Synthesis symmetrical disulfides

The standard approach to the synthesis of peptides containing disulfide bridges is to use S-protected cysteine derivatives for chain elongation and then subsequently form the disulfide by oxidation of the final S-protected or S-unprotected cysteine peptides (Section 6.1.1). The alternative approach, based on the use of suitably protected symmetrical or unsymmetrical cystine derivatives for the synthesis of disulfide bridged homo-, or heterodimers, besides exhibiting the difficulties discussed in Section 6.1.3, was recently found to generate under... 

An example of the use of a symmetrical disulfide as a protecting group can be seen in a synthesis of compound 30.4 [Scheme 5.30], a key intermediate in Bristol-Myers Squibb s Omapatrilat.60 The tethered dipeptide derivative 30.2 of homocysteine was cleaved with dithiothreitol and the thiol intermediate treated with methanesulfonic acid to cause a double cyclisation reaction. 

A rapid and general method for the synthesis of symmetrical disulfides involves reaction of sulfur with NaOH under PTC + MW irradiation conditions to give sodium disulfide, which reacts with alkyl halides to afford the disulfides in good to excellent yields (Eq. 88) [134]. 

In 2001, Braga et al. reported the synthesis of new chiral C2-symmetric oxazolidine disulfide ligands from (R)-cysteine and successfully applied them as catalysts in the asymmetric addition of ZnEt2 to various aldehydes (Scheme 3.23). In the presence of 2mol% of ligand, excellent enantioselectivities of up to >99% ee were obtained even with aliphatic aldehydes such as n-decanal or n-hexanal. These authors proposed that the active catalyst did not maintain its C2-symmetry during the reaction. The disulfide bond was probably cleaved in situ by ZnEt2. 

In 2002, Braga el al. employed a chiral C2-symmetric oxazolidine disulfide as a ligand for the enantioselective synthesis of propargylic alcohols by direct addition of alkynes to aldehydes (Scheme 3.64). Good yields but moderate enantioselectivities (<58% ee) were obtained for the enantioselective alkyny-lation of aldehydes in the presence of ZnEt2. 

FIGURE 6.22 Disulfide interchange.92 (A) Discovered in synthesis when hydrazinolysis of an unsymmetrical derivative of cystine gave two symmetrical products instead of the expected monohydrazide at the urethane-protected cysteine moiety of the derivative.95 (B) Mechanism for interchange catalyzed by strong acid,94 which is suppressed by thiols. (C) Mechanism for interchange catalyzed by weak alkali, which is enhanced by thiols. 

For the synthesis of double-stranded symmetrical and unsymmetrical monocystine peptides the formation of an intermolecular disulfide bridge is required. For homodimerization of cysteine peptides all the methods discussed in Section 6.1.1 can be applied taking into account the reactivity of the different oxidative agents toward sensitive amino acid residues present in the peptide sequences. Synthetic approaches based on the direct use of suitable cystine derivatives can be envisaged, at least for small-size peptides since disproportionation would in all cases retain the homodimeric structure 241... 

For unsymmetrical disulfides, side reactions often cause randomization of the products, leading to mixtures of symmetrical and unsymmetrical products. To avoid secondary processes, mild procedures occurring under neutral conditions have been developed for the synthesis of these disulfides as well as for trisulfides. 

The simplest synthesis of pseudothiohydantoins (8) is by condensation of thiourea (6) with substituted a-chloroacetates (7)3 5 [Eq. (1)]. Synthons6 of 7, epoxyacids,7 a-chloroacetic anhydrides,8 and dialkyl acetylenedi-carboxylate,9 have been successfully substituted for 7. Symmetrical diaryl-thioureas (9), conveniently synthesized from the corresponding arylamine and carbon disulfide, react with a-haloacetic acid derivatives to give a single thiazolidinone 108,10,11 [Eq. (2)]. 

One solid-phase synthesis of amylin has been reported in 1991 by Balasubramaniam et al. (81). Standard A -Boc chemistry was used for the synthesis, and MBHA resin was selected as the solid support. The coupling was done by using the symmetric anhydride method except for Arg, Asn, and Gin, which were coupled as their HOBt esters (refer to the section on Corticotropin-releasing factor synthesis for details). After completing the chain elongation, the peptide was cleaved from the resin using HF at 0 °C. The residue was then oxidized with K3Fe(CN)e to form the disulfide bond, followed by purihcation on semipreparative reversed phase column. The overall yield of the synthesis was between 10-20%. 

Tri and tetrasulfides are more unstable than disulfides and the unsymmetrical members are particularly liable to suffer disproportionation to give mixtures of products. Several methods are used for the synthesis of symmetrical dialkyl trisulfides (75) thus, they may be obtained by reaction of sulfur dichloride with thiols (Scheme 46). However, this route... 

Carbon disulfide is a valuable synthon (see Chapter 9, p. 147) which can be used for the synthesis of thiocarbonic acid derivatives. Thus, carbon disulfide reacts with ammonium polysulfide or hydrogen sulfide to give trithiocarbonic acid (70) or symmetrical esters (73) after reaction with an alkyl halide. With alkoxides or thiolates, carbon disulfide forms xanthates (77) or S-alkyl trithiocarbonates the latter by further treatment with alkyl, acyl or diazonium halides affords the derivatives (74)-(76) (Scheme 39). 

Thiourea (98) was first prepared in 1870 by heating ammonium thiocyanate (99) (Scheme 54). The reaction is analogous to the historic preparation of urea (Wohler, 1828) which involved heating ammonium cyanate. Thioureas generally are stable crystalline solids which are useful in the synthesis of heterocyclic compounds. Symmetrical thioureas (100) may be obtained by the action of amines on carbon disulfide, and the procedure can be extended to the synthesis of cyclic thioureas (101) (Scheme 55). The reaction occurs via the intermediate (102) which on subsequent treatment with either ammonia or an amine yields the corresponding... 

A novel method for the synthesis of alkenes is based on the coupling of aldehydes with dithioacetals to give the corresponding hydroxy thioacetals, which afford vicinal disulfides via reductive phenylthio migration.242 The syn-diastereomers are the major products from symmetrical compounds while the anti-isomers are obtained with high selectivity with unsymmetrical compounds. Separation of the diastereomers, oxidation to the 1,2-disulfones, and reductive elimination give the corresponding alkenes with moderate stereoselectivities (Eq. 137).242... 

Naumann, C., Place, S., Sherman, J. C., Synthesis and characterization of a disulfide-linked C-5-symmetric [5]carceplex. 

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