Synthesis and applications of hemicryptophane organic cages

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Enantiopure hemicryptophanes obtained by means of chiral HPLC resolution

Enantiopure compounds are very important in chemical sciences, especially in the fields of molecular recognition and host-guest systems. Furthermore, chiral molecular receptors are the basis of many biorecognition processes and have important implications for biochemistry or pharmacology. The design, preparation and purification of synthetic chiral hosts, such as molecular cages, is however a very difficult task. In order to separate two enantiomers of one chiral cage, the chiral semi-preparative high-performance liquid chromatography (HPLC) technique plays an important role for the resolution of racemic mixtures. Using this purification method, enantiopure hemicryptophane cages can be obtained by (i) resolution of CTV-based precursors first, or (ii) resolution of the final hemicryptophane racemate. In 2010, the first example of the resolution of a racemic mixture of hemicryptophane molecular cages using the chiral semipreparative HPLC purification technique was reported by Martinez, Dutasta and co-workers.[15] Through injections (8.0 mg/mL solutions in CDCl3) of the racemic mixture on a (S,S) Whelk-O1 chiral column, they successfully separated the two enantiomers of the following cage (M-8 and P-8 in Figure 1.4). The excellent enantiomeric excess values obtained for the M- and P- enantiomers of 8 (up to 96% and 99%) demonstrate the efficiency of the separation. However, this resolution of hemicryptophane enantiomers only stayed at the hundred of milligram scale, and the efficiency of the chiral HPLC separation is highly sensitive to the structure of the desired capsules. The efficiency of the chiral HPLC-separation could be significantly improved by the initial resolution of a CTV-based precursor racemate followed by its functionalization to form the enantiopure cage. In 2016, Martinez and co-workers have successfully separated 2 grams of each M- and P-enantiomers of the precursor CTV(CH2CH2Br)3 (M-11 and P-11 in Figure 1.4) with an enantiomeric excess >99.5%.

Host-guest chemistry

Host–guest chemistry is one of the defining concepts of supramolecular chemistry that describes the formation of unique complexes between two or more molecules, via non-covalent interactions. A host molecule has an internal space (the so-called ‘cavity’) in which another molecule, the guest molecule, can be incorporated. Since Pedersen, Lehn and Cram proposed the concept of host-guest chemistry, it has opened the way to the construction of supramolecular (inclusion) complexes. Several types of host molecules have been reported, including crown ethers, cryptands, spherands, carcerands and cyclodextrins (Figure 1.5). The guest molecule can be incorporated in the cavity of host molecule.
The hemicryptophanes can work as excellent receptors due to some advantages : (i) their rigid CTV scaffolds can provide cavities of variable shape and size, (ii) different kind of southern groups that offer special recognition capabilities can be incorporated, and (iii) the chirality of the CTV itself. For examples, hemicryptophanes have shown good complexation properties with ammoniums, ion pairs,[16-21] and fullerenes[22].
Among the possible non-covalent interactions between one hemicryptophane host and a guest, most of them are hydrogen bonds or interactions with charged species (ammonium, ion pairs, zwitterions). For instance, the first hemicryptophane, (1 in Figure 1.1) can interact strongly with ammonium ions through cation-π interactions with its CTV unit[7]. Hemicryptophanes can also encapsulate ion-pairs. The host– guest interactions between Me4N+Cl and cage 8 have been studied using a DFT approach (Figure 1.6a).[23] In 2008, another heteroditopic hemicryptophane cage was reported by Jabin et al.. This host interacts with the anion (chloride ion) and the cation (ammonium ion) simultaneously. [21] Interestingly, hemicryptophanes could also perform partial encapsulations. Makita and cowokers indeed reported in 2016 the partial encapsulation of acetylcholine within a hemicryptophane host : the X-ray structure indicates that the ammonium unit of the acethylcholine (Ach+) is inside the cavity (due to the cation-π interactions), while the acetyl unit and chloride counterions are outside the cavity (Figure 1.6b).[24] Finally, in 2011, Zhanting Li’s group developed a new (CTV)-based capsule that can strongly encapsulate C60 and C70 fullerenes by combining hydrogen bonding[22].

