RESUMEN
[reaction: see text] An efficient asymmetric synthesis of the vasopeptidase inhibitor BMS-189921 was accomplished. Two short enantioselective syntheses of the common key intermediate (S)-alpha-aminoazepinone 6b were developed. Olefin 3 was converted to 6b via asymmetric hydrogenation. Alternatively, enyne 12 was converted to racemic alpha-aminoazepinone 15b, which was transformed to 6b by a practical dynamic resolution.
Asunto(s)
Azepinas/química , Azepinas/síntesis química , Endotelio Vascular/enzimología , Inhibidores Enzimáticos/síntesis química , Neprilisina/antagonistas & inhibidores , Azepinas/farmacología , Inhibidores Enzimáticos/farmacología , Hidrogenación , EstereoisomerismoRESUMEN
Conversion of an alpha,alpha-dichloroester to the corresponding alpha-keto acid was unexpectedly complicated by a novel 1,4-homofragmentation. Investigation of the kinetics of this reaction revealed a mechanism involving an alpha-lactone intermediate, which can lead to both the desired alpha-keto acid and the 1,4-homofragmentation, with the product distribution being dependent upon reaction conditions. This information allowed development of a process that affords the alpha-keto acid exclusively and should be generally applicable to the preparation of alpha-keto acids from alpha,alpha-dichloroesters or acids.
Asunto(s)
Hidroxiácidos/química , Cetoácidos/química , Lactonas/química , Cinética , Estructura MolecularRESUMEN
Benzylic and allylic organozinc and Grignard reagents have been added to resin-bound imines to provide alpha-branched secondary amines. Many functional groups, including electrophilic groups, were compatible with this methodology. Three modules--a resin-bound primary amine, an aromatic aldehyde, and the organometallic--were independently varied to produce a combinatorial library of alpha-branched secondary amines designed as beta-3 adrenergic receptor agonists.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/síntesis química , Aminas/química , Benceno/química , Iminas/química , Zinc/química , Agonistas Adrenérgicos beta/química , Técnicas Químicas Combinatorias , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A survey of several electrophilic ammonia reagents for the N-amination of indole- and pyrrole-containing heterocycles revealed that monochloramine (NH(2)Cl) is an excellent reagent for this transformation. Pyrroles and indoles containing a variety of substitution were aminated on nitrogen with isolated yields ranging from 45% to 97%.