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

Two novel peptide scaffolds, viz. cyclo[(N α-Alloc)Dpr-β-Ala-(N α-Fmoc)Dpr-β-Ala] (1) and cyclo[(N α-Alloc)Dpr-α-azido-β-aminopropanoyl-(N α-Fmoc)Dpr-β-Ala] (2), composed of orthogonally protected 2,3-diaminopropanoyl (Dpr) and β-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 β-amino and carboxyl terminus, respectively, and on-resin cyclization then gives the desired orthogonally protected cyclo-β-tetrapeptides (1 and 2). The α-amino groups, bearing the Fmoc and Alloc protections and the azide mask, allow stepwise orthogonal derivatization of these solid-supported cyclo-β-tetrapeptide cores (1 and 2). This has been demonstrated by attachments of various sugar units [viz., acetyl- or toluoyl-protected carboxymethyl α-d-glycopyranosides (13−15) and methyl 6-O-(4-nitrophenoxycarbonyl)-α-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.