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Building on Cram's legacy: stimulated gating in hemicarcerands.

Liu F, Helgeson RC, Houk KN - Acc. Chem. Res. (2014)

Bottom Line: We found that the side portals of this hemicarceplex have multiple thermally accessible conformations.Gates are built onto host molecules so that the opening or closing of such gates is stimulated by reducing or oxidizing conditions, or by ultraviolet irradiation.The experimental and computational investigations of gated hemicarcerands and several potential applications of gated hemicarceplexes are described in this Account.

View Article: PubMed Central - PubMed

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

ABSTRACT
CONSPECTUS: Donald Cram's pioneering Nobel Prize-winning work on host-guest molecules led eventually to his creation of the field of container molecules. Cram defined two types of container molecules: carcerands and hemicarcerands. Host-guest complexes of carcerands, called carceplexes, are formed during their synthesis; once a carceplex is formed, the trapped guest cannot exit without breaking covalent bonds. Cram defined a quantity called constrictive binding, arising from the mechanical force that prevents guest escape. The constrictive binding in carceplexes is high. In contrast, hemicarcerands have low constrictive binding and are able to release the incarcerated guests at elevated temperatures without breaking covalent bonds. We have designed molecules that can switch from carcerand to hemicarcerand through a change in structure that we call gating. The original discovery of gating in container molecules involved our computational studies of a Cram hemicarceplex that was observed to release a guest upon heating. We found that the side portals of this hemicarceplex have multiple thermally accessible conformations. An eight-membered ring that is part of a portal changes from a "chair" to a "boat" structure, leading to the enlargement of the side portal and the release of the guest. This type of gating is analogous to phenomena often observed with peptide loops in enzymes. We refer to this phenomenon as thermally controlled gating. We have also designed and synthesized redox and photochemically controlled gated hemicarceplexes. Gates are built onto host molecules so that the opening or closing of such gates is stimulated by reducing or oxidizing conditions, or by ultraviolet irradiation. In both cases, the appropriate stimuli can produce a carceplex (closed gates) or hemicarceplex (open gates). A hemicarceplex with closed gates behaves like a carceplex, due to its very high constrictive binding energy. When the gates are opened, constrictive binding is dramatically lowered, and guest entrance and exit become facile. This stimulated switching between open and closed states controls access of the guest to the binding site. The experimental and computational investigations of gated hemicarcerands and several potential applications of gated hemicarceplexes are described in this Account.

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Synthesis of hemicarcerands 5a (5b wasstudied computationally). Blue box: reversible gate-closing and gate-opening.The disulfide-dithiol gates are colored in green. Yellow box: guestmolecules tested in complexation experiments. The first three guests(colored in blue) formed stable complexes with 5a.
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fig10: Synthesis of hemicarcerands 5a (5b wasstudied computationally). Blue box: reversible gate-closing and gate-opening.The disulfide-dithiol gates are colored in green. Yellow box: guestmolecules tested in complexation experiments. The first three guests(colored in blue) formed stable complexes with 5a.

Mentions: Disulfide-dithiolinterchange is ubiquitous in biological proteins,and the equilibrium is known to be determined by the environmentalthiol concentration. Sherman and co-workers reported a carcerand withfour disulfide bridges, which performs guest exchange under redoxconditions.25 Building on this observation,we designed a gated hemicarcerand bearing a disulfide-dithiol redox-controllable“gate”.26 Most of Cram’shemicarcerands possess four identical bridging groups, which is syntheticallyeasier to achieve than dual- or triply-bridged hosts. These triply-bridgedhemicarcerands can be obtained using similar macrocyclization reactionsin relatively low yield, followed by modification of the remainingsubstituents to form the gate. The redox-gated hemicarcerand 5a was synthesized with a unique fourth bridging group thatundergoes disulfide-dithiol interchange in the presence of base andthiol compounds (Figure 10).


