An asymmetric hydrogenation process of 3-substituted pyridine derivatives has been developed with the use of a RhTangPhos complex as the catalyst. The whole process consists of an efficient partial hydrogenation of nicotinate and a subsequent highly enantioselective, Rh-catalyzed, homogenAn increase in the demand for the production of enantiomerically pure pharmaceuticals, agrochemicals, flavors, and other fine chemicals has advanced the field of asymmetric catalytic technologies.[1] As one of the most efficient methods for the preparation of chiral compounds, asymmetric hydrogenation has been intensively studied. Tremendous success has been achieved in the reductions of the C=C, C=O, and C=N functionalities.[2-4] However, asymmetric hydrogenation of an aromatic ring, one of the most readily available unsaturated compounds, has received little attention and is generally regarded as the greatest challenge in the asymmetric hydrogenation field.[5-8] Some positive results have been reported recently concerning the asymmetric hydrogenation of polycyclic heteroaromatic compounds, [9,10] such as 2-substituted quinolines [11][12][13] and indoles. [14][15][16][17][18] Some promising results have been reported in the preparation of optically active 2-piperazine derivatives by the reduction of tetrahydropyrazines derived from pyrazines. [19][20][21] However, the asymmetric reduction of monocyclic pyridine derivatives has yet to have success. A homogeneous Rh-catalyst system has been used in the asymmetric hydrogenation of monosubstituted pyridines and furans, but only 24-27 % ee values were obtained. [22,23] Very recently, Glorius et al. reported an example of an efficient asymmetric hydrogenation of pyridine through the introduction of a chiral auxiliary, [24] and Charette et al. communicated their results regarding the asymmetric hydrogenation of N-iminopyridinium ylides. [25] [a] College of Chemistry and Molecular Sciences, Wuhan University Wuhan, 430072, P. R. As readily available heteroaromatic compounds, pyridine and its derivatives are very attractive materials for the synthesis of N-containing building blocks in pharmaceuticals and in agrochemicals (Scheme 1). The development of an efficient method for the production of enantiomerically pure piperidine derivatives can be of significant value. For example, enantiomerically pure nipecotic acid ($ 113.70/g, Aldrich) is 2000 times more expensive than its pyridine analog, nicotinic acid. Although the direct asymmetric hydrogenation of nicotinic acid to form enantiomerically enriched nipecotic acid [Scheme 1, Equation (1)] would have practical industrial applications, no such process has been successfully developed so far. Herein we report our preliminary results on the asymmetric hydrogenation of substituted pyridines. We describe a two-step method as an alternative solution for the preparation of nipecotic acid derivatives. First, partial hydrogenation of nicotinate provides the tetrahydro-intermediates under heterogeneous catalytic conditions; second, the homogeneous ...
