Thiol-thioester exchange

Fig. 6 (a) Thiol-disulfide exchange, (b) Thiol-thioester exchange, (c) Thiazolidine exchange, (d) Reversible Michael addition of thiols... 

Figures. Thiol-thioester exchange to form an amide bond. Nucleophilic attack takes place by the side chain thiol functionality in a cysteinyl peptide at a thioester segment to form an intramoiecular thioester, which undergoes intramolecular S N acyl transfer to form an amide bond.

P.J. Bracher, P.W. Snyder, B.R. Bohall, G.M. Whitesides, The relative rates of thiol-thioester exchange and hydrolysis for alkyl and aryl thioalkanoates in water. Origins Life Evol. B 41, 399 12(2011)... 

Recently, thiols have also been shown to participate in a series of new reversible reactions suitable for DCC. Such reactions include (1) the thioester exchange reaction (Fig. 6b), (2) the thiazolidine exchange reaction (Fig. 6c), and (3) the reversible Michael addition of thiols (Fig. 6d). 

Cysteine is converted into the 5-(tert-butylsulfanyl) derivative by reaction with tert-h x-tylsulfinic acid tert-butyl thioester, or preferably by exploiting the steric barriers toward dimerization of 2-methylpropane-2-thiol by air oxygen. The latter approach makes it possible to drive the thiol/disulfide exchange reaction between cystine (5) and 2-methylpropane-2-thiol in favor of the desired product, i.e. H-Cys(StBu)-OH (6), in aqueous alkaline media because the cysteine intermediate is reoxidized to cystine and transformed further (Scheme 19) [1,239] same principle has also been conveniently exploited for the conversion of short dimeric cystine peptides, prepared directly from cystine, into the related S-protected... 

The chemoselectivity of the reaction stems from the combination of a Cys specific, reversible thioester exchange (any Cys residue in either peptide can participate in this equilibrium) with an essentially irreversible intramolecular reaction that is specific to N-terminal Cys residues. Under typical ligation conditions (pH 6.5-7.5,1 mM peptide) the intermoleculartransthioesterification is rate limiting and no thioester intermediate is observed because of rapid rearrangement [47]. The reaction also utilizes the unique reactivity profile of the thioester as an activated acyl group. Compared to oxoesters with identical substituents, thioesters are much more reactive toward thiol nucleophiles [49] (and to a lesser extent toward amine nucleophiles [50]), facilitating rapid... 

Very important compounds are the carboxylic acids and their derivatives, which can be formally obtained by exchanging the OH group for another group. In fact, derivatives of this type are formed by nucleophilic substitutions of activated intermediate compounds and the release of water (see p. 14). Carboxylic acid esters (R-O-CO-R ) arise from carboxylic acids and alcohols. This group includes the fats, for example (see p.48). Similarly, a carboxylic acid and a thiol yield a thioester (R-S-CO-R ). Thioesters play an extremely important role in carboxylic acid metabolism. The best-known compound of this type is acetyl-coenzyme A (see p. 12). 

Finally, Captopril is produced. The thioester (0.85 g) is dissolved in 5.5 N methanolic ammonia and the solution is kept at room temperature for 2 hours. The solvent is removed in vacuo and the residue is dissolved in water, applied to an ion exchange column on the H+ Cycle (Dowex 50, analytical grade) and eluted with water. The fractions that give positive thiol reaction are pooled and freeze dried. The residue is crystallized from ethyl acetate-hexane, yield 0.3 g. The l-(3-mercapto-2-D-methylpropanoyl)-L-proline has a melting point of 103°C to 104°C. 

In 2004, Ramstrom and coworkers reported the first prototype DCLs based on a reversible transthioesterification reaction [47]. DCLs of potentially ten different thioesters were generated from a series of five thioesters - all prepared from 3-sulfanylpropionic acid - and one thiol (thiocholine). Transthioesterification (exchange) reactions were observed by simply mixing the different DCL components in aqueous solution. Interestingly, when added to the equilibrated mixture of thioesters, the enzyme acetylcholinesterase was able to recognize and subsequently hydrolyze its best substrate selectively. This selective hydrolysis... 

Thioesters can also be used for intramolecular ligation for the synthesis of end-to-end cyclic peptides (35, 36). The linear peptide precursor should contain both an N-terminal cysteine residue and a C-terminal thioester. Under previously described conditions, intramolecular thiol-exchange produces a thiolactone, which then undergoes S - N migration to yield an end-to-end cyclic peptide. 

Related exchange processes that could be alternatives to the transesterification reaction to produce similar DCLs of receptors under different reactions conditions are the exchange of thioesters and the exchange of amides. Thioesters have been used recently as the reversible bond in the formation of DCLs in water [39-41]. The exchange reaction is usually performed by mixing stoichiometric amounts of thiols and thioesters in aqueous solution (pH 7-9), without the need for any activation procedure. 

The synthesis of 38 began with 39. Acetal formation and chlorination adjacent to sulfur provided 40. Thiourea was used to introduce sulfur. Hydrolysis of 41 provided the free thiol and a ketal exchange (hydrolysis-protection) gave 42. This compound was configurationally stable at the anomeric center and thus, was resolved via the thioester derived from reaction with (-)-camphanyl chloride. The absolute configuration of the proper enantiomer was established by X-ray crystallography of this thioester. S-Alkylation of 43 with racemic mesylate 46 provided a mixture of diastereomers 47 (Erythronolide-6). 

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