Synthesis of Peptides with Mixed Anhydrides

Abstract

A mixed acid anhydride, or mixed anhydride, is a dehydration product of two polyoxy acids. For a mixed anhydride to be of interest for peptide synthesis, one of the components must, in general, be an alpha‐acylamino acid. The nature of the second component acid may vary widely. In this chapter the term mixed anhydride will be used in a more general sense. In addition to conventional mixed anhydrides, from polyoxyacids, reference will be made to “mixed anhydrides” otherwise recognizable as acyl halides, ethers, esters, thiol esters, O‐acylisoureas and isoimides. This chapter is limited to a review of chemistry of the acyclic alpha‐amino acid mixed anhydrides, which the well‐know alpha‐acylamino acid chlorides and azides, which have been the subject of an excellent review. In general, discussion of the application of alpha‐acyllamino acid mixed anhydrides will be limited to non‐polymeric peptide bond formation and will not be concerned with acylations other than those that lead to a peptide bonds.

Cu-MOF: an efficient heterogeneous catalyst for the synthesis of symmetric anhydrides via the C–H bond activation of aldehydes

“…Anhydrides belong to the carboxylic acid derivatives and are very useful reagents in organic synthesis 19 and various other reactions including the lactonization of silyl esters, 20 asymmetric esterifications, 21 the condensation reaction of free carboxylic acids and alcohols 22 and specially in the preparation of peptides and drugs. 23 Symmetric anhydrides are well known as advantageous acylating agents because they prevent by-product generation due to their symmetric nature. 24 The main classical synthetic procedures for anhydride synthesis involve utilizing dehydrating agents such as phosgene, acid chloride, thionyl chloride, benzenesulfonyl chloride, and phosphorous pentoxide in equivalent amounts which generally need harsh reaction conditions, are usually expensive, have inaccessible reagents and catalysts, have a time-consuming work-up etc.…”

Studies on the disproportionation of mixed anhydrides of N‐alkoxycarbonylamino acids

“…The MxAn method of coupling involves addition of an alkyl chloroformate (R'OCOCI) to an acid (RCOOH) in the presence of a tertiary amine to give the MxAn (RCO-0-COOR3), which is then reacted without isolation with the amino group of a second component (1)(2)(3)(4)(5). MxAn's of acylamino or peptide acids readily undergo cyclization to the 2-alkyl-5(4H)-oxazolone (6); this is the source of partial racemization that often occurs at the activated residue (5).…”