Di-2-pyridyl disulfide

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. 

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]. 

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. 

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... 

Polymer-bound reagents have also been used. The synthetically important Weinreb amides [RCON(Me)OMe, see 16-82] can be prepared from the carboxylic acid and MeO(Me)NH HCl in the presence of tributylphosphine and 2-pyridine-A -oxide disulfide. Di(2-pyridyl)carbonate has been used in a related reaction that generates amides directly. The reaction of a carboxylic acid and imidazole under microwave irradiation gives the amide. Microwave irradiation of a secondary amine, formic acid, 2-chloro-4,6-dimethoxy[l,3,5]tria-zine, and a catalytic amount of DMAP (4-dimethylaminopyridine) leads to the formamide. ° Ammonium bicarbonate and formamide converts acids to amides with microwave irradiation. Lactams are readily produced from y- or 8-amino acids, for example. 

Amidines are converted into 1,2,4-thiadiazoles by reaction with isothiocyanates, iminosulfenyl chlorides, di- and trichloromethyl sulfenyl chlorides, and carbon disulfide in the presence of sulfur <82AHC(32)285> for example, 5-mercapto-3-methyl-l,2,4-thiadiazole (205) is obtained by the treatment of acetamidine with carbon disulfide and sulfur under basic conditions (Equation (29)) <85JAP85255783>. A useful method for the synthesis of 5-chloro-l, 2,4-thiadiazole (206) (R = 6-methyl-2-pyridyl) involves the reaction of amidines with trichloromethylsulfenyl chloride (Equation (30)) <91JAP9183590>. 

The interesting antibiotics X-14S47A and A-23187 (calcimycin) contain a novel 2-ketopyrrole moiety, which is apparently important for biological activity. Nicolaou has developed a simple method for incorporation of this unit into the sensitive intermediates required for preparation of the natural products. Through use of the Mukaiyama protocol, formation of the 2-pyridyl tldol ester was effected with 2,2 -di-pyridyl disulfide and triphenylphosj iine. The reaction mixture was then cooled to -78 °C and was treated with a solution of pyrroylmagnesium chloride in THF (equation 21). 

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