RESUMO
Stereoselective reduction of dehydroalanine double bond in nocathiacin I afforded the primary amide 2. Enzymatic hydrolysis of the amide 2 provided the carboxylic acid 3, which upon coupling with a variety of amines furnished amides 4-32. Some of these semi-synthetic derivatives have retained very good antibacterial activity and have improved aqueous solubility.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Enterococcus faecalis/efeitos dos fármacos , Peptídeos/síntese química , Peptídeos/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Antibacterianos/química , Técnicas In Vitro , Peptídeos e Proteínas de Sinalização Intercelular , Testes de Sensibilidade Microbiana , Estrutura Molecular , Peptídeos/química , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Água/químicaRESUMO
We have evaluated various achiral templates (1a-g, 10, and 16) in conjunction with chiral Lewis acids in the conjugate addition of nucleophilic radicals to alpha-methacrylates followed by enantioselective H-atom transfer. Of these, a novel naphthosultam template (10) gave high enantioselectivity in the H-atom-transfer reactions with ee's up to 90%. A chiral Lewis acid derived from MgBr(2) and bisoxazoline (2) gave the highest selectivity in the enantioselective hydrogen-atom-transfer reactions. Non-C(2) symmetric oxazolines (20-25) have also been examined as ligands, and of these, compound 25 gave optimal results (87% yield and 80% ee). Insights into rotamer control in alpha-substituted acrylates and the critical role of the tetrahedral sulfone moiety in realizing high selectivity are discussed.