An expeditious asymmetric synthesis of the pentacyclic core of the cortistatins by an intramolecular (4+3) cycloaddition

Article abstract of DOI:10.1039/c1cc00087j

A concise, asymmetric synthesis of the pentacyclic framework of the cortistatins has been accomplished in 12 steps from commercially available starting materials, employing a highly diastereoselective intramolecular (4+3) cycloaddition of epoxy enolsilane

Full text of DOI:10.1039/c1cc00087j

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COMMUNICATION
An expeditious asymmetric synthesis of the pentacyclic core of the
cortistatins by an intramolecular (4+3) cycloadditionw
Lok Lok Liu and Pauline Chiu*
Received 5th January 2011, Accepted 26th January 2011
DOI: 10.1039/c1cc00087j
A concise, asymmetric synthesis of the pentacyclic framework of
the cortistatins has been accomplished in 12 steps from
commercially available starting materials, employing a highly
diastereoselective intramolecular (4+3) cycloaddition of epoxy
enolsilanes as the key step.
The isolation and identification of cortistatin A from the marine
sponge Corticium simplex in 2006, and subsequently its congeners
have generated much interest among organic and medicinal
chemists alike.1 This family of rearranged steroidal alkaloids were
Scheme 1 Intramolecular (4+3) cycloaddition of epoxy enolsilanes.
cycloisomerizations, dipolar cycloadditions, RCM, cyclizations
by radical, alkylation and aldol reactions.2 In light of recent
communications using cycloadditions to access ring B,5 we report
herein our efforts in the application of the (4+3) cycloaddition of
epoxy enolsilanes that we have developed (Scheme 1),7 to the
asymmetric synthesis of these molecules. We proposed to use this
reaction in the synthesis of cortistatins, not only because both
rings B and C could conceivably be obtained from this intra-
molecular (4+3) cycloaddition with furan derivatives in a
concise manner, but also to put this methodology to the test
for its compatibility and applicability in the context of complex
synthetic targets. Herein we outline the application of this (4+3)
cycloaddition to the efficient asymmetric synthesis of 5, the
pentacyclic core of cortistatins A and J.
discovered through
a cell anti-proliferation assay-guided
fractionation, in which cortistatins A (1) and J (2) were identified
to be the most potent, nanomolar anti-angiogenic natural
products (Fig. 1). With recent data showing that anti-angiogenics
are generally well-tolerated without observable drug resistance,
and when given in conjunction with traditional cancer drugs
could suppress cancer recurrence, the discovery and development
of new anti-angiogenics hold promise for future cancer therapy.
The bioactivity, therapeutic potential and architectural beauty
of the cortistatins have inspired many efforts toward the synthesis
of these molecules in the organic chemistry community.2 The
isolated quantities being too minute for further studies have
motivated their semi-, total and formal syntheses,3 as well as
quite a number of synthetic studies.4,5 Successful approaches
have enabled the preparation of cortistatin derivatives and the
assembly of a preliminary SAR profile of these compounds.6
The central bicyclic ether in the context of a seven-
membered ring B, a feature of all of the cortistatins, has been
constructed by diverse approaches, including ring expansions,
In our synthetic plan, ring D derived from meso cyclo-
pentanedione 6 would serve as the linker to unite the diene and
the dienophile for the key intramolecular (4+3) cycloaddition
(Scheme 2). Desymmetrization by reduction with (S)-CBS-B-Me
yielded cyclopentanol (2R,3R)-7a in 94% ee and its diastereomer
(2S,3R)-7b in 78% overall yield, accompanied by 12% of over-
reduced diol.8 Using (S)-CBS-B-Bu, however, resulted in 7a in
comparable yield but with only 83% ee. Protection and addition
of furanyllithium 8 to 7a provided cyclopentanol 9.9 Activation
and dehydration of the tertiary alcohol yielded cyclopentene 10. A
cross-metathesis with methyl vinyl ketone mediated by the
Hoveyda–Grubbs catalyst10 yielded the desired enone 11 without
ring-opening of the cyclopentene. Chemoselective asymmetric
epoxidation of the enone in the presence of the cyclopentene in
11 employing Deng’s cinchona-derived catalyst 12 was achieved
in 96% yield to give 13 as a single diastereomer having the correct
stereochemistry to direct the subsequent cycloaddition reaction.11
Conversion to the enolsilane yielded the requisite cycloaddition
precursor 14. Gratifyingly, the key (4+3) cycloaddition catalyzed
by TESOTf afforded the desired cycloadduct 15 having rings B,
C, and D, in 87% yield as a single diastereomer.
Fig. 1 Cortistatins A and J.
Department of Chemistry, The University of Hong Kong,
Pokfulam Road, Hong Kong, P. R. China. E-mail: pchiu@hku.hk;
Fax: +852-28571586; Tel: +852-28598949
w Electronic supplementary information (ESI) available: Detailed
experimental procedures, copies of spectra and full characterization
of all new compounds. See DOI: 10.1039/c1cc00087j/
c
3416 Chem. Commun., 2011, 47, 3416–3417
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Scheme 2 Asymmetric synthesis of pentacyclic 5.
D. Y.-K. Chen and C. C. Tseng, Org. Biomol. Chem., 2010, 8,
Dehydration of 15 generated enone 16, which was subjected to
treatment with acid to give diol 17. The C17 hydroxyl group was
deprotected at this point so that it could direct the subsequent
reduction to set the stereochemistry of ring D. Using Crabtree’s
catalyst, reduction occurred on the a-face as desired to afford
diol 18 in good yield, along with concomitant reduction of the
dihydrofuran. The bis-oxidation of diol 18 with Dess–Martin
periodinane afforded the expected ketoaldehyde, which
spontaneously underwent intramolecular aldol cyclization upon
silica gel chromatography, to afford 5 in 84% overall yield.
In this communication, we report a succinct synthesis of the
pentacyclic core of 1 and 2 in optically enriched form, in 12 steps
from commercially available substrates, using the intramolecular
(4+3) cycloaddition of epoxy enolsilanes as the key step. The
successful application of this reaction to synthesize 5 demonstrates
the power of this cycloaddition and its compatibility with various
functional groups for use in complex natural product synthesis.
The synthetic strategy enabled by this reaction gives us access to
differently functionalized cortistatin analogues complementary to
those obtained using previous approaches. We are currently
examining the use of an amine-substituted derivative of furanyl-
lithium 8 for a more convergent synthesis. Our continuing studies
on the total synthesis of the cortistatins and their analogues will be
reported in due course.
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We thank the University of Hong Kong Strategic Research
Theme on Drugs, and the Research Grants Council of Hong
Kong SAR (GRF Project No. HKU 7011/08P) for funding.
Notes and references
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2 Reviews on the synthesis of cortistatins, see: A. R. Hardin Narayan,
E. M. Simmons and R. Sarpong, Eur. J. Org. Chem., 2010, 3553;
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 3416–3417 3417