RESUMO
To facilitate a drug discovery project, we needed to develop a robust asymmetric synthesis of (2S,5S)-5-substituted-azepane-2-carboxylate derivatives. Two key requirements for the synthesis were flexibility for elaboration at C5 and suitability for large scale preparation. To this end we have successfully developed a scalable asymmetric synthesis of these derivatives that starts with known hydroxy-ketone 8. The key step features an oxidative cleavage of aza-bicyclo[3.2.2]nonene 14, which simultaneously generates the C2 and C5 substituents in a stereoselective manner.
Assuntos
Ácidos Carboxílicos/química , Ácidos Carboxílicos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Descoberta de Drogas , Cetonas/químicaRESUMO
Respiratory tract bacterial strains are becoming increasingly resistant to currently marketed macrolide antibiotics. The current alternative telithromycin (1) from the newer ketolide class of macrolides addresses resistance but is hampered by serious safety concerns, hepatotoxicity in particular. We have discovered a novel series of azetidinyl ketolides that focus on mitigation of hepatotoxicity by minimizing hepatic turnover and time-dependent inactivation of CYP3A isoforms in the liver without compromising the potency and efficacy of 1.