Double Asymmetric Synthesis by Asymmetric Catalytic Carbonyl-Ene Type Reaction with Chiral Ene Components: Asymmetric Catalytic Synthesis of Aspartyl Dipeptide Sweetener

Double asymmetric induction is described in the carbonyl-ene type reaction of glyoxylate (2) with chiral ene components, (-)-β-pinene (3a) or (+)-α-fenchene (3b), catalyzed by chiral titanium complex (1) derived from optically pure binaphthol (BINOL) and (i-PrO)₂TiCl₂. By (S)-BINOL-Ti catalyst (1) and (-)-β-pinene (3a), the usual ene pathway is favored to provide the homoallylic alcohol products (4a) in extremely high levels of 11S selectivity. By (R)-BINOL-Ti catalyst (1), however, the Friedel-Crafts type reaction leading to the allylic alcohols (4b) becomes favorable to exhibit high levels of 11R selectivity. By contrast, in double asymmetric reaction with (+)-α-fenchene (3b), (S)- and (R)-BINOL-Ti (1) catalysts provide mainly the allylic alcohol products (5b) in extremely high levels of 11S and 11R selectivity, respectively. The (11R)-allylic alcohol 5b thus obtained is converted to the α-amino ester (6), the key intermediate of aspartyl dipeptide sweeteners, via double asymmetric hydrogenation catalyzed by chiral BINAP-Ru complex. The effective mutual kinetic resolution of (Z)- and (E)-mixture 5b is attained by the racemic mixture of (S)- and (R)-BINAP-Ru catalyst to provide exo-8 in high stereoselectivity.

ene reaction - asymmetric catalyst - titanium complex - double asymmetric synthesis - aspartyl sweetener