Direct Catalytic Asymmetric Synthesis of <i>anti</i>-1,2-Amino Alcohols and <i>syn</i>-1,2-Diols through Organocatalytic <i>anti</i>-Mannich and <i>syn</i>-Aldol Reactions

Abstract

Chiral 1,2-amino alcohols and 1,2-diols are common structural motifs found in a vast array of natural and biologically active molecules. Efficient enantioselective syntheses of ketones containing syn- or anti-1,2-amino alcohols and 1,2-diols have been reported using metal-based strategies. To date, however, approaches involving organocatalysis have been limited to the syntheses of the syn-1,2-amino alcohols and anti-1,2-diols. Herein we disclose simple and efficient routes to highly enantiomerically enriched anti-1,2-amino alcohols and syn-1,2-diols through direct asymmetric Mannich, Mannich-type, and aldol reactions involving unmodified α-hydroxyketones in reactions catalyzed by primary amine-containing amino acids. These reactions exploit (Z)-enamines of α-hydroxyketones in their bond-forming transition states. This study compliments and extends our bioorganic approach to asymmetric synthesis in these two versatile synthon classes. Significantly, these reactions are practical, tolerate wet solvent, and exploit commercially available amino acids, such as threonine and tryptophan, and their derivatives as catalysts. These results provide additional support for our original hypothesis suggesting that amino acid catalysis played a key role in prebiotic chemistry facilitating the asymmetric synthesis of the molecules of life.