A Flow Chemistry Platform for Photochemical Macrocyclization of Peptides

The importance of macrocyclic peptides in drug discovery has spawned a variety of modern techniques to improve their synthesis. Although photocatalysis is now an indispensable tool in the synthesis of natural products and pharmaceuticals, it is rarely exploited in macrocyclization. Photochemical macrocyclization remains rare and is hampered by challenges in efficiency and scale-up. A "hybrid" reactor that incorporates aspects of plug flow and continuously stirred tank reactor systems is reported, which allows for slow addition strategies typically associated with batch processes. Via efficient light penetration, mixing, and gas manipulation, a macrocyclic aerobic oxidative coupling of thiols employing low catalyst loadings (1 mol %) was developed to access a variety of peptidic macrocycles on preparative scales. Preparation of "macromulticycles" was also demonstrated. The hybrid reactor outperformed existing technologies and permitted rare gram-scale photochemical macrocyclization.