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A twist on facial selectivity of hydride reductions of cyclic ketones: twist-boat conformers in cyclohexanone, piperidone, and tropinone reactions.

Neufeldt SR, Jiménez-Osés G, Comins DL, Houk KN - J. Org. Chem. (2014)

Bottom Line: 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).

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of California , Los Angeles, California 90095, United States.

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).

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Lowest energytransition structures for the addition of LTBH to(A) the equatorial face of chair 6ch and (B) the pro-equatorial face of twist-boat 6tb. Optimized structures were calculatedat the SMD(THF)/B3LYP/6-311+G(2d,p)//B3LYP/6-31G(d,p) level. ActivationGibbs free energies (ΔG⧧)are referenced to the lowest energy prereaction coordination complexand are given in kcal mol–1; distances are givenin angstroms and angles in degrees.
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fig12: Lowest energytransition structures for the addition of LTBH to(A) the equatorial face of chair 6ch and (B) the pro-equatorial face of twist-boat 6tb. Optimized structures were calculatedat the SMD(THF)/B3LYP/6-311+G(2d,p)//B3LYP/6-31G(d,p) level. ActivationGibbs free energies (ΔG⧧)are referenced to the lowest energy prereaction coordination complexand are given in kcal mol–1; distances are givenin angstroms and angles in degrees.

Mentions: Due to exceedingly large steric repulsions between LTBH andthesubstrate 2,6-substituents, only equatorial-face addition transitionstructures could be located for the reaction of piperidone 6 (Figure 12) and tropinone 7 (Figure 13) with this bulky hydridereagent.18 The energetic degeneracy predictedfor the pro-equatorial addition of LAH to both the chair and twist-boatconformations of 6 is not conserved with LTBH, for whichthe twist-boat transition state is disfavored by ∼3 kcal mol–1 due to a simultaneous reduction in the torsionalstrain of 6ch-TS-LTBHeq (ψ = 10°) and increase in torsionalstrain of 6tb-TS-LTBHeq (ψ = 33°). Taken together withthe results using LAH, these studies show that twist-boat conformationscan be relevant for both reactivity and selectivity of cis-2,6-disubstitutedpiperidones for reduction by small hydride reagentsbut not with LTBH or, presumably, other bulky nucleophiles.


A twist on facial selectivity of hydride reductions of cyclic ketones: twist-boat conformers in cyclohexanone, piperidone, and tropinone reactions.

Neufeldt SR, Jiménez-Osés G, Comins DL, Houk KN - J. Org. Chem. (2014)

Lowest energytransition structures for the addition of LTBH to(A) the equatorial face of chair 6ch and (B) the pro-equatorial face of twist-boat 6tb. Optimized structures were calculatedat the SMD(THF)/B3LYP/6-311+G(2d,p)//B3LYP/6-31G(d,p) level. ActivationGibbs free energies (ΔG⧧)are referenced to the lowest energy prereaction coordination complexand are given in kcal mol–1; distances are givenin angstroms and angles in degrees.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4260662&req=5

fig12: Lowest energytransition structures for the addition of LTBH to(A) the equatorial face of chair 6ch and (B) the pro-equatorial face of twist-boat 6tb. Optimized structures were calculatedat the SMD(THF)/B3LYP/6-311+G(2d,p)//B3LYP/6-31G(d,p) level. ActivationGibbs free energies (ΔG⧧)are referenced to the lowest energy prereaction coordination complexand are given in kcal mol–1; distances are givenin angstroms and angles in degrees.
Mentions: Due to exceedingly large steric repulsions between LTBH andthesubstrate 2,6-substituents, only equatorial-face addition transitionstructures could be located for the reaction of piperidone 6 (Figure 12) and tropinone 7 (Figure 13) with this bulky hydridereagent.18 The energetic degeneracy predictedfor the pro-equatorial addition of LAH to both the chair and twist-boatconformations of 6 is not conserved with LTBH, for whichthe twist-boat transition state is disfavored by ∼3 kcal mol–1 due to a simultaneous reduction in the torsionalstrain of 6ch-TS-LTBHeq (ψ = 10°) and increase in torsionalstrain of 6tb-TS-LTBHeq (ψ = 33°). Taken together withthe results using LAH, these studies show that twist-boat conformationscan be relevant for both reactivity and selectivity of cis-2,6-disubstitutedpiperidones for reduction by small hydride reagentsbut not with LTBH or, presumably, other bulky nucleophiles.

Bottom Line: 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).

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of California , Los Angeles, California 90095, United States.

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).

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