This paper reports the asymmetric synthesis of an important pharmaceutical intermediate (3S)-1-[(1R)-2-hydroxy-1-phenylethyl]-3-methylpiperidin-2-one (compound 1 ) from commercially available D-plenylglycinol and delta-valerolactone. During the alkylation process, the hydroxyl group can be protected or unprotected, resulting in a different consumption of s-BuLi, and leading to a different diastereomeric excess (de) of compound 1 . When 1-[(1R)-2-hydroxy-1-phenylethyl]-piperidin-2-one (compound 2 ) was alkylated with 2.5 eq. of s-BuLi, compound 1 was obtained as a single isomer detected by chiral high performance liquid chromatography (HPLC) columns with an overall yield of 91%. With the hydroxyl group protected, (R)-1-(2-[(tert-butyldimethylsil) oxy]-1-phenylethyl) piperidine-2-one (compound 6 ) could be alkylated with 1.5 eq. of s-BuLi, giving compound 1 and its diastereoisomer 8 in a ratio of 1:2.5 and a yield of methylation of 90%. Compounds 1 and 8 could be separated completely and easily by flash chromatography. The absolute configuration of compound 8 was determined by singlecrystal X-ray analysis. The mechanism of the alkylation process is discussed based on experimental results.

中文翻译：

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N-保护的3-甲基哌啶-2-酮及其非对映异构体的不对称合成

本文报道了重要的医药中间体（3S）-1-[（1R）-2-羟基-1-苯乙基] -3-甲基哌啶-2-酮（化合物 1 ）的不对称合成， 由市售D-异戊二烯醇和δ -戊内酯。在烷基化过程中，羟基可以被保护或未被保护，导致s-BuLi的消耗量不同，并导致化合物 1 的不同的非对映异构体过量（de） 。当1-[（（R）-2-羟基-1-苯基乙基]-哌啶-2-酮（化合物 2 ）用2.5当量烷基化时。s-BuLi的化合物 1 通过手性高效液相色谱（HPLC）柱检测得到的单一异构体异构体，收率为91％。在羟基被保护的情况下，（R）-1-（2-[（叔丁基二甲基硅氧基）]-1-苯基乙基）哌啶-2-酮（化合物 6 ）可以用1.5当量烷基化。得到 1％的s-BuLi，以1∶2.5的比例得到化合物 1 及其非对映异构体 8 ，甲基化产率为90％。化合物 1 和 8 可以通过快速色谱法完全轻松地分离。通过单晶X射线分析确定化合物 8 的绝对构 型。根据实验结果讨论了烷基化过程的机理。