Stereodivergent Synthesis of C5-α-Substituted Linezolid Derivatives From D-Mannitol and Structure–Antibacterial Activity Evaluation

Abstract

A stereodivergent synthetic strategy enabling access to enantiopure C5-α-substituted linezolid analogues has been developed from D-mannitol as an inexpensive chiral pool precursor. The approach provides controlled access to both syn- and anti-configured derivatives bearing ethyl or phenyl substituents at the α-position of the C5 acetamidomethyl side chain, thereby introducing a second stereogenic center with high diastereocontrol. Key steps include highly selective nucleophilic additions of organometallic reagents to chiral N-benzyl imines derived from protected D-glyceraldehyde and base-promoted condensation of enantiopure N-Boc-aminoepoxides with aryl carbamates to construct the 2-oxazolidinone core. Comparative analysis of both configurational series revealed marked differences in cyclization efficiency, particularly for α-phenyl-substituted intermediates in the anti series, highlighting the steric sensitivity of oxazolidinone formation. In vitro assays against Gram-positive and Mycobacterium spp. species showed complete loss of antibacterial activity for all α-substituted derivatives, irrespective of configuration. These results establish a clear structural limitation at C5 and demonstrate that steric expansion at the α-position overrides stereochemical effects. This study underscores the value of stereodivergent synthesis for rigorously disentangling configurational and substituent contributions in chiral bioactive scaffolds.