Asymmetric Hydrogenation of Pyridines: Enantioselective Synthesis of Nipecotic Acid Derivatives

Abstract

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 ...

Enantioselective Synthesis of Endocyclic β-Amino Acids with Two Contiguous Stereocenters via Hydrogenation of 3-Alkoxycarbonyl-2-Substituted Quinolines

“…6 Subsequently, Zhang and co-workers developed a multistep strategy of combining the Pd/C catalyzed partial hydrogenation with a homogeneous rhodium-catalyzed hydrogenation to afford N-protecting 3-(alkoxycarbonyl)piperidines. 7 Recently, a relay catalytic Friedländer condensation and transfer hydrogenation in the presence of an achiral Lewis acid and chiral Brønsted acid to furnish 3-alkoxycarbonyl-substituted tetrahydroquinolines was successfully described by Gong's group. 8 Very recently, our research group reported an efficient iridiumcatalyzed asymmetric hydrogenation of 4-(alkoxycarbonyl)isoquinolines with excellent enantioselectivity and diastereoselectivity.…”

Sequential C–H Arylation and Enantioselective Hydrogenation Enables Ideal Asymmetric Entry to the Indenopiperidine Core of an 11β-HSD-1 Inhibitor

“…26 We thus pursued the asymmetric reduction of pyridinium salt 13 with rhodium catalysts in the presence of different families of chiral phosphine ligands including bisphosphines with axial chirality, Solvias’ ferrocene-based ligands, Ferringa’s monophosphoramidite ligands, and other reported chiral ligands. Disappointingly, both low conversion and low enantioselectivities were observed for all the ligands evaluated (Figure 2).…”

Transition Metal‐Catalyzed Homogeneous Asymmetric Hydrogenation

“…Despite of the high enantioselectivity and mild reaction condition of this method, the deprotection of product requires strong reducing agents such as Raney nickel and lithium -ammonia, which may limit the method from practical applications. The Zhang group reported another approach involving a two -step hydrogenation process [398] . The aromaticity of pyridine derivatives was fi rst broken by a partial heterogeneous hydrogenation catalyzed by Pd/C.…”