Controlling Diastereodivergent Light-Driven Processes: The Impact of the Light Source and Steric Factors on the Paternò-Büchi Reaction

Abstract By conducting in-depth mechanistic investigations to rationalize reaction manifolds, chemists can expand the generality of synthetic processes and discover novel reactivities. The challenge is to use the resulting information to control the selectivity of a given synthetic process. A particular challenge for organic chemists is to use an external stimulus to switch a reactivity on or off. Here, we mechanistically investigated light-driven [2+2] heterocycloadditions (Paternò-Büchi reactions) between indoles and ketones. We used ground-state UV-Vis absorption and transient absorption spectroscopy (TAS) at ns and fs timescale, together with DFT and TD-DFT calculations. We found that the reaction can proceed via an exciplex or electron-donor-acceptor (EDA) complex manifold, which are key intermediates in determining the reaction’s stereoselectivity. We used this discovery to control the reaction’s diastereoselectivity, gaining access to previously inaccessible diastereoisomeric variants. When moving from 370 to 456 nm irradiation, the EDA complex is increasingly favored, and the diastereomeric ratio dr (en-do:exo) moves from >99:<1 up to 47:53. In contrast, a simple Methyl-to-iPropyl favors the exciplex, reversing the dr from 89:11 to 16:84. Our study shows how light and steric parameters can be rationally used to control the diastereoselectivity of syn-thetically relevant photoreactions, creating new mechanistic pathways to previously inaccessible stereochemical variants.