Avidinorubicin

Challenges for stereoselective glycosylation of deoxy sugars are notorious in carbohydrate chemistry. We herein report a novel strategy for the construction of the less investigated β-glycosidic bonds of 3,5- trans-3-amino-2,3,6-trideoxy sugars (3,5- trans-3-ADSs), which constitute the core structure of several biologically important antibiotics. Current protocol leverages a C-3 axial sulfonamide group in 3,5- trans-3-ADSs as a hydrogen-bond (H-bond) donor and repurposes substoichiometric phosphine oxide as an exogenous nucleophilic reagent (exNu) to establish an intramolecular H-bond between the former and the derived α-oxyphosphonium ion. This pivotal interaction stabilizes the α-face-covered intermediate to inhibit the formation of the more reactive β-intermediate, thereby yielding reversed β-selectivity, which is unconventional for an exNu-mediated glycosylation system. A wide range of substrates was accommodated, and good to excellent β-selectivities were ensured by this H-bonding-assisted exNu effect. The robustness of the current strategy was further attested by the architectural modification of natural products and drugs containing 3,5- trans-3-ADSs, as well as the synthesis of a trisaccharide unit in avidinorubicin.

Avidinorubicin (MW 1,214, C60H86N4O22) was isolated from the cultured broth of strain NR0576 (which was identified as Streptomyces avidinii Stapley et al.) by butyl alcohol extraction, Sephadex LH-20 column chromatography and preparative HPLC. Avidinorubicin inhibited thrombin-induced platelet aggregation with an IC50 being 7.9 microM and was determined to be a novel anthracycline possessing two units of a new aminosugar, avidinosamine, in place of two decilonitrose groups in decilorubicin.