Tandem metathesis reactions of oxabicyclo[2.2.1]heptenes: Studies on the spirocyclic core of cyclopamine

Article abstract of DOI:10.1021/ol200706f

Chemical equations presented. A rapid approach to the spirocyclic core of cyclopamine was achieved in four steps from 2-pentenyl-furan. A furan Diels-Alder reaction followed by a one-pot dehalogenation/amination sequence provides the oxabicyclic triene that upon treatment with Grubbs catalyst undergoes smooth rearrangement to the tricyclic core.

Full text of DOI:10.1021/ol200706f

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2433–2435
Tandem Metathesis Reactions of
Oxabicyclo[2.2.1]heptenes: Studies on the
Spirocyclic Core of Cyclopamine
E. Zachary Oblak, Narendran G-Dayanandan, and Dennis L. Wright*
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut
06269, United States
dennis.wright@uconn.edu
Received March 16, 2011
ABSTRACT
A rapid approach to the spirocyclic core of cyclopamine was achieved in four steps from 2-pentenyl-furan. A furan DielsÀAlder reaction followed
by a one-pot dehalogenation/amination sequence provides the oxabicyclic triene that upon treatment with Grubbs’ catalyst undergoes smooth
rearrangement to the tricyclic core.
Natural products have long served as new sources of
diverse therapeutic agents for the treatment of various
cancers, often acting through previously unrecognized
cellular pathways. Although these compounds often func-
tion as general cytotoxins by targeting the cell cycle
machinery of fast growing cells, there are also naturally
occurring compounds that target some of the underlying
mechanisms responsible for cell dysregulation.1 One such
natural agent that has attracted considerable interest is the
steroidal alkaloid cyclopamine (Figure 1).
This unusual and complex plant-derived steroid has
been known for over 50 years and was originally isolated
owing to its severe teratogenic effects, inducing cyclopia in
Figure 1. Structure of cyclopamine, veratramine, and IPI-926.
the offspring of pregnant sheep that grazed on corn lilies
(Veratrum californicum).2 It would not be until 1998 that
the cellular target of cyclopamine was identified as the
hedgehog pathway.3 The hedgehog (Hh) signaling path-
way is active in the development of multiple tissue types
during the embryonic stage and can become reactivated
during tissue repair and in certain malignancies.4 Secreted
Hh protein binds the twelve transmembrane protein
patched (Ptch) which, in turn, relieves the inhibition of
the seven transmembrane protein smoothened (Smo). This
allows Smo to transduce the signal to the nucleus and activate
the downstream targets, through the Gli family of transcrip-
tion factors, which regulate numerous gene products involved
in tissue growth and differentiation. Cyclopamine was shown
to bind directly to Smo and antagonize Gli activation by Hh
and produce strong antiproliferative effects.5
(1) Sarkar, F. H.; Lia, Y.; Wanga, Z.; Konga, D. Cell. Signal 2009,
21, 1541.
(2) (a) Keeler, R. F.; Binns, W. Proc. Soc. Exp. Biol. Med. 1964, 116,
123. (b) Keeler, R. F.; Binns, W. Teratology 1968, 1, 5. (c) Keeler, R. F.
J. Agric. Food. Chem. 1969, 17, 473.
(3) Cooper, M. K.; Porter, J. A.; Young, K. E.; Beachy, P. A. Science
1998, 280, 1603.
(4) Scales, S. J.; de Sauvage, F. J. Trends Pharmacol. Sci. 2009, 30,
303.
(5) Chen, J. K.; Taipale, J.; Cooper, M. K.; Beachy, P. A. Genes Dev.
2002, 16, 2743.
r
10.1021/ol200706f
2011 American Chemical Society
Published on Web 04/01/2011

