ORGANIC
LETTERS
2
006
Vol. 8, No. 5
11-814
Pipecolic Acid-Catalyzed Direct
Asymmetric Mannich Reactions
8
†
§
§
§
Paul Ha-Yeon Cheong, Haile Zhang, Rajee Thayumanavan, Fujie Tanaka,
,
†
,§
K. N. Houk,* and Carlos F. Barbas III*
Department of Chemistry and Biochemistry, UniVersity of California,
Los Angeles, California 90095-1569, and The Skaggs Institute for Chemical Biology
and the Departments of Chemistry and Molecular Biology, The Scripps Research
Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
houk@chem.ucla.edu; carlos@scripps.edu
Received November 25, 2005
ABSTRACT
Mannich reactions between aldehydes and N-p-methoxyphenyl-protected
acid as catalyst. The reactions give both syn- and anti-products (dr
r
-imino ethyl glyoxylate have been performed using (S)-pipecolic
−
)
1.4 2:1) with high enantioselectivities (>98% ee). In contrast, (S)-
proline-catalyzed reactions give mainly syn-products with high enantioselectivities. Computational studies reveal that the energetic preference
between the transition structures involving the s-cis-enamine and the s-trans-enamine is smaller for the pipecolic acid as compared to proline,
yielding the (2S,3R)-anti and the (2S,3S)-syn Mannich product in nearly equal amounts.
Preformed enamines of both five-membered pyrrolidine and
six-membered piperidine rings have been used as nucleo-
philes in many reactions.1,2 For the reactions involving in
situ-generated enamines, pyrrolidine-based catalysts have
been extensively examined.3 One of the most effective
routes for the synthesis of enantiomerically enriched R- and
â-amino acid derivatives is pyrrolidine derivative-catalyzed
Mannich-type reactions of an aldehyde donor. (S)-Proline
and various (S)-proline derivatives give the syn-product
(2S,3S)-1 as the major product with high diastereo- and
-5
4
enantioselectivity (Scheme 1). The six-membered analogue,
†
§
pipecolic acid, has received little attention as a catalyst for
asymmetric reactions and has proven to be ineffective for
aldol reactions involving acetone as donor. Here we report
the experimental and computational investigation of (S)-
pipecolic acid-catalyzed Mannich reaction between aldehydes
University of California, Los Angeles.
The Scripps Research Institute.
(1) Kempf, B.; Hampel, N.; Ofial, A. R.; Mayr, H. Chem.sEur. J. 2003,
3a,6
9
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(
Terrell, R. J. Am. Chem. Soc. 1963, 85, 207. (b) Hickmott, P. W.
Tetrahedron 1982, 38, 1975.
(
3) (a) Sakthivel, K.; Notz, N.; Bui, T.; Barbas, C. F., III. J. Am. Chem.
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Chem. Res. 2004, 37, 580. (c) Northrup, A. B.; Mangion, I. K.; Hettche,
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0.1021/ol052861o CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/04/2006