Synthesis of diastereoisomeric pairs of novel analogues of d4T having an isochroman glycon moiety; their enzymatic kinetic resolution, their enantiopure synthesis, molecular modeling and NMR structural study

An efficient route, starting from 2-bromobenzaldehyde, is described to synthesize racemic diastereoisomeric thymine derivatives of isochroman, which are aromatic analogues of Stavudine, an approved anti-HIV drug. The relative configurations were determined by NOE proton NMR experiments in connection with molecular modeling. Following the separation of the latter diastereoisomers, kinetic resolution was achieved via a transesterification reaction catalyzed by lipases. Using this method, moderate eeʹs were obtained (0.74–0.98). Thus, an alternative strategy starting from d-mannitol was proposed to provide pure enantiomers. The attribution of absolute configurations was made by chemical filiation on the basis of the configurations obtained from d-mannitol. The structural attributions were confirmed by studying the behavior of proton NMR shifts of the corresponding isochroman Mosherʹs esters.