New strategies for the synthesis and homologation of complex aliphatic amines

Abstract

The development of chemical methodologies for the efficient assembly and late-stage modification of complex alkylamines represents a significant and enduring challenge in synthetic chemistry. This is due to the ubiquity of this chemical motif in biologically active small molecules and therapeutic agents. This thesis describes the design and implementation of two novel synthetic methods that attempt to meet this challenge. The development of a second-generation carbonyl alkylative amination (CAA) reaction, mediated by zinc, is reported. The use of a metal-reductant-mediated mechanism provided the solution to many of the residual problems associated with the first-generation light-mediated CAA reaction, developed by the Gaunt group. The advances included addressing inherent scalability issues and competitive reductive amination associated with the hydridic silane reductant. This new mechanistic regime enabled a dramatically expanded reaction scope (>150 examples), including the synthesis of α-trialkyl tertiary amines, which cannot be accessed via carbonyl reductive amination. Preliminary mechanistic studies were undertaken implicating the productive participation of both alkyl radical and alkyl zinc intermediates. Secondly, the development of the first example of a direct, catalytic method for the homologation of benzylic tertiary amines to higher-order ω-aryl alkylamines is detailed. The one-carbon homologation reaction was found to be general across a broad range of substrates (>50 examples), including a variety of representative medicinally-relevant amines. The robustness of the reaction was further enhanced through a high-throughput screening approach, which demonstrated conditions that were tolerant of hydrolytically sensitive functional groups. Critically, the length of the carbon chain inserted as part of the process was shown to be programmable through the choice of homologating agent, enabling multi- carbon chain extensions.