Alkyl Groups Fold to Fit within a Water-Soluble Cavitand

Zhang, Kang‐Da; Ajami, Dariush; Gavette, Jesse V.; Rebek, Julius

doi:10.1021/ja501685z

Cited by 72 publications

(66 citation statements)

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“…2) and its capacity to sequester hydrophobic and amphiphilic species in water (2). The eight methyl groups of cavitand 1 broaden its upper rim and prevent dimerization through hydrogen bonding into a capsule.…”

Section: Resultsmentioning

confidence: 99%

“…The chemical shifts of the signals indicate rapidly exchanging J-shaped conformations of the guests rather than a fixed and symmetrical U-shaped conformation (SI Appendix). The reference guest in the octamethyl cavitand that appears nonmoving, is the unsymmetrical C 11 ω-amino acid (2). Nine of its methylene signals are shifted upfield, placing them within the walls of the cavitand, and reflect the various depths the alkyl chain experiences in the cavitand.…”

Section: Resultsmentioning

confidence: 99%

“…The cavitand 1, C 13 diester, C 12 monoester, C 13 monoester, and C 14 monoester were prepared according to the procedures reported in the literature (2,28). The experimental procedures for the hydrolysis of diesters under acid and base conditions with and without the cavitand and NMR spectra of the complexes are available in SI Appendix.…”

Section: Methodsmentioning

confidence: 99%

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Water-soluble cavitands promote hydrolyses of long-chain diesters

Shi

Mower

Blackmond

et al. 2016

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

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Water-soluble, deep cavitands serve as chaperones of long-chain diesters for their selective hydrolysis in aqueous solution. The cavitands bind the diesters in rapidly exchanging, folded J-shape conformations that bury the hydrocarbon chain and expose each ester group in turn to the aqueous medium. The acid hydrolyses in the presence of the cavitand result in enhanced yields of monoacid monoester products. Product distributions indicate a two-to fourfold relative decrease in the hydrolysis rate constant of the second ester caused by the confined space in the cavitand. The rate constant for the first acid hydrolysis step is enhanced approximately 10-fold in the presence of the cavitand, compared with control reactions of the molecules in bulk solution. Hydrolysis under basic conditions (saponification) with the cavitand gave >90% yields of the corresponding monoesters. Under basic conditions the cavitand complex of the monoanion precipitates from solution and prevents further reaction.M onofunctionalization of symmetrical compounds poses a general problem: When identical functional groups on a substrate are truly remote, they act independently, and reactions result in a statistical mixture of products. For example, hydrolysis of diesters ( Fig. 1) separated by a long methylene chain exhibits equal rate constants at each site (k 1 = k 2 ), which sets an upper limit of 36.8% for the yield of the monoester. This maximum occurs when comparable amounts of unreacted diester and doubly reacted diacid product are present ( Fig. 1), a factor that often complicates isolation of the desired monoester product.Special circumstances can favor monofunctionalization. When the monofunctionalized compound has fortuitously different properties (such as solubility) and can be removed to a different phase (1) as it is formed, good yields can result. Likewise, when the sites are not remote--as in diesters of oxalic acid--reaction at one site greatly modifies reactivity at the other site and affects the yield of the monofunctionalized product. We describe here the application of synthetic container compounds (cavitands) as molecular chaperones to address the monofunctionalization problem. Whereas the present examples involve only hydrolysis of long-chain diesters, the predictable influence of the cavitand promises wider applications in other reactions of symmetrical, difunctional substrates. Results and DiscussionWe recently reported the synthesis of deep cavitand 1 (Fig. 2) and its capacity to sequester hydrophobic and amphiphilic species in water (2). The eight methyl groups of cavitand 1 broaden its upper rim and prevent dimerization through hydrogen bonding into a capsule. The cavitand is stable over a wide pH range. Whereas a number of water-soluble, deep cavitand hosts are available (3-10), cavitand 1 bound long-chain guest alkanes and related difunctional compounds (bola-amphiphiles) in folded conformations (11). Folded alkyls inside a γ-cyclodextrin were initially characterized by Turro et al. (12), and folded bola-amphiphiles ...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Water-soluble cavitands promote hydrolyses of long-chain diesters

Shi

Mower

Blackmond

et al. 2016

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

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“…4). The magnetic anisotropy imparted by the lower eight aromatic panels of 1 shifts signals of nuclei held within its depths by up to Δδ −4.3 ppm (17,19). The complexes showed 1:1 stoichiometry, and when the guest was added in smaller portions to the aqueous solutions of 1, only signals for the bound guest were observed until saturation of the host occurred.…”

Section: Significancementioning

confidence: 99%

“…Longer alkanes such as tetradecane (C 14 ) often induce the formation of dimeric, capsule-like assemblies in which the alkyls assume compressed conformations involving folding and coiling (17, 18). Common, long-chain fatty acids bearing saturated or unsaturated alkyl chains are not readily accommodated in dimeric capsules (19,20) or in the vase forms of typical cavitands. Here, we report a deeper cavitand with a longer, narrower cavity that readily sequesters physiologically relevant fatty acids and derivatives from aqueous media.…”

