RESUMO
Benzimidazole 1 is the lead compound resulting from an antibacterial program targeting dual inhibitors of bacterial DNA gyrase and topoisomerase IV. With the goal of improving key drug-like properties, namely, the solubility and the formulability of 1, an effort to identify prodrugs was undertaken. This has led to the discovery of a phosphate ester prodrug 2. This prodrug is rapidly cleaved to the parent drug molecule upon both oral and intravenous administration. The prodrug achieved equivalent exposure of 1 compared to dosing the parent in multiple species. The prodrug 2 has improved aqueous solubility, simplifying both intravenous and oral formulation.
RESUMO
The asymmetric synthesis of (-)-(R)-pyrrolam A was achieved in three operations from N-Boc pyrrolidine via an alpha-(N-carbamoyl)alkylcuprate vinylation reaction followed by N-Boc deprotection and cyclization. One-pot deprotection-cyclization procedures led to mixtures of pyrrolam A and its double bond isomers. These isomerization events could be circumvented by use of a two-step procedure. To guide aspects of the experiments, a series of computational energy evaluations and chemical shift predictions were performed with molecular mechanics, semiempirical, ab initio, and density functional methods. The relative stabilities of the double bond isomers, as estimated by experiment, challenged a number of computational methods, and only the MP2 model with its moderate degree of electron correlation came close to matching the experimental data. The MP2 method was further applied to an unusual aspect of the double bond migration between pyrrolam A and its isomer 9. The reaction (1 to 9) on neat samples is irreversible without racemization, and the alumina-mediated equilibration is accompanied by complete loss of enantiomeric excess. The source of the irreversibility was traced to asymmetric charge distribution in the intermediate dienolate anion. The analysis ultimately led to a semiquantitative sketch of the pyrrolam energy surface.
Assuntos
Alcaloides de Pirrolizidina/química , Alcaloides de Pirrolizidina/síntese química , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Streptomyces/químicaRESUMO
Stereogenic 2-(N-carbamoyl)pyrrolidinylcuprates prepared from scalemic (i.e., enantioenriched) N-Boc-2-lithiopyrrolidine and THF soluble CuCN.2LiCl react with vinyl iodides, vinyl triflates, beta-iodo-alpha,beta-enoates, propargyl mesylates, and allyl bromide to afford the substitution products with excellent enantioselectivity. Excellent enantiomeric ratios are obtained in the conjugate addition reactions with methyl vinyl ketone while low enantiomeric ratios can be achieved with acrylate esters using HMPA/TMSCl activation. Enantiomeric ratios vary with substrate substitution patterns and the observed enantioselectivities appear to be more a function of cuprate-electrophile reactivities than of the reaction type (e.g., substitution, conjugate addition). Low enantiomeric ratios are obtained with the alpha-(N-carbamoyl)benzylcuprates. The lithium-copper transmetalation and cuprate vinylation reactions proceed with retention of configuration.