RESUMO
The development of a practical and scalable process for the asymmetric synthesis of sitagliptin is reported. Density functional theory calculations reveal that two noncovalent interactions are responsible for the high diastereoselection. The first is an intramolecular hydrogen bond between the enamide NH and the boryl mesylate SâO, consistent with MsOH being crucial for high selectivity. The second is a novel C-H···F interaction between the aryl C5-fluoride and the methyl of the mesylate ligand.
Assuntos
Amidas/química , Fluoretos/química , Mesilatos/química , Pirazinas/química , Pirazinas/síntese química , Triazóis/química , Triazóis/síntese química , Ligação de Hidrogênio , Ligantes , Modelos Moleculares , Estrutura Molecular , Fosfato de Sitagliptina , EstereoisomerismoRESUMO
[reaction: see text] The rearrangement of the carbamoyl group in allenyl carbamate 1 in the presence of n-BuLi in situ generates the allenolate 3, which is subsequently intercepted with aromatic aldehydes furnishing (Z)- or (E)-configured Baylis-Hillman-type adducts 4 or 5. The double bond isomers can be interconverted by a retro aldol-type reaction.