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Recognition and sequestration of ω-fatty acids by a cavitand receptor

Mosca

Ajami

Rebek

2015

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

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One of the largest driving forces for molecular association in aqueous solution is the hydrophobic effect, and many synthetic receptors with hydrophobic interiors have been devised for molecular recognition studies in water. Attempts to create the longer, narrower cavities appropriate for long-chain fatty acids have been thwarted by solvophobic collapse of the synthetic receptors, giving structures that have no internal spaces. The collapse generally involves the stacking of aromatic panels onto themselves. We describe here the synthesis and application of a deep cavitand receptor featuring "prestacked" aromatic panels at the upper rim of the binding pocket. The cavitand remains open and readily sequesters biologically relevant long-chain molecules-unsaturated ω-3, -6, and -9 fatty acids and derivatives such as anandamide-from aqueous media. The cavitand exists in isomeric forms with different stacking geometries and n-alkanes were used to characterize the binding modes and conformational properties. Long alkyl chains are accommodated in inverted J-shaped conformations. An analogous cavitand with electron-rich aromatic walls was prepared and comparative binding experiments indicated the role of intramolecular stacking in the binding properties of these deep container molecules. (1) and other open-ended host structures (2, 3) that more or less fold around their guest targets. As initially encountered by Cram et al. (4), deep cavitands are dynamic and interconvert between two conformations in organic media: a receptive "vase" form and the unreceptive "kite" form as its dimeric "velcrand" (Fig. 1) (4-8). Stacking of aromatic surfaces in the velcrand buries one face of each kite and is driven by a generalized solvophobic effect. The vase can be rigidified by covalent bonds (9-13) but in water the dynamic cavitands collapse into velcrands through the more specific hydrophobic effect. The presence of appropriate guests shifts the equilibrium to the vase conformation: The guest must fit into, fill, and solvate the cavitand host's hydrophobic interior. Binding of guest molecules by container compounds is often dependent on the volume of the host. Recognition of long-chain, linear hydrocarbons by biological receptors and synthetic supramolecular hosts generally involves ∼55% volume occupancy and relatively low surface complementarity (14-16). Cavitands with a depth of 1 nm are readily prepared and bind medium-chain n-alkanes, from octane (C 8 ) to decane (C 10 ). Longer alkanes such as tetradecane (C 14 ) often induce the formation of dimeric, capsule-like assemblies in which the alkyls assume compressed conformations involving folding and coiling (17, 18). Common, long-chain fatty acids bearing saturated or unsaturated alkyl chains are not readily accommodated in dimeric capsules (19,20) or in the vase forms of typical cavitands. Here, we report a deeper cavitand with a longer, narrower cavity that readily sequesters physiologically relevant fatty acids and derivatives from aqueous media. ResultsSynthesis and Characte...

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Molekulare Erkennung in chemischen und biologischen Systemen

2015

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Strukturbasiertes Ligandendesign in der medizinischen Chemie und im Pflanzenschutz beruht auf der Identifizierung und Quantifizierung von schwachen, nichtkovalenten Wechselwirkungen und dem Verständnis der Rolle von Wasser. Ein wichtiges Werkzeug zum Abrufen von vorhandenem Wissen ist die Suche in Datenbanken von kleinen Molekülen und Proteinen. Die Erstellung eines thermodynamischen Profils zusammen mit der Röntgenstrukturanalyse und theoretischen Untersuchungen ist der Schlüssel zur Aufklärung des Energieprofils der Wasserverdrängung durch den Liganden. Biologische Bindungsstellen unterscheiden sich stark in ihrer Form, konformativen Dynamik und Polarität, weshalb verschiedene Entwicklungsstrategien für Liganden benötigt werden, wie hier anhand mehrerer Fallstudien gezeigt ist. Die Wechselwirkung zwischen Dipolen ist zu einem zentralen Baustein der molekularen Erkennung geworden. Orthogonale Wechselwirkungen, Halogenbrücken und Amid⋅⋅⋅π‐Stapelung bieten neue Möglichkeiten für innovative Leitstrukturoptimierung. Die Kombination von Untersuchungen an synthetischen Modellen und biologischen Rezeptoren ist notwendig, um verlässliche Informationen über schwache, nichtkovalente Wechselwirkungen und die Rolle von Wasser zu erlangen.

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Alkyl Groups Fold to Fit within a Water-Soluble Cavitand

Cited by 72 publications

References 19 publications

Water-soluble cavitands promote hydrolyses of long-chain diesters

Water-soluble cavitands promote hydrolyses of long-chain diesters

Recognition and sequestration of ω-fatty acids by a cavitand receptor

Molekulare Erkennung in chemischen und biologischen Systemen

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