Enzymatic Kinetic Resolution of 1,3-Dioxolan-4-one and 1,3-Oxathiolan-5-one Derivatives: Synthesis of the Key Intermediate in the Industrial Synthesis of the Nucleoside Reverse Transcriptase Inhibitor AMDOXOVIR

摘要

The resolution of racemic 1,3-dioxolan-4-one and 1,3-oxathiolan-5-one derivatives such as (4-oxo-1,3-dioxolan-2-yl)methyl 2-methylpropanoate (2) by enzymatic solvolysis was investigated. The resolution of 2, a precursor for the synthesis of the nucleoside reverse transcriptase inhibitor Amdoxovir, was optimized in terms of solventucleophile, reaction conditions, and enzyme. The use of lipase from Candida antarctica B (CALB) and methanol as nucleophile and solvent resulted in an effective resolution and the product (R)-2 could be easily isolated. Products of substrate decomposition can be isolated and reused for the synthesis of racemic 2. The broad range of application for this enzymatic resolution was demonstrated by the resolution of further substrates with different substitution patterns. This process gives a new and unprecedented access to enantiopure 1,3-dioxolan-4-ones and 1,3-oxathiolan-5-ones.