version of the PKR has been applied to the syntheses of a
few natural products,10 but its use has overwhelmingly been
limited to forming fused bicyclo[3.3.0]octenones and bicyclo-
[4.3.0]nonenones.11,12
Having thus established the underlying viability of using
PKRs to form azabicyclo[3.3.1]bicyclononanes fused with
cyclopentenones, a retrosynthetic approach to (-)-alstonerine
(1) was formulated as shown in Scheme 2. We envisioned
Our ongoing efforts to develop concise routes for the
elaboration of azabridged bicyclic structures led us to query
whether the scope of the PKR might be extended to include
cyclizations of cis-2,6-disubstituted piperidine enynes. Con-
sidering the absolute lack of precedent for such a PKR, the
simple model substrate 4 was first prepared to explore the
feasibility of such a construction (Scheme 1). Thus, by
Scheme 2. Retrosynthesis
Scheme 1. Model System
that 1 could be accessed from the lactone 6, which would in
turn be accessed via regioselective oxidation of the cyclo-
pentenone 7 that would arise from the pivotal PKR of the
known enyne 8.4
In the event, the PKR of enyne 8 with stoichiometric
amounts of Co2(CO)8 gave cyclopentenone 7 in excellent
yield as a single diastereomer (Scheme 3). It was essential
analogy with previous work in our laboratories,4,13 reaction
of 4-methoxypyridine (2) with the anion derived from
trimethylsilylacetylene in the presence of Cbz-Cl gave the
unsaturated piperidinone 3. Lewis acid mediated conjugate
addition of allyltribuyltin followed by treatment of the
intermediate silyl acetylene with TBAF provided the enyne
substrate 4 in >19:1 diastereoselectivity. To our delight, the
ensuing PKR proceeded cleanly to give 5 as a single
diastereomer. To our knowledge, this represents the first
example of a PKR to provide an azabridged bicyclic product.
Scheme 3. The Pauson-Khand Reaction
(8) For selected recent examples, see: (a) Fellows, I. M.; Kaelin, D. E.,
Jr.; Martin, S. F. J. Am. Chem. Soc. 2000, 122, 10781. (b) Ito, M.; Clark,
C. W.; Mortimore, M.; Goh, J.; Martin, S. F. J. Am. Chem. Soc. 2001, 123,
8003. (c) Humphrey, J. M.; Liao, Y.; Ali, A.; Rein, T.; Wong, Y.-L.; Chen,
H.-J.; Courtney, A. K.; Martin, S. F. J. Am. Chem. Soc. 2002, 124, 8584.
(d) Martin, S. F. Acc. Chem. Res. 2002, 35, 895. (e) Washburn, D. G.;
Heidebrecht, R. W., Jr.; Martin, S. F. Org. Lett. 2003, 5, 3523. (f) Deiters,
A.; Chen, K.; Eary, T.; Martin, S. F. J. Am. Chem. Soc. 2003, 125, 4541.
(g) Brenneman, J. B.; Machauer, R.; Martin, S. F. Tetrahedron 2004, 60,
7301. (h) Amorde, S.; Judd, A.; Martin, S. F. Org. Lett. 2005, 7, 2031. (i)
Andrade, R. B.; Martin, S. F. Org. Lett. 2005, 7, 5733. (j) Simila, S. T. U.;
Reichelt, A.; Martin, S. F. Tetrahedron Lett. 2006, 47, 2933. (k) Deiters,
A.; Pettersson, M.; Martin, S. F. J. Org. Chem. 2006, 71, 6547.
(9) Ashfeld, B. L.; Miller, K. A.; Smith, A. J.; Tran, K.; Martin, S. F.
Org. Lett. 2005, 7, 1661.
(10) (a) Cassayre, J.; Zard, S. Z. J. Am. Chem. Soc. 1999, 121, 6072.
(b) Jiang, B.; Xu, M. Angew. Chem., Int. Ed. 2004, 43, 2543. (c) Ishizaki,
M.; Niimi, Y.; Hoshino, O.; Hara, H.; Takahashi, T. Tetrahedron 2005,
61, 4053.
(11) (a) Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 56, 3263. (b)
Bon˜aga, L. V. R.; Krafft, M. E. Tetrahedron 2004, 60, 9795.
(12) For examples of PKR to synthesize carbon bridged bicycles: (a)
Kerr, W. J.; McLaughlin, M.; Morrison, A. J.; Pauson, P. L. Org. Lett.
2001, 3, 2945. (b) Lovely, C. L.; Seshadri, H.; Wayland, B. R.; Cordes, A.
W. Org. Lett. 2001, 3, 2607. (c) Winkler, J. D.; Lee, E. C. Y.; Nevels, L.
I. Org. Lett. 2005, 7, 1489.
to utilize high-quality Co2(CO)8 and DMSO as the promoter
to obtain optimal yields. Numerous catalytic variants only
provided recovered starting material.14
The next stage of the synthesis involved elaboration of
the cyclopentenone ring to a lactone, and we anticipated that
protection of the indole would be required to prevent
inadvertent oxidation of the indole ring. Thus, the Boc-
carbamate 9 was prepared from 7 in virtually quantitative
yield (Scheme 4). We then hoped to generate an enolate or
silyl enol ether regioselectively by reduction of the cyclo-
pentenone moiety. However, numerous attempts employing
dissolving metal,15 copper hydride reagents,16 and Stryker’s
reagent17 and attempted trapping of the enolate thus produced
with various oxidants or silylating agents were unsuccessful.
(14) (a) Pagenkopf, B. L.; Livinghouse, T. J. Am. Chem. Soc. 1996, 118,
2285. (b) Tang, Y.; Deng, L.; Zhang, Y.; Dong, G.; Chen, J.; Yang, Z.
Org. Lett. 2005, 7, 593. (c) Jeong, N.; Sung, B. K.; Choi, Y. K. J. Am.
Chem. Soc. 2000, 122, 6771. (d) Koga, Y.; Kobayashi, T.; Narasaka, K.
Chem. Lett. 1998, 249.
(13) (a) Brown, J. D.; Foley, M. A.; Comins, D. L. J. Am. Chem. Soc.
1988, 110, 7445. (b) Comins, D. L.; Joseph, S. P.; Goehring, R. R. J. Am.
Chem. Soc. 1994, 116, 4719.
(15) Caine, D. Org. React. 1976, 23, 1.
1114
Org. Lett., Vol. 9, No. 6, 2007