Additionally, we have studied the synthesis of the cor-
tistatin skeleton by B-ring homologation of readily accessible
estrone derivatives. Our group has in the past few years
developed three efficient and simple enantioselective routes
to estrone (and analogues).5 This chemistry is potentially
useful for the total synthesis of the cortistatins, as well as
for simple analogues. A retrosynthetic sequence for such a
synthesis is outlined in Scheme 1.
Scheme 2
.
First-Generation Functionalization of (+)-Estrone
and Ring-Expansion Studies
Scheme 1
.
Retrosynthetic Analysis of Cortistatin A and
Structural Analogues
Exposure of mesylate 6 (or the corresponding C19
chloride) to a variety of ionizing conditions (e.g., NaOAc,
AcOH, reflux; AgNO3, MeCN, reflux) did not yield any of
the required B-ring homologated compound 7. Analysis of
the products isolated from these reactions indicated that
substitution occurred at C19 rather than B-ring expansion
of the intermediate phenonium ion (Figure 2).
The two key steps in our retrosynthetic analysis (Scheme
1) are as follows: (1) cationic ring-expansion of intermediate
4 to expand ring B and (2) oxidative dearomatization of
intermediate 3 to install the required [3.2.1]oxabicyclic ring
system.
Figure 2. (A) Compounds that were prepared/isolated during the
According to this plan, (+)-estrone was converted to the
C11 ketone 5 in five steps: dehydrogenation,6 methylation
and ketalization, epoxidation with dioxirane, and LiClO4-
catalyzed epoxide-ketone rearrangement7 (Scheme 2). R-Hy-
droxymethylation of 5 and mesylation gave 6.
ring-expansion studies of 6. (B) Hypothetical R-acyl cation inter-
mediate.
We turned our attention to an alternative strategy which
would allow the direct functionalization of the C9 benzylic
position of estrone without requiring the presence of a
carbonyl group at C11. We were guided by literature
examples for the simultaneous oxidation/benzylic cyanation
of various simple aromatic hydrocarbons using DDQ/
TMSCN in CH2Cl2 or MeCN.8
After extensive experimentation, conditions were found
in which compound 8 could be converted to the correspond-
ing C9 benzylic cyanide derivative 9 in nearly quantitative
yield (Scheme 3 and 4). During the optimization studies, we
(4) For recent total syntheses 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, 7241–7243. (b) Nicolaou, K. C.; Sun, Y.-P.; Peng, X.-S.; Polet, D.;
Chen David, Y. K. Angew. Chem., Int. Ed. 2008, 47, 7310–7313. For other
studies toward the synthesis of cortistatins, see: (c) Simmons, E. M.; Hardin,
A. R.; Guo, X.; Sarpong, R. Angew. Chem., Int. Ed. 2008, 47, 6650–6653.
(d) Yamashita, S.; Iso, K.; Hirama, M. Org. Lett. 2008, 10, 3413–3415.
(5) (a) Yeung, Y.-Y.; Chein, R.-J.; Corey, E. J. J. Am. Chem. Soc. 2007,
129, 10346–10347. (b) Canales, E.; Corey, E. J. Org. Lett. 2008, 10, 3271–
3273. (c) Hu, Q.-Y.; Rege, P. D.; Corey, E. J. J. Am. Chem. Soc. 2004,
126, 5984–5986.
(6) Brown, W.; Findlay, J. W. A.; Turner, A. B. Chem. Commun. 1968,
10, 11.
(7) (a) Rickborn, B.; Gerkin, R. M. J. Am. Chem. Soc. 1968, 90, 4193–
4194. (b) Rickborn, B.; Gerkin, R. M. J. Am. Chem. Soc. 1971, 93, 1693–
1700.
(8) Lemaire, M.; Doussot, J.; Guy, A. Chem. Lett. 1988, 1581–1584.
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