General synthesis route to benanomicin-pradimicin antibiotics

A general approach to the regio- and stereoselective total synthesis of the beiianomicin-pradimicin antibiotics (BpAs) is described. Construction of the aglycon has been achieved by 1) the diastereoselective ring-opening of a biaryl lactone by using (R)-valinol as a chiral nucleophile and 2) the stereocontrolled semi-pinacol cyclization of the aldehyde acetal by using SMI2 in the presence of BF3 center dot OEt2 and a proton source to afford the ABCD tetracyclic monoprotected diol. This strategy enabled us to control the two stereogenic sites in the B ring (C-5 and C-6) and the regioselective introduction of the carbohydrate moiety. ne ABCD tetracycle could serve as an ideal platform for the divergent access to various BpAs. ne amino acid (D-alanine) was introduced onto the ABCD tetracycle. Glycosylation was promoted by the combination of Cp2HfCl2 and AgOTf (1:2 ratio). Construction of the E ring followed by deprotection completed the first total synthesis of benanomicin A (2a), benanomicin B (2b), and pradimicin A (1a). The route is flexible enough to allow the synthesis of other congeners differing in their amino acid and carbohydrate moieties.