α‐N‐Protected dipeptide acids: a simple and efficient synthesis via the easily accessible mixed anhydride method using free amino acids in DMSO and tetrabutylammonium hydroxide

Abstract

The importance of dipeptides both in medicinal and pharmacological fields is well documented and many efforts have been made to find simple and efficient methods for their synthesis. For this reason, we have investigated the synthesis of α-N-protected dipeptide acids by reacting the easily accessible mixed anhydride of α-N-protected amino acids with free amino acids under different reaction conditions. The combination of TBA-OH and DMSO has been found to be the best to overcome the low solubility of amino acids in organic solvents. Under these experimental conditions, the homogeneous phase condensation reaction occurs rapidly and without detectable epimerization. The present method is also applicable to side-chain unprotected Tyr, Trp, Glu, and Asp but not Lys. This latter residue is able to engage two molecules of mixed anhydride giving the corresponding isotripeptide. Moreover, the applicability of this protocol for the synthesis of tri- and tetrapeptides has been tested. This approach reduces the need for protecting groups, is cost effective, scalable, and yields dipeptide acids that can be used as building blocks in the synthesis of larger peptides.

Sodium Borohydride Reduction of Carbamoyl Azide Function: A Synthesis of N‐Protected N′‐Formyl‐gem‐diaminoalkyl Derivatives

“…The critical steps in the overall reaction were the synthesis of mixed anhydride 9 and its reaction with NaN 3 through a Curtius rearrangement of the corresponding acyl azide to lead to carbamoyl azide 10 25. In fact, as previously reported,31 the ESI‐MS analysis of the intact mixture that was obtained after the synthesis of mixed anhydride 9 showed the complete conversion of 9 into the corresponding 2,4‐disubstituted‐5(4 H )‐oxazolone 11 , which was prone to racemization under basic conditions32 (see Table 4).…”

“…General Methods: N ‐protected dipeptide acids 8 were prepared by a reported procedure 31. All solvents and reagents were purchased from Aldrich Chemical Company and used without further purification.…”

Peptide‐Chain Elongation Using Unprotected Amino Acids in a Micro‐Flow Reactor

“…In fact, Verardo et al. examined dipeptide synthesis using Imai's conditions and observed undesired racemization . Therefore, they reported an improved mixed carbonic anhydride‐based amidation using ClCO 2 i Pr or ClCO 2 i Bu and N ‐methylmorpholine (NMM) in dimethyl sulfoxide (DMSO) and water in the presence of a stoichiometric amount of n Bu 4 NOH.…”

“…[20] In fact, Verardo et al examined dipeptide synthesis using Imai's conditions and observedu ndesired racemization. [21] Therefore, they reported an improved mixed carbonic anhydride-based amidation using ClCO 2 iPr or ClCO 2 iBu and N-methylmorpholine (NMM) in dimethyl sulfoxide (DMSO) and water in the presence of as toichiometric amount of nBu 4 NOH. The nBu 4 NOH improved the solubility of unprotected amino acids against DMSO.H owever,u se of somewhat expensive nBu 4 NOH and less easily removable DMSO remains ap roblem.…”