Thiol protecting groups

An asterisk in the text indicates that a pertinent review can be found at the end of the chapter. 

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DF Veber, JD Milkouski, SL Varga, RG Denkewalter, R Hirschmann. Acetamidomethyl. A novel thiol protecting group for cysteine. J Am Chem Soc 94, 5456, 1972. 

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. 

An interesting approach based entirely on the solid-phase route has been reported for the synthesis of a-conotoxin SI (Scheme 14) where a combination of acid-labile and acid-stable thiol protecting groups are employed for the required orthogonality.[107]... 

X = thiol protecting groups Y, = Y = amino protecting groups of attachment sites Z = side-chain protecting groups... 

Most thiol protecting groups in common use are 5-alkyl derivatives because thiol esters and carbonates are much more easily hydrolysed than their oxygen counterparts. 

Iodinolysis in a protic solvent such as methanol easily cleaves the 5-trityl group and oxidises the liberated thiol to a disulfide. The acetamidomethyl group, another common thiol protecting group (see below), cleaves as well but at a much slower rate when non-polar or weakly nucleophilic solvents such as chloroform. 

Denis B, Trifilieff E. Synthesis of palmitoyl-thioester T-cell epitopes of myelin proteohpid protein (PLP). Comparison of two thiol protecting groups (StBu and Mmt) for on-resin acylation. J. Pept. Sci. 2000 6 372-377. 

Table 1 The Most-Common Thiol Protecting Groups Used in Peptide Synthesis ...

Independent of the thiol protecting groups used in the synthesis of cysteine peptides, the facile racemization of the Cys residue has been recognized as a serious problem since the early days of peptide chemistry (see Section 1.2.1.2 and Vol. E22b, Section 7.4).It is well established that N,S-protected cysteine active esters are unusually prone to racemization via a C -proton-abstraction mechanism in the presence of excess amines (Scheme More... 

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