Synthesis of [(3S,5R)-3-Hydroxy-5-methylpiperidin-1-yl](2-methylpyridin-3-yl)methanone

There remain challenges for effectively synthesizing heterocycles containing both piperidine and pyridine rings, mainly due to the inefficient synthetic process mostly requiring long reaction times. This paper reports a simple and efficient method for the synthesis of [(3S,5R)-3-hydroxy-5-methylpiperidin-1-yl](2-methylpyridin-3-yl)methanone through six steps starting from D-pyroglutaminol. The key step involved the introduction of a chiral methyl group by alkylation of lithiated (3S,7aR)-3-phenyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one with methyl iodide, followed by reduction and rearrangement to generate a benzyl-protected piperidine intermediate. After deprotection and amide formation, the final product was obtained with an overall yield of 32% in a total time of ~80 h). With readily available and inexpensive starting material through an operationally simple process, the method holds potential for applications in organic synthesis of other piperidine- and pyridine-containing heterocycles.