Expeditious Racemic and Enantiodivergent Synthesis of 1-Deoxymannojirimycin and 1,4-Dideoxymannojirimycin

The racemic and enantiodivergent syntheses of 1-deoxymannojirimycin (DMJ) and 1,4-dideoxymannojirimycin have been realized through key enamide ester intermediates obtained by converting cis-4,5-dihydroxylated δ-valerolactam derivatives into the corresponding enol phosphates and subjecting them to Pd-catalyzed methoxycarbonylation. Further elaborations of these intermediates included stereocontrolled catalytic hydrogenation, for the synthesis of racemic 1,4-dideoxymannojirimycin, and hydroboration/oxidation, for the synthesis of DMJ. Enantiodivergency was attained by optical resolution before exhaustive functional group deprotection, through the formation of diastereomeric camphanic esters. As the key racemic intermediate esters were easily prepared in a few steps on a large scale, and the final chromatographic separation of the camphanic esters was straightforward, this approach represents a convenient way to obtain both enantiomers of DMJ for medicinal chemistry studies.