Cage-Catalyzed Knoevenagel Condensation under Neutral Conditions in Water

Murase, Takashi; Nishijima, Yuki; Fujita, Makoto

doi:10.1021/ja210068f

Cited by 263 publications

(137 citation statements)

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“…conversion of a neutral, hydrophobic substrate that binds strongly in a water-soluble cavitand to an anionic, hydrophilic product which is accordingly released, facilitating turnover and catalysis. 19 Examples of catalysis in cage cavities now vary from the Knoevenagel reaction 20 to the enantioselective hydrolysis of an organophosphate dichloride, 21 with the best example reported so far being an acid-catalysed Nazarov cyclisation of pentamethylcyclopentadienol in the cavity of an anionic cage, which displays a rate enhancement of 2.1 million compared to the uncatalysed reaction with hundreds of turnovers. 22 We report here a new example of catalysis in a coordination cage cavity, which occurs with very high rate enhancements and multiple turnovers making this system comparable to the best that are currently known in supramolecular catalysis.…”

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confidence: 99%

Highly efficient catalysis of the Kemp elimination in the cavity of a cubic coordination cage

et al. 2016

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The hollow cavities of coordination cages can provide an environment for enzyme-like catalytic reactions of small-molecule guests . We report here a new example (catalysis of the Kemp elimination -reaction of benzisoxazole with hydroxide to form 2-cyanophenolate) in the cavity of a water-soluble M8L12 coordination cage, with two features of particular interest. Firstly, the rate enhancement is amongst the largest so far observed: at pD 8.3, kcat/kuncat is 2 x 10 5 , due to the accumulation of a high concentration of partially desolvated hydroxide ions around the bound guest arising from ion-pairing with the 16+ cage. Secondly, the catalysis is based on two orthogonal interactions: (i) hydrophobic binding of benzisoxazole in the cavity, and (ii) polar binding of hydroxide ions to sites on the cage surface, both of which were established by competition experiments. Hundreds of turnovers occur with no loss of activity due to expulsion of the hydrophilic, anionic product. 2Since the realisation that hollow molecular container molecules can accommodate guest molecules in their central cavities, 1-3 their ability to modify the reactivity of their bound guests has been of great interest. [4][5][6][7][8] Well known examples include Cram's stabilisation of highly-reactive cyclobutadiene; 4 Fujita's 'ship-in-a-bottle' synthesis of cyclic silanol oligomers; 5 Nitschke's stabilisation of P4 in a tetrahedral cage; 6 and the demonstration of unusual regioselectivity in a Diels-Alder reaction when the two reacting molecules are co-confined in a host cavity. 7 The ultimate expression of this behaviour is efficient catalysis of a reaction occurring in the cavity of a container molecule. 8 These synthetic systems have the potential to achieve the selectivity and catalytic rate enhancements displayed by biological systems. For example, artificial container molecules provide relatively rigid and hydrophobic central cavities that may mimic binding pockets in enzymes. These containers may be purely organic hydrogen-bonded assemblies (such as Rebek's 'softball' dimer) 9 or may be metal-ligand polyhedral coordination cages [such as Fujita's Pd6/tris(pyridyl)triazine cage]. 10 Coordination cages offer particular promise in this field because of the ease with which they can be formed by a self-assembly process from very simple component parts, using the predictable coordination geometries of metal ions to provide the three-dimensional ordering of the components which generates the necessary cavity. [1][2][3]8,11,12 In order for a container molecule to act as an efficient catalyst it needs to (i) recognise and bind the guest(s); (ii) accelerate the reaction by increasing the local concentration of reactants and/or stabilising the transition state; and (iii) expel the product to allow catalytic turnover. 8 Guest binding in cage cavities has been very well studied and is becoming a mature field, 1 to the extent that a modeling tool for quantitative prediction of guest binding has recently been reported by us. 13 For a reaction of t...

