The ever-expanding role of asymmetric covalent organocatalysis in scalable, natural product synthesis.

Following the turn of the millennium, the role of asymmetric covalent organocatalysis has developed into a scalable, synthetic paradigm galvanizing the synthetic community toward utilization of these methods toward more practical, metal-free syntheses of natural products. A myriad of reports on asymmetric organocatalytic modes of substrate activation relying on small, exclusively organic molecules are delineating what has now become the multifaceted field of organocatalysis. In covalent catalysis, the catalyst and substrate combine to first form a covalent, activated intermediate that enters the catalytic cycle. Following asymmetric bond formation, the chiral catalyst is recycled through hydrolysis or displacement by a pendant group on the newly formed product. Amine- and phosphine-based organocatalysts are the most common examples that have led to a vast array of reaction types. This Highlight provides a brief overview of covalent modes of organocatalysis and applications of scalable versions of these methods applied to the total synthesis of natural products including examples from our own laboratory.