Catalysis in confined space

Catalysis plays an important role in the development of the chemical industry and society. A large number of materials and chemical intermediates are synthesized directly and indirectly with catalysts. In nature, many chemical reaction processes require enzymatic catalysis, usually with the advantages of high efficiency and high selectivity. However, the enzymes are not so easy to mimic, because the structure of enzymes is complicated, and some reactions are performed in specific confined spaces displaying multiple functionalities.
Advances in transition state theory and computer technology have made possible the simulation and understanding of the enzyme’s active-sites [25]. In order to mimic the efficient chemistry found in enzymes, the catalysis in confined space aims at reproducing the second coordination sphere of enzymes. In the past decades, metal-organic cages, metal-organic frameworks, organic hosts, and nanoreactors have therefore attracted a growing interest.[26] In the following, some related research examples of homogeneous catalysis in confined spaces, will illustrate the effect of constrained mediums on catalytic selectivity and efficiency. Among the various examples of supramolecular catalysis, we will particularly focus on the examples where catalysis takes place inside the cavity of hemicryptophanes cages.
Inspired by enzymes, chemists have tried to mimic their confined environment through the development of organic architectures, such as cyclodextrins or calixarenes,[27] which contain well-defined cavities. Similarly, the hemicryptophanes show potential to work as ligand for complexing metal ion. Because the hemicryptophane cavity can be modified and adapted to different substrates, selective transformations could be envisioned. In 2009, Martinez and co-workers have shown, for the first time, that hemicryptophane-based transition metal complexes are efficient supramolecular catalysts (Figure 1.7).[28] The diastereomeric hemicryptophane−oxidovanadium(V) complexe 12 successfully oxidized the sulfide substrates to sulfoxide with 10 mol% catalyst and cumene hydroperoxide (CHP) as oxygen source. It was found to be an efficient supramolecular catalyst in the oxidation of thioanisol with yields up to 95%. Comparing with its parent model ligand, devoid of cavity, the hemicryptophane catalyst show higher yield due to the role of hemicryptophane hydrophobic cavity (protect the metal-active site).
In 2013, the group of Alexandre Martinez used a Copper-Hemicryptophane (13) complex as a catalyst for the oxidation of cycloalkane by H2O2 (Figure 1.8).[29] By comparing with the open model complex (Figure 1.8b) and the Cu(II) salt Cu(ClO4)2(H2O)6, the reaction with the Cu(II)-hemicryptophane complex shows better yield (28% and 15%, respectively) demonstrating the great potential of such an approach for the C-H oxidation. The stability of the catalyst is improved by encapsulating the active site in the molecular cavity. Other reasons may be the preferential encapsulation of the alkane substrate in the hydrophobic cavity and the ejection of the first oxidation product (alcohol).
In addition, the group of Martinez reported a new functionalized cage in 2018, which contains a Verkade’s superbase motif and can be used as a tool to create frustrated Lewis pairs.[30] They tested the reaction between p-chlorobenzaldehyde and cyclopentenone with the cage 14 and the model Verkade’s superbase 15 lacking cavity (Figure 1.9). Performances are improved with the cage system. The cage 14 was more efficient due to confinement of the Verkade’s superbase in the cavity of the hemicryptophane host. The key role of the cavity has been highlighted: the acid-base reaction with the Lewis acidic partner (TiCl4) cannot take place due to the confinement of the Verkade’s superbase in the cavity of the hemicryptophane host, thus providing an effective system for the reaction.
Hemicryptophane ligands have also been used for the oxidation of methane: Sorokin, Martinez, and co-workers have compared the iron cage-complex FeII(Hm-TPA) with the model FeII(TPA) for this reaction ( shown in Figure 1.10).[31] The cage-complex shows better results in terms of efficiency (total turnover number TON are double) and selectivity in the mono-oxidized methanol product (multiplied by a factor 2). This improvement results from several factors: (i) the hemicryptophane acts as an efficient receptors for CH4, (ii) the confined iron catalyst is more stable and therefore more efficient, and (iii) the over-oxidation of the polar CH3OH product is limited due to its ejection from the cage’s cavity .
Figure 1.10 The result of oxidation of CH4 by H2O2 using FeII(TPA) and FeII(Hm-TPA). Structure of the hemicryptophane catalysts FeII(Hm-TPA) and its corresponding model FeII(TPA) (top left). Comparison of the turnover numbers (TON) and selectivity in methanol observed during the oxidation of CH4 by H2O2 catalyzed by FeII(TPA) (blue) and FeII(Hm-TPA) (purple).
Finally, it should be noted that organic cages are not only supramolecular structures, which could be used to achieve confined catalysis. Numerous self-assembled cages and coordination cages have been used as nano-reactors. These molecular capsules are structured by weaker interactions than covalent bonds, such as metal coordination or hydrogen bonding. They have different geometric shapes, which may induce unexpected regioselectivity or stereoselectivity. For instance, Fujita and coworkers compared an organopalladium cage (16 in Figure 1.11) to a bowl system, for the stoichiometric Diels-Alder reaction between anthracene and phthalimide guests. The Diels-Alder reaction of anthracenes in the presence of the bowl 17 yields the expected product 19 (9,10-position ring). On the contrary, the use of the cage leads to an unusual isomer, the 1,4-adduct 18 (Figure 1.11).[32] When a reaction is performed in such a capsule, different selectivities might be observed due to the existence of the confined space.

