Synthesis of CD-ring structure of cortistatin A, an anti-angiogenic steroidal alkaloid from marine sponge

Article abstract of DOI:10.1016/j.tetlet.2008.09.157

Stereoselective synthesis of the CD-ring structure of cortistatin A (1), a novel anti-angiogenic steroidal alkaloid from Indonesian marine sponge, was achieved. The stereogenic tertiary carbon center bearing the isoquinoline moiety was constructed by 1,3-chiral transfer method using Johnson-Claisen rearrangement of the chiral allylic alcohol 5. Subsequent intramolecular Michael-aldol reaction afforded the targeted trans-hydrindane skeleton with moderate stereoselectivity.

Full text of DOI:10.1016/j.tetlet.2008.09.157

Tetrahedron Letters 49 (2008) 7078–7081
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of CD-ring structure of cortistatin A, an anti-angiogenic
steroidal alkaloid from marine sponge
*
Naoyuki Kotoku, Yuji Sumii, Takeshi Hayashi, Motomasa Kobayashi
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereoselective synthesis of the CD-ring structure of cortistatin A (1), a novel anti-angiogenic steroidal
alkaloid from Indonesian marine sponge, was achieved. The stereogenic tertiary carbon center bearing
the isoquinoline moiety was constructed by 1,3-chiral transfer method using Johnson–Claisen rearrange-
ment of the chiral allylic alcohol 5. Subsequent intramolecular Michael-aldol reaction afforded the
targeted trans-hydrindane skeleton with moderate stereoselectivity.
Received 1 September 2008
Revised 26 September 2008
Accepted 29 September 2008
Available online 2 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Cortistatin A
Anti-angiogenesis
Marine sponge
Johnson–Claisen rearrangement
Michael-aldol reaction
Angiogenesis, a formation of new blood capillaries from preex-
isting blood vessels, is critical for tumor growth and metastasis. A
growing tumor needs an extensive network of capillaries to pro-
vide nutrients and oxygen. In addition, the new blood vessels pro-
vide a way for tumor cells to enter in the circulation and to
metastasize to another organ. Therefore, substances that inhibit
angiogenesis have a considerable potential to be novel therapeutic
agents for the treatment of cancer.1
N
18
13
17
HO 19
9
HO
N
1
10
O
H
5
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 anti-angiogenic substances and isolated cortistatins,2 a family of
novel abeo-9(10-19)-androstane-type steroidal alkaloids, from the
Indonesian marine sponge of Corticium simplex. We found that cor-
tistatin A (1, Fig. 1), a major active constituent having unique
chemical structure, showed highly selective anti-proliferative
activity against HUVECs and also inhibited migration and tubular
cortistatin A (1)
Figure 1. Chemical structure of cortistatin A (1).
able.Here, we present a synthesis of the CD-ring structure of cor-
tistatin A (1) through 1,3-chiral transfer method and Michael-
aldol double cyclization.5
2
formation of HUVECs induced by VEGF or bFGF. The scarcity of
Our strategy for the total synthesis of cortistatin A (1) is illus-
trated in Figure 2. The core structure was divided into two frag-
ments, that is, A-ring fragment (2) and CD-ring fragment (3).
These two fragments could be coupled by using B-alkyl Suzuki–
Miyaura coupling,6 and subsequent intramolecular cyclization
would afford an oxygen-bridged 7-membered B-ring moiety. The
trans-hydrindane skeleton of the CD-ring fragment could be elabo-
rated by Michael-aldol double cyclization. The stereogenic carbon
center bearing the isoquinoline moiety of 4 would be created
through 1,3-chiral transfer method from an optically active
(E)-allylic alcohol (5).
natural supply prompted us to engage in synthetic study of 1 for
further biological evaluation. Some synthetic studies of 1 including
two completed total syntheses have recently been reported.3,4 As
both the total syntheses utilized palladium-catalyzed cross-cou-
pling reaction and hydrogenation for introduction of isoquinoline
moiety, an essential component for potent anti-angiogenic activity
of 1, in moderate yields, another synthetic method is desir-
* Corresponding author. Tel.: +81 6 6879 8215; fax: +81 6 6879 8219.
E-mail address: kobayasi@phs.osaka-u.ac.jp (M. Kobayashi).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.157

