Orthogonally Protected Cyclo-β-tetrapeptides as Solid-Supported Scaffolds for the Synthesis of Glycoclusters

Abstract

Two novel peptide scaffolds, viz. cyclo[(N(alpha)-Alloc)Dpr-beta-Ala-(N(alpha)-Fmoc)Dpr-beta-Ala] (1) and cyclo[(N(alpha)-Alloc)Dpr-alpha-azido-beta-aminopropanoyl-(N(alpha)-Fmoc)Dpr-beta-Ala] (2), composed of orthogonally protected 2,3-diaminopropanoyl (Dpr) and beta-alanyl residues, have been described. Fmoc chemistry on a backbone amide linker derivatized resin has been used for the chain assembly. Selective removal of the 4-methyltrityl (Mtt) and 1-methyl-1-phenylethyl protections (PhiPr) exposes the beta-amino and carboxyl terminus, respectively, and on-resin cyclization then gives the desired orthogonally protected cyclo-beta-tetrapeptides (1 and 2). The alpha-amino groups, bearing the Fmoc and Alloc protections and the azide mask, allow stepwise orthogonal derivatization of these solid-supported cyclo-beta-tetrapeptide cores (1 and 2). This has been demonstrated by attachments of various sugar units [viz., acetyl- or toluoyl-protected carboxymethyl alpha-d-glycopyranosides (13-15) and methyl 6-O-(4-nitrophenoxycarbonyl)-alpha-d-glycopyranosides (22-24)] to obtain diverse di- and trivalent glycoclusters (33-42). Acidolytic release (TFA) from the support, followed by conventional NaOMe-catalyzed transesterification (33-40) or hydrazine-induced acyl substitution in DMF (41 and 42), gives the fully deprotected clusters (43-52) as final products.