Peptide thiocarboxylic acids

The linear precursor 91 of the cyclic peptide 86b was synthesized on a thiol benzhydryl resin 88 using the Boc chemistry protocol as described in Section 14.1.6.5 the assembly was capped at the amino-terminus with Boc-Cys(Npys), cleaved, and deprotected by HF to afford the peptide thiocarboxylic acid 91. Cyclization was initiated immediately after HF cleavage in 25% MeCN in H20 containing 0.05% TFA (pH 2), giving a final concentration of 1.75 mM. The progress of the cyclization was monitored by RP-HPLC and completed in 1 h. The pH of the soln was adjusted to 6 with solid NaOAc after 10 min, DTT or TCEP was added (1-3 equiv) to the soln to reduce the hydrodisulfide 92 to afford the cyclic peptide 86b with a Cys-Gly bond the progress was again monitored and then the product was purified by RP-HPLC overall yield 36%. The characterization of 86b is similar to those described in Section 14.1.6.5. 

In this method, the cyclic peptide is generated through cysteine-perthioester cyclization to afford a Xaa-Cys bond whose thiol is then used for the second ligation step to the core through a thiol addition reaction (Scheme 25).[S71 For the perthioester cyclization, the linear precursor 91 consists of an activated N-terminal Cys(Npys) and a C-terminal thiocarboxylic acid which favors cyclization due to intramolecular mixed disulfide formation between them. 

DCC can be used to prepare 5-alkyl and 5-aryl thiocarboxylates (1) from carboxylic acids and thiols according to equation (5). This method has been successfully applied to the synAesis of thiol esters with sensitive substituents, e.g. 5-methyl thioacrylate, a natural product. In particular, N-protected amino acid and peptide 5-phenyl esters, which are useful building blocks in peptide synthesis, are obtained in excellent yields without racemization. N-Hydroxyphthalimide and DMAP have been used as cocatalysts to facilitate the reaction. The preparation of the Wittig reagent (5) by this route is shown in equation (6). 

Acid anhydrides in the presence of basic catalysts can be used instead of acyl chlorides in acylation reactions of thiols.Mixed anhydrides of N-protected amino acids and ethyl carbonate yield the corresponding S-f-butyl thiocarboxylic esters, which are useful reagents for peptide syntheses (equation 22). Acylation of thiols with ketenes (equation 23) is a method of long standing. In many cases the yields are nearly quantitative. Functionalities such as acetamino groups or carbon-carbon double bonds in the thiol are not attacked under the mild reaction conditions and optically active thiol esters are obtained without racemization. 3 ... 

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