Precisely Designed Difunctionalized Cyclodextrin Produces a Solid-State Organic Porous Hierarchical Supramolecular Assembly.

Regioselective di-functionalization of a cyclodextrin allows hydrophobic domains to be directed in a geometrically controlled manner. This controlled orientation ultimately gives access to an original hierarchical assembly in the solid state. This assembly spans over three levels of hierarchy which are governed by synergistic host-guest inclusions, directed hydrophobic effect and hydrogen bonding. This combination of interactions precisely positioned in space through regioselective functionalization of a cyclodextrin creates a porous organic architecture.

Programmed Synthesis of Hepta-Differentiated ß-Cyclodextrin: 1 out of 117655 Arrangements.

Cyclodextrin poly-functionalization has fueled progress in their use in multiple applications such as enzyme mimicry, but also in the polymer sciences, luminescence, as sensors or for biomedical applications. However, regioselective access to a given pattern of functions on ß-cyclodextrin is still very limited. We uncover a new orienting group, the thioacetate, that expands the toolbox available for cyclodextrin poly-hetero-functionalization using diisobutylaluminum hydride (DIBAL-H) promoted debenzylation. The usefulness of this group is illustrated in the first synthesis of a precisely hepta-hetero-functionalized ß-cyclodextrin. By way of comparison, a random hepta-functionalization would give 117655 different molecules. This synthesis is not simply the vain quest for the Holy Grail of CD hetero-functionalization, but it illustrates the versatility of the DIBAL-H oriented hetero-functionalization strategy, opening the way to a multitude of useful functionalization patterns for new practical applications.

Capturing the Monomeric (L)CuH in NHC-Capped Cyclodextrin: Cavity-Controlled Chemoselective Hydrosilylation of α,ß-Unsaturated Ketones.

The encapsulation of copper inside a cyclodextrin capped with an N-heterocyclic carbene (ICyD) allowed both to catch the elusive monomeric (L)CuH and a cavity-controlled chemoselective copper-catalyzed hydrosilylation of α,ß-unsaturated ketones. Remarkably, (α-ICyD)CuCl promoted the 1,2-addition exclusively, while (ß-ICyD)CuCl produced the fully reduced product. The chemoselectivity is controlled by the size of the cavity and weak interactions between the substrate and internal C-H bonds of the cyclodextrin.

Orchestrating Communications in a Three-Type Chirality Totem: Remote Control of the Chiroptical Response of a Möbius Aromatic System.

Among the various types of chirality (central, axial, helical, planar, etc.), that inherent to Möbius topology remains almost unexplored, partly due to the difficulty to access Möbius compounds. Over the past decade, [28]hexaphyrins have been revealed to be among the best candidates to build on Möbius aromaticity. Whereas their flexibility needs to be controlled to get P/M twist enantioselectivity, it could be of great interest to sustain dynamic chirality transfer. In this context, we report herein the first example of a Möbius aromatic ring capped by a cavity, consisting of a Möbius [28]hexaphyrin doubly linked to an α-cyclodextrin. This unique design affords a "totem" of three different chirality elements arising from the cyclodextrin (fix central chirality), the bridging pattern (dynamic planar chirality), and the hexaphyrin (dynamic topological chirality). Chirality transfers (as shown in the TOC graphic) are characterized by a stereospecific planar-to-topological communication (diastereomeric excess >95%; the highest asymmetric selectivity reported to date for a Möbius ring) combined to a stereoselective central-to-planar communication (up to 60% diastereomeric excess). Interestingly, the stereoselectivity is remotely controlled by coordination of an achiral effector to the hexaphyrin, increasing up to 5 times the chiroptical response of the Möbius aromatic π-system. These results highlight the advantageous use of dynamic chirality transfers to further incorporate Möbius chirality and aromaticity into all kinds of stimuli-responsive devices.

Cyclodextrin-Sandwiched Hexaphyrin Hybrids: Side-to-Side Cavity Coupling Switched by a Temperature- and Redox-Responsive Central Device.

