Direct Formation of Oxocarbenium Ions under Weakly Acidic Conditions: Catalytic Enantioselective Oxa-Pictet–Spengler Reactions

Two
catalysts, an amine HCl salt and a bisthiourea, work in concert
to enable the generation of oxocarbenium ions under mild conditions.
The amine catalyst generates an iminium ion of sufficient electrophilicity
to enable 1,2-attack by an alcohol. Catalyst turnover is achieved
by amine elimination with concomitant formation of an oxocarbenium
intermediate. The bisthiourea catalyst accelerates all of the steps
of the reaction and controls the stereoselectivity via anion binding/ion
pair formation. This new concept was applied to direct catalytic enantioselective
oxa-Pictet–Spengler reactions of tryptophol with aldehydes.