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Abstract: 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 single-crystal X-ray analysis. The mechanism of the alkylation process is discussed based on experimental results.

This article describes the use of a chiral auxiliary for the asymmetric synthesis of 3-methylpiperidin-2-one. Key the success of this approach is the discovery of a highly diastereoselective alkylation of lithium elongate dianions of N-hydroxy phenethyl substituted piperidin-2-one.

(3S)-1-[(R)-2-羟基-1-苯乙基]-3-甲基-2-哌啶酮的合成

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