Synthesis of CCL-1 using Bifunctional Thioacid-Mediated Strategy
In the previous total chemical synthesis, the N-glycan part is usually incorporated by SPPS, which causes waste of precious N-glycans during coupling steps. To solve this problem, a novel synthetic strategy without using SPPS to obtain glycopeptide might be a powerful tool toward glycoprotein. In 2021, the Nomura and Kajihara group reported a novel synthetic strategy by the chemical insertion of N-glycosyl asparagine based on a bifunctional thioacid derivative.[29] in this synthetic strategy, instead of incorporating N-glycan by SPPS, the N-glycan is inserted utilizing N-glycosylated asparagine thioacid 86 as a ligation junction. The full-length glycoprotein could be efficiently prepared after only two coupling reactions: In the first step diacyl disulfide coupling (DDC), the N terminal peptide thioacid 87 was coupled with (N-glycan)Asn thioacid 86 under oxidative condition to afford the desired glycopeptide 88 as thioacid form (Fig.10). The reaction was carried out in a chemoselective and epimerization-free manner without undesired coupling byproduct. In the second step, the coupling product 88 was ligated with C terminal peptide 89 via thioacid capture ligation (TCL)[30-31] through a nitro pyridyl sulfide (Npys) modified N-terminal Cys (Fig.10). Based on such N-glycan insertion strategy, the author synthesized full-length glycoprotein CCL-1 93 and interleukin-3 (IL-3) in only few chemical conversion steps efficiently. This novel thioacid-mediated strategy provides a robust option for the convergent synthesis of glycoprotein without the need for preparing glycopeptide by SPPS.
