Kamiya-disulfide

A way out to the problems of conventional reductive acylation of Kamiya disulfides was devised after the observation that thioacids displace mercapto-benzothiazole from these intermediates rapidly and quantitatively at room temperature in organic solvents [55]. Obtained acyldithioazetidinones 147 were smoothly desulfurized by PPh3 to afford target thioesters 127. In this process, complete retention of C4 configuration was observed with substrates 147a d... 

A final mention of Kamiya disulfides in penem synthesis relates to their use as intermediates for 4-chloroazetidinones these in turn can be converted to 4-thioesters [55]. However, chlorinolysis of azetidinone-4-sulfides and -disulfides finds its most important application in the 1,5-ring closure strategy to penems, so that it will be discussed at a later point in this review. 

A convenient variant of this process was achieved by reversing the order of the displacement-ozonation sequence. Ozonolysis of the appropriate Kamiya disulfide 145 followed by exposure to the phosphorane reagent afforded 272e i as the phosphonium salts. With a second molar equivalent of the reagent acting as a base, this reaction led in one step to penems 276e i, since... 

Penams constitute a convenient starting material when R is methyl. Kamiya disulfides 149 were converted to the enol mesylates 150 (O3, then MsCl/TEA), which underwent chlorinolysis to generate a mixture of the required chloro-mesylates 331 and the undesired p-chloro epimers. Unfortunately, the latter prevailed (Rj = R2 = H) or were the exclusive product (R = PhCH2CONH, R2 = H), so that biologically inactive (5S)-2-methylpenems were predominantly or exclusively obtained [191, 192]. 

Independent experiments at Farmitalia s showed that direct cyclization to the hydroxyethyl-substituted 2-thiacephem 382 occurred when the Kamiya disulfide 381a was allowed to react with a hydrosulfide salt, e.g. NaSH, although immediate removal of the reagent (partition between water and an organic solvent) was necessary to avoid extensive degradation of the product [209]. Similar results were obtained on thiosulfonate 381b and sulfenimide 381c. 

Sulfur-Sulfur Bond Cleavage of Kamiya s Disulfides.159... 

The disulfide (156) has proven to be a valuable and versatile intermediate. Treatment with bromine or chlorine resulted in the corresponding halomethylpenam in high yield (Kamiya et al., 1973), which on dissolution in dimethylformamide afforded an efficient conversion to the 3-halocephams 168 and 169, respectively. It was postulated that the initial product formed on treatment of 156 with the halogen was the highly reactive sulfenyl halide (170) which on addition to the olefin yielded the episulfonium ion (171) (see Scheme 5). The penicillins derived from 171 represented the kinetic products, whereas the corresponding thermo-... 

Startg. disulfide dissolved in aq. NaHCOg bis(azetidin-2-on-4-yl) disulfide deriv. and bis-(2-benzothiazolyl) disulfide. Y almost 100%. T. Kamiya et al., Tetrah. Let. 1973, 3001. 

Muramoto, K., and Kamiya, H., 1990, The positions of the disulfide bonds and glycosylation site in a lectin of the acorn barnacle Megabalanus rosa, Biochim. Biophys. Acta 1039 52-60. 

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