A 4-hydroxypyrrolidine-catalyzed mannich reaction of aldehydes: control of anti-selectivity by hydrogen bonding assisted by Brønsted acids.

An anti-selective Mannich reaction of aldehydes with N-sulfonyl imines has been developed by using a 4-hydroxypyrrolidine in combination with an external Brønsted acid. The catalyst design is based on three elements: the alpha-substituent of the pyrrolidine, the 4-hydroxy group, and the Brønsted acid, the combination of which is essential for high chemical and stereochemical efficiency. The reaction works with aromatic aldehyde-derived imines, which have rarely been employed in previously reported enamine-based anti-Mannich reactions. Additionally, both N-tosyl and N-nosyl imines can be successfully used and the Mannich adducts can be easily reduced or oxidized, and after N-deprotection the corresponding beta-amino acids and beta-amino alcohols can be obtained with good yields. The results also show that this ternary catalytic system may be practical in other enamine-based reactions.