Efforts toward rapid construction of the cortistatin A carbocyclic core via enyne-ene metathesis

Article abstract of DOI:10.1039/c004275g

Our efforts toward the construction of the carbocylic core of cortistatin A via an enyne-ene metathesis are disclosed. Interestingly, an attempted S _N2 inversion of a secondary mesylate in our five-membered D-ring piece gave a product with rete

Full text of DOI:10.1039/c004275g

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Efforts toward rapid construction of the cortistatin A carbocyclic core via
enyne-ene metathesis†
Corinne Baumgartner, Sandy Ma, Qi Liu and Brian M. Stoltz*
Received 17th March 2010, Accepted 4th May 2010
First published as an Advance Article on the web 24th May 2010
DOI: 10.1039/c004275g
Our efforts toward the construction of the carbocylic core
of cortistatin A via an enyne-ene metathesis are disclosed.
Interestingly, an attempted SN2 inversion of a secondary
mesylate in our five-membered D-ring piece gave a product
with retention of stereochemistry.
diene 4 as a model precursor for the key enyne-ene metathesis to
give pentacyclic model diene 2. Alkynyl diene 4 could arise from
alkyl iodide 5 and nitrile 6. Nitrile 6, in turn, could be derived
from ketone 7, which has been synthesized in enantiopure form,6
thus providing a direct route for an asymmetric synthesis of the
cortistatin A carbocyclic core.
Our synthesis of the A-ring portion of cortistatin A commenced
from cyclohexanone 8, which was converted to the allylic alcohol
9 through treatment with PBr3 and DMF followed by a DIBAL
reduction of the resulting aldehyde (Scheme 2).7 PMB protection
of the allylic alcohol yielded ether 10, which was coupled to
vinyltributylstannane to afford diene 11. Hydroboration of diene
11 and subsequent exposure of the resultant primary alcohol to
triphenylphosphine and iodine produced iodide 5.
The discovery of novel anti-angiogenic agents has become an
active area of drug therapy research given their therapeutic
applications in the treatment of cancer, autoimmune diseases,
macular degeneration, as well as other diseases.1 A series of unique
abeo-9(10,19)-androstane-type steroidal alkaloids were isolated
from the marine sponge Corticium simplex in 2006 and 2007,2
some of which possessed significant anti-angiogenic activity.
The most potent member, cortistatin A (1) demonstrated highly
selective growth inhibition of human umbilical vein endothelial
cells (IC50 = 1.88 nM, selectivity index > 3000) with relatively no
general toxicity toward other cell types. The biological activity,
as well as the intriguing molecular structure of 1, have led to
several total syntheses3 and efforts toward the construction of the
cortistatin A core.4
In our approach to the synthesis of cortistatin A (1), we
envisioned that the [6,7,6,5] core could arise via an intramolec-
ular tandem enyne-ene metathesis (Scheme 1).5 To examine the
feasibility of such a step, we focused on the synthesis of alkynyl
Scheme 2
With the A-ring precursor 5 in hand, we set out to make the
D-ring portion in an asymmetric manner (Scheme 3). Treatment
of dione 12 with baker’s yeast provided a 9 : 1 mixture of
chromatographically separable alcohols 7 and 13.5 We envisioned
that subjecting the major product alcohol 78 to SN2 displacement
conditions would install the final carbon of the D-ring moiety and
set the desired absolute and relative stereochemistry. However,
mesylation of alcohol 7 followed by treatment with potassium
cyanide in DMSO surprisingly afforded nitrile 15, a product
with net retention of stereochemistry at C(14). This unexpected
result was confirmed via NOESY correlations of alcohols 7 and
13 and nitrile 15, and by X-ray diffractometry of crystalline
compounds derived from alcohol 7 and nitrile 15.9 A possible
explanation for this unexpected outcome is that the mechanism
proceeds via oxetane 16, which is postulated to arise from
reversible cyanohydrin formation of mesylate 14. Ring cleavage
by nucleophilic attack of cyanide at C(14) of oxetane 16 would
ultimately afford nitrile 15.
Scheme 1
The Arnold and Mabel Beckman Laboratories of Chemical Synthesis,
