A traceless approach to amide and peptide construction from thioacids and dithiocarbamate-terminal amines

Abstract

A novel and traceless strategy has been devised that allows a coupling of thioacids and dithiocarbamateterminal amines. This strategy had been assumed to be dependent on the attachment of a functional equivalent of a cysteine side chain in earlier native chemical ligation approaches. This approach enables the traceless removal of CS 2 to directly generate the desired amide bond and is compatible with a range of unprotected side chains of amino acid. The ability to produce amide or peptides by a traceless removal of the auxiliary is a significant virtue of the method. Meanwhile, the application of this new peptide-bond-forming reaction to the synthesis of novel endomorphin (EM) derivatives with various binding potencies was realized.

Amide Synthesis from Thiocarboxylic Acids and Amines by Spontaneous Reaction and Electrosynthesis

“…So far, there are two main strategies for the formation of amide bonds from thioacids. One is that thioacids react with some chemical reagents such as Sanger reagents & Mukaiyama reagents, organoisonitriles, Cu II reagents, carbon disulfide, organonitrite, and nanocatalysts to form more reactive thio‐intermediates, which can react with amines to give the amides (Scheme a). The other one is that thioacids can be converted to disulfides, which can be nucleophilically substituted by amines to form the corresponding amides .…”

“…A good yield was obtainedb yu sing nBu 4 NAc (entry 4), but it was also able to provide ag ood yield if no acyl source was involved.N one of the other electrolytes achievedt he yield observed with nBu 4 NBF 4 .T he electrosynthesis with aqueous electrolytes( KCl) in MeCN was also tested, which gave 57 %y ield (entry 7). Next, other commonly used solvents were also screened( entries [8][9][10][11], and the yield was significantly increasedt o9 7% if EtOAcw as used as the solvent (entry 11). There was no reactionw ithout the electrolyte because the conductivity of the solution was not high enough for our equipment( entry 12).…”

A New Wave of Amide Bond Formations for Peptide Synthesis

“…The procedure is tolerant towards unprotected side-chain functional groups. 60 For the introduction of the dithiocarbamic acid entity, CS 2 was used in combination with pyridine as a base. The latter was deemed crucial to prevent the formation of side products: 2-thioxoimidazolidin-4-ones 56 and thioureas 57 (Scheme 23).…”

Inverse Peptide Synthesis via Activated α‐Aminoesters

“…A number of innovative strategies for the synthesis of peptides have been reported: decarboxylative condensation of N-alkyl hydroxylamines and a-ketoacids, [10] the use of nitroalkanes as acyl-anion equivalents, [11] and various strategies involving amino thioacids as the acyl donor with isonitriles, [12] with azides, [13] and very recently, with dithiocarbamate terminal amines. [14,15] However, all these methods require the prior modification of both amino acids, which considerably limits their attractiveness. The reaction of carboxylic acids with isocyanates also constitutes an interesting alternative, [16] although the need to prepare the sensitive isocyanate reaction partners hinders the application of this methodology in peptide synthesis.…”