2-thiopyridyl derivatives

Disaccharide Formation. Treatment of glycoside (3) with 2,2 -dipyridyl disulfide and Tri-n-butylphosphine in CH2CI2 rapidly yields thiopyridyl derivative (4) as a mixture of anomers. Activation of (4) with iodomethane, followed by treatment with glycoside acceptor (5), affords the disaccharide fragment of aver-mectin (6), exclusively a-linked in 78% yield (eq 4). Although other methods are available, this protocol offers advantages in practicality and stereoselectivity. 

Carbon-carbon bonds can be similarly formed at the anomeric centerof carbohydrates. Oxonium ions, formed by the treatment of l-(2 -thiopyridyl)glycosides v/ith Silver(I) Trifluoromethanesul-fonate, can be trapped with silyl enol ethers, silyl ketene acetals, and reactive aromatic compounds, where the stereoselectivity of the addition is determined by solvent and nucleophile choice. The intramolecular version of this process has also been examined (eq 5). Similarly, bicyclic piperazinediones are available by the intramolecular trapping of iminium ions, generated from the appropriate thiopyridyl derivatives with PhHgC104 (eq 6). ... 

General Reactions of Diaryl DisuIfldesL 2,2 -Dipyridyl disulfide reacts with a variety of carbon nucleophiles, yielding the corresponding thiopyridyl derivatives. These include phosphonate stabilized anions, bromouridine derivatives, indole anions, and heterocyclic stabilized anions. ... 

Alkene Formation. The elimination of pyridinethione or 2-pyridylsulfenic acid forms the basis of a number of alkene syntheses. For example, treatment of dithioacetal anions with 2,2 -dipyridyl disulfide affords the a-thiopyridyl derivative, which undergoes elimination at below room temperature to give ketene dithioacetals. Ester enolates have been similarly treated, although m-Chloroperbenzoic Acid is first used to generate the sulfoxide which reacts further to yield an a,p-unsaturated ester. This methodology has been applied to the synthesis of methyl dehydrojasmonate (7) (eq 7). ... 

Other Reactions. Treatment of an active hydroxy compound with 2,2 -dipyridyl disulfide and n-BuyP yields the corresponding thiopyridyl derivative. This methodology has been applied to the preparation of 5-arylthio-5 -deoxyribonucleosides (eq 8). Monophosphate esters [R0P(0)(0H)2] will react similarly to form the activated triphenylphosphonium adduct, which, in the absence of an added external nucleophile, dimerizes yielding a pyrophosphate. A-Methylimidazole has been found to catalyze this transformation. The addition of alcohols or amines, however, traps the phosphoryloxyphosphonium salt as the mixed diphosphate ester or mixed ester/amide, respectively (eq 9). Chlorotrimethylsilane and (pyS)2 have also been reported to facilitate the oxidation of phosphites to phosphates. ... 

With both building blocks 103 and 109 in hand, the total synthesis of lb was completed as shown in Scheme 17. Coupling of acid 103 and alcohol 109 under Yamaguchi conditions to give ester 110 and subsequent desilylation followed by chemoselective oxidation provided hydroxy acid 111. Lactonization of the 2-thiopyridyl ester derived from 111 in the presence of cupric bromide produced the macrodiolide 112 in 62% yield, which was finally converted to pamamycin-607 (lb) via one-pot azide reduction/double reductive AT-methylation. In summary, 36 steps were necessary to accomplish the synthesis of lb from alcohols 88 and 104, sulfone 91, ketone 93, and iodide rac-97. 

In 2003, a new Sml2-mediated carbon carbon bond-forming reaction was reported by Skrydstrup for the direct synthesis of peptide mimics for evaluation as protease inhibitors.90 For example, the low-temperature coupling of 4-thiopyridyl ester 100, derived from Cbz-protected phenylalanine, with the dipeptide acrylamide 101 gave the peptide analogue 102 in a 61% yield (Scheme 7.43). Ketone 102 represents a ketomethylene isostere of the tetra-peptide Phe Gly Leu Phe. Ketomethylene isosteres and the corresponding reduced analogues, hydroxyethylene isosteres, represent important and pharmaceutically relevant classes of protease inhibitors.91,92... 

---