Scheme 1. Retrosynthetic Analysis of (-)-Epibatidine
Scheme 3. Preparation of Key Intermediate 12a
metathesis (RCM) on the chiral homoallylic amine precursor
using the very established Grubbs’ catalysts.7 The homo-
allylic amine may be prepared by a Barbier-type allylation
between the chiral imine 9 and the chloro-nicotinyl bromide
6.8 Our experience with imine allylation suggested that the
ability to control the stereochemistry at C1 and C2 may be
related to the judicious choice of chiral auxiliary used.9
The synthesis commences from the reduction of the
commercially available methyl chloro-nicotinate 2, which
then undergoes Swern oxidation to afford the aldehyde 4
(∼100% over two steps). Aldehyde 16 then undergoes a
Grignard addition with vinylmagnesium bromide in THF to
provide the allylic alcohol 5 in 96% yield, and a further
bromination led to the formation of 6 in 98% yield. With a
practical synthesis of the chloro-nicotinyl bromide 6 realized
(97% yield over four steps), our studies entered into the next
synthetic phase (Scheme 2).
the syn homoallylic amine 10 was isolated in excellent yield
as a single isomer (93% yield), it is evident that with trans
relative stereochemistry, the late-stage epimerization proce-
dure could be omitted. To base our design on the epimer-
ization in the last step was initially not on the agenda, but
efforts to invert the stereochemistry were unsuccessful.12
The RCM of 10 catalyzed by the first-generation catalyst
11a provided the desired product 12 without much success
(39%).13 Gratifyingly, the robust 11b managed to catalyze
the RCM to afford the key cyclohexenylamine intermediate
12 in 94% yield with only 10 mol % loading at ambient
temperature (Scheme 3).14
Scheme 2. Preparation of Chloro-nicotinyl Bromide 6a
Initial attempts for the one-pot synthesis of the 7-azabicyclo-
[2.2.1]heptane ring utilizing N-bromosuccinimide (NBS) in
order to effect an intramolecular cyclization with the second-
ary amine as a nucleophile proved to be futile.15 Nevertheless,
bromination of 12 in excess Et4N+Br- provided two isomers,
13 and 14, in admirable yield and moderate selectivity (92%;
66:34). A single-crystal X-ray structure of 13 confirmed that
The synthesis of the homoallylic amine 10 began via
allylation of the chiral imine 9 (Scheme 3).10 After the pent-
4-enal 7 has successfully condensed with the chiral auxiliary
8 ((S)-phenylglycine acid-methyl ester),11 Zn metal, followed
by 6 (0.5 M solution in THF), was introduced. Even though
(11) For an excellent review, see: (a) Yamamoto, Y.; Asao, N. Chem.
ReV. 1993, 93, 2207. For some representative examples, see: (b) Yamamoto,
Y.; Ito, W. Tetrahedron 1988, 44, 5415. (c) Tanaka, H.; Inoue, K.; Pokorski,
U.; Taniguchi, M.; Torii, S. Tetrahedron Lett. 1990, 31, 3023. (d) Laschat,
S.; Kunz, H. J. Org. Chem. 1991, 56, 5883. (e) Alvaro, G.; Martelli, G.;
Savoia, D. J. Chem. Soc., Perkins Trans. 1998, 1, 777.
(12) Efforts to afford the anti isomer proved to be futile where (a)
different metals (Sn, In, Ga, and Mg) were used; (b) other chiral auxiliaries
((S)-valine acid methyl ester and (R)-methyl benzylamine) were tried; and
(c) catalytic amounts of various Lewis acids were added.
(13) (a) Fu¨rstner, A.; Langemann, K. Synthesis 1997, 792. (b) Wright,
D. L.; Schulte, J. P., II; Page, M. A. Org. Lett. 2000, 2, 1847.
(14) For excellent reviews on the RCM with nitrogen-containing
compounds, see: (a) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199.
(b) Pandit, U. K.; Overkleeft, H. S.; Borer, B. C.; Biera¨ugel, H. Eur. J.
Org. Chem. 1999, 959. (c) Philips, A. J.; Abell, A. D. Aldrichimica Acta
1999, 32, 75.
(7) For a general review, see: (a) Handbook of Metathesis; Grubbs, R.
H., Ed.; Wiley-VCH: Weinheim, Germany, 2003. (b) Trnka, T. M.; Grubbs,
R. H. Acc. Chem. Res. 2001, 34, 18. (c) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413. (d) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000,
39, 3012-3043.
(8) For a discussion of the mechanism, see: Molle, B. J. Am. Chem.
Soc. 1982, 104, 348175.
(9) (a) Huang, J.-M.; Xu, K.-C.; Loh, T.-P. Synthesis (Stuttgart) 2003,
5, 755. (b) Loh, T.-P.; Huang, J.-M.; Xu, K.-C.; Goh, S.-H.; Vittal, J. J.
Tetrahedron Lett. 2000, 41, 6511. (c) Loh, T.-P.; Wang, R.-B.; Tan, K.-L.;
Sim, K.-Y. Main Group Met. Chem. 1997, 20, 237. (d) Loh, T.-P.; Ho, D.
S. C.; Xu, K.-C.; Sim, K.-Y. Tetrahedron Lett. 1997, 38, 865.
(10) Lee, C. L. K.; Ling, H. Y.; Loh, T.-P. J. Org. Chem. 2004, 66,
7787.
(15) Corey, E. J.; Loh, T.-P.; Achyutha Rao, S.; Daley, D. C.; Sarshar,
S. J. Org. Chem. 1993, 58, 5600.
2966
Org. Lett., Vol. 7, No. 14, 2005