Total synthesis of (+)-cortistatin A

Article abstract of DOI:10.1002/anie.200803550

(Chemical Equation Presented) Marine engineering: A modular strategy featuring an intramolecular 1,4-addition/aldol/dehydration cascade sequence (see scheme; TBS=tert-butyldimethylsilyl) has enabled the total synthesis of cortistatin A, a potent anti-angi

Full text of DOI:10.1002/anie.200803550

Communications
DOI: 10.1002/anie.200803550
Natural Products
Total Synthesis of (+)-Cortistatin A**
K. C. Nicolaou,* Ya-Ping Sun, Xiao-Shui Peng, Damien Polet, and David Y.-K. Chen*
Angiogenesis is an important physiological phenomenon
whose imbalance may result in several disease states, includ-
ing malignant, inflammatory, ischaemic, infectious, and
immune disorders.[1] The inhibition of angiogenesis has been
considered for some time as an attractive way to improve such
conditions. With the recent introduction of the first anti-
angiogenic agents to treat cancer and blindness, the search for
new inhibitors of angiogenesis assumed a new level of priority
and urgency.
human umbilical vein endothelial cells (HUVECs)) and
cortistatin J (2, Scheme 1; IC50 = 8 nm against HUVECs) are
the most potent. Furthermore, these compounds demon-
strated a striking selectivity index against HUVECs when
their activities against normal human dermal fibroblast
(NHDF) and several tumor cells (KB3–1, K562, and
Neuro2A) were compared (1: selectivity index > 3000; 2:
selectivity index 300–1100). The low natural abundance of
these compounds combined with their unprecedented molec-
ular architectures and promising biological properties
prompted us to undertake their chemical synthesis. Herein
we report a total synthesis of cortistatin A (1)[5] through a
flexible synthetic strategy which may be applied to the
construction of other members of the class, natural or
designed.
In 2006[2] and 2007,[3,4] the Kobayashi research group
disclosed a series of novel steroidal alkaloids possessing
remarkable anti-angiogenic properties that endow them with
potent anti-proliferative activities. Isolated from the sponge
Corticium simplex, and named cortistatins, these molecules
boast
a heptacyclic skeleton featuring an oxabicyclo-
[3,2,1]octene and, some, an isoquinoline structural motif.
From the 11 naturally occurring members of the cortistatin
family, cortistatin A (1, Scheme 1; IC50 = 1.8 nm against
Upon cursory inspection, cortistatin A (1) reveals a
unique abeo-9(10-19)-androstane steroidal skeleton onto
whose E ring is attached an isoquinoline moiety. Our
chosen retrosynthetic analysis (Scheme 2) converted 1 into
Scheme 1. Structures of cortistatins A (1) and J (2).
[*] Prof. Dr. K. C. Nicolaou, Dr. Y.-P. Sun, Dr. X.-S. Peng, Dr. D. Polet,
Dr. D. Y.-K. Chen
Chemical Synthesis Laboratory@Biopolis
Institute of Chemical and Engineering Sciences (ICES)
Agency for Science, Technology, and Research (A*STAR)
11 Biopolis Way, The Helios Block, # 03-08, Singapore 138667
(Singapore)
Fax: (+1)858-784-2469
E-mail: kcn@scripps.edu
david_chen@ices.a-star.edu.sg
Prof. Dr. K. C. Nicolaou
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
Scheme 2. Retrosynthetic analysis of cortistatin A (1). a) Sonogashira
coupling; b) Suzuki–Miyaura coupling. TBS=tert-butyldimethylsilyl;
Tf =trifluoromethanesulfonyl.
10550 N. Torrey Pines Rd., La Jolla, CA 92037 (USA)
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
cyclohexanone derivative 3, for whose construction we
envisaged a cascade reaction[6] involving an intramolecular
1,4-addition/aldol/dehydration sequence to forge the penta-
cyclic framework of the molecule, followed by a Suzuki–
Miyaura[7] coupling to install the isoquinoline structural motif
(5!4!3). The required hydroxy dicarbonyl precursor 5 was
then dismantled through a retro-Sonogashira[8] reaction into
cyclohexenone triflate 6 and terminal acetylene 7.
