RESUMEN
An electrochemical method to synthesize the core macrolactam of diazonamides is described. Large ring-forming dehydrogenation is initiated by anodic oxidation at a graphite surface. The reaction requires no tailoring of the substrate and occurs at ambient temperature in aqueous DMF in an undivided cell open to air. This unique chemistry has enabled a concise, scalable preparation of DZ-2384; a refined analog of diazonamide A slated for clinical development as a cancer therapeutic.
Asunto(s)
Amidas/química , Lactamas Macrocíclicas/química , Oxazoles/química , Preparaciones Farmacéuticas/química , Amidas/síntesis química , Compuestos Azo/química , Cristalografía por Rayos X , Ciclización , Grafito/química , Lactamas Macrocíclicas/síntesis química , Conformación Molecular , Oxazoles/síntesis química , Oxidación-Reducción , Propiedades de SuperficieRESUMEN
We report a versatile method for cross-coupling of NH-sulfoximines with (hetero)aryl chlorides, as well as bromide and sulfonate electrophiles, that makes use of the air-stable, commercial precatalyst (PhPAd-DalPhos)Ni(o-tol)Cl. Under optimized conditions a diverse electrophile scope is established, including the N-arylation of the pharmaceutical Clozapine. While 5 mol % Ni and 80 °C are commonly employed in this chemistry, successful examples utilizing 1 mol % Ni and/or 25 °C are presented. Competition experiments establish the superiority of NH-sulfoximine over primary sulfonamide as nucleophiles under these conditions.
RESUMEN
The nucleophilic aromatic substitution reaction between electron-deficient aryl fluorides and terminal alkynes is shown to be efficiently promoted by sodium bis(trimethylsilyl)amide as a base. Moderate to excellent yields of 2-ethynylnitrobenzene products can be obtained under mild conditions.
Asunto(s)
Alquinos/química , Fluoruros/química , Hidrocarburos Aromáticos/química , Catálisis , Metales , Conformación Molecular , Solventes , EstereoisomerismoRESUMEN
[structure: see text]. The total synthesis of cystothiazole A is described. Key steps of the synthesis include an Evans asymmetric catalytic aldol reaction, which established the required C4-C5 stereochemistry. The [2,4']-bis(thiazole) was obtained applying our methodology of electrophilic activation of amide. Semistabilized Wittig reaction between the phosphonium salt 3 and the aldehyde 2 afforded 1 in nine linear steps and 38% overall yield.
RESUMEN
A series of aryl thiotetrazolylacetanilides were synthesized and found to be potent inhibitors of the HIV-1 wild type and K103N/Y181C double mutant reverse transcriptases. The incorporation of an alkynyl fragment on the aniline provided inhibitors with excellent cellular activity and extensive SAR led to the identification of one inhibitor having good oral bioavailability in rats.