A General Strategy to Elisabethane Diterpenes: Stereocontrolled Synthesis of Elisapterosin B via Oxidative Cyclization of an Elisabethin Precursor

Article abstract of DOI:10.1021/ja035898h

Described is an efficient synthesis of the complex bioactive natural product, elisapterosin B, a potent in vitro inhibitor of Mycobacterium tuberculosis H37Rb. The synthesis elisapterosin B, prepared in its enantiomeric form, proceeds by a highly stereocontrolled sequence commencing with a simple glutamic acid derived compound. Pivotal steps in the sequence include (a) a pinacol-type ketal rearrangement to transfer chirality, (b) an IMDA reaction of an E,Z-diene to construct the elisabethin skeleton, and (c) a biosynthesis-inspired oxidative cyclization of the elisabethin precursor to elisapterosin B. Copyright

Full text of DOI:10.1021/ja035898h

Published on Web 10/04/2003
A General Strategy to Elisabethane Diterpenes: Stereocontrolled Synthesis
of Elisapterosin B via Oxidative Cyclization of an Elisabethin Precursor
Nobuaki Waizumi,§ Ana R. Stankovic, and Viresh H. Rawal*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois 60637
Received May 1, 2003; E-mail: vrawal@uchicago.edu
Scheme 1
Over the past few years, Rodr´ıguez and co-workers have reported
the isolation of a series of structurally novel metabolites (e.g., 1-4)
from the gorgonian sea whip Pseudopterogorgia elisabethae,
collected from the waters near San Andre´as Island, Colombia.1 The
more intricate members of the family were suggested to be
biosynthesized from elisabethin A, which in turn arises from
geranylgeranyl pyrophosphate via a serrulatane precursor. The
confluence of structural complexity and interesting biological
activity has made these terpenes attractive targets for chemical
synthesis.2 In connection with the development of a general strategy
to these natural products, we describe here the stereocontrolled
asymmetric synthesis of the elisabethin skeleton and its oxidative
cyclization to elisapterosin B (2),3 a potent in vitro inhibitor of
Mycobacterium tuberculosis H37Rb.1
Scheme 2 a
Our synthetic plan to elisabethin and elisapterosin B (Scheme
1) involves a series of diastereoselective reactions to set all of the
stereocenters commencing with the single asymmetric center of
5-oxo-2-tetrahydrofurancarboxylic acid (9), both enantiomers of
which are commercially available. The latent quinone functionality
as well as the required “anti” relative stereochemistry in aryl acetic
ester 6 would be introduced by a pinacol-type ketal rearrangement,
a highly stereocontrolled process that has seen few applications in
complex molecule synthesis.4 The tricyclic elisabethin framework
would be constructed by an intramolecular Diels-Alder (IMDA)
reaction of an E,Z-diene unit with quinone portion of 5, a trans-
formation that was expected to create three of the remaining five
a (a) ArMgBr, ZnCl2, cat. PdCl2(PPh3)2, THF (75%); (b) cat. TsOH,
chiral centers of elisapterosin B. The final two stereocenters would
HC(OMe)3, MeOH; t-BuOK, THF, (83%); (c) NaHMDS, MeI, THF, (86%);
(d) DIBAL, toluene; (e) (MeO)2P(O)CHN2, t-BuOK, THF (70% overall);
be installed through a biosynthesis-inspired oxidative cyclization.
The desired rearrangement product, alkyne-ester 16 (Scheme 2),
was synthesized starting with S-(+)-tetrahydro-5-oxo-2-furancar-
boxylic acid, which was prepared from the inexpensive L-enanti-
omer of glutamic acid.5 The selection of the simple dimethoxyaryl
precursor was predicated on the expectation that it could be oxidized
selectively at a later stage to the required methoxy-p-quinone. The
coupling of acid chloride 116 to the Grignard reagent of aryl
(f) MsCl, 2,6-lutidine, 50 °C; (g) CaCO3, wet MeOH, 50 °C (72%, 2 steps).
bromide (10)7 was mediated by ZnCl2 and a palladium catalyst,8
and the resulting ketone was subjected to ketal-forming conditions.
The expected methyl ketal was accompanied by the lactone meth-
anolysis product, so that the crude product was treated with t-BuOK
to yield lactone 12 in 83% overall yield. Methylation of the lithium
enolate of lactone 12 afforded the desired trans product (13) with
8:1 diastereoselectivity. The required one-carbon homologation of
