| The lithiation-substitution reactions of N-(1 'phenylethyl)-3-(ortho-methoxyphenyl)propionamide, N-Boc-N-(p-methoxyphenyl)cinnamylamine, and N-Boc-N-(p-methoxyphenyl)-3-cyclohexylallylamine all proceed via chiral homoenolate synthetic equivalents. These three reactions have been studied from mechanistic, structural, and kinetic perspectives, respectively. Lithiation-substitution sequences of N-(1 'phenylethyl)-3-phenylpropionamide provide beta-substituted products in yields between 40% and 72% with diastereomeric ratios between 88:12 and 98:2. Dynamic kinetic resolution of diastereomeric organolithium intermediates is believed to be the diastereodetermining step in these reactions.;In a structural study, the (-)-sparteine coordinated, diastereomerically and enantiomerically pure, lithiated intermediate of N-Boc-N-(p-methoxyphenyl)cinnamylamine was characterized in the solid state by X-ray crystallography. This key intermediate exists as a monomeric, eta3 delocalized complex, and arises from selective removal of the pro-R proton of the cinnamylamine. Assignment of absolute configuration to this complex permits definitive assignment of stereochemical course for subsequent reactions. Reactions with cyclohexanone, methyl chloroformate, and 5,6-dihydro-2H-pyran-2-one all proceed with retention of configuration, while those with benzyl bromide, trimethylsilyl triflate, trimethyltin chloride, diethyl benzalmalonate, and carbon dioxide all proceed with inversion of configuration.;The lithiation of N-Boc-N-( p-methoxyphenyl)-3-cyclohexylallylamine by n-BuLi/(-)-sparteine was examined kinetically by means of in situ infrared spectroscopy. The reaction is first order in allylic amine and zero-order in 1:1 base/ligand complex. When the relative concentrations of n-BuLi and (-)-sparteine are not held constant, the reaction exhibits an inverse dependence on n-BuLi concentration. The experimental results are rationalized by a generalized mechanism that is consistent with thermodynamic parameters, an extremely high isotope effect, and computer simulations. |
