Enantioselective [2+2]-cycloadditions with triplet photoenzymes

Abstract Over the last half century, the remarkable advance in the field of asymmetric catalysis has drastically innovated the procedures of chemical synthesis of enantiomerically pure compounds. However, the vast majority of these transformations are centred on thermochemistry wherein the product chirality is generally established at the ground state. Stereochemical control of photochemical reactions remains a formidable challenge owning to the intrinsic high reactivity of the excited state, for which the small molecules catalysts do not provide a general solution. Here we show that this challenge can be tackled by genetically encoded, chemically evolved triplet photoenzymes embedded with a proficient synthetic photosensitizer. Structural optimization through four founds of rational mutagenesis afforded a proficient enzyme. It promoted enantioselective intramolecular [2+2] photocycloaddition of indole derivatives with marked substrate generality and excellent enantioselectivites (up to 99% enantiomeric excess). X-ray crystal structure of photoenzyme-substrate complex elucidated the important multiple noncovalent interactions that work synergistically to induce high enantioselectivity. This study shows that by merging the empowering mechanism of triplet energy transfer catalysis with the delicate supramolecular cavity of proteins, the triplet photoenzymes artificially expand the fundamental reactivity with respect to enzyme catalysis and unlock an integrated approach to valuable enantioselective photochemical synthesis that are not accessible with either the synthetic or the biological world alone.