A Twist on Facial Selectivity of Hydride Reductions of Cyclic Ketones: Twist-Boat Conformers in Cyclohexanone, Piperidone, and Tropinone Reactions

Abstract

The role of twist-boat conformers of cyclohexanones in hydride reductions was explored. The hydride reductions of a cis-2,6-disubstituted N-acylpiperidone, an N-acyltropinone, and tert-butylcyclohexanone by lithium aluminum hydride and by a bulky borohydride reagent were investigated computationally and compared to experiment. Our results indicate that in certain cases, factors such as substrate conformation, nucleophile bulkiness, and remote steric features can affect stereoselectivity in ways that are difficult to predict by the general Felkin–Anh model. In particular, we have calculated that a twist-boat conformation is relevant to the reactivity and facial selectivity of hydride reduction of cis-2,6-disubstituted N-acylpiperidones with a small hydride reagent (LiAlH4) but not with a bulky hydride (lithium triisopropylborohydride).

A Benchmark of Density Functional Approximations For Thermochemistry and Kinetics of Hydride Reductions of Cyclohexanones

“…For solvent based calculations, a more realistic model would consist of the lithium counterion being coordinated with solvent molecules. However, previous computational work has indicated that non‐solvated models are sufficient to accurately reproduce experimentally obtained selectivity of hydride reductions …”

“…In the presence of EWG, the trans isomer is also predicted as the most stable product, while experimental data indicate that the cis isomer is obtained as the major compound. However, the stereoselectivity of hydride reductions of cyclohexanones is kinetically controlled and the ratio of reaction products is usually obtained from the Gibbs free energy of the different transition states –. For the methoxy substituent, the B3LYP−D3 functional (MUE=0.15 kcal mol −1 ) reproduces the best the isomer's relative energies, outperforming the Minnesota functionals.…”

“…A powerful tool to elucidate the importance of the different factors controlling the high stereoselectivity of hydride reductions of cyclic ketones relies on quantum chemistry. Indeed, the reaction mechanism of the hydride reductions in cyclohexanones has been extensively investigated through computational methods, principally by the group of Houk . Overall, the quantum chemical studies support the Felkin‐Anh torsional strain model, although additional factors including steric effects, substrate conformation and nucleophile bulkiness also affect the stereoselectivity of such reactions –.…”

“…So far, most of the computational studies dealing with hydride reductions of cyclic ketones were performed using density functional theory (DFT) methods, in particular with the popular B3LYP hybrid functional –. Only recently, the reduction of several cyclic ketones was also investigated with the M06‐2X hybrid functional, but better agreement with experimental results was observed for B3LYP . Nevertheless, recent benchmark results on wavefunction and DFT methods have shown that the B3LYP functional often performs worse as compared to other hybrid functionals for general main group thermochemistry and kinetics, discouraging its usage as standard method .…”

Continuous Flow Synthesis of Urea‐Containing Compound Libraries Based on the Piperidin‐4‐one Scaffold

“…The workup of this reaction was performed offline after the reaction mixture was completely collected in the corresponding vial. The reduction of ketone 2b was performed in batch using N ‐Selectride to give alcohol 12…”