Cysteine displacement reaction

For the synthesis of selenocysteine derivatives that are suitable for peptide synthesis essentially two approaches have been used to date (1) conversion of p-chloroalanine 23 or serine-O-tosylate derivatives 24 into the desired selenocysteine derivatives by a nucleophilic displacement reaction with an areneselenol and (2) full reduction of selenocystine and in situ reaction with aryl halides to produce the aryl selenides. 7 25 In this context, reduction of selenocystine in 2 M NaOH with 2-methyl-2-propanethiol for concomitant formation of the mixed selenide/sulfide derivative 5e-(tert-butylsulfanyl)selenocysteine in analogy to the formation of 5-(fett-butylsulfanyl)cysteine 26 fails as a consequence of the difficult reduction of the diselenide with monothiols. 27 ... 

An ingenious procedure for replacing sulfur in a thiolactam by a -CH COR group involves alkylation of sulfur with an a-haloketone, followed by sulfur extrusion either with triphenyl phosphine or by heating in DMF (with or without added sodium ethoxide). Th reaction has been successfully applied thus far to isoqu oline-l(2H)-thione, quinazoline-4(3H)-thlone, and 6-mercaptopurine. A closely related intramolecular sulfur displacement reaction with intriguing synthetic potential is Illustrated by the conversion of the S-alkylation product from 6-chloropurine ribonucleosld gand cysteine to the isomeric N-alkylated product by treatment with alkali. 

After completion of the cysteine-sugar reaction the mixture was diluted with water to a solids content of about 20% and sent through a column of Bio-Rad AG 50W-X4 (H cation exchange resin of 200-400 mesh. The column was washed with two column volumes of demineralized water and ftie adsorbed substances were displaced from the column with 0.3 M ammonia. The thiazolidine came off the column first followed by the Amadori compound and cysteine. The fraction containing ftie Amadori compoimd was concentrated in vacuo to dryness. The residue was dissolved in a small volume of water and just enough ethanol was added to cause cloudiness. The Amadori compound separated slowly in the form of a colorless crystalline product. 

The mercaptan group is an extremely powerful nucleophile and readily undergoes nucleophilic displacement reactions. This property is the basis of several quantitative tests for cysteine and/or cystine, including the Sullivan test, which involves nucleophilic displacement by mercaptide ion on iodoacetate [86]. 

Affinity labeling experiments with bromoacetyl compounds are biased by two important limitations, which often make them inferior to comparable photoaffinity labels. The number of properly oriented amino acid functional groups that can undergo a nucleophilic displacement reaction in the active site of a protein is limited to histidine, lysine, tyrosine, cysteine, and glutamic acid. Reactions are strongly influenced by the intrinsic piC of the respective amino acid residue and by the pH of the incubation mixture. It should be noted that bromoacetyl compounds can also react with RNA . The other limitation is that the time point for the affinity labeling reaction to occur cannot be freely chosen. One can only incubate the reactants and let them react for a given time. Reactions are usually quite slow and take considerable time for completion, which can vary between 1 and 20 hr. - ... 

Displacement of the sulfhydryl group in primary thiols, like L cysteine and 2-diethylaminoethanethiol, requires elemental fluorine, the most active oxidant Elemental sulfur is the major by-product in those reactions [7] (equation 2)... 

The preparation of a trisulfide bridge between two different linear peptides is outlined in Scheme 3. In a first step, the free thiol of one peptide forms an activated mixed disulfide by reaction with TV,A1 -1hiobisphthalimide, and upon the subsequent addition of the second cysteine peptide, nucleophilic displacement of the phthalimide moiety by the free thiol yields the desired interchain trisulfide bridged peptide 3.1 3 Homodimeric analogues, e.g. 4, are prepared similarly.[13]... 

This tripeptide (y-glutamic acid-cysteine-glycine) contains a thiol moiety which is an excellent nucleophile. In other enzymatically catalyzed hydrolyses, another amino acid nucleophile, the carboxylate anion of aspartate, is used (Li et al., 1998 Janssen et al., 2001). In both cases, the leaving group is displaced in an SN2 reaction process (see Chapter 13.2). 

The synthesis of substituted cysteines can be accomplished via Michael addition reactions,]67124-126] by nucleophilic displacement,]127] from racemic thiazolines,]128] via aziridine ring opening,]129 and by asymmetric synthesis using a chiral auxiliary.]130] The details for some of these methods are described. 

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