Scalable De Novo Synthesis of Aldgarose and Total Synthesis of Aldgamycin N.

Since the accompanying study had shown that the introduction of the eponymous aldgarose sugar to the C5-OH group of the macrocyclic aglycone of aldgamycin N is most difficult, if not even impossible, the synthesis route was revised and the glycosidation performed at an earlier stage. To mitigate the "cost" of this strategic amendment, a practical and scalable de novo synthesis of this branched octose was developed. The glycoside formation required mild conditions; it commenced with the reaction of the aglycone with the trichloroacetimidate donor to give a transient orthoester, which slowly rearranged to the desired aldgaropyranoside. The presence of the polar peripheral groups in the product did not impede the selective late-stage functionalization of the macrolide ring itself: the contained propargylic alcohol entity was readily transformed into the characteristic acyloin motif of the target by a ruthenium-catalyzed trans-hydrostannation followed by a modified Chan-Lam-type coupling.