Thiol esters, hydrolysis preparation

Substituted, 2,3-disubstituted, and 2,3-annulated thiophenes can be prepared by reactions of ketone enolates with carbonodithioic acid O-ethyl 5-(2-oxoethyl)ester. Hydrolysis of the resulting aldols, intramolecular addition of thiol group to the carbonyl group, and elimination of two molecules of water lead to the thiophenes (116) (Scheme 38) (92HCA907). 

Some strategies used for the preparation of support-bound thiols are listed in Table 8.1. Oxidative thiolation of lithiated polystyrene has been used to prepare polymeric thiophenol (Entry 1, Table 8.1). Polystyrene functionalized with 2-mercaptoethyl groups has been prepared by radical addition of thioacetic acid to cross-linked vinyl-polystyrene followed by hydrolysis of the intermediate thiol ester (Entry 2, Table 8.1). A more controllable introduction of thiol groups, suitable also for the selective transformation of support-bound substrates, is based on nucleophilic substitution with thiourea or potassium thioacetate. The resulting isothiouronium salts and thiol acetates can be saponified, preferably under reductive conditions, to yield thiols (Table 8.1). Thiol acetates have been saponified on insoluble supports with mercaptoethanol [1], propylamine [2], lithium aluminum hydride [3], sodium or lithium borohydride, alcoholates, or hydrochloric acid (Table 8.1). 

The hydrolysis of thiol esters is achieved in either acidic or basic media. Alcoholic solutions of hydrogen chloride or potassium hydroxide are the most common reagents. Dithiols, hydroxy mercaptans/ and mercapto ethers, ketones, and acids have been prepared by this method. The corresponding thiol esters are obtained by the addition of thioacetic acid to oxides and olefinic acids or by the action of its potassium salt on halo ketones or sulfonic esters. ... 

In contrast to the free acids, sulfenate esters, amides and halides are more stable. Disulfides (52) can be obtained from thiols by mild oxidation (see p. 57), and sulfenyl chlorides () can in turn be prepared from disulfides (52) by treatment with chlorine (Scheme 30). Sulfenyl chlorides (51) react with alcohols to give esters, e.g. the methyl sulfenate (53) which on alkaline hydrolysis yields the sulfenic acid (45) (Scheme 30). 

Formal replacement of an aromatic hydroxyl group by a thiol group is shown in the preparation of thiophenols by way of O-aryl iV,A-dialkylthio-carbamates, which undergo rearrangement to. the S-esters, whence hydrolysis gives the thiophenols.373 The same reaction occurs in the heterocyclic series. Good yields are obtained in all the steps. 

The application of papain in peptide synthesis is well established [23-25]. Papain can be used for fhe preparation of di- and tripepfides in an aqueous medium wifh cosolvent addition (up to 40%) and at high pH to promote synthetic activity. The enzyme is a sulfhydryl protease with no homology to the trypsin or subtilase families of hydrolases. Since the catalytic nucleophile is a cysteine and because thioesters are relatively more prone to aminolysis than oxo-esters, the enzyme could be very attractive for synfhesis. However, unlike the case with the thiol variants of some serine hydrolases, fhe proteolytic activity is still high, and the broad substrate range of proteolysis makes peptide substrate and product hydrolysis more problematic than trypsin or chymotrypsin. Extensive enzyme engineering studies on papain are lacking, probably due to the laborious procedure for isolation of active papain from inclusion bodies formed in E. coli. 

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