Peptide Bond Formation of Amino Acids by Transient Masking with Silylating Reagents

Abstract

A one-pot peptide bond-forming reaction has been developed using unprotected amino acids and peptides. Two different silylating reagents, HSi[OCH(CF 3 ) 2 ] 3 and MTBSTFA, are instrumental for the successful implementation of this approach, being used for the activation and transient masking of unprotected amino acids and peptides at C-termini and N-termini, respectively. Furthermore, CsF and imidazole are used as catalysts, activating HSi[OCH(CF 3 ) 2 ] 3 and also accelerating chemoselective silylation. This method is versatile as it tolerates side chains that bear a range of functional groups, while providing up to >99% yields of corresponding peptides without any racemization or polymerization.

Amidation of α-Amino Acids Using Dichloro(methyl)(3,3,3-trifluoropropyl)silane and Imidazole without Conventional Protection and Deprotection of α-Amino Group

“…In 2021, Muramatsu and Yamamoto reported the direct peptide-bond formation starting from unprotected amino acids achieved by combining HSi[OCH(CF 3 ) 2 ] 3 , acting as a condensation reagent, with N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide, acting as a transient masking group. 12 This method provided the corresponding not epimerized dipeptides in high yield, without the implementation of a conventional deprotection process after the condensation step.…”

Synthesis of Silacyclic Dipeptides: Peptide Elongation at Both N- and C-Termini of Dipeptide

“…Therefore, there is no choice but N-terminal elongation in the next step. Although our group has reported efficient dipeptide synthesis using N-,C-termini unprotected amino acids very recently, remaining tert -butyl ester in the product is inevitable . However, with the growing application of these dipeptide syntheses, attractive outcomes emerged.…”

An economical approach for peptide synthesisviaregioselective C–N bond cleavage of lactams

“…25 f , g ,26 One-pot amidation of H-Gly-OH with H- l -Ala-O t -Bu through transient masking with silylating agents produced 7 in 78% yield. 27 In the presence of HSi[OCH(CF 3 ) 2 ] 3 , 28 CsF, and imidazole, 27,29 peptide segment coupling of 7 with Cbz-Gly- l -Ala-OH, which can be obtained by classical methods in two steps from commercially available Cbz-Gly-OH and H- l -Ala-OMe, 30 followed by hydrogenation furnished 9 in excellent yields. The subsequent C–N bond cleavage/new amide bond formation/deprotection sequence afforded target peptide 11 with >99 : 1 dr (Scheme 4).…”