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In this part, the synthesis of hemicryptophane organic cages has been described. In terms of molecular recognition and restricted-space catalysis, hemicryptophanes have great potential, because their CTV part can bring unique chirality and help structuring the three-dimensional cavity of the cage. Furthermore hemicryptophanes have been reported as particularly useful scaffold for homogeneous catalysis in confined space often yielding to stable, efficient, and more selective catalysts. By comparing with some model catalysts, it has been proved that the catalytic process occurred inside the hemicryptophane cavity. Importantly, no inhibition of the catalysis by the product has been observed by using this kind of capsules. These results therefore demonstrate that hemicryptophanes are flexible structures that allow for the ejection of the products that is not blocked inside the cage.
More new hemicryptophane cages need to be designed for host-guest chemistry or for enantioselective catalysis. Such hemicryptophane cages can be tested and applied in various catalytic reactions that are presently under consideration in our laboratory. It is also very interesting to study if the chirality of the CTV could be transferred to the bottom part to prepare new chiral cage-ligands with controlled chirality.

Table of contents :

General Introduction
Chapter I: Bibliography
I.1: Synthesis and applications of hemicryptophane organic cages
I.1.1 Introduction
I.1.2 Synthesis of hemicryptophanes
I.1.3 Enantiopure hemicryptophanes obtained by means of chiral HPLC resolution
I.1.4 Host-guest chemistry
I.1.5 Catalysis in confined space
I.1.6 Conclusions
I.1.7 References
I.2 Chirality transfer in tripodal supramolecular cages Control and transfer of chirality within well-defined tripodal cages
I.2.1 Abstract
I.2.2 Introduction
I.2.3 Propagation of the chirality in tripodal cages
I.2.4 Chiral-sorting in tripodal cages
I.2.5 Control of the host chirality through guest binding
I.2.6 Conclusion and discussion
I.2.7 References
Chapter II: New small tris(2-pyridylmethyl)amine-based hemicryptophane for predictable control of the ligand’s helicity by chirality transfer
II.1 Chirality Transfer in a Cage Controls the Clockwise / Anticlockwise Propeller-like Arrangement of the tris(2 pyridylmethyl)amine Ligand
II.2 Annex N°1:
II.3 Preliminar catalytic tests on copper-catalyzed asymmetric transformations using enantiopure 1 CuI(Cl) catalyst
II.4 Computational calculations: explanation of the chirality transfer and molecular dynamic of cage
II.4.1 Computational details:
II.4.2 Chirality transfer (issue 1):
II.4.3 Dynamic Aspects (issue 2) :
II.5 Conclusions
II.6 Reference
Chapter III: Design, preparation, and applications of novel tris-triazole based hemicryptophanes
III.1 Introduction
III.1.1 Site selective and enantioselective CuAAC reaction.
III.1.2 Construction of rotaxane and cages by mean of CuAAC reaction
III.2 Result and discussion
III.2.1 Synthesis
III.2.2 CuAAC in confined space : first catalytic tests
III.3 Conclusions
III.4 References
Chapter IV: Design and preparation of a novel hemicryptophane cage with two different metal binding-site
IV.1 Introduction
IV.2 Result and discussion
IV.2.1 Synthesis and characterization of cage
IV.2.2 Preparation and 1H-NMR characterisation of the corresponding diamagnetic Zinc complex.
IV.2.3. Solid states studies
IV.2.4 Study of the interaction of CuII(cage 4)(OTf)2 with N3.
IV.3 Conclusion and perspectives
IV.4 References
Chapter V: Synthesis of CTV-based self-assembled supramolecular cages
V.1 Introduction
V.2 Result and discussion
V.2.1 Synthesis and characterization of pyridine-based CTV ligands
V.2.2 First self-assembly results (group of M. Hardie)
V.3 Conclusions
V.4 References
General conclusions and perspectives


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