Pyridyl disulfide

A cyclohexadienyl Lewis adduct or salt formed by the reaction of a Lewis base with an aromatic compound. Such an adduct is apparently formed from the reaction of OH with 4-(A/-2-aminoethyl-2 -pyridyl disulfide)- -nitrobenzo-2-oxa-l,3-diazole (2PROD). 2PROD is a two-protonic-state electrophile used as a probe for enzyme active site nucleophiles and as a fluorescent re-... 

The 4 mM soln of the crude peptide [H-(Gly-Pro-Hyp)5-Gly-Pro-Gln-Gly-Leu-Leu-Gly-Ala-Hyp-Gly-Ile-Leu-Gly-Cys(Acm)-Cys-Gly-Gly-OH] 28 in degassed argon-sat. DMF/AcOH (95 5) was added dropwise to a 100 mM soln of di[5-nitro(2-pyridyl)]disulfide (5 equiv) in DMF/AcOH (95 5) with exclusion of air oxygen. The reaction was monitored spectroscopically at 430 nm, and after completion (1 to 2 h), the solvent was removed under reduced pressure. The resulting residue was dissolved in H20 and the excess reagent was filtered off. The H20 was removed under reduced pressure and the residue was reprecipitated from TFE with methyl /ert-butyl ether and purified by preparative HPLC to give 29 yield 13% the product was characterized by MALDI-TOF-MS, HPLC, and amino acid analysis. 

Alternatively, both peptide chains could be protected at one cysteine residue as a 5-Acm derivative and at the second cysteine residue by an acid-labile [Trt, Mob, Xan, or Bzl(4-Me)], base-labile (Fm), or reduction-labile (5-tBu) group. Both peptide chains may then be separately converted into the free thiol/Acm-protected form for selective activation of one chain as S-SPy or. S -Npys derivatives by reaction with di(2-pyridyl)disulfide or di[5-nitro(2-pyridyl)]disulfide, or as a sulfenohydrazide derivative by reaction with azodicarbocylic acid derivatives for formation of the first interchain disulfide bridge. 

For the synthesis of bombyxin IV (53) 192 regioselective formation of three disulfide bonds was achieved by exploiting the differentiated acid-stability of the 5-Trt vs the 5-tBu protection in 49 that allowed the air-mediated intramolecular disulfide formation in the A-chain (Scheme 23). For subsequent activation of the third cysteine residue from the precursor S-tBu derivative the rather drastic conditions of TfOH/TFA (1%) were applied in presence of di(2-pyridyl) disulfide which despite the strong acidity allowed a concomitant deprotection/ activation of this residue to give 50. Subsequent reaction of 50 with the B-chain derivative 51 established the intrachain heterodisulfide cross-link in 52 which on oxidation gave bombyxin IV (53). 

In this approach an orthogonal S-protection consisting of the acid-labile Mob and the Acm group was selected. Free thiol peptides were prepared by acid treatment of the precursors and activated with di(2-pyridyl) disulfide to afford the 5-SPy derivatives which served for the preparation of the two heterodimers 60 and 62 via thiolysis with a second cysteine peptide. In both heterodimers 60 and 62 the Acm group was cleaved with silver(I) trifluoroacetate in TFA to generate the mercaptide. Following gel filtration in acidic media the free thiol from 62 was activated as the S-SPy derivative 63 and subsequent thiolysis with the second heterodimer 61 in the free thiol form produced the heterotetramer 64. 

Di(2-pyridyl)disulfide (3.3 mg, 15 pmol) in propan-2-ol (0.3 mL) was added to a soln of [Cys, Cys(Acm)-II] (12.2 mg, 5 pmol) in 2 M AcOH (1 mL). The mixture was stirred at rt for 1 h. The soln was applied to a Sephadex G-10 column and the fractions corresponding to the front main peak were collected and lyophilized. The resulting powder (8.7 mg) was further purified by HPLC to give the product as a white fluffy powder yield 3.8mg (30%) the product was characterized by LSIMS and HPLC. 

