A hypervalent iodine-induced double annulation enables a concise synthesis of the pentacyclic core structure of the cortistatins

Article abstract of DOI:10.1021/ol902168g

"Chemical Equation Presented" A stereocontrolled synthesis of a complex pentacycle embodying the molecular architecture of the cortistatin class of natural products was achieved from the (+)-Hajos-Parrish ketone. The cornerstone of our approach Is a hyper

Full text of DOI:10.1021/ol902168g

ORGANIC
LETTERS
2009
Vol. 11, No. 23
5394-5397
A Hypervalent Iodine-Induced Double
Annulation Enables a Concise Synthesis
of the Pentacyclic Core Structure of the
Cortistatins
Jessica L. Frie, Christopher S. Jeffrey, and Erik J. Sorensen*
Department of Chemistry, Princeton UniVersity, Frick Chemical Laboratory,
Princeton, New Jersey 08544
ejs@princeton.edu
Received September 18, 2009
ABSTRACT
A stereocontrolled synthesis of a complex pentacycle embodying the molecular architecture of the cortistatin class of natural products was achieved
from the (+)-Hajos-Parrish ketone. The cornerstone of our approach is a hypervalent iodine induced tandem intramolecular oxidative dearomatization
and nitrile oxide cycloaddition. The manner in which these ring formations were orchestrated has yielded a rather concise strategy for synthesis.
Since the discovery of the antiangiogenic properties of
fumagillin and TNP-470 by Folkman and co-workers,1 there
has been an active interest in the identification of new natural
products and druglike small molecules that are capable of
inhibiting the proliferation of endothelial cells in vitro and
tumor-induced angiogenesis in vivo. Inhibitors of this process
are of considerable interest as potential therapeutic agents
because unregulated angiogenesis can contribute to the
growth and metastasis of malignant tumors and inflammatory
diseases.2 In three publications, Kobayashi and co-workers
described the intricate structures of 11 rearranged steroidal
alkaloids of which several members are potent and selective
inhibitors of endothelial cell growth.3 These compounds were
isolated from the Indonesian marine sponge Corticium
simplex and aptly named the cortistatins. Cortistatin A (1)
Figure 1. Molecular structure of (+)-cortistatin A (1).
(Figure 1), the parent and most active member of this family,
inhibits human umbilical vein endothelial (HUVEC) cells
with an IC50 of 1.8 nM.3 A remarkable aspect of cortistatin
A is that it suppresses HUVEC cell growth without killing
the cells;4 cortistatin A is thus cytostatic, not cytotoxic.
Though the mechanism for the promising biological activity
remains unknown, a recent report identifies cortistatin A as
a high-affinity ligand of various protein kinases.5
(1) Ingber, D.; Fujita, T.; Kishimoto, S.; Sudo, K.; Kanamaru, T.; Brem,
H.; Folkman, J. Nature 1990, 348, 555.
(2) (a) Folkman, J. New Engl. J. Med. 1971, 285, 1182. (b) Folkman, J.
New Engl. J. Med. 1995, 333, 1757. (c) Folkman, J. Nat. Med. 1995, 1, 27.
(d) Giannis, A.; Ru¨bsam, F. Angew. Chem. 1997, 109; Angew. Chem., Int.
Ed. Engl. 1997, 36, 588. (e) Taunton, J. Chem. Biol. 1997, 4, 493.
(3) (a) Aoki, S.; Watanabe, Y.; Sanagawa, M.; Setiawan, A.; Kotoku,
N.; Kobayashi, M. J. Am. Chem. Soc. 2006, 128, 3148. (b) Aoki, S.;
Watanabe, Y.; Tanabe, D.; Setiawan, A.; Arai, M.; Kobayashi, M.
Tetrahedron Lett. 2007, 48, 4485. (c) Watanabe, Y.; Aoki, S.; Tanabe, D.;
Setiawan, A.; Kobayashi, M. Tetrahedron 2007, 63, 4074.
All of the cortistatins share a unique pentacyclic core
structure and differ mostly in the nature of the substituent
attached to C-17 (steroid numbering) and/or the degree of
(4) 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.
