ORGANIC
LETTERS
2008
Vol. 10, No. 23
5497-5499
Silver Ion-Induced Grob Fragmentation
of γ-Amino Iodides: Highly
Stereoselective Synthesis of
Polysubstituted Piperidines
Guillaume Barbe, Miguel St-Onge, and Andre´ B. Charette*
De´partement de chimie, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Que´bec, Canada H3C 3J7
Received October 24, 2008
ABSTRACT
A new concerted silver ion-mediated Grob fragmentation process is described in which a 1,2-dihydropyridinium ion is formed and trapped in
situ with Grignard reagents in a highly regio- and diastereoselective fashion. Using this methodology, 2,3,6-trisubstituted piperidines were
synthesized in good yields and further derivatized to polysubstituted indolizidine.
Piperidines are ubiquitous heterocycles in a growing family
of biologically interesting alkaloids. They constitute one of
the most common substructures in many natural products1a
and represent a privileged motif in drug development.1b Over
the past decades, impressive efforts have been directed
toward their preparation2 and particularly toward the ste-
reoselective synthesis of functionalized polysubstituted non-
racemic piperidines.2c,e However, the large number of
substitution patterns inherently associated with such a
saturated heterocycle makes the development of new ste-
reocontrolled routes to polysubstituted piperidines desirable.
Herein, we describe a highly diastereoselective synthesis of
2,3,6-trisubstituted piperidines.3
thesis of enantiopure aza- bicyclo[2.2.2]octene 1.5 Recogniz-
ing the fixed antiperiplanar relationship between N-C(γ) and
C(R)-C(ꢀ) bonds, we envisioned a Grob fragmentation6 of
the corresponding γ-amino halide 27,8 as a precursor of 2,3-
dihydropyridinium salt B (Scheme 1). The iminium could
then be trapped by a nucleophile leading to 2,3,6-trisubsti-
(3) For recent examples, see: (a) Garnier, E. C.; Liebeskind, L. S. J. Am.
Chem. Soc. 2008, 130, 7449. (b) Takahashi, M.; Micalizio, G. C. J. Am.
Chem. Soc. 2007, 129, 7514. (c) Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc.
2005, 127, 12234. (d) Lemire, A.; Charette, A. B. Org. Lett. 2005, 7, 2747.
For other recent stereoselective synthesis of substituted piperidines, see:
(e) Hayashi, Y.; Gotoh, H.; Masui, R.; Ishikawa, H. Angew. Chem., Int.
Ed. 2008, 47, 4012. (f) Sarkar, N.; Banerjee, A.; Nelson, S. G. J. Am. Chem.
Soc. 2008, 130, 9222. (g) Terada, M.; Machioka, K.; Sorimachi, K. J. Am.
Chem. Soc. 2007, 129, 10336. (h) Legault, C.; Charette, A. B. J. Am. Chem.
Soc. 2005, 127, 8966. (i) Weston, M H.; Nakajima, K.; Back, T. G. J. Org.
Chem. 2008, 73, 4630. (j) Amat, M.; Pe´rez, M.; Minaglia, A. T.; Bosch, J.
J. Org. Chem. 2008, 73, 6920. (k) Davis, F. A.; Xu, H.; Zhang, J. J. Org.
Chem. 2007, 72, 2046.
As part of our research program directed toward the
asymmetric synthesis of substituted piperidines,4 we recently
developed a three-step, multigram-scale stereoselective syn-
(4) (a) Larive´e, A.; Charette, A. B. Org. Lett. 2006, 8, 3955, and
references therein. (b) Charette, A. B.; Grenon, M.; Lemire, A.; Pourashraf,
M.; Martel, J. J. Am. Chem. Soc. 2001, 123, 11829.
(1) (a) Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005,
68, 1556. (b) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679.
(2) For recent reviews, see: (a) Buffat, M. G. P. Tetrahedron 2004, 60,
1701. (b) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R.
Tetrahedron 2003, 59, 2953. (c) Laschat, S.; Dickner, T. Synthesis 2000,
1781. (d) Mitchinson, A.; Nadin, A.; Ito, Y. J. Chem. Soc., Perkin Trans.
1 2000, 2862. (e) Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem.
Commun. 1998, 633.
(5) (a) Barbe, G.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 13873.
(b) Sales, M.; Charette, A. B. Org. Lett. 2005, 7, 5773.
(6) Grob, C. A. Angew. Chem., Int. Ed. 1969, 8, 535.
(7) See the Supporting Information for more details.
(8) For the chemoselective reduction of tertiary amides, see: Barbe, G.;
Charette, A. B. J. Am. Chem. Soc. 2008, 130, 18
.
10.1021/ol8024605 CCC: $40.75
Published on Web 11/12/2008
2008 American Chemical Society