Asymmetric substitutions of 2-lithiated N-boc-piperidine and N-Boc-azepine by dynamic resolution.
Proton abstraction of N-tert-butoxycarbonyl-piperidine (N-Boc-piperidine) with sBuLi and TMEDA provides a racemic organolithium that can be resolved using a chiral ligand. The enantiomeric organolithiums can interconvert so that a dynamic resolution occurs. Two mechanisms for promoting enantioselectivity in the products are possible. Slow addition of an electrophile such as trimethylsilyl chloride allows dynamic resolution under kinetic control (DKR). This process occurs with high enantioselectivity and is successful by catalysis with substoichiometric chiral ligand (catalytic dynamic kinetic resolution). Alternatively, the two enantiomers of this organolithium can be resolved under thermodynamic control with good enantioselectivity (dynamic thermodynamic resolution, DTR). The best ligands found are based on chiral diamino-alkoxides. Using DTR, a variety of electrophiles can be used to provide an asymmetric synthesis of enantiomerically enriched 2-substituted piperidines, including (after Boc deprotection) the alkaloid (+)-beta-conhydrine. The chemistry was extended, albeit with lower yields, to the corresponding 2-substituted seven-membered azepine ring derivatives.
Coldham
Iain
I
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK. i.coldham@sheffield.ac.uk
Raimbault
Sophie
S
Whittaker
David T E
DT
Chovatia
Praful T
PT
Leonori
Daniele
D
Patel
Jignesh J
JJ
Sheikh
Nadeem S
NS
D001381:Azepines / Q000737:chemistry*; D003500:Cyclization; D007700:Kinetics; D008024:Ligands; D018020:Lithium Compounds / Q000737:chemistry*; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry*; D013237:Stereoisomerism; D013816:Thermodynamics
D001381:Azepines; D008024:Ligands; D018020:Lithium Compounds; C454939:N-(tert-butoxycarbonyl)piperidine; D010880:Piperidines