agents utilized earlier. Furthermore, the enolate
intermediate thus formed proved entirely amenable to stereoselective C-acylation
with methyl cyanoformate [11] and fumished 15 in a single laboratory operation
(Scheme II). As a direct consequence of the relatively high acidity of the proton
OMOM OMOM
/ O /
It
1. LICH(CN)SIMe3 1. NaBH4, PhSeCO
HMPA, THF
MeOH, -20 "C
^. MeOOC I MeOOC.
2. KF.aqCHgCN, 2. COC^.py,
OMOM 3. LDA, NCCOOMe THF; PhSeH -^ OMOM
14 15 16
OMOM
/
NaBH4.
(MegSij^SIH. CoClg, MeOH;
*- O,
AIBN'. CBHC MeOOC KOH, MeOH;
A \ HgO*
OMOM
17
Scheme II
positioned central to the p-keto ester subunit of 15, enolization is facile. It is
therefore not known whether the a orientation of the carbomethoxy substituent is
the result of kinetic or thermodynamic control. Suffice it to indicate, however,
that this stereogenic center has been improperly set and requires subsequent
inversion.
Since utilization of the ketone carbonyl was now complete, its removal was
implemented via an efficient three-step sequence involving reductive cleavage of
the derived selenocarbonate with tris(trimethylsilyl)silane [12] under free radical
conditions [13]. With the acquisition of 17 in this manner, the serviceability of the
reagent produced by adding sodium borohydride to cobaltous chloride for
chemoselective reduction of the nitrile group [14] was assessed. Indeed, treatment
of 17 in this manner, followed directly by basification with potassium hydroxide
in methanol, secured 18. In this step as well as in the subsequent progression to
the N-methyl derivative 19, no epimerization was seen within ring A.
To our mind, the enolate of 19 should exhibit a decided kinetic bias for
kinetically controlled protonation on its a face because of the steric encumbrance
associated with p proton delivery. In actual fact, rapid introduction of its lithium
salt into a 1:4 mixture of water and tetrahydrofuran at -78 °C resulted in its
quantitative conversion to 20 (Scheme HI). Once the MOM groups had been
removed, controlled oxidation with manganese dioxide led to 21, a very pivotal
intermediate. To arrive at magellaninone (2), 21 was treated with methyllithium
and the resulting unprotected diol 22 was directly reduced with lithium aluminum
hydride. Subsequent Jones oxidation proceeded with the customary allylic
rearrangement.
The plan now called for producing mageUanine (1) by standard borohydride
reduction of 2. However, in contrast to the directionality observed earlier for a
carbonyl group in this locale, only the p alcohol 23 was obtained perhaps because
of the presence of the fused piperidine ring on the convex surface. In any event,
Mitsunobu inversion [15] was successful in delivering the targeted alkaloid and in
demonstrating that these unusual Lycopodium alkaloids can indeed be prepared in
stereocontrolled fashion by three-fold annulation of 2-cyclopentenone.
OMOM 0
/
if
{ ) 1. HOI.
\\ HgO.THF 0^ \
^^^ 2. MnOg, J
H OMOM CHCb H^-- \^ •^*H OH
20 21
HaC,
-OH
1. UAIH4.
CH3M THF. A NaBH4
^>
THF 2. Jones EtOH
-78 °C 1\. » oxid.
•^ H OH
22
1. PhgP. DEAD
HCOOH, THF
2. 10%KOH,
H2O
H3C'
23
Scheme HI
B. THE MOST HIGHLY CONDENSED PENTALENOLACTONE
ANTIBIOTIC
Ecological concerns have prompted chemists to become increasingly "atom-
economic" in their synthetic pathways. The goals associated with this concept are
near-perfectly realized in the course of efficient isomerization reactions.
Accordingly, we have incorporated a number of stereocontrolled rearrangements
into our synthetic undertakings. Illustrated here is proper application of the oxadi-
TC-methane rearrangement to a total synthesis of pentalenolactone P methyl ester
(24b) [16], the stable esterified form of naturally occurring 24a. Pentalenolactone
P is the only member of the pentalenone family of antibiotics to possess a fused
three-membered ring, which notably resides on the highly congested concave
luifaeo or me moidouio [17].
