Chemoenzymatic Functionalization of Quinolines with Carbene Transferases

Quinoline is a sp2-rich heteroaromatic compound that has gained significant recognition in the medicinal chemistry community because of its presence in numerous pharmacologically active substances, presenting a broad range of biological activities. Notably, the molecule’s lack of unsaturated, chiral centers indicates potentially unexplored chemical space within its scaffold. Given precedent in the Arnold group, we posited that reduction and carbene transfer could significantly increase quinoline’s sp3 centers. Here, we present a heme-enzyme, Aeropyrum pernix protoglobin (ApPgb), that can perform olefin cyclopropanation on products derived from quinoline reduction. This cyclopropanation occurs with significant chemo- and diastereoselectivity. Additionally, it is expected that the enzyme’s chemo-, diastereo-, and enantioselectivity can be refined with directed evolution. These findings further elucidate the new-to-nature chemistry for heme enzymes and could lead to the discovery of new molecules with promising biological activity.