RESUMEN
ß-Hydroxy difluoromethyl ketones represent the newest class of agonists of the GABA-B receptor, and they are structurally distinct from all other known agonists at this receptor because they do not display the carboxylic acid or amino group of γ-aminobutyric acid (GABA). In this report, the design, synthesis, and biological evaluation of additional analogues of ß-hydroxy difluoromethyl ketones characterized the critical nature of the substituted aromatic group on the lead compound. The importance of these new data is interpreted by docking studies using the X-ray structure of the GABA-B receptor. Moreover, we also report that the synthesis and biological evaluation of ß-amino difluoromethyl ketones provided the most potent compound across these two series.
Asunto(s)
Agonistas de Receptores GABA-B/farmacología , Cetonas/farmacología , Propilaminas/farmacología , Sitios de Unión , Agonistas de Receptores GABA-B/síntesis química , Agonistas de Receptores GABA-B/química , Células HEK293 , Humanos , Cetonas/síntesis química , Cetonas/química , Simulación del Acoplamiento Molecular , Propilaminas/síntesis química , Propilaminas/química , Receptores de GABA-B/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Deuterodifluoromethyl ketones and sulfones were assembled in three synthetic steps from methyl ketones and sulfones, respectively. The key synthetic transformation is the deuteration of the difluorocarbanion generated by the release of trifluoroacetate from highly α-fluorinated gem-diols. High levels of deuterium on the "CF2D" group were routinely observed. This strategy is mild and versatile and it can be applied to both ketones and sulfones without additional concerns of over- or under-fluorination. Additional examples address issues of over-deuteration when compounds with other acidic protons are subjected to the reaction conditions. This process not only demonstrates a new method to install a "CF2D" group but also extends the scope of trifluoroacetate release to sulfones.
RESUMEN
Pentafluoro-gem-diols are substrates that enable the synthesis of valuable difluoromethylene-containing organic molecules through the release of trifluoroacetate. Currently, only one synthetic strategy is available to assemble these important precursors. Herein, two new synthetic strategies to a complex pentafluoro-gem-diol are compared to the existing route, and an improved synthetic route has completed. Moreover, the first synthesis of a CF2Br-glucopyranose was finished by a tandem trifluoroacetate-release halogenation/cyclization protocol.
RESUMEN
Three series of α-halo-α,α-difluoromethyl ketones are prepared from highly α-fluorinated gem-diols by exploiting the facile release of trifluoroacetate, followed by immediate trapping of the liberated α,α-difluoroenolate with an electrophilic chlorine, bromine, or iodine source. The products are typically isolated in good yields, even in the case of sensitive, α-iodo-α,α-difluoromethyl ketones. Also, we demonstrate that an α-iodo-α,α-difluoromethyl ketone will participate in a copper-promoted reaction to forge a new carbon-carbon bond.
Asunto(s)
Cetonas/síntesis química , Ácido Trifluoroacético/síntesis química , Halogenación , Cetonas/química , Estructura Molecular , Estereoisomerismo , Ácido Trifluoroacético/químicaRESUMEN
An efficient method for the α-methylenation of carbonyl groups is reported, and this transformation is accomplished by a facile elimination of trifluoroacetate during the formation of the olefin. This method represents an improvement beyond existing protocol in cases of steric hindrance, and we have demonstrated the utility of the process across a series of ketones, lactams, and lactones. Additionally, we have applied this method to produce semisynthetic derivatives of the natural products (+)-sclareolide and (-)-eburnamonine, in which the carbonyl group is proximal to bulky functional groups. Mechanistic insight is also provided from a time course of (19)F NMR. Biological evaluation of the natural-product-derived enones led to the identification of a derivative of (-)-eburnamonine with significant cytotoxicity (LC(50) = 14.12 µM) in drug-resistant MDA-MB-231 breast cancer cells.
Asunto(s)
Diterpenos/química , Cetonas/química , Metano/análogos & derivados , Ácido Trifluoroacético/química , Alcaloides de la Vinca/química , Línea Celular Tumoral , Humanos , Concentración 50 Inhibidora , Metano/química , Alcaloides de la Vinca/síntesis química , Alcaloides de la Vinca/farmacologíaRESUMEN
Synthesis of plakortethers F and G has been performed by taking advantage of the symmetry in the structure. The structures of the prepared compounds have been confirmed by COSY, 1D NOE, and chemical transformation studies. The synthetic plakortether F was found to match the natural product by all physical data. The synthetic plakortether G exhibited several disagreements in (13)C NMR data with the reported values. However, on the basis of an extremely close match in appearance of its (1)H NMR spectrum to the obtained (1)H NMR spectrum of the natural product, as well as matching optical rotations, the two compounds are believed to be identical.
Asunto(s)
Furanos/síntesis química , Productos Biológicos/síntesis química , Productos Biológicos/química , Furanos/química , Espectroscopía de Resonancia MagnéticaRESUMEN
Selectivity of six- vs. five- membered ring formation in C-H insertion on alkylsulfonyl diazoacetates is sensitive to the substrate structure and catalyst used.
RESUMEN
[reaction: see text] Carbethoxy diazosulfones and sulfonates, easily available from corresponding sulfones and sulfonates, undergo C-H insertion with preferential formation of six membered cyclic sulfones and sulfonates.