[**] We thank Doris Tan (ICES) for high-resolution mass spectrometric
assistance and Dr. Tommy Wang Chern Hoe (Institute of Molecular
and Cell Biology (IMCB)—A*STAR) for X-ray crystallographic
analysis. Financial support for this work was provided by A*STAR,
Singapore.
The construction of the required acetylenic compound 7 is
summarized in Scheme 3. Thus, starting with enantiomerically
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803550.
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Scheme 3. Construction of acetylene 7. Reagents and conditions:
a) OsO4 (0.02 equiv), NMO (2.5 equiv), acetone/H2O (8:1), 238C,
16 h, 73%; b) Me2C(OMe)2 (5.0 equiv), p-TsOH (0.04 equiv), acetone,
238C, 1 h, 87%; c) NaHMDS (1.0m in THF, 1.2 equiv), PhNTf2
(1.1 equiv), THF, 08C, 2 h; d) [Pd(PPh3)4] (0.05 equiv), Et3N
(3.0 equiv), CO, DMF/MeOH (5:2), 708C, 3 h, 72% for the two steps;
e) DIBAL-H (1.0m in toluene, 3.0 equiv), toluene, ꢀ788C, 3 h, 79%;
f) DMP (1.5 equiv), NaHCO3 (4.6 equiv), CH2Cl2, 238C, 30 min, 86%;
g) HS(CH2)3SH (3.0 equiv), BF3·OEt2 (3.5 equiv), CH2Cl2, ꢀ788C, 1.5 h,
70%; h) SO3·py (3.0 equiv), Et3N (5.0 equiv), CH2Cl2/DMSO (4:1),
238C, 1.5 h, 72%; i) p-TsN3 (1.5 equiv), dimethyl-2-oxopropylphospho-
nate (13) (1.5 equiv), K2CO3 (3.5 equiv), CH3CN, 238C, 2 h; then
aldehyde from 12, MeOH/THF/MeCN (1:1:3), 238C, 16 h, 45% after
two cycles. NMO=N-methylmorpholine N-oxide; p-TsOH=para-tolue-
nesulfonic acid; NaHMDS=sodium hexamethyldisilazide;
Scheme 4. Construction of pentacyclic dienone 16 through a hydroxy
1,4-addition/aldol/dehydration cascade. Reagents and conditions:
a) [Pd(PPh3)4] (0.1 equiv), CuI (0.1 equiv), Et3N (3.0 equiv), 6
(1.4 equiv, from 1,3-cyclohexadione, Tf2O, and Et3N), DMF, 238C, 1 h,
85%; b) IBX (4.0 equiv), DMSO, 0 ! 238C, 4 h, 81%; c) Pd/BaSO4
(5% wt/wt, 0.24 equiv), H2, MeOH/THF (1:1), 238C, 30 min, 64%;
d) K2CO3 (1.2 equiv), dioxane, 1258C, 12 h, 52%. IBX=o-iodoxyben-
zoic acid.
aldehyde functionality from 14 with IBX,[12] followed by
chemoselective hydrogenation (H2, Pd/BaSO4), then led to
the desired cascade precursor 5 in 52% overall yield for the
two steps. Pleasingly, the much anticipated 1,4-hydroxy enone
addition/aldol/dehydration cascade proceeded smoothly upon
heating hydroxy enone-enal 5 at reflux in dioxane in the
presence of K2CO3 to afford pentacyclic dienone 16[5b] in 52%
yield, presumably through the intermediacy of 4 and 15, as
shown in Scheme 4.
