toward the assembly of the azaspirobicyclic and azaspiro-
tricyclic cores,4 only three total syntheses of 15-7 and two
total syntheses of 2 have been reported;7,8 there have been
two formal syntheses of 1 and 2.9,10
Our approach to 1 and 2 was guided by a longstanding
interest in developing new applications of olefin metathesis
for the synthesis of complex natural products, particularly
alkaloids.11,12 We thus envisioned a unified strategy for the
preparation of both of these alkaloids that would feature
chemoselective cross metathesis reactions involving the key
intermediate 10 (Scheme 1).
metathesis catalyst (7).14 Similarly, a cross metathesis
reaction between 10 and a dienoate such as 9, which bears
a leaving group R, would lead to 6, a possible intermediate
en route to halichlorine (2). The opportunity to extend the
scope of olefin cross metathesis15 rendered this general
approach to 1 and 2 particularly attractive. Olefin 10 would
in turn be prepared by a Curtius rearrangement of a
compound derived from 11, whose synthesis via an efficient
three-component reaction was reported by Heathcock.16
The formal synthesis of pinnaic acid (1) is summarized
in Scheme 2. Selective silylation of the diol 12 with
Scheme 2. Formal Synthesis of Pinnaic Acid (1)
Scheme 1. Retrosynthesis of Pinnaic Acid (1) and Halichlorine
(2)
TBDPSCl, Et3N, and catalytic DMAP afforded 13 in 87%
yield. Jones oxidation of 13 furnished carboxylic acid 14,
which was subjected to a Curtius rearrangement with
diphenyl phosphoryl azide (DPPA)17 and t-BuOH to afford
10 in 51% yield for the two steps.
With the common intermediate 10 in hand, the stage was
set for the pivotal cross metathesis reaction. Heating a
mixture of 10 and dienoate 8 under reflux (CH2Cl2) for 3 h
in the presence of Grubbs II catalyst (7) (10 mol %) provided
an inseparable mixture of 5 and the dimer of 8.18,19 Pure 5
(E/Z ) 10:1) could be obtained by a sequence of reactions
involving removal of the N-Boc group, purification of the
intermediate amine, and reinstallation of the N-Boc group
(29% overall yield). Owing to the inefficiency of this process
and practical considerations, we decided to telescope three
reactions. In the event, the azaspirobicycle 15 was prepared
A novel route to the diene 5, a known intermediate that
had been previously transformed into pinnaic acid (1) via
3,5 would entail a cross metathesis reaction between 10 and
the dienoate 813 in the presence of Grubbs’ second generation
(5) (a) Carson, M. W.; Kim, G.; Hentemann, M. F.; Trauner, D.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 4450. (b) Carson, M.
W.; Kim, G.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 4453.
(6) Hayakawa, I.; Arimoto, H.; Uemura, D. Heterocycles 2003, 59, 441.
(7) Christie, H. S.; Heathcock, C. H. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 12079.
(8) Trauner, D.; Schwartz, J. B.; Danishefsky, S. J. Angew. Chem., Int.
Ed. 1999, 38, 3542.
(9) Matsumura, Y.; Aoyagi, S.; Kibayashi, C. Org. Lett. 2004, 6, 965.
(10) Zhang, H.-L.; Zhao, G.; Ding, Y.; Wu, B. J. Org. Chem. 2005, 70,
4954.
(11) For a review, see: Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104,
2199 and references therein.
(12) For some selected examples, see: (a) Martin, S. F.; Humphrey, J.
M.; Liao, Y.; Ali, A.; Rein, T.; Wong, Y.-L.; Chen, H.-J.; Courtney, A. K.
J. Am. Chem. Soc. 2002, 124, 8584. (b) Deiters, A.; Martin, S. F. Org.
Lett. 2002, 4, 3243. (c) Martin, S. F.; Neipp, C. E. J. Org. Chem. 2003, 68,
8867. (d) Washburn, D. G.; Heidebrecht, R. W., Jr.; Martin, S. F. Org.
Lett. 2003, 5, 3523. (e) Brenneman, J. B.; Machauer, R.; Martin, S. F.
Tetrahedron 2004, 60, 7301.
(14) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(15) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360.
(16) Wallace, G. A.; Heathcock, C. H. J. Org. Chem. 2001, 66, 450.
See ref 4s for a related tandem sequence to prepare an analogue of 11.
(17) Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974, 30, 2151.
(18) For a similar synthesis of R-bromo-R,â,δ,γ-dienoates, see: Funk,
T. W.; Efskind, J.; Grubbs, R. H. Org. Lett. 2005, 7, 187.
(13) Piers, E.; Jung, G. L.; Ruediger, E. H. Can. J. Chem. 1987, 65,
670.
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Org. Lett., Vol. 7, No. 25, 2005