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

Abstract

Abstract 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 solvent/nucleophile, 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.