Pyridines asymmetric hydrogenation

In the heterocyclic series several heteroarylalanines have been obtained by asymmetric hydrogenation using chiral homogeneous catalysts. For example, replacement of the phenyl ring by furan, thiophene, selenophene, pyridine, or indole yields fiirylalanines, thienyManines, 2- and 3-selenienyManines,... 

Very recently, chiral 6-DPPon derivatives, the phospholanes 4b and 5b and the phosphepine 6b, have been prepared and studied as ligands in asymmetric hydrogenation (Figure 2.4) [14]. For comparison, the corresponding 2-alkoxypyridine systems 4a-6a were studied, too. The latter should behave as truly monodentate ligands while the pyridine systems 4b-6b should allow for complementary hydrogenbonding. 

In recent years, a few stereoselective methods for the asymmetric hydrogenation of pyridines and related heterocycles have been developed <20050BC4171>. A chiral auxiliary method starts with an oxazolidinone-substituted pyridine which on reduction with H2/Pd(OH)2 in acetic acid affords the corresponding piperidine in good yield and high enantiopurity. The chiral auxiliary is cleaved during the reaction and can be recovered (Equation 100) <2004AGE2850>. 

Glorius F, Spielkamp N, Holle S, Goddard R, Lehmann CW (2004) Efficient asymmetric hydrogenation of pyridines. Angew Chem Int Ed Engl 43 2850-2852... 

Synthesis of Chiral 3-Amido Esters. The use of 1 as a chiral auxiliary in the asymmetric hydrogenation (Hz/PtOz) of stere-ogenic p-acetamidocrotonates has also been reported. Reaction of 1 with diketene in the presence of TEA and acetone as solvent, followed by saturation with NH3, then AczO-pyridine, and finally hydrogenation (PtOz, 3-5 bars of Hz) afforded the p-amido esters (22) in high selectivity (96% de) (eq 11). 

The asymmetric hydrogenations of substituted pyridines would produce chiral... 

Scheme 6.8 The auxiliary directed asymmetric hydrogenation of pyridines.

Table 6.8 Asymmetric hydrogenation of activated pyridines with a chiral iridium catalyst.

The asymmetric hydrogenation of pyridine derivatives is a practical and direct method to chiral piperidine derivatives that are important synthetic intermediates and the structural unit of many biologically active compounds. Recently, some attempts to develop enantioselective hydrogenation of pyridine derivatives have been made. 

Chiral oxazolidinones are also common chiral auxiliary used in the organic synthesis to provide chiral compounds. In 2004, Glorius et al. described an example of the efficient asymmetric hydrogenation of pyridines through the introduction of a chiral oxazolidinone auxiliary to the 2 position of the pyridine derivatives [52]. 

Scheme 10.38 Asymmetric hydrogenation of 2 oxazolidinone substituted pyridines.

Scheme 10.39 Asymmetric hydrogenation process of 3 substituted pyridine derivatives.

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