Building on Cram's legacy: stimulated gating in hemicarcerands.

Liu F, Helgeson RC, Houk KN - Acc. Chem. Res. (2014)

Synthesis of hemicarcerands 5a (5b wasstudied computationally). Blue box: reversible gate-closing and gate-opening.The disulfide-dithiol gates are colored in green. Yellow box: guestmolecules tested in complexation experiments. The first three guests(colored in blue) formed stable complexes with 5a.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4215849&req=5

fig10: Synthesis of hemicarcerands 5a (5b wasstudied computationally). Blue box: reversible gate-closing and gate-opening.The disulfide-dithiol gates are colored in green. Yellow box: guestmolecules tested in complexation experiments. The first three guests(colored in blue) formed stable complexes with 5a.
Mentions: Disulfide-dithiolinterchange is ubiquitous in biological proteins,and the equilibrium is known to be determined by the environmentalthiol concentration. Sherman and co-workers reported a carcerand withfour disulfide bridges, which performs guest exchange under redoxconditions.25 Building on this observation,we designed a gated hemicarcerand bearing a disulfide-dithiol redox-controllable“gate”.26 Most of Cram’shemicarcerands possess four identical bridging groups, which is syntheticallyeasier to achieve than dual- or triply-bridged hosts. These triply-bridgedhemicarcerands can be obtained using similar macrocyclization reactionsin relatively low yield, followed by modification of the remainingsubstituents to form the gate. The redox-gated hemicarcerand 5a was synthesized with a unique fourth bridging group thatundergoes disulfide-dithiol interchange in the presence of base andthiol compounds (Figure 10).

Bottom Line: We found that the side portals of this hemicarceplex have multiple thermally accessible conformations.Gates are built onto host molecules so that the opening or closing of such gates is stimulated by reducing or oxidizing conditions, or by ultraviolet irradiation.The experimental and computational investigations of gated hemicarcerands and several potential applications of gated hemicarceplexes are described in this Account.

View Article: PubMed Central - PubMed

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

ABSTRACT
CONSPECTUS: Donald Cram's pioneering Nobel Prize-winning work on host-guest molecules led eventually to his creation of the field of container molecules. Cram defined two types of container molecules: carcerands and hemicarcerands. Host-guest complexes of carcerands, called carceplexes, are formed during their synthesis; once a carceplex is formed, the trapped guest cannot exit without breaking covalent bonds. Cram defined a quantity called constrictive binding, arising from the mechanical force that prevents guest escape. The constrictive binding in carceplexes is high. In contrast, hemicarcerands have low constrictive binding and are able to release the incarcerated guests at elevated temperatures without breaking covalent bonds. We have designed molecules that can switch from carcerand to hemicarcerand through a change in structure that we call gating. The original discovery of gating in container molecules involved our computational studies of a Cram hemicarceplex that was observed to release a guest upon heating. We found that the side portals of this hemicarceplex have multiple thermally accessible conformations. An eight-membered ring that is part of a portal changes from a "chair" to a "boat" structure, leading to the enlargement of the side portal and the release of the guest. This type of gating is analogous to phenomena often observed with peptide loops in enzymes. We refer to this phenomenon as thermally controlled gating. We have also designed and synthesized redox and photochemically controlled gated hemicarceplexes. Gates are built onto host molecules so that the opening or closing of such gates is stimulated by reducing or oxidizing conditions, or by ultraviolet irradiation. In both cases, the appropriate stimuli can produce a carceplex (closed gates) or hemicarceplex (open gates). A hemicarceplex with closed gates behaves like a carceplex, due to its very high constrictive binding energy. When the gates are opened, constrictive binding is dramatically lowered, and guest entrance and exit become facile. This stimulated switching between open and closed states controls access of the guest to the binding site. The experimental and computational investigations of gated hemicarcerands and several potential applications of gated hemicarceplexes are described in this Account.

Show MeSH
Related in: MedlinePlus