Synthesis
(C) Asymmetric reduction reaction using a chiral spiroborate catalyst to convert O-benzyl pyridyl alkyl ketoxime 13 to the target product. This was carried out as follows: 2-, 3- or 4-pyridyl alkyl oxime ethers were prepared and reduced in the presence of catalyst 5, depending on the reaction conditions, as shown in Figure 6 and Table 8. In the case of 4-acetylpyridine O-benzyl oxime (13a), the reduction was carried out using 5 equivalents of BH3-THF in dioxane at 0 °C to give N-(1-pyridinyl-4-ethyl)-acetamide (14a), which achieved an enantiomeric excess (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 still showed unreacted feedstock. Attempts to reduce 4-pyridyl oxime ether (entries 1-3) using THF and tert-butyl methyl ether as solvents revealed dioxane as the best solvent. To improve the conversion, the reduction was switched to THF at room temperature, and the reaction was completed after two days, but with a decrease in the ee value (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% catalyst loaded dioxane solution with an 84% yield of the isolated product and an ee value >98% (entry 8). A similar optimization study was conducted for the reduction of 13c and found that moderate yields and ee values of 60% were obtained in the presence of 1.0 equiv. of catalyst 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) were unsatisfactory. The addition of BF3 increased the yield but decreased the enantioselectivity (entry 12). For the reduction of 2-pyridyl oxime benzyl ether, a chemically calculated amount of catalyst 5 was required to complete the reaction, but the ee value was moderate (entry 10). The reaction products listed in Table 8 were separated by column chromatography and the ee values were determined by GC analysis of the acetyl derivatives (using a chiral column CP-Chirasil-DexCB).
