Stereoselective synthesis of core structure of cortistatin A

Article abstract of DOI:10.1021/ol201327u

A stereoselective synthesis of the core structure of cortistatin A (1), a novel antiangiogenic steroidal alkaloid from Indonesian marine sponge, is described. An 8-oxabicyclo[3.2.1]octene system, a characteristic B-ring structure of 1, was elaborated by a 7-endo selective intramolecular Heck cyclization and a subsequent acid-mediated oxy-Michael reaction.

Full text of DOI:10.1021/ol201327u

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3514–3517
Stereoselective Synthesis of
Core Structure of Cortistatin A
Naoyuki Kotoku,* Yuji Sumii, and Motomasa Kobayashi*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka,
Suita, Osaka 565-0871, Japan
kotoku@phs.osaka-u.ac.jp; kobayasi@phs.osaka-u.ac.jp
Received May 17, 2011
ABSTRACT
A stereoselective synthesis of the core structure of cortistatin A (1), a novel antiangiogenic steroidal alkaloid from Indonesian marine sponge, is
described. An 8-oxabicyclo[3.2.1]octene system, a characteristic B-ring structure of 1, was elaborated by a 7-endo selective intramolecular Heck
cyclization and a subsequent acid-mediated oxy-Michael reaction.
Angiogenesis, a formation of new blood capillaries from
preexisting blood vessels, is critical for tumor growth and
metastasis. A growing tumor needs an extensive network
of capillaries to provide nutrients and oxygen, etc. In
addition, the new blood vessels provide a way for tumor
cells to enter into the circulation and to metastasize to
another organ. Therefore, substances that inhibit angio-
genesis have considerable potential to be novel therapeutic
agents for the treatment of cancer.1
In the course of our study on the bioactive substances
from marine organisms, we focused on a search for
selective inhibitors of proliferation of human umbilical
vein endothelial cells (HUVECs) as antiangiogenic
substances and found cortistatins,2 a family of novel
abeo-9(10ꢀ19)-androstane-type steroidal alkaloids, from
the Indonesian marine sponge of Corticium simplex
(1ꢀ11, Figure 1). Cortistatin A (1), a major constituent,
showed remarkably selective antiproliferative activity
against HUVECs and also inhibited migration and
tubular formation of HUVECs induced by VEGF
or bFGF.2a A structureꢀactivity relationship study
among cortistatins revealed that the isoquinoline unit
is crucial and the 9(11),10(19)-diene unit in the core
structure (such as cortistatins A (1) and J (9)) might be
important for selective antiproliferative activity against
HUVECs.2d
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r
10.1021/ol201327u
Published on Web 06/09/2011
2011 American Chemical Society

