RESUMEN
A generic activation mode for asymmetric LUMO-lowering catalysis has been developed using the long-established principles of oxy-allyl cation chemistry. Here, the enantioselective conversion of racemic α-tosyloxy ketones to optically enriched α-indolic carbonyls has been accomplished using a new amino alcohol catalyst in the presence of electron-rich indole nucleophiles. Kinetic studies reveal that the rate-determining step in this S(N)1 pathway is the catalyst-mediated α-tosyloxy ketone deprotonation step to form an enantiodiscriminant oxy-allyl cation prior to the stereodefining nucleophilic addition event.
Asunto(s)
Compuestos Alílicos/química , Indoles/síntesis química , Cetonas/química , Oxígeno/química , Catálisis , Cationes/química , Indoles/química , Estructura Molecular , EstereoisomerismoRESUMEN
The asymmetric total syntheses of the natural products (+)- and (-)-frondosin B and (+)-frondosin A are reported based on a diastereoselective cycloaddition between tetrabromocyclopropene and an annulated furan to provide a highly functionalized common building block. The bridged bicyclic intermediate could be stereo- and chemoselectively manipulated to produce the two structurally distinct members of the frondosins. Both syntheses feature regioselective palladium-coupling reactions and an unprecedented phosphine-mediated ether bridge cleavage. Surprisingly, the planned enantioselective synthesis of frondosin B led to the opposite epimer of the natural product, suggesting an unusual late stage stereoinversion at C8. Frondosin A, but not frondosin B, was shown to have selective antiproliferative activity against several B-cell lines.
Asunto(s)
Compuestos Bicíclicos con Puentes/síntesis química , Ciclopropanos/química , Furanos/química , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Bicíclicos con Puentes/química , Cristalografía por Rayos X , Ciclización , Compuestos Heterocíclicos de 4 o más Anillos/química , Modelos Moleculares , Conformación Molecular , EstereoisomerismoRESUMEN
An improved methodology for the preparation of enantiopure oxabicyclo[3.2.1]octadienes via a stereodivergent resolution is reported. High catalyst control proximal to the oxabridged stereocenter produces readily separable diastereomers in high yield (>92%) and with excellent optical purity (>95% ee). This resolution strategy is amenable to large-scale preparations, and the utility of the resolution was further demonstrated in the asymmetric preparation of a key intermediate used in the synthesis of the antibiotic (-)-platensimycin.
Asunto(s)
Adamantano/síntesis química , Aminobenzoatos/síntesis química , Anilidas/síntesis química , Productos Biológicos/química , Compuestos Bicíclicos con Puentes/química , Cetonas/química , Adamantano/química , Aminobenzoatos/química , Anilidas/química , Estructura Molecular , EstereoisomerismoRESUMEN
A direct route to analogs of the naturally occurring tropolone ß-thujaplicin has been developed in just four steps from furan. Using this method, a series of derivatives were synthesized and evaluated. Several of these compounds demonstrated very high levels of potency against bacterial and fungal pathogens with good selectivity over mammalian cells.
Asunto(s)
Antibacterianos/farmacología , Antifúngicos/farmacología , Antineoplásicos/farmacología , Furanos/química , Monoterpenos/farmacología , Tropolona/análogos & derivados , Tropolona/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antifúngicos/síntesis química , Antifúngicos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Candida glabrata/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Enterococcus faecalis/efectos de los fármacos , Humanos , Células MCF-7 , Estructura Molecular , Monoterpenos/síntesis química , Monoterpenos/química , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-Actividad , Tropolona/síntesis química , Tropolona/químicaRESUMEN
Natural products have long been recognized as a rich source of potent therapeutics but further development is often limited by high structural complexity and high molecular weight. In contrast, at the core of the thujaplicins is a lead-like tropolone scaffold characterized by relatively low molecular weight, ample sites for diversification, and metal-binding functionality poised for targeting a range of metalloenzyme drug targets. Here, we describe the development of this underutilized scaffold for the discovery of tropolone derivatives that function as isozyme-selective inhibitors of the validated anticancer drug target, histone deacetylase (HDAC). Several monosubstituted tropolones display remarkable levels of selectivity for HDAC2 and potently inhibit the growth of T-cell lymphocyte cell lines. The tropolones represent a new chemotype of isozyme-selective HDAC inhibitors.
RESUMEN
A stereocontrolled approach to a key platensimycin intermediate was achieved from a commercially available furylcarboxylate. Key to our approach is the highly efficient formal [4 + 3] cyclocondensation of a substituted furan with tetrabromocyclopropene along with an intramolecular γ-alkylation to construct the final ring of the caged intermediate.
Asunto(s)
Adamantano/síntesis química , Aminobenzoatos/síntesis química , Anilidas/síntesis química , Antibacterianos/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Furanos/química , Compuestos de Oxígeno/química , Alquilación , Estructura Molecular , Estereoisomerismo , Streptomyces/químicaRESUMEN
A rapid approach to the spirocyclic core of cyclopamine was achieved in four steps from 2-pentenyl-furan. A furan Diels-Alder reaction followed by a one-pot dehalogenation/amination sequence provides the oxabicyclic triene that upon treatment with Grubbs' catalyst undergoes smooth rearrangement to the tricyclic core.