Abstract
The 2-hydroxy-4-methoxybenzyl(Hmb)backbone modification can prevent amide bond-mediated side-reactions(e.g.,aspartimide formation,peptide aggregation)by installing the removable Hmb group into a peptide bond,thus improving the synthesis of long and challenging peptides and proteins.However,its use is largely precluded by the limited Hmb's installation sites.In this report,an improved installa-tion of Hmb(iHmb)method was developed to achieve the flexible installation and the convenient re-moval of Hmb.The iHmb method involves two critical steps:(1)oxidative diazotization of the readily in-stalled 2-hydroxy-4-methoxy-5-amino-benzyl(Hmab)to give 2-hydroxy-4-methoxy-5-diazonium-benzyl(Hmdab)by combining soamyl nitrite(1AN)/HBF4,and(2)reductive elimination of Hmdab to give the de-sired Hmb by 1,2-ethanedithiol(EDT).The iHmb method enables the installation of Hmb at any primary amino acid including the highly sterically hindered amino acids(e.g.,valine and isoleucine).The practical-ity and utility of the iHmb method was demonstrated by one-shot solid-phase synthesis of a challenging aspartimide-prone peptide,the mirror-image version of a hydrophobic peptide and a long-chain peptide up to 76-residue.Furthermore,the iHmb method can be utilized to facilitate chemical protein ligation,as exemplified by the synthesis of the single-spanning membrane protein sarcolipin.The iHmb method expands the toolkit for peptide synthesis and ligation and facilitates the preparation of peptides/proteins.
基金项目
国家重点研发计划(2019YFA0706900)
国家自然科学基金(22022703)
国家自然科学基金(22177108)
Collaborative Innovation Program of Hefei Science Center,CAS(2022HSC-CIP013)
维普
万方数据