Thiophenyl esters

A number of anomolies exist. The high reactivity of the thiophenyl ester (R=SC H ) may be due to low, compared to oxygen analogues, electron density about phosphorus, the result of poor... 

At present, it appears that the most powerful method for the coupling of two unprotected peptide segments is the Native Chemical Ligation (NCL) developed by Dawson and Kent [21], As indicated by its name, NCL gives rise to the formation of a natural peptide bond. This reaction was described in principle as early as 1953, by Wieland, who reported that the reaction between the (S)-valine thiophenyl ester 22 and cysteine 23 proceeded by transfer of... 

M-1 s-1 alkyl phenyl selenides, aryl bromides, vinyl bromides, a-chloro esters, a-thiophenyl esters 104-102M 1 s-1 alkyl chlorides, alkyl phenyl sulfides, a-chloro and a-thiophenyl ethers. 

Phenolic esters are obtained similarly. The presence of a nitro group in the aromatic nucleus and the use of pyridine as solvent facilitates the reaction. This reaction is recommended for the characterization of phenols. 2,4,5-Trichlorophenyl-, pentachlorophenyl-, 4-nitrophenyl- and thiophenyl esters of N-acylamino acids are prepared in this manner. These aromatic esters are used in the stepwise lengthening of peptides, du Vigneaud and coworkers synthesized lysine vasopressin from a nonapeptide which they prepared stepwise using the nitrophenyl ester method. Room temperature esterification of dicarboxylic acids and diphenols are also carbodiimide mediated using the 1 1 complex derived from DMAP and p-toluenesulfonic acid as catalyst Methacrylic acid is also esterified with phenols using carbodiimides and DMPA to mediate the reaction. ... 

Examples of the application of this chemistry to the preparation of cyclobutanones, cyclobutenones, and P-lactams are presented in the Table. The mesityl thiol ester has proven to be particularly effective in reactions with less ketenophilic alkenes, although with the more reactive ketenophiles nearly identical results are obtained using either the mesityl a-diazo thiol ester or the more readily available thiophenyl ester. In the case of readily available ketenophiles, the reaction is best conducted using excess alkene, alkyne, or imine, but in other cases the cycloaddition can be carried out with excess diazo thiol ester. The efficiency of the reaction with unactivated alkenes is especially notable, and compares favorably with results obtained previously employing dichloroketene. For example, addition of dichloroketene to methylenecyclohexane is reported to proceed in 55% yield," while up to 81% of the desired [2-1-2] cycloadduct is produced in the reaction of (mesitylthio)ketene with this olefin under our conditions. 

Shibasaki has reported the preparation of y3-lactams by cyclization of thiophenyl esters in the presence of CuOTf [39]. The /3-aminothioester 60 was cyclized in 80 % yield to afford 61 (Sch. 16). The cyclization of 62 was noted to proceed with replacement of the trimethylsilyl group with a phenylsulfide group via the intermediacy of a PhSSPh-CuOTf complex which was formed in situ. Optimized conditions afforded 63 in 63 % yield, with some of the protonated product 64. 

Boron or tin (II) Z-enolates are generated by reaction with the corresponding triflates with a carbonyl compound in the presence of tertiary amines like r-P NEt or. M-ethylpiperidine (except when using dicyclopentylboron triflate [407]). E-Enolates are prepared by using dicyclohexyl- or other cyclic chloroboranes in the presence of Et3N or Me NEt [407, 685, 686, 1246, 1247, 1248], Because enolization does not take place under such conditions with esters or aliphatic tertiary amides, thiophenyl esters RGH COSPh have been used as ester/amide substitutes. Furthermore, Z-boron enolates of ketones can be prepared by conjugate addition of acid derivatives of dialkylboranes to a-enones [687],... 

The ORD curves of the sulfur isologs L-phenylalanine and L-leucine thiophenyl esters resemble those of the selenium derivatives in the general shape of the first Cotton effect, except that they are centered at shorter wavelengths (AX ca. 15 nm). 

