ORGANIC
LETTERS
2003
Vol. 5, No. 21
3855-3857
Asymmetric Synthesis of Functionalized
trans-2,6-Disubstituted Piperidines with
N-Sulfinyl δ-Amino â-Ketoesters.
Synthesis of (−)-Lasubine I
,†
Franklin A. Davis,* Ashwin Rao,† and Patrick J. Carroll‡
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122, and
Department of Chemistry, UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
Received July 24, 2003
ABSTRACT
The hydroxy-directed reduction of 1,2-dehydropiperidines with the “ate” complex of DIBAL-H and n-BuLi affords functionalized trans-2,6-
disubstituted piperidines. This methodology was employed in the asymmetric synthesis of the quinolizidine alkaloid (−)-lasubine I.
Piperidines are key structural units of numerous alkaloids
and pharmaceuticals.1 Simple 2,6-disubstituted piperidines,
isolated from fire ant venom, are reported to possess a broad
range of activities (necrotic, insecticidal, antibacterial, an-
tifungal, anti-HIV).2 Polyhydroxylated piperidines (azasug-
ars) are potent inhibitors of carbohydrate-processing en-
zymes, which suggests they will find utility in treating viral
infections, cancer, diabetes, and tuberculosis.3 In addition,
piperidines serve as building blocks for the synthesis of more
complex alkaloids including the indolizidine and quinolizi-
dine ring systems, which in themselves exhibit a broad range
of biological activities.4 As a consequence of the central role
played by this ring system, numerous methods have been
devised for the asymmetric syntheses of simple, unfunction-
alized cis- and trans-2,6-disubstituted piperidines.5 However,
most of these approaches are target specific and few provide
access to trans-2,6-disubstituted piperidines having ring
functionality.6 Such functionality is necessary for the con-
struction of more complex bioactive alkaloids.
Recent efforts in our laboratory have focused on N-sulfinyl
δ-amino â-ketoesters 1, a new sulfinimine (N-sulfinyl imine)
derived polyfunctionalized chiral building block for piperi-
dine7 and pyrrolidine8 alkaloid syntheses (Scheme 1).9 While
these building blocks afforded mono- and bicyclic piperidine
alkaloids with appropriate ring functionality for further
(5) For reviews see: (a) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.;
Borcherding, D. R. Tetrahedron 2003, 59, 2953. (b) Laschat, S.; Dickner,
T. Synthesis 2002, 1781.
(6) (a) Ratni, H.; Kundig, E. P. Org. Lett. 1999, 1, 1997. (b) Gardette,
D.; Gelas-Mialhe, Y.; Gramanin, J.-C.; Perring, B.; Remuson, R. Tetrahe-
dron: Asymmetry 1998, 9, 1823. (c) Chalard, P.; Remuson, R.; Gelas-Mialhe,
Y.; Gamain, J.-C. Tetrahedron: Asymmetry 1998, 9, 4361. (d) Castro, P.;
Overman, L. E.; Zhang, X.; Mariano, P. S. Tetrahedron Lett. 1993, 34,
5243. (e) Comins, D. L.; LaMunyon, D. H. J. Org. Chem. 1992, 57, 5807.
(f) Comins, D. L.; LaMunyon, D. H. Tetrahedron Lett. 1989, 30, 5053.
(7) (a) Davis, F. A.; Chao, B.; Fang, T.; Szewczyk, J. M. Org. Lett.
1999, 1, 1041. (b) Davis, F. A.; Chao, B. Org. Lett. 2000, 2, 2623. (c)
Davis, F. A.; Fang, T.; Chao, B.; Burns, D. M. Synthesis 2000, 2106. (d)
Davis, F. A.; Chao, B.; Rao, A. Org. Lett. 2001, 3, 3169.
(8) (a) Davis, F. A.; Fang, T.; Goswami, R. Org. Lett. 2002, 4, 1599.
(b) Davis, F. A.; Yang, B.; Deng, Y. J. Org. Chem. 2003, 68, 5147.
(9) For a review see: Davis, F. A.; Chao, B.; Andemichael, Y. W.;
Mohanty, P. K.; Fang, T.; Burns, D. M.; Rao, A.; Szewczyk, J. M. Heteroat.
Chem. 2002, 13, 486.
† Temple University.
‡ University of Pennsylvania.
(1) (a) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435. (b) Watson, P. S.;
Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679 and references therein.
(2) Leclercq, S.; Braekman, J. C.; Daloze, D.; Pasteels, J. M. Prog. Chem.
Org. Nat. Prod. 2000, 79, 115.
(3) For leading references see: (a) Davis, B, G.; Maughan, M. A. T.;
Chapman, T. M.; Villard, R.; Courtney, S. Org. Lett. 2002, 4, 103. (b) Davis,
B. G. Chem. ReV. 2002, 102, 579.
(4) (a) Michael, J. P. Nat. Prod. Rep. 2001, 18, 520. (b) Mitchinson, A.;
Nadin, A. J. Chem. Soc., Perkin Trans. 1 2000, 2862. (c) Michael, J. P.
Nat. Prod. Rep. 2000, 17, 579.
10.1021/ol035390j CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/16/2003