A convenient synthesis of orthogonally protected 2-deoxystreptamine (2-DOS) as an aminocyclitol scaffold for the development of novel aminoglycoside antibiotic derivatives against bacterial resistance

Abstract

The development of new aminoglycoside analogues to reduce the emergence of bacterial resistance has become a topic of high interest. We describe here a rapid and facile access to orthogonally protected 2-deoxystreptamine (2-DOS), a meso-diaminocyclitol known to be a pivotal component of most active aminoglycosides. Our synthetic approach started from highly protected methyl α-D-glucopyranoside which in turn was converted by a Ferrier rearrangement into an enantiopure polyfunctionalized cyclohexane ring. Finally, two different N-protected groups were successively introduced. The first one was inserted as an oximino benzylether followed by a diastereofacial hydride reduction, working with Me₄NBH(OAc)₃ only in TFA at low temperature rather than in AcOH as usual. The second group was introduced by displacement of a hydroxyl group through a Mitsunobu reaction using a DPPA–DIAD–Ph₃P system for azide transfer.