Synthesis of 1-O-silylated 3-azido- and 3-N-trifluoroacetamido-2,3,6- trideoxy-L-arabino and L-lyxo-hexopyranoses, convenient glycosyl donors for preparation of anthracycline antibiotics and related DNA-binding agents

Over the years our studies have been aimed at the preparation of DNA-binding agents containing L-daunosamine, L-acosamine, or their derivatives, and we have found 1-O-silylated 2-deoxy-hexopyranoses to be very valuable as synthetic intermediates and glycosyl donors. We present here efficient strategies for the synthesis and separation of 1-O-silylated 3-azido- and 3-amino-2,3,6-trideoxy-L-hexopyranoses and the design of suitable glycosyl donors towards synthesis of doxorubicin analogs modified at C-4′ and C-14. By using a set of known reactions, we generated a mixture of 3-azido-hexopyranoses with L-arabino and L-ribo configurations, hitherto practically unexplored as glycosylating reagents. Two new approaches are described for producing efficient and scaleable resolution of 1-O-silylated azides (epimeric at C-3). The selection of 4-O-protecting groups able to withstand glycosylation conditions, yet suitably labile to allow deprotection under acidic or mild basic conditions, led to strategically important glycosyl donors that allow preparation of previously inaccessible doxorubicin-based DNA-binding glycosides. The described use of 3-azido-2,3,6-trideoxyhexoses constitutes a new strategy for pre- and postglycosylation functionalization of anthracycline antibiotic precursors.