Access to allosteric enzyme mimics that ideally associate communicating compartments for catalysis and regulation is still challenging. Whereas a sandwich "cavity-catalyst-cavity" approach, developed mainly with cyclodextrins and porphyrins, appears promising, its counterpart with hexaphyrins featuring rich conformation, aromaticity, and coordination behavior has not been prospected at all. We thus developed sandwich hybrids made of two cyclodextrins triply linked on each side of a hexaphyrin. The latter displays switchable oxidation states with interconvertible conformations (28π antiaromatic and 26π aromatic, each adopting rectangular and dumbbell forms). These four states are connected by two orthogonal switches under redox [aromaticity] and thermal [shape] control. This leads to twin compartmentalized confined spaces either locked or unlocked depending on the conformation of the hexaphyrin, and the reversibility of the lock↔unlock transition relies on the aromaticity of the hexaphyrin. The sandwiched heteroannulene thus behaves as an unprecedented dual-responsive double-latched device. Such hybrid systems open interesting perspectives in the allosteric regulation of receptors, catalysts, and machineries.

Bridging ß-Cyclodextrin Prevents Self-Inclusion, Promotes Supramolecular Polymerization, and Promotes Cooperative Interaction with Nucleic Acids.

A bridge to assemble: Cyclodextrins bridged with an ammonium linker bearing a hydrophobic substituent can efficiently form supramolecular polymers and avoid the competing self-inclusion and head-to-head processes. Furthermore, the self-assembling cyclodextrin derivative interacts in a highly cooperative manner with DNA, as demonstrated by compaction experiments. It also interacts cooperatively with siRNA and allows its transfection.

Beta cyclodextrins bind, stabilize, and remove lipofuscin bisretinoids from retinal pigment epithelium.

Accumulation of lipofuscin bisretinoids (LBs) in the retinal pigment epithelium (RPE) is the alleged cause of retinal degeneration in genetic blinding diseases (e.g., Stargardt) and a possible etiological agent for age-related macular degeneration. Currently, there are no approved treatments for these diseases; hence, agents that efficiently remove LBs from RPE would be valuable therapeutic candidates. Here, we show that beta cyclodextrins (ß-CDs) bind LBs and protect them against oxidation. Computer modeling and biochemical data are consistent with the encapsulation of the retinoid arms of LBs within the hydrophobic cavity of ß-CD. Importantly, ß-CD treatment reduced by 73% and 48% the LB content of RPE cell cultures and of eyecups obtained from Abca4-Rdh8 double knock-out (DKO) mice, respectively. Furthermore, intravitreal administration of ß-CDs reduced significantly the content of bisretinoids in the RPE of DKO animals. Thus, our results demonstrate the effectiveness of ß-CDs to complex and remove LB deposits from RPE cells and provide crucial data to develop novel prophylactic approaches for retinal disorders elicited by LBs.

Cyclodextrin Cavity-Induced Mechanistic Switch in Copper-Catalyzed Hydroboration.

N-heterocyclic carbene-capped cyclodextrin (ICyD) ligands, α-ICyD and ß-ICyD derived from α- and ß-cyclodextrin, respectively give opposite regioselectivities in a copper-catalyzed hydroboration. The site-selectivity results from two different mechanisms: the conventional parallel one and a new orthogonal mechanism. The shape of the cavity was shown not only to induce a regioselectivity switch but also a mechanistic switch. The scope of interest of the encapsulation of a reactive center is therefore broadened by this study.

Hexaphyrin-Cyclodextrin Hybrids: A Nest for Switchable Aromaticity, Asymmetric Confinement, and Isomorphic Fluxionality.

Conformational control over the highly flexible π-conjugated system of expanded porphyrins is a key step toward the fundamental understanding of aromaticity and for the development of molecular electronics. We have synthesized unprecedented hexaphyrin-cyclodextrin (HCD) capped hybrids in which the hexaphyrin part is constrained in a planar rectangular conformation in either a 26 or a 28 π-electron oxidation state ([26]/[28]HCD). These structures display strong aromaticity and antiaromaticity, respectively, exhibit markedly different chiroptical properties, and are interconvertible upon the addition of DDQ or NaBH(OAc)3, thus affording a rare switchable aromatic-antiaromatic system with a free-base expanded porphyrin. Conformational analysis revealed discrimination of the two coordination sites of the hexaphyrin, one of which was coupled to a confined asymmetric environment, and fluxional behavior consisting of apparent rotation of the hexaphyrin cap through a shape-shifting mechanism.

Cyclodextrin polyrotaxanes as a highly modular platform for the development of imaging agents.

Selectively functionalized cyclodextrins with a bodipy fluorescent tag or Gd(3+) complex were synthetized and threaded onto a polyammonium chain to form polyrotaxanes. This modular supramolecular assembly makes an ideal platform for bimodal (fluorescent and MRI) imaging applications.

