Agustí Lledó

Switchable Catalysis with a Light‐Responsive Cavitand

Host–guest systems that display catalytic behavior represent a promising area of supramolecular chemistry.[1] Supramolecular approaches to cataylst design include ligand-templated encapsulation,[2] self-assembled ligands, coordination compounds, and artificial biomacromolecules.[3] Generally, these systems operate by binding substrates and stabilizing transition states and/or increasing the effective concentration of reactive species within confined space.[4] In most catalytic host–guest systems the substrate is a guest and substrates that adequately fill the host’s interior are required to ensure activity. Alternatively, there are few instances where the guest is the catalyst.[5] These examples incorporate transition metal guests and enhanced reaction rates are rare.[6] Here we report a complementary approach where the bound guest is an organocatalyst in a deep cavitand. We find that the cavitand/piperidinium complex accelerates the Knoevenagel condensation and show that the rate of the reaction can be controlled using light to stimulate structural changes in the cavitand’s shape.

Recognition and Organocatalysis with a Synthetic Cavitand Receptor

The cyclization reaction of an epoxyalcohol is catalyzed by a synthetic cavitand receptor with an inwardly directed carboxylic acid function. The receptor features a hydrophobic pocket in which the substrate is bound and positioned to react in a regioselective manner. The nature of this substrate-catalyst complex and its dynamic properties were investigated by NMR methods and with the aid of a model compound lacking the epoxide function. The kinetic parameters of the cyclization reaction were also studied. A catalytic cycle is proposed and diverse inhibition mechanisms are identified that parallel those encounterd in enzymology.

Enantioselective Syntheses of Carbanucleosides from the Pauson-Khand Adduct of Trimethylsilylacetylene and Norbornadiene

A new enantioselective approach to carbanucleosides from Pauson-Khand (PK) adduct 1 is disclosed. The chiral cyclopentenone 1 is readily accessible in enantiomerically pure form via PK reaction of trimethylsilylacetylene and norbornadiene using N-benzyl-N-diphenylphosphino-tert-butyl-sulfinamide as a chiral P,S ligand. (-)-Carbavir and (-)-Abacavir were enantioselectively synthesized starting from (-)-1. The key steps of the sequence are a photochemical conjugate addition of a hydroxymethyl radical, a retro-Diels-Alder reaction, and a palladium catalyzed allylic substitution to introduce the nucleobase.

Allenes, versatile unsaturated motifs in transition-metal-catalysed [2+2+2] cycloaddition reactions

We gratefully acknowledge the financial support of our own research in this area by the Spanish Ministry of Education and Science (MINECO) (Project CTQ2014-54306-P and a RyC contract to A. L.) and the DIUE of the Generalitat de Catalunya (Project 2014-SGR-931)

Deep cavitand receptors with pH-independent water solubility

Pendant oligoethyleneglycol groups confer water solubility to a cavitand over a wide pH range. The kinetic stability of the host-guest complexes reveals an effective stabilization through hydrogen bonding even in the highly competitive aqueous environment.

Dehydrogenative [2 + 2 + 2] Cycloaddition of Cyano-yne-allene Substrates: Convenient Access to 2,6-Naphthyridine Scaffolds

A rhodium-catalyzed [2 + 2 + 2] cycloaddition of cyano-yne-allene scaffolds followed by a dehydrogenative process enabling the direct synthesis of unsaturated pyridine-containing compounds that can be conveniently converted to 2,6-naphthyridine derivatives is reported.