Division of Chemistry and Chemical Engineering, California Institute of
Technology, 1200 E. California Boulevard, MC 164-30, Pasadena, CA
91125, USA. E-mail: stoltz@caltech.edu; Fax: +1 626 564 9297; Tel: +1
626 395 6064
† Electronic supplementary information (ESI) available: General experi-
mental procedures, characterization data, NMR, and IR spectra. See DOI:
10.1039/c004275g
Despite this unusual result we wished to continue the synthesis
of the model system due to our interest in testing the enyne-ene
metathesis. To advance ketone 15, we protected the ketone as the
acetal to give 17. Nitrile 17 was then reduced to the aldehyde
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Subsequent TIPS cleavage with TBAF gave a 2.2 : 1 mixture of the
desired alcohol 20 (Felkin-Anh product) and the undesired alcohol
21. After separation by column chromatography, PMB ether 20
was converted to allylic acetate 22. Treatment of 22 with MgBr2
gave a 1 : 1 mixture of substituted tetrahydrofurans 23 and 24,10
which were inseparable by column chromatography. Nonetheless,
subjection of the mixture of 23 and 24 to Grubbs second-
generation catalyst produced the desired enyne-ene metathesis
[6,7,6,5]-core 25 in 37% yield and the enyne metathesis product
26 in 44% yield.
We planned to establish the absolute and relative stereo-
chemistry of our metathesis products via derivatization to give
compounds suitable for X-ray crystallography analysis. Attempts
to convert the [6,7,6,5]-core 25 or the enyne product 26 to
crystalline compounds were not successful. However, we were able
to derivatize the undesired alcohol 21 by proceeding through a
similar route as outlined in Scheme 4 for 20 to ultimately afford
enyne product 27. Enyne product 27 was then transformed to
oxime 28, which was acylated with p-bromobenzoylchloride to
furnish 29, a compound that was amenable to X-ray diffraction
(Scheme 5). As a result, we were able to assign the relative
and absolute stereochemistry of [6,7,6,5]-core 25 and enyne
product 26.
Scheme 3
and after treatment with TIPS–acetylene and EtMgBr, afforded
alcohol 18 as a mixture of diastereomers. Alcohol 18 was oxidized
with Dess–Martin periodinane (DMP) to give ketone 19.
With our A-ring (5) and epi-D-ring (19) precursors in hand, we
then coupled the two together by treating vinyl iodide 5 with t-BuLi
and adding the resultant lithio species to ketone 19 (Scheme 4).
11
Scheme 5
Herein, we have established the enyne-ene metathesis as a
rapid method for the construction of the carbocylic core of
cortistatin A. We have also reported an unusual reaction in
which an attempted SN2 displacement of a secondary mesylate
on our five-membered D-ring piece gave product with retention
of stereochemistry. Further studies directed toward the synthesis
of cortistatin A and related analogs are underway and will be
reported in due course.
Acknowledgements
C. B. thanks the Schweizerischer Nationalfonds (SNF) for a
fellowship. This publication is based on work supported by Award
No. KUS-11-006-02, made by King Abdullah University of Sci-
ence and Technology (KAUST). Additionally, the authors thank
Abbott, Amgen, Boehringer-Ingelheim, Bristol-Myers Squibb,
Merck, Sigma-Aldrich and Caltech for generous funding. Mr
Lawrence Henling and Dr Michael Day are gratefully acknowl-
edged for X-ray crystallographic structural determination. The
Scheme 4
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Bruker KAPPA APEXII X-ray diffractometer was purchased
via an NSF CRIF:MU award to the California Institute of
Technology, CHE-0639094. Dr David VanderVelde and Dr Scott
Ross are acknowledged for NMR assistance. Dr Scott Virgil is
acknowledged for helpful discussions.
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8 The enantiomeric excess of the benzoate derivative of alcohol 7 was
determined by chiral HPLC to be >99% ee. See the ESI for details†.
9 See the ESI for details†.
10 Determined by 1H NMR. See the ESI for details†.
11 The percentage probability chosen for the ellipsoids is 50%.
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The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2915–2917 | 2917
©