10.1021/ol902168g CCC: $40.75
Published on Web 10/30/2009
 2009 American Chemical Society

functionalization found in ring A. The rigid core framework
of the cortistatins, with its seven-membered B ring and
challenging tetrahydrofuran heterocycle, has inspired a
growing number of creative undertakings in the area of
chemical synthesis. The laboratories of Baran,6 Nicolaou and
Chen,7 and Shair8 have achieved impressive syntheses of
the full structure of cortistatin A (1), while the groups of
Sarpong,9 Hirama,10 Danishefsky,11 Gung,12 Yang,13 Koba-
yashi,14 and Magnus15 have described conceptually interest-
ing approaches to key elements of the cortistatin structure.
Our laboratory was also drawn to the problem of synthesizing
the polycyclic ring system that distinguishes the cortistatin
class. In the course of dealing with this problem, we
discovered that the reagent [bis(acetoxy)iodo]benzene is
capable of triggering a productive double annulation that
serves the synthesis by establishing three required bonds and
two ring systems. Our construction of the pentacyclic core
framework of the cortistatins featuring this hypervalent
iodine-mediated transformation is described in this report.
In the design phase, we envisioned that the pentacyclic
core of cortistatin A might arise from three independent
cyclization events, two of which would be nitrone/alkene [3
+ 2] dipolar cycloadditions. The first dipolar cycloaddition
would accomplish a merger of fragments (2 + 3 f 4,
Scheme 1) and simultaneously construct the crowded C8-O
bond as well as the C6-C7 bond. After dismantling the
newly formed isoxazolidine ring system in 4 by an unprec-
edented type of double reduction,16 we would then elaborate
complex nitrone 5 as a prelude to the key transformation of
the synthesis. In principle, a structure of the type 5 could be
directly transformed to a cortistatin-like pentacycle (cf. 7)
by an oxidative cyclodearomatization with interception of
the resulting dienone by an intramolecular nitrone/alkene
cycloaddition (see 5 f 6 f 7); an analysis of a molecular
model of 6 suggested that such a cycloaddition should be
diastereoface-selective and facile owing to an enforced
proximity of the nitrone moiety and one of the alkenes of
the cyclic dienone. If successful, this one laboratory operation
would fashion two carbon-oxygen bonds as well as the
central B-ring of the cortistatin system. From an intermediate
of type 7, a synthesis of (+)-cortistatin A (1) would require
Scheme 1. Plan for Synthesizing (+)-Cortistatin A (1) Featuring
Two Nitrone/Alkene Cycloadditions and an Oxidative
Cyclodearomatizationa
a R ) alkyl group; P ) protecting group.
a reductive cleavage of the isoxazolidine N-O bond,
elimination of the amino function, functionalization of the
newly desymmetrized A ring, and the introduction of the
C-17 isoquinoline system.
At the outset, we favored the idea of constructing the
cortistatin core structure on the foundation provided by the
(+)-Hajos-Parrish ketone (8) (Scheme 2).17 This popular
building block for asymmetric synthesis18 comprises two
rings, both of which are expressed in the structures of the
cortistatins, and furnishes the methyl-bearing, quaternary
stereogenic center corresponding to position 13 in the goal
system. This one stereocenter was expected to direct the
stereochemical development of the entire effort. Thus, from
(+)-Hajos-Parrish ketone (8), key intermediate 2 (P ) Sit-
BuMe2) was fashioned by an improved method19 through
the following sequence of reactions (Scheme 2): (1) a site-
selective reduction of the unconjugated ketone in 8 with
sodium borohydride, (2) protection of the resulting secondary
alcohol in the form of a tert-butyldimethylsilyl ether, (3)
(5) Cee, V. J.; Chen, D. Y.-K.; Lee, M. R.; Nicolaou, K. C. Angew.
Chem., Int. Ed. [Online early access]. DOI: 10.1002/anie.200904778.
Published Online: October 20, 2009.
(6) Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C. C.; Baran, P. S. J. Am.
Chem. Soc. 2008, 130, 7241.
