enantioselective synthesis of 2,6-disubstituted piperidines, which
include such alkaloids as (-)-solenepsin and (-)-dihydropini-
dine.9
Strategy for the Enantioselective Synthesis of
trans-2,4-Disubstituted Piperidines: Application
to the CCR3 Antagonist IS811
The literature does provide a number of protocols for
preparing trans-2,4-disubstituted piperidines in racemic form.
In certain cases, cyanation of the 2-position of 4-alkylpiperidines
under oxidative conditions,10 addition of Grignard reagents to
a 2-methoxy-4-alkylpiperidine formamidine,11 nucleophilic ad-
ditions to acyliminium ions,12 and even radical cyclizations13
have all been demonstrated to provide high levels of trans-
diastereoselectivity. The combination of any of these protocols
with a suitable nonracemic substrate could in principle provide
an enantioselective synthesis. Moreover, Hanessian and co-
workers prepared an entire library of enantiopure 2,4-disubsti-
tuted piperidines by conjugate addition of organocuprates to an
optically enriched 4,5-unsaturated 2-substituted 6-oxopiperidine
nucleus and diastereomer separation.14
Goss S. Kauffman,† Paul S. Watson,‡ and
William A. Nugent*
Process Research and DeVelopment Department, Bristol-Myers
Squibb Company, P.O. Box 4000, Princeton, New Jersey 08543
ReceiVed August 15, 2006
Several of these protocols rely on the A(1,3) strain15 which
arises between an N-acyl or N-alkoxycarbonyl group and a
substituent on a carbon atom adjacent to the nitrogen of a
piperidine ring. This effect forces the substituent at C2 into the
axial position. One consequence is that, with a sufficiently
electron-withdrawing substituent at either the 2-position16 or the
4-position,17 a cis-2,4-disubstituted piperidine can be epimerized
to its thermodynamically favored trans-diastereomer. We previ-
ously reported an approach to trans-2,4-disubstituted piperidines
based on A(1,3) strain, namely, the dissolving metal reduction
of 2-substituted N-acylpiperidines bearing an exocyclic alky-
lidene group at the 4-position.18 The 2,3-dihydro-4-pyridone
starting materials used in that approach are readily available
using the efficient chemistry developed by Comins and co-
A strategy for the enantioselective synthesis of trans-2,4-
disubstituted piperidines is proposed and applied to the
preparation of IS811, a potent CCR3 antagonist. The C2
stereocenter is derived from commercial (R)-epichlorohydrin,
while the C4 stereocenter is installed via diastereoselective
hydrogenation of an R,â-unsaturated lactone intermediate.
Inversion of the original stereocenter via an efficient in-
tramolecular SN2 amination affords the piperidine core of
IS811. An improved protocol for the lithiation of ethyl
propiolate is reported.
(6) Hannam, J. C.; Kulagowski, J. J.; Madin, A.; Ridgill, M. P.; Seward,
E. M. World Patent Appl. 2006043064, 2006; Chem. Abstr. 2006, 144,
432693.
(7) Janssens, F. E.; Schoentjes, B.; Coupa, S.; Poncelet, A. P.; Simonnet,
Y. R. F. World Patent Appl. 2005097795, 2005; Chem. Abstr. 2005, 143,
145815.
(8) Tegtmeier, F.; Jansenns, F. E.; Leenaerts, J. E.; Van Rossem, K. A.;
Alcazar-Vaca, M. J.; Martinez-Jimenez, P.; Bartoleme-Nebreda, J. M.;
Gomez-Sanchez, A.; Fernandez-Gadea, F. J.; Van Reempts, J. L. H. World
Patent Appl. 2003044023, 2003; Chem. Abstr. 2003, 139, 6872.
(9) For reviews, see: (a) Laschat, S.; Dickner, T. Synthesis 2000, 1781.
(b) Buffat, M. G. P. Tetrahedron 2004, 60, 1701. (c) Weintraub, P. M.;
Sabol, J. S.; Kane, J. M.; Borcherding, Tetrahedron 2003, 59, 2953.
