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
SAR studies and optimization of various modified Hygromycin A fluoroalkyl ethers, which led to the discovery of the highly potent 4'-(2-cyclopropyl-2-fluoroethyl ether) antibacterial CE-156811 (1) derived from truncation of the ribose ring and difluorination of the phenyl found in Hygromycin A, are discussed.
Assuntos
Antibacterianos/química , Cinamatos/química , Dioxóis/química , Higromicina B/análogos & derivados , Administração Oral , Animais , Antibacterianos/síntese química , Antibacterianos/farmacocinética , Cães , Avaliação Pré-Clínica de Medicamentos , Haplorrinos , Higromicina B/química , Camundongos , Testes de Sensibilidade Microbiana , Ratos , Relação Estrutura-AtividadeRESUMO
Novel hygromycin A derivatives bearing a variety of functionalized aminocyclitol moieties have been synthesized in an effort to increase the antibacterial activity and drug-like properties of this class of agents. A systematic study of the effect of alkylation and removal of the hydroxyls of the aminocyclitol directed us to a series of alkylated aminocyclitol derivatives with improved gram-positive activity.