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Communication

Direct Asymmetric anti-Mannich-Type Reactions Catalyzed by a Designed Amino Acid

Supporting Info

Susumu Mitsumori,^† Haile Zhang,^† Paul Ha-Yeon Cheong,^§ K. N. Houk,*^§ Fujie Tanaka,*^† and Carlos F. Barbas, III*^†; ;

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, and Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569

J. Am. Chem. Soc., 2006, 128 (4), pp 1040–1041

DOI: 10.1021/ja056984f

Publication Date (Web): January 4, 2006

†

The Scripps Research Institute.

University of California, Los Angeles.

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

, carlos@scripps.edu, ; , ftanaka@scripps.edu, ; , houk@chem.ucla.edu

Abstract

The development of catalysts for Mannich-type reactions that afford anti-products with excellent diastereo- and enantioselectivities under mild conditions and low catalyst loadings (1−5 mol %) is reported. Based on principles gained from the study of (S)-proline-catalyzed Mannich-type reactions that afford enantiomerically enriched syn-products, (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid (RR35) has been designed to catalyze the direct enantioselective anti-selective Mannich-type reactions. Computational studies of the above reaction using HF/6-31G* level of theory suggested that this design would be highly effective. The catalyst was subsequently synthesized and studied in organocatalytic Mannich-type reactions between unmodified aldehydes and N-PMP-protected α-imino esters. In accord with the design principles and in quantitative agreement with the theoretical predictions, reactions catalyzed by this catalyst afforded anti-products in good yields with excellent diastereo- and enantioselectivities (anti:syn 94:6 to 98:2, >97 to >99% ee).