Ring closing metathesis of unprotected peptides

Abstract

An efficient and expedient route to the synthesis of dicarba peptides from protecting group-free sequences is reported using Ru-alkylidene catalysed olefin metathesis. A range of cyclic peptides was prepared from linear peptides containing two Z-crotyl glycine residues. Free amine groups were masked as salts with Brønsted acids preventing in situ catalyst decomposition. Excellent RCM conversion was obtained in both DMF and methanol.

Insulin in motion: The A6-A11 disulfide bond allosterically modulates structural transitions required for insulin activity

“…An unsaturated C=C dicarba bond is considerably more rigid than a disulfide bond and adopts either a cis or trans configuration, with an insurmountable barrier to exchange under physiological conditions. Introduction of a dicarba bond into a number of small polypeptides 18 (oxytocin 19 , calcitonin 20 , and H3-relaxin 21 ) has been shown to improve their stability and, in some cases, their activity. Our synthetic techniques permit generation of both the cis and trans configuration of the A6-A11 dicarba bond within insulin (Fig.…”

Negating coordinative cysteine and methionine residues during metathesis of unprotected peptides

“…5 Importantly, the use of Z-Crt eliminates a competing hydrogen extraction within the metallocyclobutane intermediate and prolongs activity of the catalyst by avoiding cycle generation of Ru-methylidene species. 5,6 The generic process was used to generate several cyclic peptides with varying sequence and ring size and demonstrated the high tolerance of the process to wideranging functionality. 5 Considerable effort in the literature has been directed towards metathesis-driven dicarba replacement of single cystine bridges.…”

“…5,6 The generic process was used to generate several cyclic peptides with varying sequence and ring size and demonstrated the high tolerance of the process to wideranging functionality. 5 Considerable effort in the literature has been directed towards metathesis-driven dicarba replacement of single cystine bridges. 1 However, several bioactive peptides have multiple S-S bridges and regioselective replacement provides potent and target-selective peptidomimetics.…”

Macrocyclization strategies for cyclic peptides and peptidomimetics

“…The choice of solvent here was crucial, as the conversion of oxytocin proceeded quantitatively in DMF and with 84% and 66% conversion in MeOH and EtOH, respectively, while no product formation was observed in DMSO, MeCN, or solvent mixtures containing water. 247 Cochrane et al showed that the cyclization of unprotected peptides through allyl cysteinyl residues in solution with t BuOH/H 2 O as the solvent could be achieved by adding 5000 eq. of MgCl 2 , 239 which was thought to act as a mild Lewis acid to effectively block potential peptide coordination sites to the Ru catalyst.…”