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Transition state analysis of enantioselective Brønsted base catalysis by chiral cyclopropenimines.

Bandar JS, Sauer GS, Wulff WD, Lambert TH, Vetticatt MJ - J. Am. Chem. Soc. (2014)

Bottom Line: Experimental (13)C kinetic isotope effects have been used to interrogate the rate-limiting step of the Michael addition of glycinate imines to benzyl acrylate catalyzed by a chiral 2,3-bis(dicyclohexylamino) cyclopropenimine catalyst.The reaction is found to proceed via rate-limiting carbon-carbon bond formation.The origins of enantioselectivity and a key noncovalent CH···O interaction responsible for transition state organization are identified on the basis of density functional theory calculations and probed using experimental labeling studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Columbia University , 3000 Broadway, New York, New York 10027, United States.

ABSTRACT
Experimental (13)C kinetic isotope effects have been used to interrogate the rate-limiting step of the Michael addition of glycinate imines to benzyl acrylate catalyzed by a chiral 2,3-bis(dicyclohexylamino) cyclopropenimine catalyst. The reaction is found to proceed via rate-limiting carbon-carbon bond formation. The origins of enantioselectivity and a key noncovalent CH···O interaction responsible for transition state organization are identified on the basis of density functional theory calculations and probed using experimental labeling studies. The resulting high-resolution experimental picture of the enantioselectivity-determining transition state is expected to guide new catalyst design and reaction development.

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Labeling studies as anexperimental probe of CH···Ointeraction.
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fig7: Labeling studies as anexperimental probe of CH···Ointeraction.

Mentions: While the contribution of the CH···O interactionto transition state stabilization is significant, its role in determiningenantioselectivity is expected to be minimal since bothTS5bSE and TS5aRZ benefit from the stabilizationafforded by this interaction. Nevertheless, we envisioned that slightperturbation of enantioselectivity could be used as an experimentalprobe of this interaction–since the CH···O distanceis slightly different in the key transition structures. With thisin mind, we synthesized the deuterated version of the catalyst 1a with all four Cy–CHs substituted by deuterium. Toobserve even a small KIE on the enantioselectivity, a catalyst mixtureof 50% (S)-d4-1 and 50% (R)-1 was employed for the addition of glycine imine 2 to 3a (Figure 7). A KIE would be manifestedin the reaction in the form of a nonracemic product. The product fromthis reaction was essentially racemic (<5% ee), however, indicatinga KIE of ∼1.0. The lack of an observed KIE does not underminethe importance of a transition state CH···O interaction.Indeed, because the relevant hydrogen is not participating in anybond-forming or bond-breaking events, and because both the major andminor enantiomer transition states likely benefit from this interactionto similar extents, it is not unreasonable that any KIE would be toosmall to measure.22


Transition state analysis of enantioselective Brønsted base catalysis by chiral cyclopropenimines.

Bandar JS, Sauer GS, Wulff WD, Lambert TH, Vetticatt MJ - J. Am. Chem. Soc. (2014)

Labeling studies as anexperimental probe of CH···Ointeraction.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230825&req=5

fig7: Labeling studies as anexperimental probe of CH···Ointeraction.
Mentions: While the contribution of the CH···O interactionto transition state stabilization is significant, its role in determiningenantioselectivity is expected to be minimal since bothTS5bSE and TS5aRZ benefit from the stabilizationafforded by this interaction. Nevertheless, we envisioned that slightperturbation of enantioselectivity could be used as an experimentalprobe of this interaction–since the CH···O distanceis slightly different in the key transition structures. With thisin mind, we synthesized the deuterated version of the catalyst 1a with all four Cy–CHs substituted by deuterium. Toobserve even a small KIE on the enantioselectivity, a catalyst mixtureof 50% (S)-d4-1 and 50% (R)-1 was employed for the addition of glycine imine 2 to 3a (Figure 7). A KIE would be manifestedin the reaction in the form of a nonracemic product. The product fromthis reaction was essentially racemic (<5% ee), however, indicatinga KIE of ∼1.0. The lack of an observed KIE does not underminethe importance of a transition state CH···O interaction.Indeed, because the relevant hydrogen is not participating in anybond-forming or bond-breaking events, and because both the major andminor enantiomer transition states likely benefit from this interactionto similar extents, it is not unreasonable that any KIE would be toosmall to measure.22

Bottom Line: Experimental (13)C kinetic isotope effects have been used to interrogate the rate-limiting step of the Michael addition of glycinate imines to benzyl acrylate catalyzed by a chiral 2,3-bis(dicyclohexylamino) cyclopropenimine catalyst.The reaction is found to proceed via rate-limiting carbon-carbon bond formation.The origins of enantioselectivity and a key noncovalent CH···O interaction responsible for transition state organization are identified on the basis of density functional theory calculations and probed using experimental labeling studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Columbia University , 3000 Broadway, New York, New York 10027, United States.

ABSTRACT
Experimental (13)C kinetic isotope effects have been used to interrogate the rate-limiting step of the Michael addition of glycinate imines to benzyl acrylate catalyzed by a chiral 2,3-bis(dicyclohexylamino) cyclopropenimine catalyst. The reaction is found to proceed via rate-limiting carbon-carbon bond formation. The origins of enantioselectivity and a key noncovalent CH···O interaction responsible for transition state organization are identified on the basis of density functional theory calculations and probed using experimental labeling studies. The resulting high-resolution experimental picture of the enantioselectivity-determining transition state is expected to guide new catalyst design and reaction development.

Show MeSH