Direct access to chiral nitrogen-rich (semi-)saturated heterocycles

Nitrogen-enriched (partially) saturated fused heterocycles have emerged as highly relevant scaffolds for improved pharmaceuticals. Increased solubility, along with fine-tuneable target affinity and specificity, differentiate them from their nitrogen-poor aromatic counterparts. Contrary to their growing demand, applications are severely limited by arduous bottom-up synthesis routes and the lack of a general solution for facile access. Herein, we report an efficient method for the synthesis of chiral (semi-)saturated pyridine-fused heterocycles and their respective N-permutations by enantioselective arene hydrogenation with a newly developed ruthenium catalyst. We obtained versatile and highly valuable product motifs, including pyridine- and piperidine-fused scaffolds with up to four newly formed stereocenters, of which several have not been previously reported. We conducted extensive in silico studies to elucidate a rare inverse-pressure-dependent enantioselectivity and to develop a rational model for predicting the stereochemical outcome. This contribution is expected to accelerate the exploration of new frameworks in drug discovery. • Enantioselective (partial) hydrogenation of pyridine-fused heterocycles • Highly selective one-pot synthesis of heterocycles with up to four new stereocenters • In silico study of catalyst and inverse-pressure-dependent enantioselectivity Nitrogen-rich (partially) saturated heterocycles are a structurally diverse class of compounds abundant in drug motifs. Synthetically, the facile access to these structures and their respective nitrogen permutations can be limited. In this work, we employed enantioselective arene hydrogenation as an efficient strategy to directly access a wide variety of chiral 6,5-heterocycles from available aromatic building blocks. For this purpose, we optimized and studied a highly selective ruthenium-N-heterocyclic carbene (Ru-NHC) catalyst by means of mechanistic experiments and density functional theory (DFT) calculations. With this catalyst, we obtained various partially saturated heterocycles and distinct nitrogen permutations, some of which have not been previously reported in the literature. We elucidated a rare pressure-dependent enantioselectivity and provide a rational model of enantioselectivity. We also extended the hydrogenation protocol to access fully saturated heterocycles and their derivatives in a one-pot procedure with up to four defined stereocenters. These findings extend the accessible chemical space and are expected to lead to the development of improved drug candidates. The bread and butter of drug discovery in the pharmaceutical industry is the synthesis of complex scaffolds, including chiral heterocyclic motifs. However, general access remains a long-standing goal and challenge. Despite the high demand, the synthesis of some entities is limited by step-intensive and costly routes. To address these challenges, we herein present the development of a highly selective ruthenium-NHC catalyst that enables direct access to a broad range of chiral 6,5-heterocycles from readily available arenes.