Bifunctional Cinchona Alkaloid Thiourea Catalyzed Highly Efficient, Enantioselectiye Aza-Henry Reaction of Cyclic Trifluoromethyl Ketimines: Synthesis of Anti-HIV Drug DPC 083

摘要

The aza-Henry reaction is a powerful method for C—C bond formation. Moreover, the versatile nitro group can be conveniently transformed into a variety of new functional groups, which are highly valuable in the preparation of related analogues in drug discovery. In recent years, significant efforts have been directed toward the development of catalytic asymmetric aza-Henry reactions. However, the electrophilic substrates have been largely confined to imines derived from aldehydes. The development of an efficient protocol for an enantioselective aza-Henry reaction of ketimines to generate a chiral quaternary center remains elusive because of the lower reactivity of ketimines and difficulties in enantiofacial discrimination. To our knowledge, to date, there has been only one report, by Feng and co-workers, of a chiral N,N'-dioxide copper complex (20mol%) catalyzed asymmetric aza-Henry reaction between acyclic ketimines and nitro-methane; this reaction proceeded with good enantioselectiv-ities (71-96% ee) but generally in poor yields (21-70%).