N. Kotoku et al. / Tetrahedron Letters 49 (2008) 7078–7081
7079
N
N
N
Cl
Cl
EtO
HO
C
D
N
HO
N
O
O
O
O
H
H
1
Cl
TBDPSO
3
4
R1O
Y
R1O
X
A
TBDPSO
OH
5
R2O
2
Figure 2. Retrosynthetic analysis.
chiral allylic alcohol 5 with triethyl orthopropionate in the pres-
ence of catalytic amount of propionic acid in refluxing toluene,
to give an ester 4 as a 1:1 diastereomixture at the tertiary carbon
center bearing methyl group. The absolute configuration of the
newly generated stereogenic carbon center bearing the isoquino-
line moiety in 4 was ascertained by X-ray crystallographic analy-
sis of its derivative.10
b
a
D-mannitol
O
O
6
Cleavage of the TBDPS group of 4 with tetrabutylammonium
fluoride (TBAF) and subsequent hydrogenation of the allyl alcohol
moiety, using platinum oxide (PtO2) as a catalyst, gave an alcohol
10. Hydrogenation using Pd–C resulted in concomitant reduction
of isoquinoline ring. Following Swern oxidation and Wittig reac-
tion with phosphorane 11 smoothly proceeded to give a keto-ester
12 with high E-selectivity. The desired keto-aldehyde 13, a precur-
sor of Michael-aldol cyclization, was obtained by reduction of 12
N
O
O
B
O
Cl
c
d ,e
O
O
O
8
7
N
N
N
c,d
Cl
a,b
Cl
EtO
4
Cl
f
EtO
O
O
10
HO
RO
4
TBDPSO
OH
N
9: R = H
5: R = TBDPS
N
Cl
Cl
O
EtO
Scheme 1. Reagents and conditions: (a) Ref. 8; (b) pinacolborane, Cp2ZrHCl, Et3N,
92%; (c) 7-bromo-1-chloroisoquinoline, Pd(dppf)Cl2, K2CO3, 1,4-dioxane, 82%; (d)
80% TFA; (e) TBDPSCl, imidazole, DMF, 57% (two steps); (f) CH3CH2C(OEt)3,
propionic acid, toluene, reflux, 99%.
e,f
O
O
13
12
O
N
Access to the chiral allylic alcohol (5) was as follows (Scheme
1). Zirconium-catalyzed regioselective hydroboration7 to the
Cl
known chiral alkyne 6, easily obtained in three steps from
nitol,8 gave an (E)-alkenyl borate 7 in good yield and stereoselec-
tively. Subsequent Suzuki–Miyaura cross-coupling with
D-man-
g
H
: Key NOE
commercially available 7-bromo-1-chloroisoquinoline proceeded
selectively at the bromide position to give a coupling product 8.
Cleavage of the cyclohexylidene group and following TBDPS pro-
tection of the primary hydroxyl group of 9 afforded a desired
allylic alcohol 5. Optical purity of the product was ascertained
by NMR analysis of its MTPA ester. Successful Johnson–Claisen
rearrangement9 reaction was achieved by the treatment of the
O
H
14
Scheme 2. Reagents and conditions: (a) TBAF, THF, 96%; (b) H2/PtO2, AcOEt, 93%;
(c) (COCl)2, DMSO, Et3N, CH2Cl2, 79%; (d) Ph3P@CHCOCH3 (11), THF, 60 °C, 97%; (e)
DIBAL-H, THF, 87%; (f) (COCl)2, DMSO, Et3N, CH2Cl2, 83%; (g) NaOMe, THF, rt to
70 °C, 69%.