hindrance of the tert-alcohol moiety (OR2) placed at the
C5 position would make the 6-exo-cyclizing intermediate
much more disfavored. A cyclization precursor was di-
vided into two fragments of A-ring fragment E and CD-
ring fragment F.
Figure 1. Structures of cortistatins AꢀL (1ꢀ11).
The unique structure and characteristic biological prop-
erty of cortistatin A (1) attracted many synthetic chemists,
and five total syntheses,3 two formal syntheses,4 and many
synthetic studies5 have been reported so far. We also
engaged in the synthetic study of cortistatin A (1) and
accomplished a stereoselective synthesis of the core struc-
ture of 1 through a 7-endo-selective intramolecular Heck
reaction,6 which will be described in this paper.
Cortistatin A (1) has a characteristic rearranged steroid
skeleton, particularly with an 8-oxabicyclo[3.2.1]octene
system in the B-ring. Our plan toward the synthesis of its
complex ring system is a direct ring closure giving a seven-
membered carbocycle through an intramolecular Heck-
type reaction (C to B) and subsequent oxa-bridge forma-
tion (B to A) (Figure 2). In the cyclization intermediate for
the Heck reaction, a 7-endo pathway was expected to be
sterically more accessible than a 6-exo pathway, since steric
Figure 2. Retrosynthetic analysis of core structure A and plau-
sible intermediate for intramolecular Heck reaction.
Preparation of the chiral A-ring fragment is summarized
in Scheme 1. CBS reduction toward the known ketone 12,7
prepared from 2-cyclohexenone, gave an allylic alcohol 13
in 95% yield. The absolute stereochemistry and enantio-
meric excess (82ꢀ90% ee) of 13 was determined by
preparing its (þ)- and (ꢀ)-MTPA esters. Subsequent
vanadium-mediated diastereoselective epoxidation and
Swern oxidation provided a chiral epoxy ketone 14 in
good yield. Nucleophilic addition of the lithium enolate
of tert-butyl acetate toward the ketone 14 proceeded only
in the presence of CeF38 to give compound 15 as a single
diastereomer. An NOE experiment revealed that nucleo-
philic attack occurred from the opposite side of the ep-
oxide, which provided a tert-alcohol moiety with the
desired stereochemistry. MOM protection of the tert-
alcohol moiety gave compound 16 in quantitative yield,
(4) (a) Simmons, E. M.; Hardin-Narayan, A. R.; Guo, X.; Sarpong,
R. Tetrahedron 2010, 66, 4696. (b) Simmons, E. M.; Hardin, A. R.; Guo,
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Chen, Y.; Huang, J.; Liu, L.; Quan, J.; Li, C.-C.; Yang, Z. J. Org. Chem.
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C.-C.; Yang, Z. Chem. Commun. 2009, 662.
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Wang, Z.; Danishefsky, S. J. Tetrahedron Lett. 2008, 49, 6613. (d)
Kotoku, N.; Sumii, Y.; Hayashi, T.; Kobayashi, M. Tetrahedron Lett.
€
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2008, 49, 7078. (e) Kurti, L.; Czako, B.; Corey, E. J. Org. Lett. 2008, 10,
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C. S.; Sorensen, E. J. Org. Lett. 2009, 11, 5394. (i) Baumgartner, C.; Ma,
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2010, 12, 5135. (k) Liu, L. L.; Chiu, P. Chem. Commun. 2011, 47, 3416.
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For reviews, see:(l) Nising, C. F.; Brase, S. Angew. Chem., Int. Ed. 2008,
47, 9389. (m) Chen, D. Y.-K.; Tseng, C.-C. Org. Biomol. Chem. 2010, 8,
2900. (n) Hardin-Narayan, A. R.; Simmons, E. M.; Sarpong, R. Eur. J.
Org. Chem. 2010, 19, 3553.
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Tetrahedron 2006, 62, 7355.
(6) (a) Kotoku, N.; Sumii, Y.; Hayashi, T.; Kobayashi, M. Hetero-
cycles 2011, DOI: 10.3987/COM-11-12195. (b) Iimura, S.; Overman,
L. E.; Paulini, R.; Zakarian, A. J. Am. Chem. Soc. 2006, 128, 13095.
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Org. Lett., Vol. 13, No. 13, 2011
3515

and the following DIBAL reduction and subsequent iodi-
nation afforded a requisite A-ring fragment, 18.
Scheme 2. Synthesis of Cyclization Precursors 28 and 29
Scheme 1. Synthesis of A-Ring Fragment 18
Coupling of A-ring fragment 18 and CD-ring fragment
199 using Molander’s method10 gave compound 20 in
moderate yield (Scheme 2). The following hydrogenation
toward the dienol silyl ether generated from 20 proceeded
diastereoselectively3e,6a to provide compound 21 having a
trans-hydrindane skeleton. After removal of the two TBS
groups by TBAF treatment, an exo-methylene moiety at the
A-ring was constructed through iodination of the primary
alcohol of 22 and subsequent reductive opening of the R-
iodo epoxide with zinc dust in methanol. The resulting
secondary alcohol moiety of 24 was protected as a TBDPS
ether. Then, the following several conversions were executed
to provide two desired cyclization precursors for Heck
reaction. Thus, Rubottom oxidation at C11 position, R-
diketone formation using Cu(OAc)2, tautomerization by
DBU treatment, and triflation11 provided compound 27.
The C11 ketone of 27 was further converted to an acetoxy
group (in the cyclization precursor 28) by DIBAL reduction
and Ac2O treatment. To investigate the steric effect of the
tert-alcohol moiety, a TMS-protected precursor 29 was also
prepared by further two-step manipulations.
might be formed through the desired 7-endo cyclization, and
compound 31a, having a different conjugated diene system,
might be formed through the undesired 6-exo cyclization
and ring expansion.13 We examined various conditions
(ligand, base, and additive). However, low yield and low
selectivity (30a: 32%; 31a: 25%) were obtained even in
optimized conditions (entry 3). On the other hand, endo-
cyclization product 30b was obtained selectively in the case
of 29 as a substrate, albeit in low yield (entry 4). After
extensive study, the use of nBu4NOAc as an additive was
found to furnish the desired cyclization product 30b in 56%
yield (entry 5).
The final oxa-bridge formation was accomplished as
follows (Scheme 3). Selective desilylation at the tert-alco-
hol moiety gave compound 32, and subsequent DIBAL-
mediated deacetylation and DessꢀMartin oxidation pro-
vided enone 33 in good yield. The following oxy-Michael
reaction proceeded only by acid treatment of 33, using 10-
camphorsulfonic acid (CSA) in THF, togivecompound34
With two cyclization precursors 28 and 29 in hand,
intramolecular Heck reaction was investigated (Table 1).12
In the case of 28, no cyclization product was obtained by
using the conditions in our previous study6a (entry 1), while
the addition of tetra-n-butylammonium bromide (TBAB)
provided two cyclization products 30a and 31a with 69%
recovery of the starting material (entry 2). Compound 30a
(13) Plausible mechanism toward compound 31a is shown below. No
interconversion occurred between 30a and 31a under the cyclization
conditions, which implied that those two compounds might be formed
through different pathways. And, no cyclization product was obtained
using C11-ketone compound 27 as a substrate.
(9) Lepage, O.; Stone, C.; Deslongchamps, P. Org. Lett. 2002, 4,
1091.
(10) (a) Molander, G. A.; Quirmbach, M. S.; Silva, L. F., Jr.; Spencer,
K. C.; Balsells, J. Org. Lett. 2001, 3, 2257. (b) Hajos, Z. G.; Parrish,
D. R.; Oliveto, E. P. Tetrahedron 1968, 24, 2039.
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M. Tetrahedron 2005, 61, 5057.
(12) For a review of the Heck reaction, see: Beletskaya, I. P.; Cheprakov,
A. V. Chem. Rev. 2000, 100, 3009.
3516
Org. Lett., Vol. 13, No. 13, 2011