The direct application of cyclopamine has been compli-
cated by some of the features of this complex natural
product including poor aqueous solubility and instability
in acid, whereby cyclopamine undergoes a dehydrative
aromatization to give the inactive veratramine.6 Currently,
a semisynthetic analog of cyclopamine, IPI-926, with an
expanded D-ring is in phase II trials for the treatment of
metastatic pancreatic cancer.7 The interesting structure
and exciting biological activity of this natural product
has prompted us to develop synthetic routes to the natural
product and various analogs. A retrosynthesis was for-
mulated that would rely on some key metathesis chemistry
we have developed over the past several years.
upon treatment with Grubbs’ catalyst to deliver various
oxaspiro systems.9 We wished to examine an extension of
this method whereby ring opening of a suitably functiona-
lized oxabicyclo[2.2.1]heptene would be coupled to two
independent ring-closing metathesis reactions. This would
allow a direct conversion of a bicyclic intermediate such as
3 into the tricyclic core of these alkaloids. It was antici-
pated that the highly substituted oxabicyclic derivative
that contains four contiguous stereogenic centers (C-17/
20/22/23) could be derived easily from simple furans 4
through a DielsÀAlder reaction (Scheme 1).
Scheme 2. DielsÀAlder Reaction of a 2-Substituted Furan
Scheme 1. Retrosynthetic Analysis of Cyclopamine
Lithiation of furan and treatment with 1-bromopentene
gave the 2-substituted furan 5 that was reacted with
acetylenic dienophiles under both thermal and Lewis acid
conditions. Reaction of 5 with methylpropriolate under
thermal conditions (rtÀ90 °C, neat or 3.0 M in benzene)
failed to deliver the desired adduct 6, returning only
unreacted starting materials. The addition of mixed alu-
minum catalysts that had been effective in some related
intramolecular cycloadditions10 resulted in a rapid conver-
sion to the phenol 7, likely through opening of the primary
bridged adduct. Ultimately, we were pleased to find that
the more deactivated 3-bromomethyl propriolate11 under-
went a high yielding and highly selective DielsÀAlder
reaction to give the oxabicyclo[2.2.1]heptadiene 8a along
with small amounts of the undesired regioisomer 8b
(Scheme 2). The resultant β-bromoenoate moiety derived
from the alkyne offered a direct access point for installa-
tion of the C22Ànitrogen side chain (Scheme 3).
This retrosynthetic analysis of cyclopamine8 is centered
upon an overall convergent pathway that anticipates a late
stage union of fragments 1 and 2 with subsequent forma-
tion of the cyclopentyl C-ring. Key to this strategy is the
development of a route to a suitable DEF-tricycle such as
1. As this unit contains an integral and highly substituted
tetrahydrofuran substructure, with both spiro (C17) and
linear (C22/23) annulations, we were attracted to the use of
a furan-based strategy to access these types of systems. We
have previously shown that oxabicyclic systems containing
a pendant olefin undergo efficient bond reorganization
(6) Borzillo, G. V.; Lippa, B. Curr. Top. Med. Chem. 2005, 5, 147.
(7) (a) Tremblay, M. R.; Nevalainen, M.; Nair, S. J.; Porter, J. R.;
Castro, A. C.; Behnke, M. L.; Yu, L. C.; Hagel, M.; White, K.; Faia, K.;
Grenier, L.; Campbell, J. C.; Woodward, C. N.; Hoyt, J.; Foley, M. A.;
Read, M. A.; Sydor, J. R.; Tong, J. K.; Palombella, V. J.; McGovern, K.;
Adams, J. J. Med. Chem. 2008, 51, 6646. (b) Tremblay, M. R.;
Lescarbeau, A.; Grogan, M. J.; Tan, E.; Lin, G.; Austad, B. C.; Yu,
L. C.; Behnke, M. L.; Nair, S. J.; Hagel, M.; White, K.; Conley, J.;
Manna, J. D.; Alvarez-Diez, T. M.; Hoyt, J.; Woodward, C. N.; Sydor,
J. R.; Pink, M.; MacDougall, J.; Campbell, J. C.; Cushing, J.; Ferguson,
J.; Curtis, M. S.; McGovern, K.; Read, M. A.; Palombella, V. J.; Adams,
J.; Castro, A. C. J. Med. Chem. 2009, 52, 4400. (c) Tremblay, M. R.;
Nesler, M.; Weatherhead, R.; Castro, A. C. Expert Opin. Ther. Pat.
2009, 19, 1039.
Initial attempts to substitute the β-bromide with amine
nucleophiles were frustrated by the propensity for rapid
overaddition, likely driven by relief of ring strain upon
removal of two sp2 centers from the bridged system. To
prevent this unwanted overaddition, initial reduction of
the β-bromide was investigated. Exposure of 8a to a
buffered zincÀsilver couple12 produced the desired enoate
(9) (a) Wright, D. L.; Schulte, J.P. II; Page, M. A. Org. Lett. 2002, 2,
1847. (b) Usher, L. C.; Estrella-Jimenez, M.; Ghiviriga, I.; Wright, D. L.
Angew. Chem., Int. Ed. 2002, 41, 4560.
(10) Wright, D. L.; Robotham, C. V.; Aboud, K. Tetrahedron Lett.
2002, 43, 943.
(11) (a) For a preparation, see: Leroy, J. Org. Synth. 1998, 9, 129. (b)
For a similar example, see: Rainier, J. D.; Xu, Q. Org. Lett. 1999, 1, 27.
Xu, Q.; Weeresakare, M.; Rainier, J. D. Tetrahedron 2001, 57, 8029.
(8) (a) For a semisynthetic total synthesis, see: Giannis, A.; Heretsch,
€
P.; Sarli, V.; Stossel, A. Angew. Chem., Int. Ed. 2009, 48, 7911. (b) For an
estrone derived analog, see: Winkler, J. D.; Isaacs, A.; Holderbaum, L.;
Tatard, V.; Dahmane, N. Org. Lett. 2009, 11, 2824. (c) For an excellent
review, see: Heretsch, P.; Tzagkaroulaki, L.; Giannis, A. Angew. Chem.,
Int. Ed. 2010, 49, 3418.
2434
Org. Lett., Vol. 13, No. 9, 2011

