RESUMO
A systematic study of the asymmetric deprotonation of a dimethyl-substituted phosphine sulfide using organolithium bases in the presence of (-)-sparteine has been carried out. Use of nBuLi and (-)-sparteine in Et(2)O at -78 °C gave trapped adducts in â¼88:12 er via a kinetically controlled process that was successfully predicted using a computational approach at the B3LYP/6-31+G(d) level. This initial kinetic enantioselectivity could be enhanced up to 97:3 er by trapping the lithiated intermediate with a prochiral electrophile (e.g., pivaldehyde or tBuPCl(2)). In addition, it was found that the R(P) and S(P) stereoisomers of the lithiated methylphosphine sulfide could interconvert at temperatures above 0 °C. Such interconversion is unprecedented and differs from the configurational instability of organolithiums that are stereogenic at a lithiated carbon atom. The major, thermodynamically preferred diastereomeric (-)-sparteine-complexed lithated phosphine sulfide was investigated by X-ray crystallography and computational methods at the B3LYP/6-31+G(d) level. Through the interconversion of the R(P) and S(P) stereoisomers of the lithiated methylphosphine sulfide, a novel dynamic thermodynamic resolution of a racemic lithiated phosphine sulfide has been developed. Thus, the phosphine sulfide was lithiated with nBuLi, and then (-)-sparteine was added. After equilibration at 0 °C for 3 h, electrophilic trapping generated an adduct in 81:19 er with the configuration opposite to that obtained under kinetic control. Thus, the methodology provides access to P-stereogenic compounds with the opposite sense of induction using (-)-sparteine as the ligand simply by changing the reaction conditions (kinetic or thermodynamic control).
Assuntos
Fosfinas/síntese química , Esparteína/química , Sulfetos/síntese química , Termodinâmica , Cristalografia por Raios X , Cinética , Lítio/química , Modelos Moleculares , Conformação Molecular , Simulação de Dinâmica Molecular , Compostos Organometálicos/química , Fosfinas/química , Estereoisomerismo , Sulfetos/químicaRESUMO
Herein we describe the identification of 4-{[1,2,4]triazolo[1,5-a]pyridin-5-yl}benzonitrile-based inhibitors of the hypoxia-inducible factor prolylhydroxylase domain-1 (PHD-1) enzyme. These inhibitors were shown to possess a novel binding mode by X-ray crystallography, in which the triazolo N1 atom coordinates in a hitherto unreported monodentate interaction with the active site Fe2+ ion, while the benzonitrile group accepts a hydrogen-bonding interaction from the side chain residue of Asn315. Further optimization led to potent PHD-1 inhibitors with good physicochemical and pharmacokinetic properties.