In 1951, Feodor Lynen (1911-1979) and his coworker E. Reichert demon-started that S-acetyl coenzyme A is a more generally implicated form of active acetate than acetyl phosphate that was recognized in this role by Fritz Lipmann in 1940. The thiol ester character of 5-acetyl Co A called the attention of Th. Wieland to energy-rich S-acyl compounds as promising intermediates for the formation of the peptide bond. In 1951, the same year when the isolation of 5-acetyl CoA was published [3], Wieland and his coworkers described [4] the preparation of thiophenyl esters of benzyloxycarbonyl-amino acids and benzyloxycarbonyl-peptides and their application in the synthesis of blocked peptides ... 

Acylamino acid thiophenyl esters prepared by Th. Wieland and his coworkers via mixed anhydrides were the first realization of the active ester concept enhancement of the electrophiUc character of the carbon atom in the ester carbonyl by an electronwithdrawing alcohol , in this case thiophenol [4]. 

A few years after the first publication on acylamino acid thiophenyl esters [4] the peptide research team of the CIBA laboratories in Basel, led by Robert Schwyzer, described a systematic study of the aminolysis of methyl esters substituted with various electron-withdrawing groups [20]. From a series of esters examined with respect to their reaction rates in aminolysis cyanomethyl esters were selected as best suited for peptide synthesis. Cyanomethyl esters were readily prepared through the reaction of acylamino acid salts with chloroaceto-nitrile and they showed satisfactory rates in the acylation of amino acid esters... 

Noting the fairly pronounced reactivity of phenyl esters in aminolysis Bodanszky concluded [21] that the enhanced aminolysis rates observed with thiophenyl esters [4] are due only in part to their thiol ester character and perhaps to a major extent to the fact that they are aryl esters. This conclusion was based on the fundamental studies of Gordon, Miller and Day [22] who found extremely high rates in the ammonolysis of phenyl and vinyl esters. To further increase the electronic effect operative in phenyl esters, their nitro-derivatives were prepared and examined. For practical application p-nitrophenyl esters were... 

In 1955, almost simultaneously with the first publication on nitrophenyl esters, Farrington, Kenner and Turner proposed [23] the use of p-nitro-thiophenyl esters in peptide synthesis but in spite of the high reactivity of these intermediates their recommendation found few followers. 

The rate constants for the cyclomaltohex- and -hept-aoses catalysed hydrolysis of thiophenyl esters are almost identical to those for the corresponding phenyl esters. However, although the rate of hydrolysis of alkyl esters is inhibited by cyclomaltoheptaose and unaffected by cyclomaltohexaose that of thioalkyl esters is accelerated by both cyclomalto-hex- and -hept-aoses. This difference is rationalized by the relative rates of breakdown of the tetrahedral intermediates caused by differences in pkf, of the leaving groups. 

T. Wieland No, that means the thiophenyl ester doesn t attack the amino group... 

Dicyclohexylcarbodiimide added at —25° to N-carbobenzoxy-L-alanylglycyl-glycine and thiophenol in tetrahydrofuran, ethyl acetate, and dimethylform-amide, kept several hrs. in the refrigerator -> N-carbobenzoxy-L-alanylglycyl-glycine thiophenyl ester. Y 97%. F. e. s. F. Weygand and W. Steglich, B. 93, 2983 (1960). 

Using similar methodology, Leyendecker and Comte prepared the a-phenyl-sulphoxy-acrylates (184) from a-bromo-esters (182) by substitution with thio-phenol followed by a-chlorination and subsequent thermal elimination and oxidation of the a-chloro-a-thiophenyl esters (183). An alternative use of the... 

Active esters. Thiophenol and POGI3 added to a soln. of carbobenzoxyglycine in tetrahydrofuran, cooled to —15°, pyridine added dropwise, vigorously shaken, and allowed to stand ca. 1 hr. at room temp. carbobenzoxyglycine thiophenyl ester. Y 85%.—Similarly with p-nitrophenol carbobenzoxyglycine... 

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