Synthesis of cyclic peptides from unprotected precursors using removable N^α‐(1‐(4‐methoxyphenyl)‐2‐mercaptoethyl) auxiliary

Abstract

A new method to cyclize unprotected peptides is presented. The method involves the use of a 1-phenyl-2-mercaptoethyl derivative on the N-terminal glycine. This template acts as an auxiliary thiol-containing group in order to drive cyclization with a counterpart thioester moiety on the same molecule. Subsequent facile removal of the derivative generates products with only native peptide structure. The successful, high-yield cyclization of the peptide GSPYSSDTTPA is described.

Native chemical ligation with Nα acyl transfer auxiliaries

“…Botti et al42 introduced two acid‐labile auxiliaries N α ‐(1‐(4‐methoxyphenyl)‐2‐mercaptoethyl 4 and N α ‐(1‐(2,4‐di‐methoxyphenyl)‐2‐mercaptoethyl 5 . Ligation properties were similar to the mercaptoethyl auxiliary 1 (Table I), and cyclization with different unprotected peptides was reported 43, 44. The synthesis of the auxiliaries 4 and 5 was refined and improved as building blocks by the Botti group43 and others45, 58; however, coupling of the protected alanine auxiliary proceeded with significant epimerization.…”

Auxiliary-assisted chemical ubiquitylation of NEMO and linear extension by HOIP

“…The ligation of two large fragments, full-length synthetic ubiquitin and NEMO CoZi , at low mM concentration, was complete on a practical time-scale (6 h), which was critical in this case because of the aggregation-prone product. Interestingly, hdmb ligation occurred comfortably below pH 7, in contrast to other auxiliaries that work in a narrow pH range, typically above pH 7.4 28,43 . The greater pH tolerance of hdmb was indispensable here because it avoided having to readjust the pH on a very small reaction volume after addition of the fragments as their TFA salts.…”

Site‐Selective Peptide Macrocyclization

“…The popularity of this method has led to its expansion by several other groups. [50,[53][54][55][56][57] Tam and coworkers introduced novel thioester surrogates for cyclization that are compatible with Fmoc chemistry for facile synthesis. [53] They used a thioethylamido moiety as a surrogate to create a thiolactone ring expansion method of cyclization.…”