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Highly efficient catalysis of the Kemp elimination in the cavity of a cubic coordination cage

et al. 2016

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“…In a growing effort to emulate the efficacy of biological receptors and enzymes, studies of the preparative, guest-binding, and catalytic properties of synthetic assemblies have been pursued (14)(15)(16)(17)(18)(19)(20)(21). Whereas guest encapsulation has been reported in a variety of media, association processes of organic guests are generally more thermodynamically favorable in water (22,23).…”

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Protein-like proton exchange in a synthetic host cavity

Hart‐Cooper

Sgarlata

Perrin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The mechanism of proton exchange in a metal-ligand enzyme active site mimic (compound 1) is described through amide hydrogendeuterium exchange kinetics. The type and ratio of cationic guest to host in solution affect the rate of isotope exchange, suggesting that the rate of exchange is driven by a host whose cavity is occupied by water. Rate constants for acid-, base-, and watermediated proton exchange vary by orders of magnitude depending on the guest, and differ by up to 200 million-fold relative to an alanine polypeptide. These results suggest that the unusual microenvironment of the cavity of 1 can dramatically alter the reactivity of associated water by magnitudes comparable to that of enzymes.W ater-mediated proton transfer in molecular cavities plays an essential role in the function of nature's remarkable metabolic machinery (1, 2). Of the broad diversity of enzymecatalyzed reactions, those involving transfer of hydrogen are ubiquitous and of high fundamental importance (3). For instance, ATP synthase employs an internal chain of water molecules to mediate proton transfer across an electrochemical gradient (4, 5). This process drives ATP synthesis, which allows organisms to broadly meet their basic energy needs. Recent studies of tunneling in enzymatic hydron transfer reactions have other far-reaching and broad implications, namely the importance of the dynamic enzyme motions in driving catalysis (6, 7).Of the methods used to study hydron transfer, kinetic studies of the mechanisms of amide hydrogen-deuterium exchange (HDX) have helped to elucidate the dynamic interactions between water and protein surfaces that are central to the unique capabilities of enzymes (8-13). Noncovalent interactions, such as electrostatic effects and hydrogen bonding, have also been shown to exert a significant influence on amide HDX rates. These properties are manifest in amide HDX rate constants that can vary by a factor of a billion for residues on the same protein (8). How these variations arise, and how such a property could be harnessed to drive enzyme-like reactivity, remain challenging questions.In a growing effort to emulate the efficacy of biological receptors and enzymes, studies of the preparative, guest-binding, and catalytic properties of synthetic assemblies have been pursued (14-21). Whereas guest encapsulation has been reported in a variety of media, association processes of organic guests are generally more thermodynamically favorable in water (22, 23). Central to these studies is the notion that the displacement of a high-energy water cluster from a receptor drives guest association, and in some cases, subsequent catalysis. However, despite the abundance of structural data documenting diverse water clusters encapsulated in various host cavities, mechanistic descriptions of the dynamic processes between water and host are rare (24-32).As part of the broader field of synthetic hosts previously mentioned, our group has developed a class of biologically inspired, anionic K 12 Ga 4 L 6 assemblies that exhibit cat...

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“…Yet the data from literature [28] and of the current work indicate that polar solvents alone can promote this reaction if the active hydrogen compound contains strong electron withdrawing group(s). For example, spontaneous condensation of 1 and Meldrum's acid (with a highly dissociative proton of methylene bridge) was observed in pure aqueous solution at room temperature [28].…”

Section: Spontaneous Condensation In Ethanol-watermentioning

confidence: 65%

Lipase-catalyzed Knoevenagel condensation in water–ethanol solvent system. Does the enzyme possess the substrate promiscuity?

et al. 2015

Biochemical Engineering Journal

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Cage-Catalyzed Knoevenagel Condensation under Neutral Conditions in Water

Cited by 263 publications

References 40 publications

Highly efficient catalysis of the Kemp elimination in the cavity of a cubic coordination cage

Highly efficient catalysis of the Kemp elimination in the cavity of a cubic coordination cage

Protein-like proton exchange in a synthetic host cavity

Lipase-catalyzed Knoevenagel condensation in water–ethanol solvent system. Does the enzyme possess the substrate promiscuity?

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