from the exo-face, giving 9 as the only diastereomer, which
will necessitate an overall inversion in the eventual trans-
formation of the pendant ester to the corresponding
methyl group. With the key triene system in hand, metath-
esis-mediated bond reorganization could be investigated
(Scheme 4).
Scheme 3. Elaboration of an Oxabicyclo[2.2.1]heptadiene
Exposure of the ether bridged triene to the second-
generation Grubbs catalyst led to a rapid reaction and
the formation of the spiroannulated furan 11 in excellent
yield. Overall, the reaction involves a ring-opening metath-
esis of the strained endocyclic double bond and two
consecutive ring-closing metathesis reactions. Based on
the direct and high-yielding conversion of 10, a more
difficult case was targeted that would deliver a seven-
membered rather than six-membered D-ring surrogate as
that found in IPI-926 (Scheme 5).
Scheme 5. Synthesis of a Cyclopamine Model with an Expanded
D-Ring
6 which washighly unstable. Fortunately, itwaspossibleto
develop a one-pot sequence that involved initial dehalo-
genation followed by immediate conjugate addition of
allylamine to produce ester 9 as a single diastereomer as
determined by NOE correlation.
Scheme 4. A Domino Metathesis Approach to the DEF-Rings
of Cyclopamine
Alkylation of 2-lithiofuran with 1-bromo-5-hexene gave
the heterocycle 12, which was taken on through the routes
described above to the bicyclic ether 13. Treatment of this
triene with Grubbs’ catalyst again led to a smooth reorga-
nization to the highly substituted tetrahydrofuran 14,
albeit with a longer reaction time and slightly diminished
yield as compared to the six-membered case. Overall, we
have described an approach to the spirocyclic region of
cyclopamine by pairing a furan DielsÀAlder reaction with
a domino metathesisprocess. Our current efforts are aimed
at the synthesis of a fully functionalized DEF subunit of
cyclopamine and the development of methods for the
stereocontrolled annulation of an AB-ring system.
The addition of the amine had occurred, as expected,
from the exo-face, which establishes the correct relative
stereochemical relationships between C-23 and C-17/22.
This conjugate addition also sets the configuration at what
would be C-20 of cyclopamine upon protonation of the
intermediate enolate. Initially, it was hoped that the ally-
lamino and pentenyl chains flanking this center would
favor endo-protonation to position the carbomethoxy
group in the exo-position as a direct precursor to the
methyl group. However, protonation occurred exclusively
Acknowledgment. We are grateful to the National
Science Foundation (CHE-0616760) for generous support
of this work.
Supporting Information Available. Experimental pro-
cedures and full characterization data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org
(12) (a) Clark, R. D.; Heathcock, C. H. J. Org. Chem. 1976, 41, 636.
(b) Novak, L.; Baan, G.; Marosfalvi, J.; Szantay, C. Tetrahedron Lett.
1978, 19, 487.
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