Enantioselective hydrogenation with chiral frustrated Lewis pairs.

The development of transition-metal-catalyzed asymmetric hydrogenation could be stated as the cradle of modern enantioselective catalysis. Since the early asymmetric hydrogenation example from Knowles and Sabacky in 1968, the method has rapidly advanced over the years into an important tool in academia and chemical industry. In general, for these transformations the development of effective transition-metal complexes having chiral ligands was a basic prerequisite. However, since the pioneering work of Stephan and coworkers in 2006, the field of homogenous hydrogenation has been extended to the possibility of metal-free hydrogenation based on the utilization of frustrated Lewis pairs (FLPs) for hydrogen activation. Combinations of the strong Lewis acid tris(perfluorophenyl)borane (B(C6F5)3) with a variety of sterically encumbered Lewis bases—phosphines, nitrogen bases, and carbon-derived bases—can be used to activate hydrogen at ambient conditions. The concept was subsequently broadened from variations of the Lewis base to modifications of the Lewis acid structure, which resulted in intramolecular FLPs and borane derivatives with increased activity and stability. Furthermore, these chemical peculiarities rapidly found application in catalytic hydrogenation reactions. Some of the FLPs were found to serve as catalysts for the hydrogenation of imines, nitriles, and functionalized alkenes. In the absence of bulky Lewis bases also imine substrates could adopt the function of the FLP partner, and B(C6F5)3 was discovered to be sufficient as the catalyst for their hydrogenation. Additionally, recent mechanistic investigations and preparative experiments corroborated the assumption that for asymmetric transformations, the element of chirality has to be favorably incorporated into the Lewis acid structure. In early experiments employing a-pinene-derived chiral borane, asymmetric reduction of imines was achieved, albeit with low enantioselectivity (13% ee). With these initial findings the synthesis of effective chiral Lewis acids for application in asymmetric hydrogenation reactions was envisioned. On the basis of this concept, the first example of the highly enantioselective hydrogenation of imines with chiral FLPs is demonstrated herein. The initial example with a-pinene-derived chiral borane confirmed the effectiveness of this catalyst structure. However, the stability of the Lewis acid emerged as a major drawback. For the further investigations a chiral borane derived from camphor was considered to be a more suitable structural motif. Reaction of (1R)-(+)-camphor (1) with phenylmagnesium bromide (2) resulted in the tertiary alcohol 3 (Scheme 1). Subsequent dehydration with thionyl chloride/