Table 1. Study on Intramolecular Heck Reaction
Scheme 3. Synthesis of 35 through Oxy-Michael Reaction
entry substrate ligand base
additive
yielda
b
1
2
28
28
dppb KOAc none
ꢀ
dppb KOAc TBAB
dppb CsOAc TBAB
dppp CsOAc TBAB
30a: 4%, 31a: 21%
(28: 69%)
3
28
29
29
30a: 32%, 31a: 25%
(28:30%)
4
30b: 13%, 31b: 0%
(29: 73%)
dehydration using Burgess’ reagent, to afford compound
35 possessing the needed core structure of cortistatin A (1).
In summary, we achieved a stereoselective synthesis of
the core structure of cortistatin A (1) through a 7-endo
intramolecular Heck reaction and subsequent oxy-Mi-
chael reaction. Now we are trying to accomplish a total
synthesis of 1 and to develop some analogues thereof,14
which will be presented in due course.
5c
dppp CsOAc nBu4NOAc 30b: 56%, 31b: 0%
(29:12%)
a Isolated yield of cyclization products. b Not obtained (66% recov-
ery of 28). c 0.7 equiv of Pd2(dba)3, 1.4 equiv of dppp, and 4.0 equiv of
nBu4NOAc were used.
having an objective 8-oxabicyclo[3.2.1]octene structure.
Some bases such as K2CO3 or Et3N did not promote this
reaction, and surprisingly, CSA treatment in CH2Cl2 did
not provide 34 and resulted in decomposition. Finally, a
9(11),10(19)-conjugated diene system was elaborated
through NaBH4 reduction of the C11 ketone and
Acknowledgment. This study was financially supported
by a Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science, and Technology
of Japan. The authors are also grateful to The Uehara
Memorial Foundation.
(14) (a) Sato, Y.; Kamiyama, H.; Usui, T.; Saito, T.; Osada, H.;
Kuwahara, S.; Kiyota, H. Biosci. Biotechnol. Biochem. 2008, 72, 2992.
(b) Shi, J.; Shigehisa, H.; Guerrero, C. A.; Shenvi, R. A.; Li, C.-C.;
Supporting Information Available. Experimental pro-
cedure, spectroscopic data, and 1H and 13C NMR spectra
for compounds 12ꢀ35. This material is available free of
charge via the Internet at http://pubs.acs.org.
ꢀ
€
Baran, P. S. Angew. Chem., Int. Ed. 2009, 48, 4328. (c) Czako, B.; Kurti,
L.; Mammoto, A.; Ingber, D. E.; Corey, E. J. J. Am. Chem. Soc. 2009,
131, 9014.
Org. Lett., Vol. 13, No. 13, 2011
3517