Synthesis and utility of fluorinated acylsilanes and corresponding enol silyl ethers

Synthesis and utility of fluorinated acylsilanes and corresponding enol silyl ethers were studied. A variety of fluorinated acylsilanes such as mono-, di-, and trifluorinated acylsilanes were synthesized. Fluorinated acylsilanes are synthetic equivalents of fluorinated acetaldehydes. Novel observation, the generation of silylated difluoroenol silyl ether from difluorinated vinyl anion by means of retro-Brook isomerization, was discovered. A variety of fluorinated enol silyl ethers were also synthesized. As synthetic utilizations of fluorinated acylsilanes and corresponding enol silyl ethers, metal mediated allylation reaction in aqueous media was studied. A variety of homoallylic alcohols were obtained. Total suppression of Brook isomerization was observed. On the other hand, Lewis acid mediated Sakurai-type allylation reactions with mono- and difluorinated acylsilanes gave alpha-silylated ketones by means of Brook-, retro-Brook isomerization, and defluorination. However, reaction with trifluorinated acylsilane gave a homoallylic alcohol. The synthesis of fluorinated beta-amino acid derivatives was also studied. Lewis acid-promoted Mannich reaction of 1,1-difluoro-2-trialkylsilyl-2-trialkyloxyethenes with a variety of N-alkylidene- and N-arylidenearylsulfonamides resulted in the formation of Mannich adducts in good to moderate yields. Reactions with mild Lewis acid such as rare earth metal triflates, lanthanide triflates, and trialkylsilyl triflates gave better results due to the prevention of hydrolysis of sulfonylimines. Conversion of acylsilane moiety to carboxylic acid derivative such as ester was successful by a treatment with H2O2 in the presence of tetrabutylammonium fluoride followed by esterification. Amide derivatives were also obtained by reaction of ester compounds with amines. Direct peptide coupling reaction of beta-amino acid ester with amino acid in the absence of peptide coupling reagent resulted in the formation of dipeptide. The synthesis of new aminomethylene analogs of pyrazinamide (PZA) and in vivo activity against M. tuberculosis in murine models of infection were investigated. The new analogs have an activity equal to or greater than PZA in 7H12 broth at three different pHs. New analogs are active against a PZA-resistant strain with the same MICs as against the susceptible strains. An examination of the effectiveness of new analogs in combination with rifalazil in murine models of infection clearly showed that new analogs were superior or equivalent to PZA in reducing CFUs.