Total Synthesis of Mannopeptimycins α and β.

Abstract

The mannopeptimycins are a class of glycopeptide natural products with unusual structures and potent antibiotic activity against a range of Gram-positive multidrug-resistant bacteria. Their cyclic hexapeptide core features a pair of unprecedented β-hydroxyenduracididines (L- and D-βhEnd), an O-glycosylated D-Tyr carrying an α-linked dimannose, and a β-methylated Phe residue. The D-βhEnd unit also carries an α-linked mannopyranose at the most hindered N of its cyclic guanidine ring. Herein, we report the first total synthesis of mannopeptimycin α and β with fully elaborated N- and O-linked sugars. Critically, a gold-catalyzed N-glycosylation of a D-βhEnd substrate with a mannosyl ortho-alkynylbenzoate donor enabled the synthesis of the most challenging N-Man-D-βhEnd unit with excellent efficiency and stereoselectivity. The L-βMePhe unit was prepared using a Pd-catalyzed C-H arylation method. The L-βhEnd, D-Tyr(di-Man), and L-βMePhe units were prepared in gram quantities. A convergent assembly of the cyclic peptide scaffold and a single global hydrogenolysis deprotection operation provided mannopeptimycin α and β.