Supramolecular Architecture with a Cavitand - Capsule Chimera

Signalling events in biological systems often make use of macromolecules featuring separated binding compartments and some means of communication between the sites. In synthetic, self-assembled systems, early attempts to arrange confinement in two very different capsules were thwarted by the formation of hybrid capsule structures.1 The hybridization was unexpected, given the sorting of self- and non-self generally at work in such molecular assemblies.2 We report here the preparation and molecular recognition properties of a molecule (1) featuring covalently linked binding sites that do not hybridize yet provide unambiguous self-assembly. The compartments (a deep cavitand and a dimeric capsule) are orthogonal in binding behavior and allow the simultaneous molecular recognition and exchanges of their respective guests. Chimeric host 1 was accessed through a convergent sequence, in which copper catalyzed azide alkyne cycloadditions (Click reactions)3 played a key role in the final stage of the synthesis. The octaamide cavitand portion was prepared in 8 steps starting from the previously reported monofunctionalized resorcinarene 2 (Scheme 1).2e After protection of the hydroxyl anchor on the “feet” as the benzoate ester and debenzylation of the phenolic functions, the “walls” of the cavitand were incorporated using the standard condensation with 3,4-difluoro-1,2-dinitrobenzene. The resulting octanitro compound was reduced, acylated and deprotected at the hydroxyl terminus to yield 4. Functional group interconversion was easily accomplished to yield the key azide building block 5. Scheme 1 Synthesis of azide-functionalized cavitand module 5. The sequential click coupling sequence between 5, azide functionalized resorcinarene 6 and pentadeca-1,14-diyne allowed an efficient assembly of the two main building blocks. After debenzylation, the final build-up of the imide capsule-forming skeleton was accomplished by condensation of 7 with dichloropyrazine 8 following an optimized protocol (Scheme 2).4 Scheme 2 Completion of the synthesis. Upon addition of trans-4,4’-dimethylstilbene (9a) to a solution of 1 in mesitylene-d12 (a non-competing solvent) a singlet corresponding to the methyl groups of 9a appears at δ-2.80 ppm, indicating the formation of a 1:1 capsule with two molecules of 1 (Figure 2). There are two ways to form this capsule and while both diastereomers are doubtlessly formed, the guest inside is oblivious to the differences of the assemblies as revealed by the sharp signal for its methyl groups. Addition of 1-adamantylcarbonitrile (10a) to this solution brings about three more resonances in the upfield region which are assigned to the adamantyl protons bound to the cavitand region of 1. The adamantyl guest binds to its complementary binding site without disruption of the initial capsular assembly. With excess 10a (two-fold per binding site) present in solution, integration reveals a 2:2:1 stoichiometry of assembly components as all cavities are saturated. Figure 2 The NMR spectra of host 1 (mesitylene-d12, 320 K, [1] = 1.8 mM) upon addition of guests 9a (top) and 10a (bottom) are shown. Red circles indicate the methyl resonance of bound 9a and green squares correspond to the buried 1-adamantylcarbonitile protons. ... The formation of a unique and discrete supramolecular assembly of formula 12•9a•10a2 is confirmed by Diffusion Ordered Spectroscopy (DOSY)5 experiments (Figure 3). The rigidity and kinetic stability of this assembly provides an unambiguous and graphical result: all the resonances corresponding to the cavitand-capsule hybrid and their guests lie in a narrow trace in the diffusion dimension (D = 1.7 × 10−6 cm2 s−1) which is clearly distinguished from the much faster diffusing small molecules present in solution (mesitylene-d11 D = 1.6 × 10−5 cm2 s−1, 9a D = 1.2 × 10−5 cm2 s−1, 10a D = 1.6 × 10−5 cm2 s−1). The same diffusion values are obtained (within experimental error) at either long (Δ = 100 ms) or short (Δ = 50 ms) diffusion times. Figure 3 1H DOSY NMR spectrum (mesitylene-d12, 300 K, [1] = 1.8 mM) showing distinct diffusion coefficients (D) for assembly 12•9a•10a2 and small, faster diffusing molecules. We next tested the orthogonality of the binding sites by way of the controlled release of guests (Figure 4). Capsule 12 was charged with 4,4’-dimethylbiphenyl (9b, Figure 4a) and then the