Preparation of Peptide Thioesters through Fmoc‐Based Solid‐Phase Peptide Synthesis by Using Amino Thioesters

Abstract

An effective procedure for the synthesis of peptide alkyl thioesters by 9‐fluorenylmethoxycarbonyl (Fmoc) solid‐phase peptide synthesis was developed. The free C terminus of a fully protected peptide was coupled in solution with the free amino group of an amino thioester. This furnished the fully protected peptide thioester, which was globally deprotected to afford the desired unprotected peptide thioester. The method is compatible with labile groups such as phosphoryl and glycosyl moieties.

Total Chemical Synthesis and Folding of All-l and All-d Variants of Oncogenic KRas(G12V)

“…23, 24 Peptide thioesters were synthesized via Sakakibara elongation of protected peptides with pre-formed C-terminal residue thioesters following SPPS or alternatively by C-terminal hydrazide oxidation. 25,26 In a retrosynthetic fashion, taking primary advantage of the native cysteine residues within the full sequence reduces the synthetic challenge to three NCLs at assembly points Cys51, Cys80, and Cys118. However, in our hands, preliminary attempts to synthesize KRas[118–166] in its entirety by Fmoc-based SPPS proved inefficient and resulted in poor recovery of the desired peptide.…”

“…The synthesis of HRas has been previously described utilizing Boc-based solid phase peptide synthesis (SPPS) combined with native chemical ligation (NCL) assembly as well as via a semisynthesis approach . Our synthetic approach toward KRas­(G12V) relies on the use of Fmoc-based SPPS to generate five peptidyl sequences, which are subsequently assembled via combined NCL and isonitrile-mediated activation strategies to access a biotinylated variant of KRas­(G12V). , Peptide thioesters were synthesized via Sakakibara elongation of protected peptides with preformed C-terminal-residue thioesters following SPPS or alternatively by C-terminal hydrazide oxidation. , In a retrosynthetic fashion, taking primary advantage of the native cysteine residues within the full sequence reduces the synthetic challenge to three NCLs at assembly points Cys51, Cys80, and Cys118. However, in our hands, preliminary attempts to synthesize KRas[118–166] in its entirety by Fmoc-based SPPS proved inefficient and resulted in poor recovery of the desired peptide.…”

Dissecting the role of protein phosphorylation: a chemical biology toolbox

“…[125][126][127] With the mainstream use of Fmoc-based solid-phase peptide synthesis, researchers developed alternative strategies for the generation of thioesters. 128,129 Kenner's ''safety catch'' resin, an N-acylsulfonamide linker, found wide use early on due to its stability under Fmoc SPPS conditions [130][131][132] (Fig. 12A).…”

Fully Synthetic Granulocyte Colony-Stimulating Factor Enabled by Isonitrile-Mediated Coupling of Large, Side-Chain-Unprotected Peptides

“…Peptide thioesters 4 , 5 , and 7 were prepared using microwave-mediated Fmoc-based SPPS 20,30 with selected use of pseudoproline dipeptides 31 and late-stage installation of thioester-containing residues by a modified Sakakibara elongation. 32 With access to C-terminal thioesters 4 , 5 , and 7 as well as polypeptide 8 , we began preliminary studies to assemble G-CSF aglycone 2a . 33 …”