RESUMEN
The hydroxyamination reagent Br-N-(CO2Me)2 underwent Markovnikov addition to various olefins in the presence of catalytic BF3·OEt2 and provides efficient access to aminoalcohols. The reaction provided the trans-1-bromo, 2-N-bis-carbamate adduct stereoisomer in all cases. The resulting adduct underwent cyclization to give an oxazolidinone, which could be readily hydrolyzed to an oxazolidin-2-one or an amino alcohol.
Asunto(s)
Alquenos/química , Amino Alcoholes/química , Amino Alcoholes/síntesis química , Carbamatos/química , Carbamatos/síntesis química , Oxazolidinonas/química , Oxazolidinonas/síntesis química , Aminación , Catálisis , Ciclización , Indicadores y Reactivos/química , Espectroscopía de Resonancia Magnética , EstereoisomerismoRESUMEN
The proteasome has emerged as the primary target for the treatment of multiple myeloma. Unfortunately, nearly all patients develop resistance to competitive-type proteasome inhibitors such as bortezomib. Herein, we describe the optimization of noncompetitive proteasome inhibitors to yield derivatives that exhibit nanomolar potency (compound 49, IC50 130 nM) toward proteasome inhibition and overcome bortezomib resistance. These studies illustrate the feasibility of the development of noncompetitive proteasome inhibitors as additives and/or alternatives to competitive proteasome inhibitors.
Asunto(s)
Imidazolinas/síntesis química , Inhibidores de Proteasoma/síntesis química , Ácidos Borónicos/farmacología , Bortezomib , Línea Celular , Humanos , Imidazolinas/farmacología , FN-kappa B/antagonistas & inhibidores , Inhibidores de Proteasoma/farmacología , Pirazinas/farmacologíaRESUMEN
We herein report a simple and convenient one-pot synthesis of highly substituted 2-imidazolines in a regiocontrolled and stereospecific matter through the ring expansion reaction of an imidoyl chloride with an aziridine, analogous to the Heine reaction.