§ Present address: Pfizer Inc., Nagoya Laboratories, 5-2 Taketoyo, Aiichi, Japan.
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J. AM. CHEM. SOC. 2003, 125, 13022-13023
10.1021/ja035898h CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3 a
Scheme 4
a (a) cat. AgNO3, NBS (1.0 equiv), acetone, rt; (b) H2NNHTs (6 equiv),
AcONa (7 equiv), MeOH, ∆, 65% 2 steps; (c) E-1-bromopropene (1.2
equiv), t-BuLi (2.4 equiv), -78 °C; ZnCl2 (1.2 equiv), PdCl2(dppf) (0.01
equiv), THF, rt, 70%; (d) DIBAL, -95 °C; (e) Wittig, 62% for 2 steps; (f)
NaSEt (10 equiv), DMF, 90 °C, 67%; (g) O2, cat. Salcomine, DMF, rt,
49%; (h) toluene, 80 °C, 67%.
In summary, we have completed a stereocontrolled asymmetric
synthesis of the enantiomer of elisapterosin B, by a route that
features (a) a pinacol-type ketal rearrangement to transfer chirality,
(b) an IMDA reaction of an E,Z-diene to construct the elisabethin
skeleton, and (c) a biosynthesis-inspired oxidative cyclization of
the elisabethin precursor to elisapterosin B (Scheme 4).
the lactone carbonyl to alkyne 14 was achieved through an efficient
two-step sequence. Reduction of the lactone with DIBAL followed
by treatment of the crude lactol intermediate with the Seyferth
reagent9 furnished acetylene 14, poised for the pivotal pinacol-type
rearrangement.4 The aryl group migration was triggered upon heat-
ing the mesylate of 14 in methanol in the presence of excess calcium
carbonate as an acid scavenger to furnish methyl ester 16 in 72%
yield.
In preparation for the IMDA reaction (Scheme 3), the acetylene
was converted to the Z-bromoalkene (17), cross-coupling of which
with E-bromopropene afforded diene 18.10 The ester functionality
was transformed into the 2-methylpropenyl side chain via DIBAL
reduction followed by Wittig olefination. Regioselective demeth-
ylation11 of the more hindered methyl ether provided phenol 19,
which upon subjection to Salcomine-catalyzed oxidation12 yielded
quinone 20, required for the IMDA reaction. Upon heating in
toluene, compound 20 underwent a clean cycloaddition to afford
the expected endo adduct as a single diastereomer. Of the two endo
transition states, the one shown below avoids potentially severe
allylic strain between the C7-Me group and propenyl unit on the
cis-double bond. The assigned relative stereochemistry is consistent
with NOE results as well as with the further conversion of 21 to
elisapterosin B (vide infra).
Acknowledgment. We thank the donors of The American
Chemical Society Petroleum Research Fund for partial support of
this work and Pfizer Inc. (Japan) for partial postdoctoral fellowship
support to N.W. (3/2000-4/2002). We are grateful to Professor
A. D. Rodr´ıguez of the University of Puerto Rico for kindly
providing spectra of elisabethin A and elisapterosin B.
Supporting Information Available: 1H and 13C NMR spectra
(PDF) of all key intermediates (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
References
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(3) While this manuscript was in preparation, the syntheses of two other
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Selective hydrogenation of the Diels-Alder product (21),
accomplished in quantitative yield with Wilkinson’s catalyst, gave
22, which is just an epimerization and O-demethylation away from
ent-elisabethin A. Contrary to expectations, however, ene-dione 22
proved recalcitrant to deprotonation at C2: no epimerization was
evident even with sodium ethoxide in refluxing ethanol. On the
other hand, the elisabethin skeleton of 22 was primed for testing
the biosynthesis-based cyclization to the elisapterosins. The methyl
ether was smoothly cleaved upon heating with LiI in 2,6-lutidine
to furnish enol ent-1â in quantitative yield. The oxidative cyclization
of ent-1â to elisapterosin B (ent-2) took place smoothly and in high
yield upon treatment with Ce(NH4)2(NO3)6, followed by addition
of pyridine and triethylamine, to enolize the presumed diketone
intermediate. The 1H and 13C NMR spectra of our synthetic sample
perfectly matched those of natural elisapterosin B.
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