An experimental and in situ IR spectroscopic study of the lithiation-substitution of N-Boc-2-phenylpyrrolidine and -piperidine: controlling the formation of quaternary stereocenters.
J Am Chem Soc
; 134(11): 5300-8, 2012 Mar 21.
Article
en En
| MEDLINE
| ID: mdl-22339321
ABSTRACT
A general and enantioselective synthesis of 2-substituted 2-phenylpyrrolidines and -piperidines, an important class of pharmaceutically relevant compounds that contain a quaternary stereocenter, has been developed. The approach involves lithiation-substitution of enantioenriched N-Boc-2-phenylpyrrolidine or -piperidine (prepared by asymmetric Negishi arylation or catalytic asymmetric reduction, respectively). The combined use of synthetic experiments and in situ IR spectroscopic monitoring allowed optimum lithiation conditions to be identified n-BuLi in THF at -50 °C for 5-30 min. Monitoring of the lithiation using in situ IR spectroscopy indicated that the rotation of the tert-butoxycarbonyl (Boc) group is slower in a 2-lithiated pyrrolidine than a 2-lithiated piperidine; low yields for the lithiation-substitution of N-Boc-2-phenylpyrrolidine at -78 °C can be ascribed to this slow rotation. For N-Boc-2-phenylpyrrolidine and -piperidine, the barriers to rotation of the Boc group were determined using density functional theory calculations and variable-temperature (1)H NMR spectroscopy. For the pyrrolidine, the half-life (t(1/2)) for rotation of the Boc group was found to be â¼10 h at -78 °C and â¼3.5 min at -50 °C. In contrast, for the piperidine, t(1/2) was determined to be â¼4 s at -78 °C.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Compuestos Organometálicos
/
Piperidinas
/
Pirrolidinas
/
Litio
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
J Am Chem Soc
Año:
2012
Tipo del documento:
Article
País de afiliación:
Reino Unido