7080
N. Kotoku et al. / Tetrahedron Letters 49 (2008) 7078–7081
N
N
N
Cl
Cl
Cl
c
a,b
d,e
14
8
O
TfO
HO
HO
H
H
H
17
CO2Me
15
16
CO2Me
CO2Me
N
N
N
Cl
Cl
Cl
f,g
h
i
C
D
O
O
O
O
H
O
H
O
H
NOE
O
HO
3
19
18
Scheme 3. Reagents and conditions: (a) NaHMDS, NCCO2Me, THF, À78 °C, 89%; (b) H2/PtO2, AcOEt, 95%; (c) PhNTf2, NaH, THF, 79%; (d) Pd(OAc)2, HCOOH, PPh3, Et3N, THF,
70 °C; (e) OsO4, NMO, acetone/H2O, 77% (two steps); (f) 2,2-dimethoxypropane, p-TsOH, acetone, 40 °C, 74%; (g) LiAlH4, THF, 93% (brsm); (h) Dess–Martin periodinane,
CH2Cl2, 83%; (i) CH3PPh3Br, NaHMDS, THF, quant.
with diisobutylaluminum hydride (DIBAL-H) and subsequent
Swern oxidation.
Acknowledgments
According to the Stork’s work,5 Michael-aldol double cyclization
of 13 was investigated, using several metal alkoxides. In the use of
sodium methoxide as a base, the desired double-cyclized product
14 with hydrindane skeleton was obtained in moderate yield
(31%) and trans/cis selectivity (5:1, determined by NMR). Elevated
reaction temperature improved yield, up to 69%, with the same
diastereoselectivity. The use of Mg(OEt)2 gave in low yield with a
little better selectivity (6:1), and zirconium tetra-n-propoxide, des-
ignated as a best reagent in the literature, did not give cyclization
product at all. The relative stereochemistry of the product was
determined by NOE experiment (Scheme 2).
Generation of the stereogenic center at C-8 was further investi-
gated. Sodium enolate of the ketone 14 reacted with methyl cyano-
formate, and following hydrogenation catalyzed by PtO2 gave a
b-keto ester 15. Then, 15 was converted to an enol triflate 16 by
the treatment with NaH and N-phenyltriflimide. Palladium-
This study was financially supported by Grant-in-Aid for
Scientific research from the Ministry of Education, Science, Sport,
and Culture of Japan. The authors are also grateful to the Takeda
Science Foundation.
References and notes
1. Carmeliet, P.; Jain, R. K. Nature 2000, 407, 249.
2. (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; (d) 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. For the total synthesis of cortistatin A, see: (a) Shenvi, R. A.; Guerrero, C. A.; Shi,
J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7241; (b) Nicolaou, K. C.;
Sun, Y.-P.; Peng, X.-S.; Polet, D.; Chen, D. Y.-K. Angew. Chem., Int. Ed. 2008, 47,
7310.
catalyzed reduction of 16 gave an
a,b-unsaturated ester, which
4. For studies towards the synthesis of cortistatins, see: (a) Yamashita, S.; Iso, K.;
Hirama, M. Org. Lett. 2008, 10, 3413; (b) Simmons, E. M.; Hardin, A. R.; Guo, X.;
Sarpong, R. Angew. Chem., Int. Ed. 2008, 47, 6650; (c) Craft, D. T.; Gung, B. W.
Tetrahedron Lett. 2008, 49, 5931; (d) Dai, M.; Danishefsky, S. J. Heterocycles;
published online, April 17th, 2008. COM-08-S(F)6; (e) Dai, M.; Danishefsky,
S. J. Tetrahedron Lett. 2008. doi:10.1016/j.tetlet.2008.09.018; (f) Dai, M.;
Wang, Z.; Danishefsky, S. J. Tetrahedron Lett. 2008. doi:10.1016/j.tetlet. 2008.
09.019.
5. (a) Stork, G.; Shiner, C. S.; Winkler, J. D. J. Am. Chem. Soc. 1982, 104, 310; (b)
Stork, G.; Winkler, J. D.; Shiner, C. S. J. Am. Chem. Soc. 1982, 104, 3767.
6. Review Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001,
40, 4544.
was subjected to dihydroxylation for generating a stereogenic
center corresponding to C-8 of cortistatin A (1). To our delight,
dihydroxylation occurred stereoselectively from
a-face of the
hydrindane ring to give a diol 17, due to steric repulsion of both
the methyl and isoquinoline groups on the b-face of the molecule.
The product 17 was further converted to an alcohol 18, by protec-
tion of the diol moiety as acetonide and subsequent treatment with
LiAlH4. An NOE correlation between the angular methyl proton and
the methylene proton of the hydroxymethyl group was observed in
the NOESY spectrum of 18, confirming stereochemistry of the
tertiary alcohol moiety corresponding to the C-8 stereogenic center
of 1. Treatment of 18 with Dess–Martin periodinane gave an alde-
hyde 19, and subsequent Wittig reaction afforded the targeted
compound 3 having vinyl moiety. The compound 3 possesses
almost all the required functional groups and stereochemistry
corresponding to the CD-ring part of cortistatin A (1) (Scheme 3).11
In summary, we achieved the stereoselective synthesis of the
CD-ring structure of cortistatin A (1) utilizing 1,3-chiral transfer
method and intramolecular Michael-aldol cyclization reaction.
Coupling reaction with the A-ring fragment and construction of
the B-ring structure leading to the total synthesis of cortistatin A
(1) are now in progress.
7. Wang, Y. D.; Kimball, G.; Prashad, A. S.; Wang, Y. Tetrahedron Lett. 2005, 46,
8777.
8. (a) Sugiyama, T.; Sugawara, H.; Watanabe, M.; Yamashita, K. Agric. Biol. Chem.
1984, 48, 1841; (b) Evans, D. A.; Burch, J. D. Org. Lett. 2001, 3, 503.
9. (a) Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.; Li, T.;
Faulkner, D. J.; Petersen, M. R. J. Am. Chem. Soc. 1970, 92, 741; (b) Takano, S.;
Sugihara, T.; Samizu, K.; Akiyama, M.; Ogasawara, K. Chem. Lett. 1989, 1781; (c)
Lee, J.; Hong, J. J. Org. Chem. 2004, 69, 6433.
10. The stereochemistry of the tertiary carbon center bearing isoquinoline moiety
was ascertained by X-ray crystallographic analysis of the hydrazone 20, which
was obtained in six steps from the alcohol 10, depicted below. Crystallographic
data (excluding structure factors) for the structure have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication
number CCDC 699923. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44-
(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).

