216753-06-9

27854-90-6

C) Asymmetric reduction of O-benzyl pyridinyl alkyl ketoxime 13 using a chiral spiroborate catalyst. According to another aspect of the present invention, 2-, 3- or 4-pyridyl alkyl oxime ethers were prepared and reduced in the presence of catalyst 5 under different reaction conditions as shown in Figure 6 and Table 8. As an example, 4-acetylpyridine O-benzyl oxime 13a was treated with 5 equivalents of BH3-THF in dioxane at 0°C to give N-(1-pyridinyl-4-ethyl)-acetamide 14a, with an ee value of 99%, but with a lower chemical yield, as shown in Table 8 entry 4. Despite stirring the reaction mixture in an ice bath for 4 days, TLC analysis showed that there were still unreacted feedstocks. THF and tert-butyl methyl ether were screened as solvents for the reduction of 4-pyridyl oxime ether (entries 1-3) and dioxane was found to be the best solvent. To improve the conversion, the reduction was attempted in THF at room temperature. The reaction was completed after two days, but the ee value was reduced (entry 2). In addition, the reduction of 3-pyridyl oxime ether was studied at different temperatures and catalyst amounts. It was found that the reaction was completed after 48 hours of stirring at 10°C using a 30% solution of dioxane with catalyst 5. The isolation gave a product in 84% yield with an ee value >98% (entry 8). A similar optimization study was carried out for the reduction of 13c. Moderate yields and ee values of 60% were obtained in the presence of 1.0 equiv. of catalyst 5 and 2.0 equiv. of borane (entry 10). Attempts to use 0.3 equivalents of catalyst 5 in dioxane at 10 °C and to protect the pyridine nitrogen with BEt3 (entry 11) resulted in unsatisfactory reactions. The addition of BF3 increased the yield but decreased the enantioselectivity (entry 12). Reduction of 2-pyridyl oxime benzyl ether required a chemically calculated amount of catalyst 5 but with a moderate ee value (entry 10). For the reactions listed in Table 8, the products were separated by column chromatography. The ee values were determined by analyzing the acetyl derivatives by GC using a chiral column (CP-Chirasil-DexCB).