Direct asymmetric anti-Mannich-type reactions catalyzed by a designed amino acid |
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Authors: | Mitsumori Susumu Zhang Haile Ha-Yeon Cheong Paul Houk K N Tanaka Fujie Barbas Carlos F |
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Institution: | The Skaggs Institute for Chemical Biology and the Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA. |
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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 alpha-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). |
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