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
[reaction: see text] Two short and efficient synthesis routes have been developed for bis-THF-alcohol 2, a key building block of the investigational HIV protease inhibitor TMC114 (1). Using S-2,3-O-isopropylideneglyceraldehyde (4) as the source of chirality, both routes are based on a diastereoselective Michael addition of nitromethane to give predominantly the syn congeners 6 followed by a Nef oxidation and cyclization to afford lactone acetals 8, which are reduced and cyclized to give 2.
Assuntos
Furanos/síntese química , Inibidores da Protease de HIV/síntese química , Sulfonamidas/síntese química , Ciclização , Darunavir , Furanos/química , Furanos/farmacologia , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , Estrutura Molecular , Estereoisomerismo , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
The resolution of racemates is revolutionized with the method presented here, in which mixtures ("families") of structurally and stereochemically related resolving agents are used to precipitate salts of acidic or basic racemates rapidly and dependably. The racemate is usually separated in a single operation into enantiomers-the enantiomeric excesses and yields are good to excellent. Reagent mixtures with racemic or achiral components have also been developed.