Development of A Continuous Flow Photoredox-catalyzed Cascade for Stereoselective Synthesis of Pyrrolidines

Polysubstituted pyrrolidines are ubiquitous structures in a wide range of bioactive compounds such as natural products, pharmaceuticals, and agrochemicals. Stereoselective and regioselective synthetic methods to access polyfunctionalized pyrrolidines have been a major research focus in the area of heterocycle synthesis for the past decades. However, the methodologies and reaction setups largely remained unchanged, and there are still intrinsic and unsolved problems that are highly desirable to be addressed. A multitude of challenges have been identified with existing syntheses of pyrrolidines, namely (1) stereo- and regioselectivities; (2) use of high-cost transition metal catalysts; (3) chiral catalysts and ligands; (4) inaccessible substrates; (4) excessive reagents and additives; (5) poor scalability; and (6) the handling of specialized equipment and labor. In the proposed study, we aim to utilize the many advantages of flow chemistry and photoredox catalysis cooperatively to address these long-standing challenges. Continuous flow chemistry is a powerful synthetic technology that provides many advantages over traditional organic synthesis, such as allowing for precise control of reaction parameters, enhanced safety, improved scalability, and increased efficiency. On the other hand, photoredox catalysis is a versatile technique that harnesses light and photocatalysts to enable mild and selective transformations. Our proposed method would replace the costly transition metal catalysts and chiral catalysts with organo-photocatalysts while readily available substrates will be used. Furthermore, the batch reaction conditions can be readily translated to continuous flow for facile scale-up and improved efficiency. Our preliminary results have verified the plausibility of the proposed study, in which our photoredox-catalyzed cascade reaction provided the desired pyrrolidine products with excellent regio- and stereoselectivity. The prototype flow system significantly intensified the process and shortened the reaction time by at least 99%. The potential of our stereoselective pyrrolidine synthesis would be fully explored in this project, including the development of a scalable continuous flow system, synthesis of natural product analogues, and synthesis of deuterated pyrrolidines. The mechanistic study will guide the development of the proposed project and provide important insights to the organic synthesis community. The fundamental and technical knowledge obtained during the development of our new stereoselective pyrrolidine synthesis will be of significant value to academic interest and industrial applications. The demonstrated flow system will serve as a model for future designs of continuous flow photochemical reactions. Currently, flow chemistry is still underdeveloped in Hong Kong. Our study would attract attention on continuous flow production and help transform the fine chemical manufacturing and pharmaceutical industry.