Attractive noncovalent interactions in asymmetric catalysis: Links between enzymes and small molecule catalysts

Knowles, Robert R.; Jacobsen, Eric N.

doi:10.1073/pnas.1006402107

Cited by 686 publications

(460 citation statements)

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“…It has been known for decades that substrate organization is one of the major modes of assistance that enzymes provide in accelerating selective catalysis. More recently similar phenomena have been convincingly documented in reactions catalyzed by synthetic organic molecules (35). Herein we have shown that one of the at least five important roles of an even smaller molecule, water, is organization of a substrate much larger than itself.…”

Section: Discussionmentioning

confidence: 48%

Entropic factors provide unusual reactivity and selectivity in epoxide-opening reactions promoted by water

Byers

Jamison

2013

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

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Despite the myriad of selective enzymatic reactions that occur in water, chemists have rarely capitalized on the unique properties of this medium to govern selectivity in reactions. Here we report detailed mechanistic investigations of a water-promoted reaction that displays high selectivity for what is generally a disfavored product. A combination of structural and kinetic data indicates not only that synergy between substrate and water suppresses undesired pathways but also that water promotes the desired pathway by stabilizing charge in the transition state, facilitating proton transfer, doubly activating the substrate for reaction, and perhaps most remarkably, reorganizing the substrate into a reactive conformation that leads to the observed product. This approach serves as an outline for a general strategy of exploiting solvent-solute interactions to achieve unusual reactivity in chemical reactions. These findings may also have implications in the biosynthesis of the ladder polyether natural products, such as the brevetoxins and ciguatoxins.entropic control | biomimetic G iven its simple structure and low molecular weight, water is a remarkably complex substance. Several landmark investigations (1) have revealed the ability of water to self-assemble to form sophisticated dynamic hydrogen bond networks, which accounts for its unusual properties, such as its high boiling point and high surface tension (2). Despite the unique properties that it offers and that nature has exploited, water is generally eschewed in synthetic chemistry largely because of chemical incompatibility with many commonly used reagents and the low aqueous solubility of many organic molecules coupled with the attendant assumption that homogeneity is required for reactivity. Although several important examples of remarkable reactivity have been documented for reactions carried out in water (3-5), on the surface of water (6, 7), or in micelles suspended in water (8, 9), utilization of the "biological solvent" in organic reactions remains uncommon.We became acutely aware of the remarkable properties of water when we discovered that neutral aqueous solutions of epoxy alcohol 1a underwent a spontaneous and selective "endo" cyclization reaction to form 6,6-fused bicyclic product 2a (Fig. 1) (10-12). Exceptional reactivity and selectivity were observed only when two criteria were satisfied: The substrate contained a sixmembered tetrahydropyran ring, and the solvent used was water at pH 7.0. These surprising results were counter to a set of general empirical rules put forth by Baldwin for cyclization reactions, which state that the smaller ring product resulting from what is commonly called an exo cyclization is favored for similar reactions (13). The tetrahydropyranol ring, therefore, appeared to "template" the endo cyclization pathway to form the larger ring product with water playing a critical yet heretofore unknown role.Moreover, 2a is a substructure found in a large family of natural products commonly referred to as the ladder polyethers (e....

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Section: Discussionmentioning

confidence: 48%

Entropic factors provide unusual reactivity and selectivity in epoxide-opening reactions promoted by water

Byers

Jamison

2013

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

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“…To be more precise, as recently elucidated by Jacobsen, many different interactions are often cooperating within the reaction mechanism in order to lead to high enantioselectivities [37]. The known non-covalent interactions scope includes charge-charge, charge-dipole, dipole-dipole, charge-induced dipole, dipoleinduced dipole forces, steric repulsion and H-bond ( Figure 9).…”

Section: Non-covalent Organocatalysismentioning

confidence: 99%

Organocatalysts for enantioselective synthesis of fine chemicals: definitions, trends and developments

Federsel¹

2014

ScienceOpen Research

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Organocatalysis, that is the use of small organic molecules to catalyse organic transformations, has been included among the most successful concepts in asymmetric catalysis and it has been used for the enantioselective construction of C-C, C-N, C-O, C-S, C-P, and C-halide bonds. Since the seminal works in early 2000, the scientific community has been paying an ever-growing attention to the use of organocatalysts for the synthesis, with high yields and remarkable stereoselectivities, of optically active fine chemicals of interest for the pharmaceutical industry. A brief overview is here presented about the two main classes of substrate activation by the catalyst: covalent organocatalysis and non-covalent organocatalysis, with a more stringent focus on some recent outcomes in the field of the latter and of hydrogen-bond-based catalysis. Finally, some successful examples of heterogenisation of organocatalysts are also discussed, in the view of a potential industrial exploitation.

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“…Hydrogen bonding interactions play a key role in noncovalent organocatalysis, [33][34][35] thus determination of pK a values facilitate the understanding of catalytic activity and catalyst design. However, the equilibrium values have their limitations for a kinetic property such as transition state stabilization.…”

Section: Pk a Measurementsmentioning

confidence: 99%

Synthesis and determination of pKa values of new enantiopure pyridino- and piperidino-18-crown-6 ethers

Kupai

Kisszékelyi

Rojik

et al. 2016

Arkivoc

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This paper reports the preparation of eight new enantiopure amide type crown ethers and their optically active precursors. Chiral diamines were transformed to amide type pyridino-crown ethers reacting them with pyridine dicarbonyl dichlorides by high dilution technique. Two of the new pyridino-crown ethers were reduced to their piperidino analogues. A preliminary study for the potential application of nanofiltration in the purification and recovery of crown ethers is presented. According to the pK a measurements these eight new macrocycles are potential organocatalysts (for instance in Michael addition reactions) thanks to their acidic and basic moieties and chiral skeletons, respectively.

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Attractive noncovalent interactions in asymmetric catalysis: Links between enzymes and small molecule catalysts

Cited by 686 publications

References 54 publications

Entropic factors provide unusual reactivity and selectivity in epoxide-opening reactions promoted by water

Entropic factors provide unusual reactivity and selectivity in epoxide-opening reactions promoted by water

Organocatalysts for enantioselective synthesis of fine chemicals: definitions, trends and developments

Synthesis and determination of pKa values of new enantiopure pyridino- and piperidino-18-crown-6 ethers

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