cavitand sites were loaded with 2-adamantanone (10b, Figure 4b). Incremental addition of 1-adamantylcarbonitrile, a better fit for the cavitand binding pocket, displaces bound 10b from the cavity without perturbing the capsule section (Figure 4c). Displacement of the biphenyl without disturbing the cavitands could be demonstrated as well: n-undecane (9c) smoothly replaces 9b. Although both guests fill slightly less than half of the space inside the capsule, the flexible alkane can find a better fit.6 The capsule can also be extended by means of a glycoluril spacer 11 in the presence of a slightly longer alkane (9d, n-pentadecane). Pentadecane fills the expanded space and displaces the undecane back into the solution.1a The formation of the new 9-component assembly is confirmed by the appearance of the signature resonances at δ 13.3 ppm of the imides’ NH’s in contact with glycoluril carbonyls.7 The newly added hydrogen bonding spacer does not engage the cavitand section and leaves this binding site unaltered. When CD3OD was added to the solution, cleavage of capsule occurred and the pentadecane guest was released. The presence of methanol disrupts the hydrogen bond network of the capsule and accelerates the rotation about the amide N-aryl bond of the cavitand (racemization of the cycloenantiomers), but the concentration of bound 10a is unchanged. The deuteration by the solvent CD3OD causes depletion of the NH resonances and the signal of the imide NH shifts upfield to δ 8.2 ppm (merges with the multiple aromatic resonances of the system, not shown) as the capsule is disrupted. The dehiscence provoked by the competing CD3OD molecules can be reversed by the addition of 9a (packing coefficient 48%), and the assembly of 5 molecules with encapsulated stilbene is restored. Figure 4 a) 12 charged with 9b (red circles), b) the cavitand sites are charged with 10b (green squares), c) addition of 10a (blue squares) releases 10b from the cavitand, d) 9c (yellow circles) replaces 9b in the capsule section, e) addition of glycoluril 11 ... Receptor molecules that self-assemble into oligomeric aggregates of respectable sizes are numerous: they can be constructed through repetitive accumulation of a single module,2a,8 and two component systems are even more plentiful.9 Here we have shown that a self-assembled, ditopic host – a cavitand-capsule chimera – can engage guests at independent binding sites without interacting directly (hybridizing). The guests can be released selectively from either site by action of external chemical stimuli and the dimensions of the capsule compartment can be altered without effect on the cavitand. The orthogonality of the two sites extends to the dynamics of the system since exchange of guests occurs in well-separated time frames: cavitand bound molecules have an encapsulated half-life of 1 to 25 s10 whereas this value is as high as 32 h for some capsule bound molecules.11 We note that 7 is itself a chimera and not without its own possibilities for assembly.12 We will report on these in the sequel.

Recognition of guests by water-stabilized cavitand hosts.

Water stabilized, deep cavitands with three walls and an open side are shown to be receptors for amines and ammonium cations bearing bulky aliphatic groups. The missing wall allows the binding of guests not accommodated by the four-walled counterparts.

Pseudo-Capsule Assemblies Characterized by 19F NMR Techniques

The formation of capsule-like dynamic assemblies which do not rely on attractions between host subunits was achieved via specific interactions with fluorinated guests. Characterization of these three component assemblies was accomplished by applications of (19)F NMR spectroscopy.

A Computational Study of the Intermolecular [2+2+2] Cycloaddition of Acetylene and C60 Catalyzed by Wilkinson's Catalyst

The functionalization of fullerenes helps to modulate their electronic and physicochemical properties, generating fullerene derivatives with promising features for practical applications. Herein, DFT is used to explore the attachment of a cyclohexadiene ring to C60 through a rhodium-catalyzed intermolecular [2+2+2] cycloaddition of C60 and acetylene. All potential reaction paths are analyzed and it can be concluded that the [2+2+2] cycloaddition of C60 and two acetylene molecules catalyzed by [RhCl(PPh3 )3 ], yielding a cyclohexadiene ring fused to a [6,6] bond of C60 , is energetically feasible.