A concise synthesis of the pentacyclic framework of cortistatins

Article abstract of DOI:10.1021/ol8012099

(Chemical Equation Presented) An efficient synthesis of the pentacyclic framework of cortistatins has been developed. The key strategy comprises assembly of the A- and the CD-ring fragments by Knoevenagel reaction, facile formation of the pyran ring via e

Full text of DOI:10.1021/ol8012099

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3413-3415
A Concise Synthesis of the Pentacyclic
Framework of Cortistatins
Shuji Yamashita,*,† Kentaro Iso,† and Masahiro Hirama*,†,‡
Department of Chemistry, Graduate School of Science, Tohoku UniVersity, and
Research and Analytical Center for Giant Molecules, Graduate School of Science,
Tohoku UniVersity, Sendai 980-8578, Japan
s-yamashita@mail.tains.tohoku.ac.jp; hirama@mail.tains.tohoku.ac.jp
Received May 28, 2008
ABSTRACT
An efficient synthesis of the pentacyclic framework of cortistatins has been developed. The key strategy comprises assembly of the A- and
the CD-ring fragments by Knoevenagel reaction, facile formation of the pyran ring via electrocyclization, and construction of the seven-
membered B-ring by radical addition to an r,ꢀ-unsaturated ketone.
Cortistatins, which are unique abeo-9(10,19)-androstane-type
steroidal alkaloids, were first isolated from the marine sponge
Scheme 1. Structure and Synthetic Plan of Cortistatin A (1)
Corticium simplex by Kobayashi et al.1 Cortistatin A (1),
the most potent congener, was found to inhibit the prolifera-
tion of human umbilical vein endothelial cells with extreme
selectivity among cell lines.1a,2 Because angiogenesis in solid
tumors involves proliferation of endothelial cells, 1 has high
potential as a selective antitumor agent. As represented by
Baran’s excellent synthesis from prednisone,3 the biological
activityanduniquestructure-includinganoxabicyclo[3.2.1]octene
moiety as well as an isoquinoline substituent-of 1 attracts
synthetic chemists. Herein, we report a stereoselective
synthesis of the ABCD-ring framework of cortistatins.
As illustrated in Scheme 1, we envisioned the construction
of 1 via the key intermediate 2 after functionalization of the
A-ring and introduction of the isoquinoline unit to the D-ring.
The pentacyclic 2 would be formed through an electrocyclic
reaction of dienone 3 followed by radical cyclization.
Knoevenagel reaction between diketone 4 and R,ꢀ-unsatur-
ated aldehyde 5 was expected to produce the conjugated
dienone 3.
First, the requisite CD-ring moiety was prepared from
commercially available (+)-Hajos-Parrish ketone 6 (Scheme
2).4 Chemo- and stereoselective reduction of 6 with NaBH4
in MeOH at low temperature and subsequent TBS protection
of the resulting secondary alcohol produced silyl ether 7 in
† Department of Chemistry.
‡ Research and Analytical Center for Giant Molecules.
(1) (a) Aoki, S.; Watanabe, Y.; Sanagawa, M.; Setiawan, A.; Kotoku,
N.; Kobayashi, M. J. Am. Chem. Soc. 2006, 128, 3148. (b) Watanabe, Y.;
Aoki, S.; Tanabe, D.; Setiawan, A.; Kobayashi, M. Tetrahedron 2007, 63,
4074. (c) Aoki, S.; Watanabe, Y.; Tanabe, D.; Setiawan, A.; Arai, M.;
Kobayashi, M. Tetrahedron Lett. 2007, 48, 4485.
(2) SAR studies of cortistatins: Aoki, S.; Watanabe, Y.; Tanabe, D.;
Arai, M.; Suna, H.; Miyamoto, K.; Tsujibo, H.; Tsujikawa, K.; Yamamoto,
H.; Kobayashi, M Bioorg. Med. Chem. 2007, 15, 6758
(3) Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am.
Chem. Soc. 2008, 130, 7241.
.
10.1021/ol8012099 CCC: $40.75
Published on Web 07/17/2008
2008 American Chemical Society

