Benzoic Acid and Thiourea Co-Catalysts.

摘要

In Chapter 1, we provide an overview of landmark experiments from the last sixty years in the study of the Pictet--Spengler reaction. Both physical organic and enzymatic studies are described.;In Chapter 2, we report a simple chiral amido-thiourea catalyst, which promotes asymmetric Pictet--Spengler reactions in combination with benzoic acid. Mild and general reaction conditions were identified that have to date resulted in the one-step preparation of nearly twenty enantioenriched (85--99% ee) tetrahydro-beta-carbolines from readily available tryptamine and aldehyde precursors. The tetrahydro-beta-carboline scaffold is a privileged substructure among biologically active natural and unnatural products.;An investigation of the mechanism of benzoic acid and thiourea co-catalysis of the Pictet--Spengler reaction is reported in Chapter 3. A kinetic isotope effect (KIE) study identified rate-limiting cleavage of the isotopically labeled C2--[²H] bond, consistent with rate- and enantioselectivity-determining rearomatization. Subsequent kinetic, computational, and structure--activity relationship studies were undertaken to identify the base in the rate-limiting C--H cleavage, studies which are consistent with the carboxylate acting as the key base. The chiral thiourea is proposed to ligate the iminium•benzoate complex; no evidence suggesting that thiourea plays a direct role in promoting rearomatization has yet been identified. Hydrogen bonding co-catalysis is instead rationalized by thiourea-induced stabilization of the reactive intermediate; i.e. thiourea binding favors partially rate-limiting ionization.;In Chapter 4, we report the extension of benzoic acid and chiral thiourea co-catalysis to the enantioselective synthesis of tetrahydro-gamma-carbolines in one step from isotryptamine, the C2 substituted structural isomer of tryptamine, and aldehyde precursors. A diverse array of enantioenriched alkaloid products has been prepared in moderate to high enantioselectivity (70--95% ee). The products can be enriched to enantiopurity (>99% ee) via tituration or recrystallization.;The projects described in Chapters 1--4 address cooperative chiral thiourea and benzoic acid catalysis, a mode of activation that shows promise as a general system for the synthesis of enantioenriched alkaloids. Additionally, our mechanistic work has revealed an unanticipated, but intriguing mode of catalysis.