(7) (a) Nicolaou, K. C.; Sun, Y.-P.; Peng, X.-S.; Polet, D.; Chen, D. Y.-
K. Angew. Chem., Int. Ed. 2008, 47, 7310. (b) Nicolaou, K. C.; Peng, X.-
S.; Sung, Y.-P.; Polet, D.; Zou, B.; Shik, C. L.; Chen, D. D. Y.-K. J. Am.
Chem. Soc. 2009, 131, 10587.
(8) Lee, H. M.; Nieto-Oberhuber, C.; Shair, M. D. J. Am. Chem. Soc.
2008, 130, 16864.
(9) Simmons, E. M.; Hardin, A. R.; Guo, X.; Sarpong, R. Angew. Chem.,
Int. Ed. 2008, 47, 6650.
(10) Yamashita, S.; Iso, K.; Hirama, M. Org. Lett. 2008, 10, 3413.
(11) (a) Dai, M.; Danishefsky, S. J. Tetrahedron Lett. 2008, 49, 6610.
(b) Dai, M.; Wang, Z.; Danishefsky, S. J. Tetrahedron Lett. 2008, 49, 6613.
(c) Dai, M.; Danishefsky, A. Heterocycles 2009, 77, 157.
(12) Craft, D. T.; Gung, B. W. Tetrahedron Lett. 2008, 49, 5931.
(13) Liu, L.; Gao, Y.; Che, C.; Wu, N.; Wang, D. Z.; Li, C. C.; Yang,
Z. Chem. Commun. 2009, 662.
(16) N-O reduction attended by benzylic C-N hydrogenolysis is an
unprecedented transformation.
(17) (a) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. (b)
For preparation of the Hajos-Parrish ketone, see: Org. Synth. 1990, 7, 363.
(18) For discussions of the utility of the Hajos-Parrish ketone for the
enantioselective synthesis of steroids see: Chapelon, A.-S.; Morale`da, D.;
Rodriguez, R.; Ollivier, C.; Santelli, M. Tetrahedron 2007, 63, 11511.
(14) Kotoku, N.; Sumii, Y.; Hayashi, T.; Kobayashi, M. Tetrahedron
Lett. 2008, 49, 7078.
(15) Magnus, P.; Littich, R. Org. Lett. 2009, 11, 3938.
Org. Lett., Vol. 11, No. 23, 2009
5395

carboxylation of the R position of the enone system in 9
with methyl magnesium carbonate (Stiles’s reagent), (4)
hydrogenation of the alkene in compound 10 to establish
the C-14 stereogenic center, and (5) introduction of the
exocyclic alkene found in 2 by reaction of compound 11
with Eschenmoser’s salt20 with concomitant loss of carbon
dioxide. Literature precedent21 provided a basis for our hope
that the newly formed enone 2 would display the desired
sense of regioselectivity in a union with a nitrone of type 3
(Scheme 1). A thermally induced, [3 + 2] dipolar cycload-
dition of nitrone 1222 with enone 2 was, in fact, completely
regioselective and afforded isoxazolidine 13 (Scheme 3); this
union also exhibited complete diastereoface selectivity owing
to the disposition of the angular methyl group at C-13
(cortistatin numbering) as well as the bias provided by the
configuration at C-14 in dipolarophile 2.23 This union
effectively established the challenging and crowded C8-O
bond and the C6-C7 bond. With the C-8 oxygen atom
suitably protected in the form of an isoxazolidine ring, we
elected to homologate the C-9 ketone (Scheme 3). This was
achieved by a low-temperature enolization of ketone 13 with
in situ triflation of the enolate oxygen atom with the Comins
reagent,24 followed by a palladium-catalyzed, carbonylative
ester formation; this two-stage sequence was effective and
gave rise to methyl ester 14. While efforts to reduce both
the N-O bond and the unneeded benzylic C-N bond in the
context of 13 with reducing metals or by hydrogenolysis were
complicated by side product formation and/or decomposition,
it was possible to achieve these objectives by the following
sequence: (1) a quantitative methylation of the isoxazolidine
nitrogen atom in 14 to give the corresponding quaternary
ammonium salt, (2) a high-yielding cleavage of the N-O
bond with zinc dust, and (3) an oxidation of the dimethy-
lamino group with meta-chloroperbenzoic acid to set the
stage for a mild Cope elimination25 of the resulting tertiary
amine N-oxide. This three-step sequence of reactions pro-
duced compound 15 in an excellent overall yield, and from
that vantage point, we could arrive at triol 16 by a
hydrogenation of the styryl double bond in 15, a complete
reduction of the methyl ester function with lithium aluminum
hydride, and a selective, fluoride-induced desilylation of the
phenolic silyl ether. Interestingly, when compound 16 was
exposed to 2 equiv of Dess-Martin periodinane, the primary,
Scheme 2.
