Novel Catalysis for Macrocyclization Processes

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Macrocycles are a unique chemotype in chemistry that impact the fields of pharmaceuticals, agrochemicals, aromachemicals and materials science, affecting the technological and economic welfare of society. The interest in complex macrocycles in biology, medicine and energy-related fields, has highlighted the need for new catalytic strategies. The proposed program will address these state-of-the-art challenges through innovative solutions in catalysis. The program recognizes the potential of unique chiral architectures in macrocycles, and describes the development of catalytic routes towards planar chiral macrocycles as short term goals. Importantly, atropisomerism is a recognized challenge in many fields, including drug discovery, where planar chiral macrocyclic scaffolds are essentially unexplored. Specifically, the proposal describes using asymmetric organo- and Bronsted acid catalysis to prepare planar chiral macrocycles from common, readily available building blocks. A common theme is the design of processes that include versatile "handles" that can be used to tailor the macrocycles for applications in various fields. The proposal describes long-term goals to address the critical need for chemoselectivity in macrocyclization via photocatalysis. The preparation of novel chemotypes of essential macrocyclic disulfides is described via a photochemical deprotection/macrocyclization sequence. Also, photocatalysis will enable new chemistry using ubiquitous functionality found in macrocycles employed by the pharmaceutical and aromachemical industries. Transformations involving nitroindoline amides will facilitate macrocyclizations to form acyl functionality, permit the synthesis of challenging macrocyclic ketones, or enable SNAr reactions that are problematic under thermally-mediated processes. In addition, the preparation of enantioenriched macrocyclic amides and esters via dynamic kinetic resolution (DKR) would exploit photocatalysis to chemoselectively racemize key secondary amines and alcohols during the DKR process. The research goals create new tools for photomacrocyclization that will be more energy efficient and generate less waste. Lastly, the development of copper-based complexes as photocatalysts for macrocyclization is proposed. Elucidating key structural features of the catalysts for application in energy transfer or for reductive quenching processes, which remain a challenge in the area of copper-based photocatalysis, is described. The development of base metal photocatalysis has considerable potential impact for sustainable molecular synthesis, particularly when developed in parallel with continuous flow methods that are compatible with industrial scale applications. In sum, the proposed research should have a significant impact and form HQP that are trained in state-of-the-art synthetic techniques.