RESUMEN
Using an electrochemical C(sp3)-H fluorination reaction, a series of α-fluorinated tropane compounds were synthesized and their druglikeness parameters were assessed to compare with the parent compounds. Improvements were observed in membrane permeability, P-gp liability, and inhibitory effects on hERG and Nav1.5 channels, accompanied with a trend of decreased aqueous solubility and microsomal stability. It was also revealed that α-fluorination reduced the basicity of tropane nitrogen atom for about 1000-fold.
Asunto(s)
Halogenación , Solubilidad , Tropanos , Humanos , Tropanos/química , Tropanos/síntesis química , Tropanos/farmacología , Relación Estructura-Actividad , Canales de Potasio Éter-A-Go-Go/metabolismo , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Permeabilidad de la Membrana Celular/efectos de los fármacos , Animales , Estructura Molecular , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidoresRESUMEN
A simple and robust method for electrochemical alkyl C-H fluorination is presented. Using a simple nitrate additive, a widely available fluorine source (Selectfluor), and carbon-based electrodes, a wide variety of activated and unactivated C-H bonds were converted to their C-F congeners. The scalability of the reaction was also demonstrated with a 100 gram preparation of fluorovaline.
RESUMEN
Catalytic asymmetric Michael and Mannich-type reactions of glycine Schiff bases with chiral two-center organocatalysts, tartrate-derived diammonium salts (TaDiASs), are described. On the basis of conformational studies, optimized TaDiASs with a 2,6-disubstituted cyclohexane spiroacetal were newly designed. These TaDiASs catalyzed the asymmetric Michael and Mannich-type reactions of glycine Schiff bases with higher enantioselectivity than previous catalysts. In the Mannich-type reaction, aromatic N-Boc-protected imines (Boc = tert-butoxycarbonyl) as well as enolizable alkyl imines were applicable. As a synthetic application of the catalytic asymmetric Mannich-type reaction with the optimized TaDiASs, we developed a catalytic asymmetric total synthesis of (+)-nemonapride, which is an antipsychotic agent.
Asunto(s)
Bases de Schiff/química , Tartratos/química , Benzamidas/síntesis química , Catálisis , Glicina/química , Conformación MolecularRESUMEN
A general catalytic allylation of simple ketoimines was developed using 1 mol % of CuF.3PPh(3) as catalyst, 1.5 mol % of La(O(i)Pr)(3) as the cocatalyst, and stable and nontoxic allylboronic acid pinacol ester as the nucleophile. This reaction constituted a good template for developing the first catalytic enantioselective allylation of ketoimines. In this case, using LiO(i)Pr as the cocatalyst produced higher enantioselectivity and reactivity than La(O(i)Pr)(3). Thus, using the CuF-cyclopentyl-DuPHOS complex (10 mol %) and LiO(i)Pr (30 mol %) in the presence of (t)BuOH (1 equiv) produced high enantioselectivity up to 93% ee from a range of aromatic ketoimines. Mechanistic studies indicated that LiO(i)Pr accelerates the reaction by increasing the concentration of an active nucleophile, allylcopper.
Asunto(s)
Compuestos Alílicos/química , Iminas/química , Compuestos Organometálicos/química , Alcanos/química , Catálisis , Cobre/química , Ciclopentanos/química , Fluoruros/química , Litio/química , Espectroscopía de Resonancia Magnética , Modelos Químicos , Estructura Molecular , Óxidos/química , EstereoisomerismoRESUMEN
Aeruginosin 298-A was isolated from the freshwater cyanobacterium Microcystis aeruginosa (NIES-298) and is an equipotent thrombin and trypsin inhibitor. A variety of analogs were synthesized to gain insight into the structure-activity relations. We developed a versatile synthetic process for aeruginosin 298-A as well as several attractive analogs, in which all stereocenters were controlled by catalytic asymmetric phase-transfer reaction promoted by two-center asymmetric catalysts and catalytic asymmetric epoxidation promoted by a lanthanide-BINOL complex. Furthermore, serine protease inhibitory activities of aeruginosin 298-A and its analogs were examined.
Asunto(s)
Leucina/análogos & derivados , Leucina/síntesis química , Leucina/farmacología , Inhibidores de Tripsina/síntesis química , Inhibidores de Tripsina/farmacología , Alquilación , Catálisis , Compuestos Epoxi/química , Concentración 50 Inhibidora , Leucina/química , Naftoles/química , Estereoisomerismo , Relación Estructura-Actividad , Inhibidores de Tripsina/químicaRESUMEN
We developed a versatile synthetic process for aeruginosin 298-A as well as several attractive analogues, in which all stereocenters were controlled by a catalytic asymmetric phase-transfer reaction and epoxidation. Furthermore, drastic counteranion effects in phase-transfer catalysis were observed for the first time, making it possible to three-dimensionally fine-tune the catalyst (ketal part, aromatic part, and counteranion).