HBTU mediated 1-hydroxybenzotriazole (HOBt) conjugate addition: synthesis and stereochemical analysis of β-benzotriazole N-oxide substituted γ-amino acids and hybrid peptides

Abstract

HBTU is a standard coupling agent commonly used for the activation of free carboxylic acids during the solution and solid phase peptide synthesis. 1-Hydroxybenzotriazole (HOBt) plays a significant role in reducing the racemization during peptide synthesis; hence it is regularly used as a coupling additive. Here, we are reporting the mild and facile conjugate addition of HOBt to E-vinylogous γ-amino acids mediated by the HBTU. The reaction is moderately diastereoselective and novel β-benzotriazole N-oxide (β-BtO) substituted γ-amino acids were isolated in moderate to good yields. The single crystal analysis of methyl esters of major (anti) and minor (syn) conjugate addition products infers the formation of exclusively N-alkylated benzotriazole N-oxides instead of O-alkylation of HOBt. In addition, we showed the utilization of β-BtO substituted γ-amino acids in peptide synthesis and studied their conformations in single crystals.

A smart tumor targeting peptide–drug conjugate, pHLIP-SS-DOX: synthesis and cellular uptake on MCF-7 and MCF-7/Adr cells

“…We choose to modify the amine group of DOX because the conjugation via the amine group is easier (Santra et al, 2011). HBTU is a coupling reagent commonly used as a carboxylic acid activating reagent (Mali et al, 2014). It has the following advantages: simple reaction conditions, short reaction time and high yield.…”

Fluorescein and Rhodamine B-Binding Domains from Autodisplayed Fv-Antibody Library

“…For the preparation of fluorescein-labeled peptides, the fluorescein was attached to the C-terminal of peptides by (1) addition of lysine residue and then (2) coupling reaction between amino groups lysine and fluorescein isothiocyanate (FITC) . The rhodamine B was labeled to the C-terminal of peptides between amino group of rhodamine and carboxylic group of peptide using the coupling reaction of hexafluorophosphate benzotriazole tetramethyl uranium (HBTU) and hydroxybenzotriazole (HOBt) …”

“…41 The rhodamine B was labeled to the C-terminal of peptides between amino group of rhodamine and carboxylic group of peptide using the coupling reaction of hexafluorophosphate benzotriazole tetramethyl uranium (HBTU) and hydroxybenzotriazole (HOBt). 42 Fusion Protein Expression. The plasmids pJY001 and pJY002, encoding an open reading frame of the CDR3 sequence (with binding activity to fluorescein and rhodamine B, respectively), Z-domain fusion, linker, and β-barrel proteins were custom-synthesized by Cosmogenetech.…”

Antioxidant and anti-aging potential of a peptide formulation (Gal2–Pep) conjugated with gallic acid

“…The HOBt used in peptide synthesis is known to inhibit the racemization and improve the efficiency of peptide synthesis. [17][18][19] In order to remove amino acid protecting groups and solvents used for synthesis, we performed washing several times using solvents such as DMF and DCM during the peptide synthesis process. Even aer the last washing step, impurities including amino acid protecting groups are still present in trace amounts.…”