Design and Evaluation of Ambiphilic Aryl Thiol–Iminium-Based Molecules for Organocatalyzed Thioacyl Aminolysis

[Image: see text] Progress toward the design and synthesis of ambiphilic aryl thiol–iminium-based small molecules for organocatalyzed thioacyl aminolysis is reported. Here we describe the synthesis of a novel tetrahydroisoquinoline-derived scaffold, bearing both thiol and iminium functionalities, capable of promoting the transthioesterification and subsequent amine capture reactions necessary to achieve organocatalyzed thioacyl aminolysis. Model studies demonstrate the ability of this designed organocatalyst to deliver critical intermediates capable of undergoing these individual reactions necessary for the proposed process. Future design improvements and directions toward cysteine-independent organocatalyzed native chemical ligation are discussed.