Mechanistic and structural studies show the high
enantioenrichments in the products from lithiation−substitutions of
N-Boc-N-(p-methoxyphenyl)benzylamine
(1) by n-BuLi/(−)-sparteine (6)
arise from an enantioselective
deprotonation of 1 to provide configurationally stable
(R)-2/6. NMR spectroscopy
establishes that 13C, 6Li
labeled
(R)-2/6 and
(S)-2/6 are monomeric with lithium
complexed to the benzylic position, the carbonyl of the Boc
group
and (−)-sparteine. Deprotonations of the tertiary protons in
(R)- and
(S)-N-Boc-N-(p-methoxyphenyl)-α-methylbenzylamine ((R)-8 and
(S)-8) with n-BuLi/TMEDA provide
(R)-9/TMEDA and
(S)-9/TMEDA, respectively,
with high enantioenrichments. Absolute configurations assigned to
(R)-2 and
(R)-1-d
1 allow analysis of
the electrophile
dependent stereochemistry of the reactions of these configurationally
stable organolithium intermediates.
The reaction pathways for the highly enantioselective, (−)-sparteine-mediated, lithiation−substitution
reactions of N-Boc-N-(p-methoxyphenyl)cinnamylamine ((E)-2) have been investigated. The solution structure
of the major allyllithium intermediate has been determined by 6Li and 13C NMR to be a monomeric η3 species,
endo-syn-anti-8·1. The complexes exo-syn-anti-8·1, endo-syn-syn-8·1, and exo-syn-syn-8·1 are also shown to
be present in solution. The enantiodetermining step in the lithiation−silylation or lithiation−alkylation of (E)-2
can involve asymmetric deprotonation, dynamic kinetic resolution, or dynamic thermodynamic resolution.
The results reported herein establish that each of these pathways can be operative. This information allows
determination of the stereochemical course for each step of these reactions and permits preparation of either
epimer at the new stereogenic carbon.
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.
The relative rates of hydride addition to the carbonyl group of the conformationally fixed bridged biaryl ketone, 1, and its R derivatives bearing methyl, methylthio, methoxy, chloro, and fluoro substituents in axial-like and equatorial-like orientations have been measured for three different reactions. The derived rate constants were partitioned, on the basis of diastereoselectivity, to provide reactivities for each face antiperiplanar to the axial substituents and anticlinal to the equatorial substituents. These face reactivities gave reasonably linear correlations with the inductive substituent parameter, σ I . The strength of the inductive effects as indicated by the slopes of the Taft plots were large and positive, small and positive, and negative for the reductions involving lithium aluminum hydride, sodium borohydride, and triethylsilane, respectively. The substituent effects on face reactivity and their stereodependencies failed to follow either the theory of Cieplak or that of Anh. The major influences of substituents can be explained on the basis of throughbond interactions with the transition state and the differences between axial and equatorial effects on electrostatic (through-space) interactions with the transition state.
Abstract:The value for the equilibrium constant representing the ratio of equatorial to axial conformers for 2-methylthio-and 2-methoxycyclohexanone has been measured in five solvents using 500 MHz 'H nuclear magnetic resonance. In cyclohexane solvent, the methylthio group is found to have a large axial preference while that for the methoxy is negligible. For both compounds the equilibrium shows a strong solvent dependence.Comparison of these results with those known for the halo derivatives shows the amount of axial to increase in the order: fluoro, methoxy, chloro, bromo, and methylthio. With the aid of molecular mechanics calculations it is concluded that the order of conformational preference can be attributed to a variation in the van der Waals interaction between the substituent and the carbonyl group in the equatorial conformer.Key words: a-substituted cyclohexanones, conformation, MMX calculations, steric and dipolar effects.Resume : Utilisant la rksonance magnCtique nuclCaire du 'H a 500 MHz et opCrant dans cinq solvants, on a mesurC la valeur de la constante d'tquilibre reprksentant le rapport des conformkres Cquatorial et axial des 2-mCthylthio-et 2-mCthoxycyclohexanones. Dans le cyclohexane comme solvant, on trouve que le groupe mtthylthio a une prCfCrence axiale alors que celle du groupe mCthoxy est negligeable. Pour les deux composts, 1'Cquilibre depend fortement du solvant. Une comparaison de ces rCsultats avec ceux connus pour les dCrivCs halogCnCs montre que la quantitC de conformkre axial augrnente dans l'ordre : fluoro, mCthoxy, chloro, bromo et rntthylthio. En se basant sur des calculs de mCcanique molCculaire, on conclut que l'ordre de prCftrences conformationnelles peut Etre attribuC a une variation de l'interaction de van der Waals entre le substituant et le groupe carbonyle du conformkre Cquatorial.
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