Synthesis of Isoxazolidine 13a
a DMF ) N,N′-dimethyl formamide; MMC ) methyl magnesium
carbonate; TBS ) tert-butyldimethylsilyl.
allylic alcohol was oxidized to the corresponding aldehyde,
and the tertiary alcohol and phenol functions participated in
an oxidative cyclodearomatization reaction; this double
oxidation process yielded tetracyclic aldehyde 17, and while
we are unaware of the ordering of the two oxidation events,
this structural change was most welcome. We suspect that
our supply of Dess-Martin periodinane may have contained
2-iodoxybenzoic acid (IBX), which is the direct precursor
to the Dess-Martin periodinane and an agent known to effect
oxidative dearomatizations.26
With four of the five rings in place, our inclination was to
transform the aldehyde function of 17 to the corresponding
nitrone for a final [3 + 2] dipolar cycloaddition. As matters
transpired, attempts to achieve condensation reactions between
17 and N-alkyl hydroxyl amines were complicated by compet-
ing 1,4-conjugate additions to both the enal moiety and the
cross-conjugated dienone. While these difficulties could not be
circumvented, they did encourage a return to opportunities
provided by the chemistry of triol 16. Specifically, we sought
a means to incorportate a dipole or its equivilent into the
precursor to the dearomatization. Conversion of the triol 16 to
the tetracycle 17 inspired us to seek conditions to oxidatively
access a reactive dipole concomitantly with cyclodearomatiza-
tion. Eventually, this concept led to the discovery of the novel
construction shown in Scheme 4.
(19) During the course of our studies we developed a scalable and
reliable synthesis of 2. Experimental details of the synthesis of this
intermediate are provided in the Supporting Information. For the first
synthesis of 2, see: Isaacs, R. C. A.; Di Grandi, M, J.; Danishefsky, S. J.
J. Org. Chem. 1993, 58, 3938.
(20) Schreiber, J.; Maag, H.; Hashimoto, N.; Eschenmoser, A. Angew.
Chem., Int. 1971, 10, 330.
(21) (a) Padwa, A.; Burgess, E. M.; Gingrich, H. L.; Roush, D. M. J.
Org. Chem. 1982, 47, 786. (b) Padwa, A.; Fisera, L.; Koehler, K. F.;
Rodriguez, A.; Wong, G. S. K. J. Org. Chem. 1984, 49, 276.
(22) Nitrone 12 was easily prepared by a condensation of N-methylhy-
droxylamine hydrochloride with the commerially available p-tert-butyldim-
ethylsiyloxybenzaldehyde. See Supporting Information for detailed proce-
dures.
(23) Isoxazolidine 13 was isolated as an inconsequential mixture of C-6
diastereoisomers. Both diastereoisomers exhibited nOe correlations with
the angular methyl.
(24) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
(25) (a) Cope, A. C.; Foster, T. T.; Towle, P. H. J. Am. Chem. Soc. 1949,
71, 3929. (b) Cope, A. C.; Trumbull, E. R. Org. React. 1960, 11, 317.
The Parikh-Doering method27 permitted an oxidation of
the primary allylic alcohol moiety of 16 to the corresponding
enal, after which a quantitative condensation between the
latter compound and hydroxyl amine hydrochloride under
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Org. Lett., Vol. 11, No. 23, 2009

Scheme 3
.
