An oxidative dearomatization cyclization model for cortistatin A

Article abstract of DOI:10.3987/COM-08-S(F)6

The feasibility of a hypervalent iodine-mediated oxidative dearomatization/cyclization to produce the oxabicyclo[3.2.1]octene of cortistatin A has been demonstrated through a model study. An interesting tandem cyclization via a Ritter intermediate has been observed when a slightly different substrate was used.

Full text of DOI:10.3987/COM-08-S(F)6

HETEROCYCLES, Vol. 77, No. 1, 2009
157
HETEROCYCLES, Vol. 77, No. 1, 2009, pp. 157 - 161. © The Japan Institute of Heterocyclic Chemistry
Received, 12th March, 2008, Accepted, 15th April, 2008, Published online, 17th April, 2008.
DOI: 10.3987/COM-08-S(F)6
AN OXIDATIVE DEAROMATIZATION CYCLIZATION MODEL FOR
CORTISTATIN A
Mingji Dai1 and Samuel J. Danishefsky1,2,*
1Department of Chemistry, Columbia University, 3000 Broadway, New York, NY
2
10027 and Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for
Cancer Research, 1275 York Ave., New York, NY 10065 (USA),
s_danishefsky@mskcc.org
Abstract – The feasibility of a hypervalent iodine–mediated oxidative
dearomatization/cyclization to produce the oxabicyclo[3.2.1]octene of cortistatin
A has been demonstrated through a model study. An interesting tandem
cyclization via a Ritter intermediate has been observed when a slightly different
substrate was used.
Dedication – We dedicate this manuscript to Professor Emeritus Keiichiro
Fukumoto for his continuing studies in organic chemistry.
The cortistatins, a novel class of steroidal alkaloids, were recently isolated by Kobayashi and coworkers
from the marine sponge, Corticium simplex (Figure 1). Cortistatin A (1), in particular, was found to be a
potent and selective inhibitor of angiogenesis, exhibiting cytostatic antiproliferative activity against
human umbilical vein endothelial cells (HUVECs) at concentrations as low as 100 pM.1 The high
selectivity observed for the endothelial (HUVEC) cell line, in comparison with other normal and
cancerous cell lines, suggests that cortistatin A (1) is, in fact, a selective angiogenesis inhibitor.
Angiogenesis, the process of forming new blood vessels, is essential to a variety of critical functions,
from reproduction to wound repair. However, persistent and unregulated angiogenesis has been
implicated in a range of maladies, including the progression of solid tumors, diabetic retinopathy,
psoriasis, and rheumatoid arthritis.2 Since tumor growth and metastasis are highly dependent on
angiogenesis, there is great interest in exploring the therapeutic potential of small molecule
anti-angiogenesis agents, such as cortistatin A (1).

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Structurally, the cortistatins are a unique family of 9(10-19)-abeo-androstane-type steroidal alkaloids
possessing both an oxabicyclo[3.2.1]octene and an isoquinoline unit or its precursor. Intrigued by the
therapeutic potential of a selective anti-angiogenic agent and the synthetic challenges presented by the
cortistatin structural framework, we have initiated an effort directed toward the total synthesis of
cortistatin A (1). Our convergent synthetic plan would be highly amenable to the preparation of a
variety of analogs through diverted total synthesis.
OH
Me
N
Me
N
HO
O
O
Me
Me
H
N
R
H
N
Me
Me
cortistatin A (1): R = H
cortistatin B (2): R = OH
cortistatin J (5)
Me
Me
OH
Me
N
HO
R
N
O
H
O
Me
Me
Me
Me
H
N
H
O
N
Me
Me
cortistatin F (6)
cortistatin C (3): R = H
cortistatin D (4): R = OH
Figure 1. Representative steroidal alkaloids from the cortistatin family.
As outlined in Scheme 1, a defining transformation of our proposed synthetic route would involve the use
of a hypervalent iodine3–mediated oxidative dearomatization to produce the oxabicyclo[3.2.1]octene of
cortistatin A (1). Under this plan, electrophilic intermediate (8) would be generated through
PIFA-mediated oxidation of phenol 7. Intramolecular interception of 8 would yield the target compound
(9). This intermediate could serve as a key launching point, from which we could prepare a range of
cortistatin analogs through diverted total synthesis.
In designing our synthetic route, we were well aware of some potential liabilities associated with the
proposed key transformation. Thus, although a variety of inter- and intramolecular nucleophiles have
been used to trap electrophilic intermediates generated through PIFA activation of phenols,4 tertiary
alcohols have rarely been used for this purpose.5 We were further mindful of the potential for
exacerbating ring strain as a consequence of the proposed transformation. With these considerations in
mind, we commenced our investigations toward cortistatin A with an admittedly early stage model study
which would seek to learn something about the feasibility of the key oxidative dearomatization
cyclization sequence.

