Direct asymmetric anti-Mannich-type reactions catalyzed by a designed amino acid.
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).
Mitsumori
Susumu
S
The Skaggs Institute for Chemical Biology and the Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA.
Zhang
Haile
H
Ha-Yeon Cheong
Paul
P
Houk
K N
KN
Tanaka
Fujie
F
Barbas
Carlos F
CF
D000447:Aldehydes / Q000737:chemistry*; D000596:Amino Acids / Q000737:chemistry*; D002384:Catalysis; D007093:Imidazoles / Q000737:chemistry; D011392:Proline / Q000737:chemistry; D011759:Pyrrolidines / Q000737:chemistry
D000447:Aldehydes; D000596:Amino Acids; D007093:Imidazoles; D011759:Pyrrolidines; D011392:Proline