(10) Bonjoch, J.; Quirante, J.; Sole, D.; Castells, J.; Galceran, M.; Bosch,
J. Tetrahedron 1991, 47, 4417; Le Gall, E.; Hurvois, J.-P.; Renaud, T.;
Moinet, C.; Tallec, A.; Uriac, P.; Sinbandhit, S.; Toupet, L. Liebigs Ann./
Recl. 1997, 2089.
Interest in 2,4-disubstituted piperidines as pharmacophores
has grown rapidly in recent years. It has been known for decades
that 4-substituted pipecolic acid1 derivatives can exhibit high
levels of biological activity; commercial examples include the
anticoagulant argatroban2 and the veterinary antibiotic pirlimy-
cin.3 However, the current flurry of activity utilizes a greatly
expanded palette of 2,4-disubsituted piperidine building blocks
and has provided promising results in therapeutic areas as
diverse as depression,4 asthma,5 Alzheimer’s disease,6 schizo-
phrenia,7 and antihistaminics.8
Despite this increasing interest, options for the synthesis of
enantiomerically pure 2,4-disubstituted piperidines remain lim-
ited. In contrast, there is substantial literature concerning the
(11) Meyers, A. I.; Shawe, T. T.; Gottlieb, L. Tetrahedron Lett. 1992,
33, 867.
(12) Veerman, J. J. N.; Klein, J.; Aben, R. W. M.; Scheeren, H. W.;
Kruse, C. J.; Van Maarseveen, J. H.; Rutjes, F. P. J. T.; Hiemstra, H. Eur.
J. Org. Chem. 2002, 3133 and references therein.
(13) Gandon, L. A.; Russell, A. G.; Gueveli, T.; Brodwolf, A. E.; Kariuki,
B. M.; Spencer, N.; Snaith, J. S. J. Org. Chem. 2006, 71, 5198.
(14) Hanessian, S.; van Otterlo, W. A. L..; Nilsson, I.; Bauer, U.
Tetrahedron Lett. 2002, 43, 1995.
(15) Johnson, F. Chem. ReV. 1968, 68, 375.
(16) Keenan, T. P.; Yaeger, D.; Holt, D. A. Tetrahedron: Asymmetry
1999, 10, 4331.
(17) Hutchison, A. J.; Williams, M.; Angst, C.; de Jesus, R.; Blanchard,
L.; Jackson, R. H.; Wilusz, E. J.; Murphy, D. E.; Bernard, P. S.; Schneider,
J.; Campbell, T.; Guida, W.; Sills, M. A. J. Med. Chem. 1989, 32, 2171.
(18) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679.
† Current address: Pfizer, Inc., Groton, CT.
‡ Current address: Inspire Pharmaceuticals, Inc., Durham, NC.
(1) Pipecolic acid is piperidine-2-carboxylic acid.
(2) Kikumoto, R.; Tamao, Y.; Tezuka, T.; Tonamura, S.; Hara, H.;
Ninomiya, K.; Hijikata, A.; Okamoto, S. Biochemistry 1984, 23, 85.
(3) Birkenmeyer, R. D.; Kroll, S. J.; Lewis, C.; Stern, K. F.; Zurenko,
G. E. J. Med. Chem. 1984, 27, 216.
(4) Rocco, V. P.; Spinnaze, P. G.; Kohn, T. J.; Honigschmidt, N. A.;
Nelson, D. L.; Wainscott, D. B.; Ahmad, L. J.; Shaw, J.; Threlkeld, P. G.;
Wong, D. T.; Takeuchi, K. Bioorg. Med. Chem. Lett. 2004, 14, 2653.
(5) Wacker, D. A.; Santella, III, J. B.; Gardner, D. S.; Varnes, J. G.;
Estrella, M.; DeLucca, G. V.; Ko, S. S.; Tanabe, K.; Watson, P. S.; Welch,
P. K.; Covington, M.; Stowell, N. C.; Wadman, E. A.; Davies, P.; Solomon,
K. A.; Newton, R. C.; Trainor, G. L.; Friedman, S. M.; Decicco, C. P.;
Duncia, J. V. Bioorg. Med. Chem. Lett. 2002, 12, 1785.
10.1021/jo0616963 CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/14/2006
J. Org. Chem. 2006, 71, 8975-8977
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