Catalytic Asymmetric Hydrogenation of Heteroarenes

INTRODUCTION Asymmetric hydrogenation of unsaturated organic compounds has been established as one of the most efficient methods for the preparation of chiral, non-racemic substrates. Among hydrogenation of various substrates, the asymmetric hydrogenation of heteroarenes provides a straightforward approach to a wide range of enantiomerically pure saturated heterocycles, which are subunits of many biologically active compounds. In addition, multiple stereocenters can be created in a single step when multi-substituted heteroarenes are used as substrates. With these advantages and potential application, the development of an efficient, cost-effective method for asymmetric hydrogenation of heteroarenes is highly desirable. However, the development of asymmetric hydrogenation of heteroarenes has been a challenging process in organic synthesis because the stability of heteroarenes and the presence of heteroatoms. More energy (10-20 kcal mol per double bond) is required for hydrogenation of heteroaromatic compounds than hydrogenation of olefins, ketones or imines. In addition, the basic heteroatoms can bind to the metal centers to deactivate the catalysts or simply serve as achiral ligands. Furthermore, in contrast to functionalized olefins and ketones, the lack of a secondary coordinating site in simple heteroarenes to interact with the metal center also accounts for the difficulties in achieving good enantioselectivity. Despite these challenges, several catalyst systems have been developed for asymmetric hydrogenation of heteroarenes in the past decade. Two basic strategies that have been employed to facilitate the asymmetric hydrogenation process are the use of bicyclic heteroarenes and the introduction of substituents next to or on the heteroatoms. The first strategy is exemplified by the hydrogenation of quinolines, indoles and benzofurans. In these substrates, the aromatic stabilization energy of the heteroaromatic ring is reduced, thereby increasing reactivity towards hydrogenation. In the second strategy, the substituent is installed to weaken the binding between the heteroatom and metal center by virtue of a steric effect or alternatively to serve as a secondary coordination site to the catalyst. To understand the chemical reactivity and future potential of this transformation, methods for asymmetric hydrogenation of various heteroarenes will be discussed.