5-Trityl-cysteine

Kamber B, Hartmann A, Eisler K, Riniker B, Rink H, Sieber P, Rittel W. The synthesis of cystine peptides by iodine oxidation of 5-trityl-cysteine and S-acetamidomethyl-cysteine peptides. Helv Chim Acta 1980 63 899-915. 

Following the cleavage reaction, the peptide is usually precipitated by the addition of cold diethyl or r-butyl methyl ether. The precipitation can be done directly from the TFA solution, or following evaporation of the TFA and volatile scavengers. The latter approach generally gives better yields, particularly of small peptides, but can lead to incomplete deprotection of 5-trityl cysteine residues due to the reversibility of the reaction. 

Table 3 Some N-desymmetrised NDIs derived from condensing the achiral amino acids shown with the NMI derived from S-trityl cysteine [14]...

Scheme 7 Selective deprotection of the trityl group for farnesylation under acidic conditions and subsequent deprotection of the second cysteine under reductive conditions.

Alternatively to using prelipidated building blocks palmitoylation on resin is possible with the hydrazine linker. In Scheme 27 the synthesis route for the palmitoylated and farnesylated N-Ras peptide 78 is shown. Here the initial loading of trityl-protected cysteine to the hydrazine linker was mediated by A,A-diisopropylcarbodiimide (DIG) and HOBt. After Fmoc removal the proline was coupled using HBTU and HOBt. The trityl-protected dipeptide 75 was subsequently S-deprotected using TFA with triethylsilane (TES) as a scavenger. Farnesylation of the free thiol was achieved with an excess of farnesyl bromide. 

A reasonable mechanism for the iodine oxidation of 5-Trt cysteine peptides is given in Scheme 6. 45 Reaction of iodine with the divalent sulfur atom leads to the iodosulfonium ion 5 which is then transformed to the sulfenyl iodide 6 and the trityl cation. Sulfenyl iodides are also postulated as intermediates in the iodine oxidation of thiols to disulfides. The disulfide bond is then formed by disproportionation of two sulfenyl iodides or by reaction between the electrophilic sulfur atom of R -S-I and the nucleophilic S-atom of a second R -S-Trt molecule. The proposed mechanism suggests that any sulfur substitution (i.e., thiol protecting group) capable of forming a stabilized species on cleavage, such as the trityl cation, can be oxidatively cleaved by iodine. 

A solution of IV-acetyl-S-trityl-L-cysteine (0.71 mmol) and 80 jxl A-methylmorpholine dissolved in 5 ml of EtOAc was stirred at -15°C, then treated with 93 jxl isobutyl chloroformate. After 15 minutes, S-acetylcysteaminehydrochloride (0.71 mmol) and an additional 80 xl A-methyl-morpholine were added and the mixture stirred for 15 minutes at — 15°C and then 3 hours at ambient temperature. A-Methylmorpholine hydrochloride was then filtered off and the mixture was washed twice with 2.5 ml of EtOAc and concentrated. The gummy residue was purified by flash chromatography with silica gel using EtOAc/30% petroleum ether and the product isolated in 55% yield as a colorless powder, mp = 111-113°C. 

The S-trityl ether of cysteine has been prepared by reaction of the amino add with triphenylmethanol in acetic add in the presence of trifluoroborane etherate43 or with triphenylmethanol in neat trifluoroacetic add.44 Slightly lower mp and spedfic rotation were recorded for the product obtained by the more... 

PS—Cl deprotects cysteine residues protected with trityl, diphenylmethyl, acetamidomethyl, f-butyl, and t-butylsulfenyl groups a mixed disulfide, CyS—S—PS, is obtained, which can form a disulfide with another SH group. Thus it can also be used to form disulfide bonds between two cysteine-containing peptides. ... 

The 5-(methoxycarbonylsulfanyl) derivatives of cysteine and cysteine peptides are prepared from 5-(acetamidomethyl)- and 5-trityl-protected precursors by reaction with SMoc-Q to produce transiently protected/activated intermediates for further chemical manipulations. According to prior experience with Nps-Cl/ even other 5-aralkyl... 

A number of other groups can be used for the protection of thiols benzyl thioethers of amino acids and peptides have been cleaved electrochemically at a platinum cathode in liquid ammonia [121], at mercury in MeOH-TMACl [122], and in DMF [123,124], and the trityl group has been used to protect cysteine cysteine was recovered in 90% yield after reduction in DMF [124]. The 4-pyridylmethyl [125,126] and diphenyl-4-pyridylmethyl groups can be cleaved in acid solution [124] at a mercury cathode. 

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