Novel Organocatalytic Strategies to Construct Pyrrolidines and Pyrrolines

Pyrrolidines and pyrrolines represent an important subclass of N-heterocycles that are notably present in a wide range of biologically relevant molecules. Among the strategies used to access these motifs, organocatalysis has emerged as a powerful synthetic approach. Over the past decade, numerous methods encompassing a wide range of mechanistically distinct strategies have been reported. A comprehensive review of organocatalytic strategies to access pyrrolidines and pyrrolines is presented herein. In Chapter 2, the development of an asymmetric synthesis of pyrrolidines via an isothiourea-catalyzed [1,2]-Stevens rearrangement of ammonium ylides is described. This project addresses a longstanding challenge within the field of synthetic chemistry. Products were obtained in up to 86% yield and in up to 90:10 er. Expansion of the substrate class beyond azetidinium salts to isoindolinium systems is also discussed. The utility of this methodology was further demonstrated through downstream derivatization of the resulting pyrrolidine products. In Chapter 3, a dual amine/copper-catalyzed direct β-functionalization of saturated aldehydes was developed. This methodology converted O-acyloximes into 1-pyrrolines in a single step in up to 82% yield. An extensive optimization revealed that the optimal conditions employed stoichiometric quantities of azepane, a bulky terpyridine ligand, and a mixed solvent system. Expansion of the substrate scope to starting materials with different steric and electronic properties was explored, but many did not proceed under the conditions evaluated. Additionally, mechanistic experiments were conducted to investigate the reaction pathway, although these studies did not conclusively support a single mechanism. Together, these studies demonstrate complementary organocatalytic and cooperative catalytic strategies for the construction of pyrrolidines and pyrrolines and expand the range of organocatalytic bond-forming processes available towards their synthesis.