Scheme 5 summarizes the final stages of the synthesis of
cortistatin A (1) that secured the attachment of the isoquino-
line structural motif on ring E and installed the required
functional groups on ring A. Our chosen sequence of
functionalization necessitated temporary protection of the
carbonyl group of 16 as its dioxolane derivative (TMSO-
(CH2)2OTMS, TMSOTf), which was subsequently converted
into ketone 17 through desilylation (TBAF, 56% yield for the
two steps) and oxidation (SO3·py, 80% yield). The enol
triflate derived from 17, through the action of PhNTf2 and
KHMDS, was then coupled to isoquinoline boronic ester 18[13]
through a Suzuki–Miyaura reaction (cat. [Pd(PPh3)4], K2CO3)
to afford alkenyl isoquinoline 19 in 50% overall yield for the
two steps. Removal of the dioxolane group from 19 (p-TsOH,
acetone/H2O, 88% yield) followed by stereo- and chemo-
selective hydrogenation (10% Pd/C, MeOH) led to isoquino-
line dienone 3 in 50% yield (plus 30% recovered starting
material). The desired stereochemical outcome of this
reduction was expected on steric grounds, an assumption
that was supported by a molecular modeling study,[14] and
which was ultimately confirmed by the synthesis of 1 (see
DMF=N,N’-dimethylformamide; DMP=Dess–Martin periodinane;
DIBAL-H=diisobutylaluminium hydride; DMSO=dimethylsulfoxide;
p-TsN3 =para-toluenesulfonylazide; py=pyridine.
enriched bicyclic enone 8,[9] acetonide 9 was prepared in 64%
overall yield through
a stereoselective dihydroxylation
(NMO, cat. OsO4) followed by exposure of the resulting
diol to Me2C(OMe)2 in the presence of a catalytic amount of
p-TsOH. Conversion of ketone 9 into its enol triflate (PhNTf2,
NaHMDS) followed by methoxy carbonylation under the
standard conditions led to methyl ester 10 in 72% overall
yield. The latter compound was then converted into aldehyde
11 through a reduction/oxidation sequence (1. DIBAL-H,
79% yield; 2. DMP, 86% yield). Treatment of aldehyde 11
with HS(CH2)3SH in the presence of BF3·OEt2 at ꢀ788C
resulted in protection of the aldehyde moiety and concom-
itant removal of the acetonide group, thereby affording
dihydroxy dithiane 12 in 70% yield. Finally, oxidation of 12
under the Parikh–Doering[10] conditions (SO3·py) furnished
the hydroxy aldehyde (72% yield), which was treated with
Ohira–Bestman[11] reagent (ketophosphonate 13, p-TsN3,
K2CO3), generated in situ, to afford the desired acetylenic
compound 7 in 45% yield.
Scheme 4 depicts the four-step elaboration of intermedi-
ate 7 to pentacyclic framework 16. Thus, Sonogashira
coupling of 7 (cat. [Pd(PPh3)4], CuI, Et3N) with freshly
prepared enol triflate 6 (1,3-cyclohexadione, Tf2O, Et3N)
furnished enynone 14 smoothly in 85% yield. Unveiling of the
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tographically separable, isomeric epoxide-opened product
(36%),[17] through the action of Me2NH in the presence of
1
Ti(OiPr)4 (45%, unoptimized). The H and 13C NMR spec-
troscopic and mass spectrometric data of synthetic 1 were
consistent with those reported for the natural product.[2,5a]
Furthermore,
synthetic
1
exhibited
[a]2D5 =
+ 30.7 degcm3 gꢀ1 dmꢀ1 (c = 0.05 gcmꢀ3, MeOH) [lit. [a]2D0 =
+ 30.1 degcm3 gꢀ1 dmꢀ1 (c = 0.56 gcmꢀ3, MeOH).[2,5a]
The described chemistry, in addition to rendering cortis-
tatin A (1) readily available for further biological investiga-
tions, opens an entry to other members of the cortistatin
family, natural and designed, for screening purposes.[18]
Received: July 21, 2008
Published online: August 14, 2008
Keywords: antitumor agents · cascade reactions ·
.
natural products · total synthesis
[1] P. Carmeliet, Nature 2005, 438, 932– 936.
