Sulfoxide Elimination Research Articles

Canrenone formation via general-base-catalyzed elimination of 7.alpha.-(methylthio)spironolactone S-oxide

The preparation of the two diastereomeric S-oxides of 7 alpha-(methylthio)spironolactone, the major metabolite of spironolactone in humans, is described. When placed in aqueous solution, these diastereomers undergo elimination reactions to give canrenone. The rate of canrenone formation from 7 alpha-(methylthio)spironolactone S-oxide was carefully investigated spectrophotometrically. In weakly acidic media, canrenone formation was found to proceed at significant rates, and the reaction was catalyzed by basic buffer species. At strongly acidic or basic pH only, specific-acid or specific-base catalysis of sulfoxide elimination, respectively, was observed. The observation that formation of canrenone could occur from nonenzymatic elimination of 7 alpha-(methylthio)spironolactone S-oxide may have toxicological significance since it has been determined that canrenone can be metabolized to mutagenic epoxides in vitro. Our studies demonstrate a novel chemical pathway leading from a major metabolite of spironolactone, 7 alpha-(methylthio)spironolactone S-oxide, to canrenone.

(1-Amino-2-propenyl) phosphonic acid, an inhibitor of alanine racemase and D-alanine:D-alanine ligase.

DL-(1-Amino-2-propenyl)phosphonic acid was synthesized through the sequential oxidation, sulfoxide elimination, and deprotection of diphenyl [1-[(benzyloxycarbonyl)amino]-3-(phenylthio)propyl] phosphonate. This analogue of vinylglycine is a strong inhibitor of the alanine racemases from Pseudomonas aeruginosa and Streptococcus faecalis and of the D-Ala:D-Ala ligase from this latter species. This molecule is ineffective against the whole bacterial cells. Unlike vinylglycine, this unsaturated phosphonate does not inhibit the following mammalian enzymes: aspartate aminotransferase, alanine aminotransferase, D-amino acid oxidase, which indicates its specificity. Thus, its incorporation in a peptide structure could induce interesting antimicrobial properties.

A novel synthetic route to 6‐azabicyclo[3.2.1]oct‐3‐enes via silicon directed N‐Acyliminium chemistry: Synthesis of (±)‐gabaculine

AbstractAlkylation of the lithium enolate, derived from 5‐ethoxy‐2‐pyrrolidone 1 (Scheme 1), using alkyl halides containing either the vinylsilane or 2‐propynylsilane moiety, provides substrates 3 for cyclization studies passing through N‐acyliminium intermediates 4 toward the 6‐azabicyclo[3.2.1]‐octanes 5 and 7. These ring‐closure experiments are unsuccessful in the case of vinylsilanes, and an explanation for this failure is presented. Ring closures of 2‐propynylsilanes lead, in high yield, to bicyclic allenes 5, which, in a few steps (ozonolysis, Shapiro reaction), are transformed into 7. This methodology constitutes the basis of a total synthesis of (±)‐gabaculine (10). The synthesis is completed from 52 by lactam hydrolysis and sulfoxide elimination.

Regioselective Alkylation of the Polyfunctional Nucleophile 1‐(Methylthio)‐3‐triethylsilyloxypentadienyllithium

Abstractγ‐Selective sulfenylation of the triethysilyloxypentadienyllithium 1 gave the versatile alkylthiodene 4 which on successive deprotonation and alkylation furnished with high regioselectivity the γ‐products 6. Fluoride‐promoted silylether cleavage 6 → 7 may be followed by intramolecular [4 + 2]‐addition 7c → 8 and sulfoxide elimination 8 → 9. The conversions 7b → 12 and 7a → 17 demonstrate the feasibility of 5 to serve as an equivalent of the hypothetical β‐deprotonated divinylketone 13 whose two enone units may be unmasked separately.