Asymmetric Hydrogenation of N-Heterocycles for Pharmaceutical Intermediates: Synthetic Strategies and Theoretical Perspectives

Abstract

Nitrogen-containing heterocycles are pivotal in modern drug discovery, constituting an escalating proportion of newly approved small-molecule drugs. Chiral derivatives of these heterocycles offer precise targeting and reduced toxicity, making them indispensable for developing safe and effective pharmaceuticals. Asymmetric catalytic hydrogenation stands as a cornerstone technology for constructing such chiral scaffolds, enabling the enantioselective synthesis of bioactive molecules. This review systematically summarizes the latest advances in applying asymmetric catalytic hydrogenation to five key nitrogen heterocycles-pyridine, pyrrole, pyrazole, piperidine, and quinoline-highlighting their roles in drug synthesis. It dissects the catalytic mechanisms and performance of metal-based (e.g., Rh, Pd, Ir), organocatalytic, and biocatalytic systems, addressing their unique advantages, limitations, and recent breakthroughs. Additionally, the integration of density functional theory (DFT) and machine learning for predicting enantioselectivity and optimizing reaction conditions is explored, showcasing data-driven strategies to enhance catalytic efficiency. By synthesizing cuttingedge research, this review underscores the critical role of asymmetric hydrogenation in addressing challenges in chiral drug synthesis, such as substrate scope, catalyst design, and sustainability. It serves as a comprehensive guide for researchers in medicinal chemistry, organic synthesis, and catalysis, offering actionable insights into selecting appropriate catalytic systems, designing novel ligands, and leveraging computational tools to streamline drug development. Moreover, it highlights emerging opportunities at the interface of experimental catalysis and theoretical modeling, inspiring innovations in both academia and industry. Ultimately, this work aims to empower readers to advance the synthesis of high-value chiral heterocycles, fostering the creation of more effective therapeutics with improved pharmacological profiles and minimized side effects.