[2] S. Aoki, Y. Watanabe, M. Sanagawa, A. Setiawan, N. Kotoku, M.
Kobayashi, J. Am. Chem. Soc. 2006, 128, 3148 – 3149.
[3] Y. Watanabe, S. Aoki, D. Tanabe, A. Setiawan, M. Kobayashi,
Tetrahedron 2007, 63, 4074 – 4079.
[4] S. Aoki, Y. Watanabe, D. Tanabe, A. Setiawan, M. Arai, M.
Kobayashi, Tetrahedron Lett. 2007, 48, 4485 – 4488.
[5] For the first synthesis of cortistatin A, see: a) R. A. Shenvi, C. A.
Guerrero, J. Shi, C.-C. Li, P. S. Baran, J. Am. Chem. Soc. 2008,
130, 7241 – 7243; for studies toward the synthesis of cortistatins,
see: b) S. Yamashita, K. Iso, M. Hirama, Org. Lett. 2008, DOI:
10.1021/o18012099; c) E. M. Simmons, A. R. Hardin, X. Guo, R.
Sarpong, Angew. Chem. 2008, DOI: 10.1002/anie.200802203;
Angew. Chem. Int. Ed. 2008, DOI: 10.1002/anie.200802203.
[6] For a recent review on cascade reactions in total synthesis, see:
K. C. Nicolaou, D. J. Edmonds, P. G. Bulger, Angew. Chem. 2006,
118, 7292 – 7344; Angew. Chem. Int. Ed. 2006, 45, 7134 – 7186.
[7] S. Kotha, K. Lahiri, D. Kashinath, Tetrahedron 2002, 58, 9633 –
9695.
[8] K. Sonogashira, Handbook of Organopalladium Chemistry for
Organic Synthesis, Vol. 1, Wiley-Interscience, New York, 2002,
pp. 493 – 529.
[9] Compound 8 was synthesized from the Hajos–Parrish ketone
according to procedure described by Danishefsky and co-
workers. For the synthesis of ent-8, see: R. C. A. Isaacs, M. J.
Di Grandi, S. J. Danishefsky, J. Org. Chem. 1993, 58, 3938 – 3941.
For the preparation of the Hajos–Parrish ketone (94% ee, as
determined by optical rotation), see: Organic Syntheses 1990,
Coll. Vol. 7, 363 – 368.
[10] J. R. Parikh, W. V. E. Doering, J. Am. Chem. Soc. 1967, 89, 5505 –
5507.
[11] a) S. Ohira, Synth. Commun. 1989, 19, 561 – 564; b) S. Müller, B.
Liepold, G. J. Roth, H. J. Bestmann, Synlett 1996, 521 – 522;
c) G. J. Roth, B. Liepold, S. G. Müller, H. J. Bestmann, Synthesis
2004, 59 – 62.
Scheme 5. Completion of the total synthesis of cortistatin A (1).
Reagents and conditions: a) TMSO(CH2)2OTMS (5.0 equiv), TMSOTf
(1.5 equiv), CH2Cl2, ꢀ60!ꢀ108C, 1.5 h; b) TBAF (1.0 m in THF,
7.0 equiv), THF, 238C, 2 h, 56% for the two steps; c) SO3·py
(6.0 equiv), Et3N (10.0 equiv), CH2Cl2/DMSO (3:1), 238C, 3 h, 80%;
d) KHMDS (0.5m in toluene, 3.0 equiv), THF, ꢀ788C, 1 h, then PhNTf2
(5.0 equiv), 0.5 h; e) 18 (3.3 equiv), [Pd(PPh3)4] (0.3 equiv), K2CO3
(3.0 equiv), THF, 808C, 2 h, 50% for the two steps; f) p-TsOH
(1.5 equiv), acetone/H2O (10:1), 238C, 1 h, 88%; g) Pd/C (10% wt/wt,
0.3 equiv), H2, MeOH, 238C, 1 h, 50% (71% based on recovered
starting material); h) TMSOTf (14 equiv), Et3N (30 equiv), THF, ꢀ78!
