Highly efficient one-pot assembly of peptides by double chemoselective coupling

Abstract

This study describes a methodological advancement in solution-phase peptide synthesis via the development of a convenient and operational protocol to synthesize oligopeptides in a one-pot three-step cascade method, in which two peptide bonds are introduced chemoselectively. Tri- to hexapeptides were obtained in high global yields (80-95%) with virtually no epimerization as determined via HPLC. The methodology described herein represents a faster, easier and milder approach to the synthesis of peptides, and it operates at equimolar amounts. This protocol comprises the formation of secondary and tertiary amides and is compatible with Z, Boc and Fmoc N-protecting groups as well as the use of d/l and non-proteinogenic amino acids.

Synthesis, Pharmacological, and Biological Evaluation of MIF-1 Picolinoyl Peptidomimetics as Positive Allosteric Modulators of D2R

“…Following standard methods in solution-phase peptide synthesis, ,, Pic ( 1 ) was activated via TBTU in the presence of N , N -diisopropylethylamine (DIEA) which was coupled with both methyl l -leucinate hydrochloride ( 2a ) and methyl l -valinate hydrochloride ( 2b ) to afford pseudodipeptides 3a and 3b , respectively, in excellent yields (98%).…”

Discovery of New Potent Positive Allosteric Modulators of Dopamine D2 Receptors: Insights into the Bioisosteric Replacement of Proline to 3-Furoic Acid in the Melanostatin Neuropeptide

“…Following a synthesis route previously developed in our research group, − , 3-Fu was activated using O -(benzotriazol-1-yl)- N , N , N ′, N ′-tetramethyluronium tetrafluoroborate (TBTU) as the coupling reagent and N , N -diisopropylethylamine (DIEA) as the tertiary base. The activated ester intermediate was then further reacted with methyl l -leucinate hydrochloride ( 1a , H-Leu-OMe·HCl, R = i Bu) and methyl l -valinate hydrochloride ( 1b , H-Val-OMe·HCl, R = i Pr), affording 2a and 2b , respectively, in excellent yields (94–99%, Scheme ).…”

Design, Synthesis, and Biological Evaluation of Hybrid Glypromate Analogues Using 2-Azanorbornane as a Prolyl and Pipecolyl Surrogate

“…Despite their efficiency, such synthetic protocols preclude the isolation of intermediates and their purification. Recently, our research group has developed a synthetic methodology in peptide synthesis for the assembly of oligopeptides in the solution phase, which enables the preparation of small peptides, avoiding the limitations associated with classical peptide coupling. − The scope of this synthetic protocol is further demonstrated, following the optimized tandem process for the preparation of perbenzylated Glypromate precursors 3­(a-d) directly from 1 , without the isolation of the intermediates, as depicted in Scheme . − …”

“…Briefly, − in this one-pot protocol (Scheme ), bicyclic amino acid 1 is reacted with either glycine or l -alanine succinimidyl esters (Cbz-Gly-OSu and Cbz- l -Ala-OSu, respectively) in the presence of N , N -diisopropylethylamine (DIEA) to afford the corresponding amide-carboxylates type A (not isolated). These intermediates are then activated in situ with coupling reagent 2-(1 H -benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU) to generate the corresponding active esters B (Scheme ).…”

“…The assembly of perbenzylated peptidomimetics 3­(a-d) was achieved with excellent global yields (87–92%, from 1 ), taking just as 7.5 h for the overall process (Scheme ); it is thus highly competitive in contrast with the classical step-and-go synthesis approach commonly used in the preparation of Glypromate peptidomimetics (ca. 72 h). − …”