Regulating Molecular Recognition with C‐Shaped Strips Attained by Chirality‐Assisted Synthesis

Liu, Xiaoxi; Weinert, Zackariah J.; Sharafi, Mona; Liao, Chenyi; Li, Jianing; Schneebeli, Severin T.

doi:10.1002/anie.201506793

Cited by 43 publications

(40 citation statements)

References 66 publications

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“…We were pleased to find that double nitration of 1 afforded the 2,6-dinitro-substituted isomer 3a as the major product. Note that, in contrast, dinitration of the corresponding cycloadduct between anthracene and tetraethyl ethylenetetracarboxylate tetraester leads19 to a near statistical mixture of 2,6- and 2,7-substituted isomers under almost identical reaction conditions. The selective formation of the 2,6-dinitro derivative 3a , therefore, indicates that the SEAr reactions must indeed be directed by the ester arms.…”

Section: Resultsmentioning

confidence: 99%

“…CAS was recently reported19 by us as a universal method to precisely control the shapes of large molecular strips. The method makes use of selective double-amination reactions26 to couple chiral building blocks in a specific, programmable manner.…”

Section: Resultsmentioning

confidence: 99%

“…The method makes use of selective double-amination reactions26 to couple chiral building blocks in a specific, programmable manner. Owing to their well-defined shapes, structures created with CAS often exhibit unique properties, including the ability to encapsulate pillar[5]arene macrocycles19 and stacks of perylene dyes27. Nevertheless, while initial success was achieved in creating C-shaped strips with CAS, it has proven difficult to couple the first generation CAS building blocks in side-on orientations.…”

Section: Resultsmentioning

confidence: 99%

“…The resulting amino-functionalized derivatives were then transformed into the second-generation CAS building blocks 4a′′ and 4b′′ , following an effective double-iodination/deiodination reaction sequence. Next, we embarked on the coupling of 4a′′ and 4b′′ under standard1926 double-amination conditions in the presence of palladium(II)acetate, RuPhos and Cs 2 CO 3 . These side-on double aminations were successful, and the coupled phenazine derivative 5 was isolated as a pure stereoisomer in ca.…”

Section: Resultsmentioning

confidence: 99%

“…Challenging side-on double-amination couplings19 have now become successful with building blocks synthesized by way of through-space-directed nitrations. This finding opens the door towards the creation of advanced shape-persistent molecules (for example, freeform molecular helices) with CAS16.…”

Section: Figurementioning

confidence: 99%

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Precise through-space control of an abiotic electrophilic aromatic substitution reaction

et al. 2017

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Nature has evolved selective enzymes for the efficient biosynthesis of complex products. This exceptional ability stems from adapted enzymatic pockets, which geometrically constrain reactants and stabilize specific reactive intermediates by placing electron-donating/accepting residues nearby. Here we perform an abiotic electrophilic aromatic substitution reaction, which is directed precisely through space. Ester arms—positioned above the planes of aromatic rings—enable it to distinguish between nearly identical, neighbouring reactive positions. Quantum mechanical calculations show that, in two competing reaction pathways, both [C–H···O]–hydrogen bonding and electrophile preorganization by coordination to a carbonyl group likely play a role in controlling the reaction. These through-space-directed mechanisms are inspired by dimethylallyl tryptophan synthases, which direct biological electrophilic aromatic substitutions by preorganizing dimethylallyl cations and by stabilizing reactive intermediates with [C–H···N]–hydrogen bonding. Our results demonstrate how the third dimension above and underneath aromatic rings can be exploited to precisely control electrophilic aromatic substitutions.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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Precise through-space control of an abiotic electrophilic aromatic substitution reaction

et al. 2017

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Chirality‐Assisted Synthesis of a Very Large Octameric Hydrogen‐Bonded Capsule