08C, 1.5 h; i) IBX·MPO (0.4 m in DMSO, 6.0 equiv), DMSO, 238C, 6 h,
46% for the two steps; j) tBuOOH (6.0 equiv), DBU (3.0 equiv),
CH2Cl2, 0!238C, 5 h, 70%; k) NaBH4 (1.0 equiv), CeCl3 (4.0 equiv),
MeOH, 08C, 10 min, 80% (ca. 1:1 mixture of diastereoisomers);
l) DMP (5.0 equiv), NaHCO3 (10.0 equiv), CH2Cl2, 238C, 2 h, 100%;
m) Me2NH (2.0m in THF, as solvent), Ti(OiPr)4 (5.0 equiv), 808C, 5 h,
45%. TBAF=tetra-n-butylammonium fluoride; KHMDS=potassium
hexamethyldisilazide, TMS=trimethylsilyl; MPO=4-methoxypyridine
N-oxide; DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
below). All that now remained to reach the target (1) was the
functionalization of ring A. To this end, dienone 3 was
transformed to trienone 20 through exposure of its TMS
enolate (TMSOTf, Et3N) to IBX·MPO[15] (46% overall yield,
unoptimized) and the latter compound was subjected to the
action of tBuOOH in the presence of DBU to afford epoxide
21 (70% yield), whose b stereochemistry was tentatively
assigned on the basis of steric considerations and supported
by a related model study.[16] This assignment was later
confirmed by reaching 1 (see below). Thus, reduction of
ketoepoxide 21 with NaBH4/CeCl3 furnished a mixture of
hydroxy epoxide 22 and its b-OH isomer 23 (ca. 1:1 d.r., 80%
total yield), which were separated by chromatography. While
the b-OH isomer 23 could be recycled by oxidation (DMP,
100% yield)—reduction (NaBH4/CeCl3), the a-OH isomer 22
was converted into cortistatin A (1), together with a chroma-
[12] K. C. Nicolaou, C. J. N. Mathison, T. Montagnon, J. Am. Chem.
Soc. 2004, 126, 5192– 5201.
[13] Prepared from 7-bromoisoquinoline by: a) [Pd(dppf)2Cl2],
KOAc, bispinacolato diboron, DMSO, 808C, 50%; for the
preparation of 7-bromoisoquinoline, see: B. R. Miller, J. M.
Frincke, J. Org. Chem. 1980, 45, 5312– 5315.
[14] Chemo- and stereoselective hydrogenation of the cyclopentenyl
isoquinoline system was first demonstrated with model system
24, and confirmed by X-ray crystallographic analysis of the
hydrogenated product 25. CCDC 684134 contains the supple-
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mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
[16] The chemo- and facial selectivity of 1,4-addition to simplified
trienone system 26 was first demonstrated in a model study
towards cortistatin J, where detailed NMR analysis of trienyl
dimethylamine 29 revealed the 1,4-addition took place from the
b face.
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
[17] The isomeric epoxide-opened product is tentatively assigned as
the C2,C3 regioisomer 30 of cortistatin A (1) on the basis of
1H NMR,
13C
NMR,
and
MS
analysis.
ORTEP drawing of 25 with thermal ellipsoids shown at the 50%
probability level.
[15] K. C. Nicolaou, D. L. F. Gray; T. Montagnon; S. T. Harrison,
Angew. Chem. 2002, 114, 1038 – 1042; T. Montagnon; S. T.
Harrison, Angew. Chem. 2002, 114, 1038 – 1042; Angew. Chem.
Int. Ed. 2002, 41, 996 – 1000.
[18] For a structural–activity relationship study of naturally occurring
cortistatins, see: S. Aoki, Y. Watanabe, D. Tanabe, M. Arai, H.
Suna, K. Miyamoto, H. Tsujibo, K. Tsujikawa, H. Yamamoto, M.
Kobayashi, Bioorg. Med. Chem. 2007, 15, 6758 – 6762.
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