Efficient Synthesis of S‐Linked Glycopeptides in Aqueous Solution by a Convergent Strategy

Abstract

In naturally occurring glycopeptides and glycoproteins the glycan residues generally possess N- and O-linkages to the peptide backbone. Here we report the synthesis of the corresponding S-linked glycopeptides by a convergent strategy to provide compounds which should be quite stable to glycosidases. To this end, peptides that contain beta-bromoalanine and gamma-bromohomoalanine were generated either directly by bromination of serine and homoserine residues, respectively, or by standard ligation of the corresponding amino acids. 1-Thiosugars of O-acetyl protected GalNAc, GlcNAc, and lactose were prepared by known procedures. Reaction of the thiosugars with these peptides in an ethyl acetate/water two-phase system, which contained TBAHS and NaHCO(3), or in a one-phase system that consists of DMF/water and which contains NaHCO(3), led to the desired S-linked glycopeptides cleanly and in almost quantitative yield. This reaction also worked well for O-unprotected 1-thiosugars.

A General Strategy toward S‐Linked Glycopeptides

“…Several procedures have since emerged to overcome this problem. [20][21][22][23][24] The most advanced among these is a method reported by Schmidt and co-workers, [24][25][26][27] in which the reaction of the thiosugar 1 with b-bromoalanine was performed in an ethyl acetate/water two-phase system containing tetra-n-butylammonium hydrogen sulfate (TBAHS) and NaHCO 3 ( Figure 2). We have used this protocol for the preparation of several different S-linked Boc-and Fmocmodified glycosyl amino acids (Boc = tert-butoxycarbonyl, Fmoc = 9-fluorenylmethyloxycarbonyl).…”

“…Such reaction conditions should meet several important criteria: first, deacetylation of the thioacetate group should be selective to generate the desired thiolate anion in situ, and to avoid belimination of the alanine derivative; second, dimethyl formamide (DMF) should be the solvent of choice, as solubility of large peptides in other solvents can be problematic; [24] furthermore, a set of optimal amino acid protecting groups should be employed to facilitate large-scale solidphase peptide synthesis (SPPS).…”

Synthesis and Application of Glycopeptide and Glycoprotein Mimetics

“…A similar approach was applied by Zhu and Schmidt for the synthesis of S-glycosylated amino acids and di-and tripeptides 44 (Scheme 8b) [74,75]. They reacted α-GlcNAc and α-GalNAc thiols 39 as well as β-GlcNAc and β-lactosyl thiols with 3-bromoalanine (42) and 4-bromohomoalanine derivatives (43) under phase transfer conditions or in a mixture of DMF and water at pH 8.5.…”

“…Separation of the diastereoisomers was achieved by selective enzymatic hydrolysis of the N α -acetyl group of the L-amino acid by acylase I. After Fmoc protection, the building blocks were used in the solidphase synthesis of neoglycopeptide analogues of the mouse hemoglobinderived decapeptide Hb (67)(68)(69)(70)(71)(72)(73)(74)(75)(76) For the synthesis of C-glycosyl alanine derivatives, Wong and coworkers used an asymmetric Strecker reaction starting from C-glycosyl acetaldehyde derivatives [100]. The stereoselectivity of this reaction was strongly solvent-dependent and was reversed by changing from THF to CH 2 Cl 2 .…”

“…The approach, however, can also be carried out in a convergent manner. To this end, Zhu and Schmidt used O-acetyl protected 1-thio derivatives of GalNAc, GlcNAc, and lactose and attached them to β-bromoalanine-or γ -bromohomoalanine-containing di-to hexapeptides to give S-linked neoglycopeptides [75]. The reaction selectively gave α-and β-S-glycosides and even worked well with O-unprotected 1-thiosugars.…”