A new approach to the solid-phase peptide synthesis of peptide alkyl-amides and esters

Epimerization-free access to C-terminal cysteine peptide acids, carboxamides, secondary amides, and estersviacomplimentary strategies

“… 7 Although several methods have been reported for C-terminal functionalization after solid-phase peptide synthesis (SPPS) is complete, 8 these approaches either result in epimerization when applied to C-terminal Cys peptides 9 or the applicability of the method to C-terminal Cys peptides is not addressed. 10 , 11 While activation of the C-terminal carboxylic acid can induce epimerization via oxazolone formation in most amino acids, 12 cysteine is also prone to epimerization via direct deprotonation during its attachment to the resin 13 and upon prolonged or repeated exposure to base ( i.e. , during peptide elongation via Fmoc SPPS).…”

Exploiting the MeDbz Linker To Generate Protected or Unprotected C‐Terminally Modified Peptides

“…Meanwhile, C‐terminal thioesters and hydrazides are critical to the synthesis of larger peptide targets through native chemical ligation (NCL) and non‐cysteine NCL . Despite the demand for C‐terminally modified peptides, there remain significant limitations in the available strategies to access them by chemical synthesis . Variations at the C‐terminus traditionally require repetition of the solid‐phase peptide synthesis (SPPS) on a different linker for each desired C‐terminal moiety, or the use of a C‐terminal glycine .…”

“…7 Despite the demand for C-terminally modified peptides, there remain significant limitations in the available strategies to access them by chemical synthesis. 8, 9 Variations at the C-terminus traditionally require repetition of the solid-phase peptide synthesis (SPPS) on a different linker for each desired C-terminal moiety 2a,2c, 10 or the use of a C-terminal glycine. 11 Solution-phase activation of protected C-terminal acids risks epimerization.…”

An ExpedientN-Terminal Attachment Methodology for the Solid Phase Peptide Synthesis

“…Recently, several publications have described the solid phase synthesis of peptide-substituted amides using C-terminal attachment methodology. [6][7][8] However these methods are not generally applicable since they require either a specific resin for each different class of amides 6 or primary aliphatic amines 7,8 and aromatic amines 8 that are not deactivated for the nucleophilic cleavage of the resin. Therefore, we sought to develop an alternative to the C-terminal attachment strategy for solid phase synthesis of peptide-substituted amides and esters.…”