Revisited photophysics and photochemistry of a Ru-TAP complex using chloride ions and a calix[6]crypturea.

The effects of the nonprotonated and protonated calix[6]crypturea 1/1(•)H(+) on the PF6(-) and Cl(-) salts of a luminescent Ru-TAP complex (TAP = 1,4,5,8-tetraazaphenanthrene) were investigated. Thus, the phototriggered basic properties of this complex were examined with 1(•)H(+) in acetonitrile (MeCN) and butyronitrile (BuCN). The Ru excited complex was shown to be able to extract a proton from the protonated calixarene, accompanied by a luminescence quenching in both solvents. However, in BuCN, the Cl(-) salt of the complex exhibited a surprising behavior in the presence of 1/1(•)H(+). Although an emission decrease was observed with the protonated calixarene, an emission increase was evidenced in the presence of nonprotonated 1. As the Cl(-) ions were shown to inhibit the luminescence of the complex in BuCN, this luminescence increase by nonprotonated 1 was attributed to the protection effect of 1 by encapsulation of the Cl(-) anions into the tris-urea binding site. The study of the luminescence lifetimes of the Ru-TAP complex in BuCN as a function of temperature for the PF6(-) and Cl(-) salts in the absence and presence of 1 led to the following conclusions. In BuCN, in contrast to MeCN, in addition to ion pairing, because of the poor solvation of the ions, the luminescent metal-to-ligand charge transfer ((3)MLCT) state could reach two metal-centered ((3)MC) states, one of which is in equilibrium with the (3)MLCT state during the emission lifetime. The reaction of Cl(-) with this latter (3)MC state would be responsible for the luminescence quenching, in agreement with the formation of photosubstitution products.

Solid-state hierarchical cyclodextrin-based supramolecular polymer constructed by primary, secondary, and tertiary azido interactions.

The crystallization of a di-azido-α-cyclodextrin revealed a polymeric self-assembly involving a variety of azido-type interactions. The crystal arrangement relies on the cooperativity of a primary azido inclusion, a secondary azido-azido interaction involving an unprecedented distribution of canonical forms, and a tertiary azido-groove interaction. The second azido group brings in a major contribution to the supramolecular structure illustrating the benefit of a difunctionalization for the generation of hierarchy.

An "against the rules" double bank shot with diisobutylaluminum hydride to allow triple functionalization of α-cyclodextrin.

Frustration leads to overreaction: when diametrically opposed regioselective debenzylation is frustrated, an unexpected double debenzylation reaction affords original tetrafunctionalized cyclodextrins in a controlled and efficient manner. A rationale of the reaction is proposed based on a kinetic study.

Cyclodextrin-induced auto-healing of hybrid polyoxometalates.

You'll never walk alone: An auto-healing process of the first host-guest complex involving a polyoxometalate hybrid and a cyclodextrin is reported. Indeed, this inclusion complex allows the complete restoration of the anchored organic moiety released by a basic stress, a process otherwise not fully reversible.

Acid-base controllable recognition properties of a highly versatile calix[6]crypturea.

Versatile concave receptors with binding properties that can be controlled by external stimuli are rare. Herein, we report on a calix[6]crypturea (1) that features two different binding sites in close proximity, that is, a tris(2-aminoethyl)amine (tren)-based tris-ureido cap that provides convergent hydrogen-bond-donor sites and a hydrophobic cavity suitable for the inclusion of organic guests. The binding properties of this heteroditopic receptor have been evaluated by NMR spectroscopic studies. Compound 1 behaves as a remarkably versatile host that strongly binds neutral molecules, anions, or contact ion pairs. Within each family of guests, compound 1 is able to discriminate between different guests with a high degree of selectivity. Indeed, neutral molecules that possess hydrogen-bond donor and acceptor groups, chloride anions, and linear ammonium ions associated to F(-) or Cl(-) are particularly well recognized. In comparison with all the related receptors, compound 1 displays several unique features: 1) charged or neutral species are also recognized in polar or protic solvents, 2) thanks to the flexibility of the calixarene structure, induced-fit processes allow the binding of large, biologically relevant ammonium salts such as neurotransmitters, and 3) the protonation of the basic cap leads to a positively charged receptor, 1.H(+), which is reluctant to host anions and in which host properties are now governed by strong charge-dipole interactions with the guests. In other words, compound 1 presents an acid-base controllable tris-ureido recognition site protected by a hydrophobic corridor that can select guests through induced-fit processes. Thus, its versatile host properties can be allosterically controlled by protonation and selective guest-switching processes are possible. To illustrate all these remarkable features, a sophisticated three-pole supramolecular switch, based on the interconversion of host-guest systems displaying either charged or neutral guests, is described.

