Kinetics and mechanism of the (-)-sparteine-mediated deprotonation of (E)-N-Boc-N-(p-methoxyphenyl)-3-cyclohexylallylamine.

The (-)-sparteine-mediated asymmetric lithiation-substitution of (E)-N-Boc-N-(p-methoxyphenyl)-3-cyclohexylallylamine ((E)-5) to afford gamma-substituted enantiomerically enriched products 6 is reported. The solution structure for the lithiated intermediate 8.1 in these reactions was determined by heteronuclear NMR to be a configurationally stable, alpha-lithio, eta(1)-coordinated monomer. This intermediate is proposed to exist as two rotamers that are rapidly equilibrating on the NMR time scale; competitive electrophilic substitution of each conformation results in the formation of Z or E products. Kinetic measurements of the lithiation by in situ infrared spectroscopy provide pseudo-first-order rate constants for reactions with a variety of concentrations of amine, (-)-sparteine, and n-BuLi. The reaction is first order in amine and zero order in 1:1 base--ligand complex. When the concentration of n-BuLi is varied independently of (-)-sparteine concentration, the reaction rate exhibits an inverse dependence on n-BuLi concentration. The deuterium isotope effect for the reaction was determined to be 86 at -75 degrees C, a result consistent with C--H bond breaking in the rate-determining step and indicative of tunneling. A reaction pathway involving a prelithiation complex is supported by kinetic simulations.

Dynamic thermodynamic resolution: control of enantioselectivity through diastereomeric equilibration.

A theoretical foundation, tools for recognition and control, and recent examples of a class of asymmetric transformation termed dynamic thermodynamic resolution are presented. Enantioselective reaction pathways that involve an induced diastereomeric equilibration to intermediates, which are configurationally stable on the time scale of a subsequent reaction, are illustrated. Dynamic thermodynamic resolution differs from the classic, well-documented pathways of kinetic resolution and dynamic kinetic resolution in that equilibration and resolution can be operative on one system in separate controllable steps. This approach offers a high level of flexibility and provides multiple opportunities for optimization of enantioselectivity.