Asymmetric synthesis of N-protected 3-methylpiperidin-2-one and its diastereoisomer

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 singlecrystal X-ray analysis. The mechanism of the alkylation process is discussed based on experimental results.

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“…Because of compounds J1−J12 containing three chiral centers in alcohol and acid moieties, the two diastereomeric isomers, less polar isomers (J1-H-Rf to J12-H-Rf) and more polar isomers (J1-L-Rf to J12-L-Rf) showed different retention factor (Rf) values, were separated from each other by silica gel column chromatography (petroleum ether/ethyl acetate = 8:1, v/v). 39 1 H NMR, 13 C NMR, and HRMS for all target compounds may be found in the Supporting Information.…”