Straightforward Synthesis of [2H2]-2-Acetyl-1-pyrroline Starting from α-Methyl N-Boc-l-Glutamate

Abstract

A straightforward and reliable three-step synthetic route for [²H₂]-2-acetyl-1-pyrroline has been developed. In the first step, [²H₂]-methyl N-Boc-prolinate was obtained in 68% yield through the reduction of α-methyl N-Boc-l-glutamate with [²H₃]-borane. This intermediate, after removal of the Boc protecting group, was then reacted with tert-butyl hypochlorite in the presence of Et₃N, undergoing a chlorination-elimination sequence to yield [²H₂]-2-(methoxycarbonyl)-1-pyrroline in 90% yield. In the final step, [²H₂]-2-(methoxycarbonyl)-1-pyrroline reacted with CH₃MgBr in the presence of Et₃N/TMSCl, producing [²H₂]-2-acetyl-1-pyrroline in 42% yield. This synthetic approach offers several advantages, including the use of readily available starting materials, a concise reaction sequence, operational simplicity, and high overall yields. Notably, the deuterium isotope introduced by the [²H₃]-borane reduction is positioned at the 5-position of the 1-pyrroline ring, demonstrating remarkable stability and resistance to exchange.