Biocatalytic Method for the Synthesis of the Key Linezolid Intermediate and Its Subsequent Conversion to Linezolid

A chemo-enzymatic approach to enantiopure ( S )-linezolid 1 is presented. The key chiral intermediate, ( R )-alcohol 4, was obtained via CRL lipase-catalyzed kinetic resolution of ( RS )- 4, affording an enantiopure ( R )-alcohol 4 with 98.5% ee s (enantiomeric excess of substrate) and an ( S )-ester with 97.1% ee p (enantiomeric excess of product). The key intermediate ( R )- 4 undergoes cyclization, followed by azide substitution, reductive acylation, and coupling with morpholine, affording enantiopure ( S )- 1 in ≥ 99% ee and 23% overall yield over six steps. This route offers an efficient biocatalytic strategy to access linezolid with high selectivity.