provided the R,ꢀ-unsaturated aldehyde 14 in 73% overall
yield from 11.
Scheme 2. Synthesis of the R,ꢀ-Unsaturated Aldehyde 14
With the requisite aldehyde 14 in hand, construction of
the oxabicyclo[3.2.1]octene B-ring was pursued (Scheme 3).
Scheme 3. Synthesis of the Framework of Cortistatins
quantitative yield.5 C-alkylation of 7 at the C8-position with
iodide 8 was accomplished under Molander’s conditions
(NaH, DMSO in THF)6 to give indanone 9 in 53% yield;
this was stereoselectively reduced by NiCl2·6H2O and NaBH4
to give the desired trans-fused ketone 10.6a,7 The stereo-
chemistry of 10 was verified by NOESY experiments (see
Supporting Information). Other reductive conditions (H2, Pd/
C; t-BuCuH; or Birch reduction)8 did not give 10 as a major
product.
Regioselective TMS-enol ether formation from 10 fol-
lowed by oxidation under Saegusa conditions9 furnished the
C11,12 double bond. Treatment of enone 11 with lithium
diisopropylamide and triflic anhydride resulted in the forma-
tion of dienyl triflate 12, which underwent Pd-catalyzed
methoxycarbonylation to give methyl ester 13.10 Finally,
DIBAL reduction and subsequent Dess-Martin oxidation11
Treatment of 14 with cyclohexane-1,3-dione (4) (1.5 equiv)
in the presence of piperidine (1.1 equiv) in EtOAc (15 mM)
for 6 h produced the desired pyran 16 along with its C8-
epimer as a 5:1 mixture in one pot (87% combined yield).
Knoevenagel reaction between 14 and 4 gave the condensed
product 15, which underwent spontaneous electrocyclization
to give 16 as a major product.12 Selective TBS removal of
the primary alcohol, without affecting the secondary one,
using HF·pyridine gave 17, which was treated with I2, Ph3P,
and imidazole13 to afford iodide 18 in 87% overall yield (10:1
diastereomeric mixture). Interestingly, when 18 was kept at
-30 °C for 12 h, it crystallized, and the 18/C8-epimer ratio
increased to 20:1, as confirmed by NMR in CDCl3. However,
the ratio changed to 7:1 when the mixture was kept for 1 h
in CDCl3, and then became 5:1 after 7 h at room temperature.
(4) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615.
(5) (a) Micheli, R. A.; Hajos, Z. G.; Cohen, N.; Parrish, D. R.; Portland,
L. A.; Sciamanna, W.; Scott, M. A.; Wehrli, P. A. J. Org. Chem. 1975, 40,
675. (b) Gardner, J. N.; Anderson, B. A.; Oliveto, E. P. J. Org. Chem.
1969, 34, 107.
(6) (a) Molander, G. A.; Quirmbach, M. S.; Silva, L. F.; Spenver, K. C.,
Jr.; Balsells, J. Org. Lett. 2001, 3, 2257. (b) Hajos, Z. G.; Parrish, D. R.;
Oliveto, E. P. Tetrahedron 1968, 24, 2039.
(10) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1985, 26, 1109.
(11) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(12) For a recent review for constructing 1-oxadecalin, see: Tang, Y.;
Oppenheimer, J.; Song, Z.; You, L.; Zhang, X.; Hsung, R. P. Tetrahedron
2006, 62, 10785.
(7) For a general review, see: (a) Ganem, B.; Osby, J. O. Chem. ReV.
1986, 86, 763. (b) Shigehisa, H.; Mizutani, T.; Tosaki, S.; Ohshima, T.;
Shibasaki, M. Tetrahedron 2005, 61, 5057
.
(8) For a review, see: (a) Jankowski, P.; Marczak, S.; Wicha, J.
Tetrahedron 1998, 54, 12071.
(13) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Chem. Commun. 1979,
978.
(9) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
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Org. Lett., Vol. 10, No. 16, 2008

These results clearly indicate that 18 equilibrates with the
C8-epimer via retrocyclization to the corresponding dienone
in solution.
Knoevenagel condensation, (2) spontaneous electrocycliza-
tion (14f16), and (3) highly chemoselective internal radical
addition (18f19). The strategy developed here will con-
tribute toward the total synthesis of cortistatins, which is
being actively investigated in our laboratory.
Finally, formation of the seven-membered B-ring was
achieved by radical cyclization. After a considerable number
of experiments, it was found that treatment of 18 with Et3B
and (TMS)3SiH furnished the most stable conjugated dienone
(19) in 78% yield as the sole product.14 The structure of 19,
the key intermediate in the total synthesis of cortistatins, was
unambiguously confirmed by X-ray crystallographic analysis
of the corresponding p-bromobenzoate 20.
In conclusion, we have developed a concise and stereo-
controlled synthetic route to the pentacyclic framework of
cortistatins. The key intermediate 19 was prepared in only
14 steps from the commercially available 6, including (1)
Acknowledgment. This work was supported financially
by a Grant-in-Aid for Scientific Research from Ministry of
Education, Culture, Sports, Science and Technology in Japan.
We are grateful to Dr. E. Kwon at the Research and
Analytical Center for Giant Molecules for his assistance with
X-ray crystallographic analysis and helpful discussions.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for synthetic compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) For selected examples of radical addition to R,ꢀ-unsaturated
carbonyl compounds, see: (a) Middleton, D. S.; Simpkins, N. S. Tetrahedron
1990, 46, 545. (b) Lee, E.; Tae, J. S.; Lee, C.; Park, C. M. Tetrahedron
Lett. 1993, 34, 4831.
OL8012099
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