Behind the Science: Synthesis of Disulfide-Bridged Cryptophanes

Behind the Science: Synthesis of Disulfide-Bridged Cryptophanes

Author: Anne Nijs, Jean-Claude Chambron

Dr. Anne Nijs, Deputy Editor of the European Journal of Organic Chemistry, talked to Dr. Jean-Claude Chambron, Université de Bourgogne Franche-Comté, Dijon, France, about his recently published article on the formation of cryptophanes in basic aqueous solutions by disulfide bridge formation.

Dr. Chambron, could you please briefly explain the focus of your article?

This article merges two concepts, cryptophanes and disulfide bonds. Cryptophanes are spheroidal, hollow molecular receptors that are able to encapsulate various substrates: atoms, ions, or molecules. They incorporate two face-to-face concave cyclotribenzylene (CTB) building blocks, which offer electron-rich π surfaces to the encapsulated substrates.

Disulfide bonds are very important in biology because they are involved in the stabilization of the tertiary structure of proteins and the redox activity of cells. In chemistry, they are known to be prone to reversible formation/cleavage under certain conditions.

Our aim was to use this property for the generation of cryptophanes by coupling presynthesized CTB components, rather than by construction by multi-step synthesis. This is possible because of the reversibility of the disulfide bond. It permits an “error” correction if the CTBs have not been coupled properly. Therefore, practically the cryptophanes are generated by stirring the CTBs in basic aqueous solution under air, with or without a template, which is a very simple process.

What was the inspiration for this study?

Cryptophanes were designed about 35 years ago by André Collet and coworkers [1]. The concept of dynamic combinatorial chemistry was raised in the mid-nineties by Jeremy Sanders [2] and Jean-Marie Lehn [3]. Later, together with Sijbren Otto [4], Sanders used disulfide exchange reactions.

Moreover, cryptophane incorporating disulfide bridges have been reported by Michaele Hardie and colleagues [5], and the generation of cryptophanes in water by dynamic covalent chemistry using imine-bond formation was reported by Ralf Warmuth’s team [6]. Therefore, there was room for the generation of cryptophanes in water using disulfide bonds.

What distinguishes cryptophanes from other macrocyclic receptors?

Cryptophanes are macropolycyclic receptors made from two concave cyclotribenzylene molecular fragments that are facing each other. As smaller homologs of Donald Cram’s carcerands, which were also developed in the eighties [7], they are related to calixarenes, resorcinarenes, and the more recent pillararenes, which all contain electron-rich aromatic walls.

Cryptophanes have a spheroidal cavity with closed poles and equatorial openings. Moreover, they can be easily made intrinsically chiral. Actually, the renewed interest in cryptophanes came from their strong affinity for the Xe atom. This gave rise to the recent development of 129Xe@cryptophane-based MRI biosensors which use hyperpolarized Xe for better sensitivity. As a matter of fact, a ligand-functionalized cryptophane can play the role of a Xe carrier for a biological target, such as a protein or a DNA fragment.

What are the most significant results of your study?

This study has many facets. The new cyclotribenzylenes and the synthetic routes that we developed will be useful for the community working in the field of cryptophanes. The most significant aspects of the work, however, are the various unexpected inhibition effects produced by some of the species present in solution. At first glance, these species were only expected to play the role of a spectator.

Stoichiometric amounts of NMe4+ template the formation of the largest cryptophane in 0.1 M alkali hydroxide. However, amounts in excess inhibit it. Likewise, the formation of the smallest cryptophane is possible in 0.1 M LiOH, but inhibited in this medium in the presence of NMe4+, or in 0.1 M CsOH. Therefore, the smallest cryptophane does not appreciably form in the conditions required for the largest cryptophane. This is one example, among many others, of the recently recognized field of “systems chemistry”. Gonen Ashkenasy, Thomas Hermans, Sijbren Otto, and Annette Taylor very recently wrote a review on this topic [8].

Which part of your work proved the most challenging?

We started our work on cryptophanes seven years ago. At first, our project involved the synthesis of a thiol-substituted cyclotribenzylene, which was new at that time. Unfortunately, this compound did not afford a cryptophane upon oxidation. It took us a long time before we realized that this was due to steric hindrance.

So, we had entered two fields that we were not familiar with: the chemistry of cryptophanes and the organic chemistry of thiols. This was quite challenging.

What are your future plans extending from this discovery?

Whereas most of the aspects of our work were pleasing, especially the discovery of the templating effect of NMe4+, the most frustrating aspect of this study was our inability to obtain cryptophanes from two different cyclotribenzylene subunits. This is an objective which would have been challenging by applying the current strategy.

As explained above, the simple dimerization of concave precursors is easier than the step-wise construction of a cryptophane. Therefore, we are working on making other cyclotribenzylene analogues and on finding conditions that favor the coupling between two different cyclotribenzylenes rather than cyclotribenzylene homocoupling by disulfide-bridge formation.

The article they talked about


Articles mentioned in the interview:

[1] J. Gabard, A. Collet, Synthesis of a (D3)-bis(cyclotriveratrylenyl) macrocage by stereospecific replication of a (C3)-subunit, J. Chem. Soc., Chem. Commun. 1981, 1137–1139.

[2] P. A. Brady, R. P. Bonar-Law, S. J. Rowan, C. J. Suckling, J. K. M. Sanders, ‘Living’ macrolactonisation: thermodynamically-controlled cyclisation and interconversion of oligocholates, Chem. Commun. 1996, 319-320.

[3] B. Hasenknopf, J.-M. Lehn, N. Boumediene, A. Dupont-Gervais, A. Van Dorsselaer, B. Kneisel, D. Fenske, Self-Assembly of Tetra- and Hexanuclear Circular Helicates, J. Am. Chem. Soc. 1997, 119, 10956–10962.

[4] S. Otto, R. L. E. Furlan, J. K. M. Sanders, Dynamic Combinatorial Libraries of Macrocyclic Disulfides in Water, J. Am. Chem. Soc. 2000, 122, 12063–12064.

[5] M. A. Little, J. Donkin, J. Fisher, M. A. Halcrow, J. Loder, M. J. Hardie, Synthesis and Methane-Binding Properties of Disulfide-Linked Cryptophane-0.0.0, Angew. Chem. Int. Ed. 2012, 51, 764–766.

[6] C. Givelet, J. Sun, D. Xu, T. J. Emge, A. Dhokte, R. Warmuth, Templated dynamic cryptophane formation in water, Chem. Commun. 2011, 47, 4511–4513.

[7] D. J. Cram, S. Karbach, Y. H. Kim, L. Baczynskyj, K. Marti, R. M. Sampson, G. W. Kalleymeyn, Host-guest complexation. 47. Carcerands and carcaplexes, the first closed molecular container compounds, J. Am. Chem. Soc. 1988, 110, 2554–2560.

[8] G. Ashkenasy, T. M. Hermans, S. Otto, A. F. Taylor, Systems chemistry, Chem. Soc. Rev. 2017, 46, 2543–2554.



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