RESUMEN
The enantioselective synthesis of (+)-tetrabenazine (TBZ) and (+)-dihydrotetrabenazine (DTBZ), agents of significant interest for therapeutic and molecular imaging applications, has been completed in 21% (TBZ) and 16% (DTBZ) overall yield and in >97% ee from the starting dihydroisoquinoline. The synthesis utilizes Sodeoka's palladium-catalyzed asymmetric malonate addition to set the initial stereocenter followed by a number of diastereoselective transformations to incorporate the remaining asymmetric centers.
Asunto(s)
Tetrabenazina/análogos & derivados , Tetrabenazina/síntesis química , Catálisis , Paladio/química , Estereoisomerismo , Especificidad por Sustrato , Tetrabenazina/químicaRESUMEN
The sulfamic acid phosphotyrosine mimetic was coupled with a previously known malonate template to obtain highly selective and potent inhibitors of HPTPbeta. Potentially hydrolyzable malonate ester functionalities were replaced with 1,2,4-oxadiazoles without a significant effect on HPTPbeta potency.
Asunto(s)
Química Farmacéutica/métodos , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Cristalografía por Rayos X , Diseño de Fármacos , Enlace de Hidrógeno , Hidrólisis , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Proteínas Tirosina Fosfatasas Clase 5 Similares a Receptores , Relación Estructura-ActividadRESUMEN
A new strategy for effecting cascade cyclization processes using nickel enolates has been developed. Nickel enolates may be cleanly generated by the oxidative cyclization of an enal and alkyne with Ni(0), and the resulting enolate may be functionalized by a variety of alkylation processes. Partially and fully intramolecular versions of the process allow the rapid synthesis of complex polycyclics from simple achiral, acyclic precursors.
RESUMEN
[structure: see text] The first total synthesis and stereochemical definition of isodomoic acid G has been achieved. The key nickel-catalyzed coupling of an alkynyl enone with an alkenylzirconium allows formation of the pyrrolidine ring and most of the stereochemical features in a single step. This report provides the first total synthesis application of this new reaction and illustrates its utility in the stereoselective preparation of highly substituted 1,3-dienes.
Asunto(s)
Ácido Kaínico/análogos & derivados , Ácido Kaínico/síntesis química , Ácido Kaínico/química , Compuestos Organometálicos/química , Pirrolidinas/química , Estereoisomerismo , Circonio/químicaRESUMEN
An enantioselective total synthesis of (+)-testudinariol A was completed. A new nickel-catalyzed allenyl aldehyde cyclization was developed in the approach. In addition, an asymmetric anti aldol reaction and a two-directional oxocarbenium ion/vinyl silane condensation were employed as key steps.
Asunto(s)
Aldehídos/química , Níquel/química , Triterpenos/síntesis química , Catálisis , EstereoisomerismoRESUMEN
[reaction: see text] 1,3-Dienes were prepared by a variety of nickel-catalyzed couplings and cyclization processes. Intermolecular or partially intramolecular couplings of alkynes, vinylzirconium reagents, and either aldehydes or enones efficiently proceeded to generate a broad range of functionalized dienes.