Date of Award

1-1-1981

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biochemistry

Abstract

The formation and stability of the azasulfonium functionality within the isothiazolidinium structure was investigated. A variety of S- and N-substituted aminothioethers, isothiazolidinium salts and sulfoxides were synthesized, isolated and characterized. Studies of the reaction of a variety of methionine derivatives and analogues with iodine indicated that cyclization occurred when a trimethylene bridge separated the amine and thioether functional groups. The amine could be primary or secondary but could not be in amide linkage and the sulfur could not exist as a sulfoxide or sulfonium salt, but only as a thioether. Significant yields of isothiazolidinium salts were obtained when N-halo compounds and lead tetraacetate were substituted for iodine. A series of N-benzyl and N-phenyl 3-(amino)thioethers with OCH(,3), CH(,3), Cl, NO(,2) substituents at the para or meta position of the aromatic ring were prepared by reacting the appropriate aldehyde and amine in the presence of sodium cyanoborohydride. The rates of reaction of these N-substituted aminothioethers with iodine were found to be pH-dependent in a manner consistent with the rate-limiting step involving attack of the unprotonated amine nitrogen on the iodosulfonium center. The rates levelled off at pH values above 9 and 5 for the N-benzyl and N-phenyl aminothioethers, respectively. Hammett plots indicated that electron-donating substituents increased the rate of cyclization within each series. Cyclization of L-methionine produced a mixture of diastereomers of dehydromethionine which were chiral at positions 1 (sulfur) and 3. Hydrolysis of each diastereomer to form the sulfoxide proceeded with inversion of configuration. Sulfoxide formation occurred partially on base hydrolysis and quantitatively on acid hydrolysis of the N-substituted isothiazolidinium salts. The ease of formation of the isothiazolidinium salts is explained by noting that the nucleophilic amine group is favorably oriented to compete with water for the iodosulfonium intermediate. The stability of the isothiazolidinium salts is due to incorporation of the azasulfonium linkage into a five-membered ring.

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