Synthesis of Tetracyclic Dienone 17a
Scheme 4
.
Synthesis of Cortistatin Pentacycle 20 Featuring
Tandem Oxidative Cyclizationsa
a Pyr ) pyridine; DMSO ) dimethylsulfoxide; Ph ) C6H5; TBS )
tert-butyldimethylsilyl.
transformation comprises three individual steps: (1) an ether
ring formation via oxidative dearomatization, (2) an oxidation
of the oxime function to a transient nitrile oxide (see 19),
and (3) a final intramolecular [3 + 2] dipolar cycloaddition
of 19 to yield compound 20. A significant level of target-
relevant complexity is produced in this single laboratory
operation, which complements the report of Ciufolini and
co-workers by showing that double cyclizations are also
possible by the action of bis(acetoxy)iodobenzene on struc-
turally complex oxime phenols.
a KHMDS ) potassium hexamethylsilylazide; THF ) tetrahydrofuran;
DMF ) N,N′-dimethyl formamide; rt ) room temperature; mCPBA ) meta-
chloroperoxybenzoic acid; TBS ) tert-butyldimethylsilyl; dppf ) 1,1′-
bis(diphenylphosphino)ferrocene.
In summary, a stereocontrolled synthesis of a complex
pentacycle embodying the molecular architecture of the cor-
tistatin class of natural products was achieved from the (+)-
Hajos-Parrish ketone. The approach described herein utilizes
a phenol as a latent cortistatin A-ring, two dipolar cycloaddition
events, and an oxidative cyclodearomatization. The manner in
which these ring formations were orchestrated has yielded a
rather concise strategy for synthesis. Our current aim is to
leverage this chemistry in syntheses of the full structure of
cortistatin A as well as new and potentially biologically active
compounds sharing its unique structural features.
the conditions shown gave rise to oxime diol 18. At this
juncture in our effort, we encountered the recent, fascinating
report by the Ciufolini laboratory demonstrating that bis(ac-
etoxy)iodobenzene is effective at converting aldoximes into
nitrile oxides and that such an oxidation may be conducted
in tandem with an oxidative dearomatization of a phenol.28
Encouraged by this precedent, we set out to fashion the
cortistatin tetrahydrofuran ring by an intramolecular oxidative
dearomatization in tandem with an intramolecular dipolar
cycloaddition. Two oxidations and two ring formations would
establish the core skeleton of the cortistatins. The outcome
of the pivotal oxidation event was most gratifying because
we discovered that exposure of compound 18 to bis(acetoxy)-
iodobenzene in trifluoroethanol directly produced compound
20, a substance possessing the full pentacyclic core archi-
tecture of cortistatin A. Compound 20 was the only diaste-
reoisomer isolated. This productive and rather efficient
Acknowledgment. This work was supported by the
National Institute of General Medical Sciences (GM065483),
a Focused Giving Award from Johnson and Johnson, and
Princeton University. Additionally, we would like to thank
Merck Research Laboratories for fellowship support of J.L.F.
and the Princeton University Council on Science and
Technology for fellowship support for C.S.J.
(26) (a) Quideau, S.; Lyvinec, G.; Marguerit, M.; Bathany, K.; Ozanne-
Beaudenon, A.; Buffeteau, T.; Cavagnat, D.; Chenede, A. Angew. Chem.
2009, 121, 4675. (b) Ozanne, A.; Pouyse´gu, L.; Depernet, D.; Francois,
B.; Quideau, S. Org. Lett. 2003, 5, 2903–2906. (c) Magdziak, D.; Rodriguez,
A. A.; Van De Water, R. W.; Pettus, T. R. Org. Lett. 2002, 4, 205–288.
(27) Parikh, J. P.; Doering, W. E. J. Am. Chem. Soc. 1967, 89, 5505.
(28) Mendelsohn, B. A.; Lee, S.; Kim, S.; Teyssier, F.; Aulakh, V. S.;
Ciufolini, M. A. Org. Lett. 2009, 11, 1539.
Supporting Information Available: Experimental pro-
cedures and full characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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