Calix[6]arene-based cascade complexes of organic ion triplets stable in a protic solvent.

Herein we report a D(3h)-symmetric tail-to-tail bis-calix[6]arene 3 featuring two divergent cavities triply connected by ureido linkages. This calix[6]tube was synthesized by a domino Staudinger/aza-Wittig reaction followed by a macrocyclization reaction. This process also afforded a C(2h)-symmetric isomer that represents a rare example of a self-threaded rotaxane based on calix[6]arene subunits. The binding properties of 3 have been evaluated by NMR studies. Thus, bis-calix[6]arene 3 is able to bind simultaneously two neutral ureido guests through an induced-fit process. The guests are located in the cavities and are recognized through multiple hydrogen-bonding interactions with the ureido bridges. Host 3 can also simultaneously bind multiple ions and is especially efficient for the complexation of organic ion triplets. The anion is recognized through hydrogen-bonding interactions at the ureido binding site and is thus located between the two ammonium ions accommodated in the cavities. The resulting [1+1+2] quaternary complexes represent rare examples of cascade complexes with organic cations. These complexes are unique: 1) They are stable even in a markedly protic solvent, 2) the recognition of the ion triplets proceeds in a cooperative way through an induced-fit process and with a high selectivity, linear cations and doubly charged anions being particularly well recognized, 3) the ions are bound as contact ion triplets thanks to the closeness of the three binding sites, 4) the cationic guests can be exchanged and thus mixed [1+1+1+1] complexes can be obtained, 5) the ureido linkers wrapped around the anion adopt a helical shape and the resulting chirality is sensed by the cations. In other words, bis-calix[6]arene 3 presents a selective inner tunnel in which multiple guests such as organic ion triplets can be aligned in a cooperative way through induced-fit processes.

Synthesis, Conformational Analysis, and Complexation Study of an Iminosugar-Aza-Crown, a Sweet Chiral Cyclam Analog.

A new family of chiral C2 symmetric tetraazamacrocycles, coined ISAC for IminoSugar Aza-Crown, incorporating two iminosugars adopting a 4C1 conformation is disclosed. Multinuclear NMR experiments on the corresponding Cd2+ complex show that the ISAC is a strong chelator in water and its tetramine cavity adopts a conformation similar to that of the parent Cd-cyclam complex. Similar behavior is observed with Cu2+ in solution, with enhanced stability compared to the Cu-cyclam complex.

Calix[6]tris(thio)ureas: heteroditopic receptors for the cooperative binding of organic ion pairs.

The straightforward syntheses of C3v symmetrical calix[6]trisureas and -thiourea have been achieved. NMR studies have shown that these flexible compounds possess a major cone conformation. While these neutral hosts can strongly bind anions such as AcO(-) or HSO4(-) through induced fit processes, they can also behave as unique heteroditopic receptors for organic ion pairs with a remarkable positive cooperativity in the complexation process, the anion acting as an allosteric effector.

Investigation by mass spectrometry of metal complexes of new molecular hosts: cyclic oligomer of sugar amino acid and sugar-aza-crown ethers.

The affinity of cyclic oligomers of sugar amino acid and sugar-aza-crown ether compounds towards various transition metal cations (Cu(II), Ni(II), Co(II), Fe(II) and Zn(II)) was investigated with positive-ion electrospray mass spectrometry. The binding between the receptors (M) and the different metals (Met) is evidenced mainly by the presence of the [M + Met(II)Cl](+) ion. The experimental results showed that all studied receptors present specificity to Cu(II). An attempt has been made with CuI but no complexation was obtained. The formation of these complexes can be rationalized by considering the presence of two oxygens and two nitrogens on the receptor rim. The lone electron pair can serve as the electron donor to Cu(II). Theoretical calculations were carried out in order to show the structure of the complex and, in particular, to determine if Cu(2+) is situated either on the outer surface, on the rim of the receptor or inside the cavity. Comparison of complex formation was carried out by mixing the four receptors with various amounts of Cu(II) (one equivalent and five equivalents). It appears that the best complexation was obtained with the sugar-aza-crown ethers (amine linker) for both benzylated and methylated compounds. In addition, the stereochemical effects have been investigated.