RESUMEN
A series of diastereomeric tetrahydroxylated azepanes featuring a carboxymethyl group at the pseudo-anomeric position have been synthesized from a common unsaturated intermediate. Syn- and anti-dihydroxylation reactions were achieved to yield the target compounds after efficient one-step deprotection of carbamate, ester and acetonide groups simultaneously. Screening of these polyhydroxylated azepanes toward a range of commercially available glycosidases was performed and one of the stereoisomers showed potent and selective inhibition toward ß-galactosidase (IC50=21 µM).
Asunto(s)
Azepinas/síntesis química , Azepinas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Glicósido Hidrolasas/antagonistas & inhibidores , Azepinas/química , Espectroscopía de Resonancia Magnética con Carbono-13 , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/química , Modelos Moleculares , Espectroscopía de Protones por Resonancia Magnética , Espectrometría de Masa por Ionización de Electrospray , EstereoisomerismoRESUMEN
The addition of trifluoromethyl(trimethyl)silane (TFMTMS) to tartaric acid derived aromatic 1,4-diketones was reported to be highly stereoselective but also chemoselective towards a monoaddition product. This chemoselectivity remained unexplained. Complementary experiments and monitoring of the reaction by electrospray ionization mass spectrometry (ESI-MS) show that: i) the countercation (tetrabutylammonium (TBA(+)) or Cs(+)) associated to the initiator and the charged intermediates in the chain reaction plays a crucial role and ii) in the case of a tetrabutylammonium salt initiator, the second addition on the preformed monoadduct does occur but the resulting bis(trifluoromethyl)carbinolate is unable to evolve through the chain-transfer process and it exhibits an intramolecular Si-O interaction.