Episulfonium ion

Scheme 6 depicts a typical penicillin sulfoxide rearrangement (69JA1401). The mechanism probably involves an initial thermal formation of a sulfenic acid which is trapped by the acetic anhydride as the mixed sulfenic-acetic anhydride. Nucleophilic attack by the double bond on the sulfur leads to an episulfonium ion which, depending on the site of acetate attack, can afford either the penam (19) or the cepham (20). Product ratios are dependent on reaction conditions. For example, in another related study acetic anhydride gave predominantly the penam product, while chloroacetic anhydride gave the cepham product (7lJCS(O3540). The rearrangement can also be effected by acid in this case the principal products are the cepham (21) and the cephem (22 Scheme 7). Since these early studies a wide variety of reagents have been found to catalyze the conversion of a penicillin sulfoxide to the cepham/cephem ring system (e.g. 77JOC2887).

A large number of DNA-alkylating agents are known and we will not attempt a comprehensive survey here. A number of excellent reviews provide an overview of this area. " Here we will review DNA alkylation by three types of reactive intermediates that are important in medicinal chemistry and toxicology— episulfonium ions, aziridinium ions, and carbocations. 

Toremifene also undergoes oxidative metabolism to form a QM.59 The 4-hydro-xytoremifene QM has a half-life of lh at physiological pH and temperature (Table 10.2), while its half-life in the presence of GSH is approximately 6 min.59 The 4-hydroxytoremifene QM reacts with two molecules of GSH and loses chlorine to yield the corresponding di-GSH conjugate (Scheme 10.9). This reaction mechanism likely involves an electrophilic episulfonium ion intermediate, which could contribute to the potential cytotoxicity of toremifene. 

The product of an episulfonium ion-mediated cyclotrimerisation previously reported as a 15-membered ring trilactam has now been shown to be a 1,3,5-triazine <060BC3120>. The tautomerism of 2,4-di(benzyloxy)-l,3,5-triazin-6(5A)-one has been studied <06MI561>. 

A more complex structure is that of leinamycin 45 (Scheme 15), a material with potent cytotoxic and antitumor properties, isolated from a Streptomyces sp. A 1,2 dithiolane-3-one ring is spiro fused to a complex macrolactam96 (and references therein). Leinamycin has the remarkable ability to cleave DNA. In brief, leinamycin reacts with a thiol and, after a profound rearrangement, forms an episulfonium ion. This ion alkylates the N7 position of guanosine residues in double stranded DNA an unstable adduct is depurinated by hydrolysis of the glycosidic bond between the alkylated base and a deoxyribose residue. Some structurally less complex l,2-dithiolane-3-one 1-oxides have a similar DNA cleaving ability.97... 

Sulfenoetherification. The reagent in combination with trifluoromethane-sulfonic acid converts suitably unsaturated alcohols into five- to seven-membered cyclic ethers. The cyclization is considered to involve an intermediate episulfonium ion. 

FIGURE 7.17 Conjugation of dibromoethane with glutathione (GSH) ultimately leads to a more reactive episulfonium ion. 

Terminal alkenes, containing tu-OH or (U-COOH functionalities, may undergo cyclization [129] with different orientation of the intramolecular attack of the nucleophilic end of the molecule on the intermediate episulfonium ion (Eq. 16). 

In 2008, Toste and coworkers reported the desymmetrization of me o-episulfonium ions 131 generated in situ from ring closure of sulfides 132 featuring a P-trichloro-acetimidate leaving group [76], Chiral BINOL-derived phosphoric acid (5)-3o (15 mol%, R = triggered the formation of the intermediate mera-epi-... 

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