Mechanism of a Dually Catalyzed Enantioselective Oxa-Pictet–Spengler Reaction and the Development of a Stereodivergent Variant

Enantioselective
oxa-Pictet–Spengler reactions
of tryptophol
with aldehydes proceed under weakly acidic conditions utilizing a
combination of two catalysts, an indoline HCl salt and a bisthiourea
compound. Mechanistic investigations revealed the roles of both catalysts
and confirmed the involvement of oxocarbenium ion intermediates, ruling
out alternative scenarios. A stereochemical model was derived from
density functional theory calculations, which provided the basis for
the development of a highly enantioselective stereodivergent variant
with racemic tryptophol derivatives.