C‐Glycoside Analogues of N⁴‐(2‐Acetamido‐2‐deoxy‐β‐D‐glucopyranosyl)‐L‐asparagine: Synthesis and conformational analysis of a cyclic C‐glycopeptide

The synthesis of C ‐glycosidic analogues 15–22 of N 4 ‐(2‐acetamido‐2‐deoxy‐β‐ D ‐glucopyranosyl)‐ L ‐asparagine (Asn( N 4 GlcNAc)) possessing a reversed amide bond as an isosteric replacement of the N ‐glycosidic linkage is presented. The peptide cyclo(‐ D ‐Pro‐Phe‐Ala‐CGaa‐Phe‐Phe‐) (CGaa = C ‐glycosylated amino acid; 24 ) was prepared to demonstrate that 3‐[(3‐acetamido‐2,6‐anhydro‐4,5,7‐tri‐ O ‐benzyl‐3‐deoxy‐β‐ D ‐glycero‐ D ‐guloheptonoyl)amino]‐2‐[(9 H ‐fluoren‐9‐yloxycarbonyl)amino]propanoic acid ( 22 ) can be used in solid‐phase peptide synthesis. The conformation of 24 was determined by NMR and molecular‐dynamics (MD) techniques. Evidence is provided that the CGaa side chain interacts with the peptide backbone. The different C ‐glycosylated amino acids 15–21 were prepared by coupling 3‐acetamido‐2,6‐anhydro‐4,5,7‐tri‐ O ‐benzyl‐3‐deoxy‐β‐ D ‐ glycero ‐ D ‐ gulo ‐heptonic acid ( 4 ) with diamino‐acid derivatives 8–14 in 83–96% yield. The synthesis of 4 was performed from 2‐(acetamido‐3,4,6‐tri‐ O ‐benzyl‐2‐deoxy‐β‐ D ‐glucopyranosyl) tributylstannane ( 2 ) by treatment with BuLi and CO 2 in 83% yield. Similarly, propyl isocyanat yielded the glycoheptonamide 7 in 52% from 2 . Compound 2 was obtained from 2‐acetamido‐3,4,6‐tri‐ O ‐benzyl‐2‐deoxy‐ D ‐glucopyranose ( 1 ) by chlorination and addition of tributyltinlithium in 74% yield. A procedure for a multigram‐scale synthesis of 1 is given.