title: 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.
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 ∼10 h at -78 °C and ∼3.5 min at -50 °C. In contrast, for the piperidine, t(1/2) was determined to be ∼4 s at -78 °C.
authors.affiliation: Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK.
authors.forename: Nadeem S
authors.initials: NS
authors.lastname: Sheikh
authors.forename: Daniele
authors.initials: D
authors.lastname: Leonori
authors.forename: Graeme
authors.initials: G
authors.lastname: Barker
authors.forename: James D
authors.initials: JD
authors.lastname: Firth
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Campos
authors.forename: Anthony J H M
authors.initials: AJ
authors.lastname: Meijer
authors.forename: Peter
authors.initials: P
authors.lastname: O'Brien
authors.forename: Iain
authors.initials: I
authors.lastname: Coldham
mesh_terms: D008094:Lithium / Q000737:chemistry*; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry*; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry*; D011789:Quantum Theory; D013055:Spectrophotometry, Infrared; D013237:Stereoisomerism
chemical_list: C573443:N-tert-butoxycarbonyl-2-phenylpyrrolidine; D009942:Organometallic Compounds; D010880:Piperidines; D011759:Pyrrolidines; D008094:Lithium