2016

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The strategy of chirality-assisted synthesis, which makes use of enantiomerically pure building blocks that are designed to associate in a single geometric orientation, was applied to synthesize an octameric hydrogen-bonded capsule with a cavity volume of 2300 3 . This cube-shaped capsule forms even host-guest complexes with tetraalkylammonium ions, and accommodates the large tetrahexadecylammonium cation in its cavity. The use of an enantiopure building block was shown to be highly beneficial for capsule formation, whereas its racemate also generates a large amount of illdefined aggregates in solution and crystallizes as a hydrogenbonded network.The synthesis of artificial viral capsids self-assembled from small molecules has attracted considerable interest since the first molecular containers were reported by the groups of Cram [1] and Collet [2] in the mid-1980s. [3] Since then, the size of covalent organic [4] and metal-organic [5] cages has continuously increased, with the largest yet reported reaching a diameter of about 8 nm while partially surrounding an open cavity volume of roughly 160 000 3 . [6] In contrast, the size of closed-shell molecular capsules that spontaneously self-assemble in solution through noncovalent interactions has stagnated since hexameric resorcinarene-and pyrogallolarene-derived capsules were discovered in the late 1990s. [7] Such capsules completely enclose the space defined by their cavity, but with cavity volumes only reaching about 1400 3 they are dwarfed by even the smallest known viruses. As such, the encapsulation of large molecules (e.g., proteins and DNA fragments) by noncovalent capsules remains a long-term objective. [8] One major difficulty in the synthesis of large noncovalently bound capsules arises from the relatively poor directionality of noncovalent interactions which can result in the formation of networks instead of discrete nanosized objects. [9] In this regard, a simple way to reduce the likelihood of network formation is to design small molecules that form dimeric capsules through multiple interactions, and it is therefore not surprising that dimeric capsules [3f, 10] far outnumber tetrameric, [11] pentameric, [12] hexameric, [7a,b, 13] and higher-order capsules.[14] However, a major drawback of this approach is that the size of the molecular units required for the construction of a dimeric capsule increases at the same rate as the targeted capsule itself. From a synthetic point of view, it is far more desirable to use several small components instead of two large ones. The strategy of chirality-assisted synthesis may help solve this problem as the use of enantiopure, inherently chiral building blocks should work against the formation of polymeric materials.[15] Herein we show that this strategy can be exploited to rationally design a small molecule that predictably self-assembles into a hydrogen-bonded capsule with a very large cavity volume.Tris(isatin) 1 (Figure 1 A) was designed by combining a tribenzotriquinacene core [16] with confor...

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Crystal‐Packing‐Driven Enrichment of Atropoisomers

et al. 2017

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Crystal-packing forces can have asignificant impact on the relative stabilities of different molecules and their conformations.T he magnitude of such effects is,h owever,not yet well understood. Herein we show, that crystal packing can completely overrule the relative stabilities of different stereoisomers in solution. Heating of atropoisomers (i.e." frozenout" conformational isomers) in solution leads to complex mixtures.I nc ontrast, solid-state heating selectively amplifies minor (< 25 mole %) components of these solution-phase mixtures.W es how that this heating strategy is successful for compounds with up to four rotationally hindered s bonds,for which as ingle stereoisomer out of seven can be amplified selectively.Our results demonstrate that common supramolecular interactions-for example,[ methyl···p]c oordination and [C À H···O] hydrogen bonding-can readily invert the relative thermodynamic stabilities of different molecular conformations.These findings open up potential new avenues to control the folding of macromolecules.Solid-state reactions offer [1] ap owerful alternative to solution-phase transformations with often unique [1d, 2] selectivity patterns.T hese distinct selectivities arise for different reasons,depending on whether asolid-state reaction is under kinetic or thermodynamic control. Under kinetic control, the product distributions are governed [1a-h] primarily by the relative orientations of the reactive functional groups in the solid starting materials and transition states.Awell-known example in this regard are [2+ +2]-photocycloadditions, [3] which often proceed [4] with very high regio-and stereochemical control in the solid state.O nt he other hand, for solid-state reactions under thermodynamic control, af undamentally different, less studied mode of reaction control starts to rule. It operates [5] by selectively producing the most stable solidstate supramolecular structure as the major product.To our knowledge,the magnitude of such effects has been limited [5,6] to the solid-state amplification of specific compounds already present in at least 50 mole %atequilibrium in solution. Furthermore,previous studies investigating selective solid-state reactions under thermodynamic control have been focused (Scheme 1) on atropoisomers with only one [5a,b] (Scheme 1a)o rt wo [5c] (Scheme 1b)r otationally hindered s bonds (highlighted in red in Scheme 1). In one of the first such studies (Scheme 1a), Pincock and Wilson resolved [5a] racemic,p olycrystalline biphenyl into one of its atropoenantiomers via solid-state heating. This finding has stimulated the field of spontaneous absolute asymmetric synthesis [7] significantly.More recently,this discovery has also been extended [5c] to the solid-state diastereoselection of pairs of atropodiastereoisomers (Scheme 1b). These pioneering prior reports thus demonstrated that crystal packing forces can indeed shift solution phase equilibria to more strongly favor an already preferred (! 50 mole %) solution-phase stereoisomer in the solid state.

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Regulating Molecular Recognition with C‐Shaped Strips Attained by Chirality‐Assisted Synthesis

Cited by 43 publications

References 66 publications

Precise through-space control of an abiotic electrophilic aromatic substitution reaction

Precise through-space control of an abiotic electrophilic aromatic substitution reaction

Chirality‐Assisted Synthesis of a Very Large Octameric Hydrogen‐Bonded Capsule

Crystal‐Packing‐Driven Enrichment of Atropoisomers

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