Peptide synthesis, thiol protection

Alkyldithio carbamates are prepared from the acid chloride (Et N, EtOAc, 0°) and amino acid, either free or as the O-silyl derivatives (70-88% yield). The N- i-propyldithio) carbamate has been used in the protection of proline during peptide synthesis. Alkyldithio carbamates can be cleaved with thiols, NaOH, Ph P/TsOH. They are stable to acid. Cleavage rates are a function of the size of the alkyl group as illustrated in the table below. 

The Hoc group was developed for tryptophan protection to minimize alkylation during BOC-mediated peptide synthesis. It is introduced with the chloroformate (NaOH, CH2CI2, Bu4N HS04 ) and can be cleaved with HF without the need to include thiols in the cleavage mixture. 

Postsynthetic intramolecular alkylation of a cysteine thiol group with a bromo amino acid has also been proposed/431 but this approach is limited by the low coupling efficiency of the bromo amino acid in the peptide synthesis due to a competing intramolecular cyclization reaction. A promising new approach consists of using suitably protected cysteine and homoserine derivatives for the peptide synthesis, whereby the side-chain hydroxy group of homoserine is protected as the TBDMS derivative which is converted on resin into the chloro derivative with freshly prepared triphenylphosphine dichloride. Upon cleavage from the resin, cyclization is performed in solution as shown in Scheme 11144]... 

Two major synthetic strategies have been applied for the synthesis of S-prenylated peptides as shown in Scheme 1. In the first approach (method A), S-alkylation is performed on the final peptide in a protected or unprotected form.13641 In method B, which has produced better results in terms of overall yield, thiol alkylation is carried out on the cysteine residue or on a small peptide fragment and then the S-prenylated synthons are coupled to the remaining peptide fragment to produce the final products.[45 501 Most of the procedures reported for the synthesis of farnesylated peptide derivatives, can also be applied to the synthesis of geranylgeranylated peptides. 

Trityl resins are particularly suitable for immobilization of nucleophilic substrates such as acids, alcohols, thiols, and amines. They are quite acid-sensitive and are cleavable even with acetic acid this is useful when acid-labile protecting groups are used. The stability of trityl resin can be tailored by use of substituted arene rings, as shown by chlorotrityl resin, which furnishes a more stable linker than the trityl resin itself. Steric hindrance also prohibits formation of diketopiperazines during the synthesis of peptides. Orthogonality toward allyl-based protective groups was demonstrated in the reverse solid-phase peptide synthesis of oligopeptides [30] (Scheme 6.1.4). 

Protection of thiol groups is a substantive issue in peptide chemistry where protection and deprotection of cysteine and the attendant problem of disulfide bond formation is a major challenge. An authoritative review of the subject by Moroder and co-workers can be found in Synthesis of Peptides and Peptidomi-metics (Houben-Weyl), Vol E22a. ... 

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... 

DCC can be used to prepare 5-alkyl and 5-aryl thiocarboxylates (1) from carboxylic acids and thiols according to equation (5). This method has been successfully applied to the synAesis of thiol esters with sensitive substituents, e.g. 5-methyl thioacrylate, a natural product. In particular, N-protected amino acid and peptide 5-phenyl esters, which are useful building blocks in peptide synthesis, are obtained in excellent yields without racemization. N-Hydroxyphthalimide and DMAP have been used as cocatalysts to facilitate the reaction. The preparation of the Wittig reagent (5) by this route is shown in equation (6). 

Ironically, a very suitable reagent for protecting the thiol group had been described in 1905 but was not applied to peptide synthesis until 1972 (Veber et al., 1972), a salutary reminder that a lot of useful chemistry may be lurking in the old... 

---