N. Kotoku et al. / Tetrahedron Letters 49 (2008) 7078–7081
7081
11. Data for 3: IR (KBr): 1549, 1732, 2926 cmÀ1
.
1H NMR (300 MHz, CDCl3) d: 0.54
N
N
(3H, s), 1.39–1.57 (5H, m), 1.62–1.99 (4H, m), 3.01 (1H, t, J = 9.8 Hz), 4.00 (1H,
s), 5.23 (1H, dd, J = 1.5, 11.0 Hz), 5.52 (1H, dd, J = 2.0, 17.0 Hz), 6.02 (1H, dd,
J = 11.0, 17.0 Hz), 7.56–7.62 (2H, m), 7.77 (1H, d, J = 8.4 Hz), 8.11 (1H, s), 8.22
(1H, d, J = 5.4 Hz). 13C NMR (125 MHz, CDCl3) d: 13.1, 20.7, 24.0, 25.3, 26.5,
28.6, 32.4, 45.0, 54.2, 57.9, 78.4, 83.9, 107.3, 116.0, 120.4, 125.2, 126.1, 126.8,
132.9, 136.6, 136.9, 140.9, 141.5, 151.3. ESI MS: m/z 424 (M+Na)+. Anal. Calcd
for C24H28ClNO2: C, 72.44; H, 7.09; N, 3.52; Cl, 8.91. Found: C, 72.33; H, 7.25; N,
3.42; Cl, 8.62.
1) Swern
Cl
Cl
2) NaClO2
EtO
EtO
3) TMSCHN2
O
O
MeO2C
HO
10
N
1) LHMDS, –78 °C
2) MgCl2•6H2O,
DMSO, 160 ˚C
Cl
N
NH
X:
3) 2,4-dinitro-
phenylhydrazine
20
O2N
NO2
X