Thiols can be linked to insoluble supports as disulfides by disulfide interchange. Mixed disulfides can be prepared on insoluble supports by treating support-bound thiols with excess activated disulfide (e.g. 2-benzothiazolyl, 2-nitrophenyl, 3-nitro-2-pyridyl disulfides [60,676] or a methanethiosulfonate MeS02-SR [677] Figure 3.33), or by treating a support-bound disulfide (e.g. a 2-pyridyl disulfide [191]) with a thiol. Resin-bound disulfides are stable under the conditions of standard Fmoc peptide synthesis, but can be cleaved by reducing agents (Entries 8 and 9, Table 3.37 [191,676,678-681]). 

To a solution of ethyl 2-pyridyl disulfide (55 mg, 0.32 mmol) and DMAP (33 mg, 0.27 mmol) in dichloromethane (2ml) was added 2-mercaptohexadecanoic acid (77 mg, 0.27 mmol). The progress of the reaction was monitored by TLC (silica, CHCl,/MeOH 9 1). Upon completion (1 h) the product mixture was passed through a column (0.5 X 5 cm) of AG MP-50 (0.5 g, 3.5 meq (ml dry resin)1, Bio-Rad Laboratories). Elution with 3 ml of dichloromethane, followed by concentration of the filtrate under reduced pressure, afforded 2-(ethyldithio)hexadecanoic acid (91 mg, 98%) as a colourless oil. 

A very convenient method has been devised [40] for the conversion of thiols to ethyldithio derivatives as a routine procedure for protection of thiol-substituted organic acids. It uses a DMAP-catalysed exchange of the ethylthio group between a thiol and ethyl 2-pyridyl disulfide, prepared from the commercially available 2,2 -dithiobispyridine. Filtration through a macroporous sulfonic acidic resin and evaporation of the solvent yielded the disulfide directly. 

To a solution of 2,2 -dithiobispyridine (4.4g, 20mmol) and a catalytic amount of BF3 OEt2 (5 ml) in dichloromethane (25 ml) was added ethanethiol (1.22g, 20 mmol). The resulting solution was stirred for 2h at ambient temperature and the solvent was removed under reduced pressure. The residue was suspended in a mixture of hexanes and ethyl acetate (50 ml, 7 3), and the insoluble 2-mercaptopyridine was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography (silica, dichloromethane), affording ethyl 2-pyridyl disulfide (2.84 g, 83%) as a pale-yellow liquid. 

In 2002, 3,5-fra s-(+)-(3/ ,5/ )-3-carbomethoxycarbapenam has been reported to be prepared via a known cyclization reaction [185] starting from enantiopure carboxy pyrrolidine with di(2-pyridyl)disulfide, triphenylphosphine, and triethyl-amine in refluxing acetonitrile for 8 h (Scheme 84), [186]. 

Cyclization of thiazolidinylacetic acids 223 in the presence of bis(2-pyridyl)disulfide and triphenylphosphine yielded isopenams 224. One isopenam was selectively epimerized to an rro-configured precursor of isopenicillin G <1999EJ02433>. 

Disulfides are generally reduced without difficulty to the mercapto derivative 8,8 -diquinolyldisulfide317 has thus been reported to be reduced in this way. The disulfide group is reduced preferentially to an -V-oxide function, e.g., bis(2-pyridyl)disulfide-di-AT-oxide.318... 

Brocklehurst, K. (1996b) Covalent Chromatography by Thiol-Disulfide Interchange Using Solid-Phase Alkyl 2-Pyridyl Disulfides, in Proteins Labfax (Price, N.C., Ed.), BIOS, Oxford. 

Activated Thiol Sepharose 4B — SH, —C = 0, —CNH Glutathione-2-pyridyl disulfide Amersham Pharmacia Biotech... 

---