RESUMO
A new and practical method for the asymmetric synthesis of γ-amino acids from ß,γ-butenolides by an in situ esterification, condensation, and reduction in a one-pot procedure is described. This method is quite general for the preparation of both enantiomers of aryl or aliphatic γ-amino acids in high yields. These γ-amino-acid derivatives were also shown to be versatile synthetic intermediates for further transformations by their conversion to γ-lactams, δ-amino alcohols, and hydrolysis products in high yields with no racemization.
Assuntos
Aminoácidos/síntese química , 4-Butirolactona/análogos & derivados , 4-Butirolactona/química , Aminoácidos/química , Estrutura Molecular , EstereoisomerismoRESUMO
A practical synthetic strategy to a chiral azabicycclooctanyl derivative (1), a potent DPP-4 inhibitor, starting from a commercially available nortropine is described. The stereogenic center of 1 was established employing a modified protocol of Ellman's diastereoselective addition of a benzylic nucleophile to tert-butanesulfinimine. Other key steps include Corey-Chaykovsky reaction, Meinwald rearrangement, and CDMT-promoted amide bond formation involving a sterically hindered amine 2.
Assuntos
Compostos Azabicíclicos/síntese química , Inibidores da Dipeptidil Peptidase IV/síntese química , Aldeídos/química , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Butanos/química , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Iminas/química , Estereoisomerismo , Compostos de Sulfônio/químicaRESUMO
A highly diastereoselective addition of substituted racemic allylic zinc reagents to chiral N- tert-butanesulfinylimines resulting in the formation of homoallylic amines is reported. This method is quite general and also efficient for the preparation of enantiomerically pure homoallylic amines bearing quaternary centers and also adjacent quaternary centers.
Assuntos
Compostos Alílicos/química , Aminas/síntese química , Compostos Organometálicos/química , Ácidos Sulfínicos/química , Zinco/química , Cristalografia por Raios X , Conformação Molecular , Estrutura Molecular , EstereoisomerismoRESUMO
We describe highly enantioselective synthesis of beta-amino acid derivatives (1a-c) using asymmetric hydrogenation of alpha-aminomethylacrylates (2a-c), which contain a free basic N H group, as the key step. The alpha-aminomethylacrylates (2a-c) were prepared using the Baylis-Hillman reaction of an appropriate aldehyde with methyl acrylate followed by acetylation of the resulting allylic alcohols (4a-b) and S(N)2'-type amination of the allylic acetates (3a-b).
Assuntos
Aminoácidos/síntese química , Metacrilatos/química , Metacrilatos/síntese química , Catálise , Hidrogenação , EstereoisomerismoRESUMO
Dipeptidyl peptidase IV (DPP-IV) inhibition has the potential to become a valuable therapy for type 2 diabetes. The synthesis and structure-activity relationship of a new DPP-IV inhibitor class, N-substituted-glycyl-2-cyanopyrrolidines, are described as well as the path that led from clinical development compound 1-[2-[5-cyanopyridin-2-yl)amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidine (NVP-DPP728, 8c) to its follow-up, 1-[[(3-hydroxy-1-adamantyl) amino]acetyl]-2-cyano-(S)-pyrrolidine (NVP-LAF237, 12j). The pharmacological profile of 12j in obese Zucker fa/fa rats along with pharmacokinetic profile comparison of 8c and 12j in normal cynomolgus monkeys is discussed. The results suggest that 12j is a potent, stable, selective DPP-IV inhibitor possessing excellent oral bioavailability and potent antihyperglycemic activity with potential for once-a-day administration.