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159
I(III)
Me
Me
H
R
HO
Y
PIFA
O
R
H
OH
Y
OH
7
8
OH
Me
Me
N
R
O
HO
O
O
Me
H
H
Y
N
Me
9
cortistatin A (1)
Scheme 1. Synthetic plan for cortistatin A (1).
We chose as our model substrates, 17 and 18. The synthesis of these compounds commenced with
7-methoxy-1-tetralone (10).6 Reduction of the latter, followed by acid promoted dehydration, afforded
olefin (11) which, without further purification, was treated with bromoform and potassium tert-butoxide
in pentane at –10 ºC to give adduct (12) in 83% yield for 3 steps.7 Solvolysis of 12 with 3 equiv of
silver perchlorate in 95/5 (v/v) acetone-water gave a 74% yield of the allylic alcohol (13), which was
immediately oxidized with MnO2 to afford ring expanded bromoenone (14). Treatment of the latter with
methyllithium led to a mixture of debrominated enone (15) and the debrominated 1,2-addition product
(16) in 34% and 30% yield respectively. Enone (15) could be transformed to allylic alcohol (16) by
further treatment of methyllithium (quantitative yield based on recovering starting material).8
Demethylation in the presence of NaSEt gave the model substrate, phenol (17). Finally, Pd-C catalyzed
hydrogenation of 17 afforded the second model compound (18).
Br
O
Br
Br
Br
MeO
MeO
MeO
MeO
MeO
a
b
c
d
O
OH
h
14
11
12
10
13
MeO
HO
MeO
HO
OH
Me
OH
Me
OH
Me
e
g
O
+
f
15
16
18
17
Scheme 2. Synthesis of model compounds for oxidative dearomatization cyclization. a) (i) NaBH4,
EtOH, rt; (ii) TsOH, PhH, reflux; b) CHBr3, KOtBu, pentane, –10 ºC → rt, 83% over 3 steps; c) AgClO4,
acetone/H2O (95:5), 50 ºC, 74%; d) MnO2, CH2Cl2, rt, 83%; e) MeLi, THF, –78 ºC → 0 ºC, 15 (34%), 16
(30%); f) MeLi, THF, –78 ºC → 0 ºC, 67% (33% recovered SM); g) NaSEt, DMF, reflux, 77%; h) Pd/C,
H2, MeOH, rt, 97%.

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With both 17 and 18 in hand, we were prepared to explore the key oxidative dearomatization cyclization.
As shown in Scheme 3, we found that, when a solution of 17 in acetonitrile was treated with 1.0 eq. of
PIFA in the presence of 2.0 eq. K2CO3, the desired cyclized product (19) was obtained in approximately
1
13
30% yield, with 30% of the starting material recycled. In addition to the H NMR and C NMR, the
structure of 19 was further verified by X-ray crystallography. Efforts to optimize the reaction through
an increase in the amount of oxidizing agent were unsuccessful, as the use of 2.0 eq. of PIFA provided a
lower yield of the desired product (19). Interestingly, when 18 was submitted to the same reaction
conditions, none of the desired product (20) was observed. Instead, a 30% yield of 23 was obtained. A
proposed mechanism for the formation of 23 is shown in Scheme 3. It appears that the electrophilic
intermediate (21) produced through PIFA activation of 18, is attacked by acetonitrile in a Ritter reaction,9
to form 22, which is further trapped by the intramolecularly situated tertiary hydroxyl group, to afford
23.10 The divergent pathways observed in the oxidative cyclization of 17 and 18 may be attributed to
conformational constraints imposed by the double bond in 17. A similar observation has in fact been
reported by Pelter and co-workers.5a In order to avoid the participation of acetonitrile, other solvents
such as toluene, CH2Cl2 and HFIP (hexafluoroisopropanol), were also explored. Unfortunately, each
suffered from low solubility of the phenols (17 and 18) or low reaction yield. However, although only
modest yields were achieved in our model study, we have demonstrated the viability of the oxidative
dearomatization cyclization sequence in generating an element of the core structure of cortistatin A.
Conceivably, means can be uncovered to deal with the solubility issues which have compromised our
efforts in the model system.
Scheme 3. Model study for oxidative dearomatization cyclization. a) PIFA (1.0 equiv), K2CO3, MeCN,
rt, 30% (30% recovered SM); b) PIFA (1.0 equiv), K2CO3, MeCN, rt, 30% 23, 0% 20.

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In summary, the feasibility of our oxidative dearomatization cyclization approach to cortistatin A has
been demonstrated through a model study. An interesting tandem cyclization via Ritter intermediate has
been observed. Efforts are currently underway to apply the oxidative dearomatization cyclization
sequence to an efficient synthesis of cortistatin A (1).
ACKNOWLEDGEMENTS
We are grateful to the National Institutes of Health (HL25848) for financial support of this research. We
thank Ms. Daniela Buccella for crystal structure analysis. M. D. thanks the Guthikonda family for a
graduate fellowship (2007-2008).
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