RESUMO
Catalytic asymmetric deprotonation-aldehyde trapping-ring expansion from a 5- to a 6-ring delivers a concise route to each stereoisomer of beta-hydroxy piperidines starting from N-Boc pyrrolidine. The methodology is utilized in a 5-step catalytic asymmetric synthesis of the neorokinin-1 receptor antagonist, (+)-L-733,060.
Assuntos
Antagonistas dos Receptores de Neurocinina-1 , Piperidinas/síntese química , Pirrolidinas/química , Estrutura Molecular , Piperidinas/química , EstereoisomerismoRESUMO
To map out the stoichiometric ligand requirements in the two-ligand catalytic asymmetric deprotonation of N-Boc pyrrolidine, 24 different ligands have been evaluated; the highest enantioselectivity (90:10 er) was obtained by using s-BuLi in the presence of 0.3 equiv of (-)-sparteine and 1.3 equiv of a cyclohexanediamine-derived ligand.
RESUMO
Using competition experiments between a range of ligands and (-)-sparteine, a reactivity series for N-Boc pyrrolidine lithiation using s-BuLi/diamines has been constructed; the results indicate that the s-BuLi/(+)-sparteine surrogate complex is more reactive than s-BuLi/(-)-sparteine and this has been exploited in the selection of ligand pairs for ligand exchange catalytic asymmetric lithiation of N-Boc pyrrolidine and lithiation of N-Boc piperidine.