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

‐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.