FoldaRotaxanes for the Versatile Synthesis of Improbable Interlocked Molecules – FoldaRotaxanes

In a first approach, specific sites of interactions for foldamers and crown ether have been introduced in molecular axles in order to synthesize foldaxanes, on one hand, and rotaxanes on the other hand. These structures consisted of starting scaffold for the preparation of the more complexed structures foldarotaxanes. In a second approach, the inedite foldarotaxanes were sytnthesized and characterized and their behavior to generate controlled motions studied.

Different targeted foldaxanes and rotaxanes have been synthesized and studied. From them, different original supramolecular architectures, called foldarotaxanes, have been obtained. These novel architectures have been characterized and studied.
We have shown that the presence and the localization of the macrocycle tremendously affected the affinity of the foldamer unit for the encircled axle. Reciprocally, the very high affinity of the foldamer for the axle allowed to sequestrate the macrocycle around a part of the axle for which it has no affinity. This allowed the synthesis of an improbable interlocked molecule.

Thanks to the different results obtained, we now designed foldarotaxane molecular shuttles, in which orchestrated and induced motions of the macrocycle and foldamer units along the encircled axle would occur. For this, different molecular targets have been synthesized and are currently studied.

[1] Interplay between a foldamer helix and a macrocycle in a foldarotaxane architecture, M. Gauthier, V. Koehler, C. Clavel, B. Kauffmann, I. Huc, Y. Ferrand and F. Coutrot, Angew. Chem. Int. Ed. 2021, 60, 8380-8384
[2] Weinreb amide as secondary station for the DB24C8 in a molecular shuttle, M. Gauthier and F. Coutrot, Eur. J. Org. Chem. 2019, 21, 3391-3395.
[3] Study of [2] and [3]rotaxanes obtained by post-synthetic aminolysis of a kinetically stable though activated carbonate-containing pseudorotaxane, P. Waelès, M. Gauthier and F. Coutrot, Eur. J. Org. Chem. 2022, e202101385.
[4] [3]Foldarotaxane-Mediated Synthesis of an Improbable [2]Rotaxane, V. Koehler, M. Gauthier, C. Yao, K. Fournel-Marotte, P. Waelès, B. Kauffmann, I. Huc, F. Coutrot and Y. Ferrand, Chem. Commun. 2022, 58, 8618-8621.
[5] Directional Threading and Sliding of a Dissymmetrical Foldamer Helix on Dissymmetrical Axles, X. Wang, Q. Gan, B. Wicher, Y. Ferrand, I. Huc, Angew. Chem. Int. Ed. 2019, 58, 4205-4209.
[6] Discrepancy regarding the dethreading of a DB24C8 macrocycle through a perfluorobutyl end in [2]pseudorotaxanes, M. Gauthier and F. Coutrot, Eur. J. Org. Chem. 2022, e202101201.
[7] Challenges and opportunities in the post-synthetic modification of interlocked molecules, P. Waelès, M. Gauthier and F. Coutrot, Angew. Chem. Int. Ed. 2021, 60, 16778-16799.
[8] Post-synthetic macrocyclization of rotaxane building blocks, M. Gauthier, P. Waelès and F. Coutrot, ChemPlusChem 2022, 87, e202100458.
[9] Foldaxanes: Rotaxane-like Architectures from Foldamers, V. Koehler, A. Roy, I. Huc and Y. Ferrand, Acc. Chem. Res. 2022, 55, 1074-1085.

Interlocked molecules are appealing compounds comprising several components usually held together not by covalent bonds, but by the mechanical consequence of their being interlaced. Their structure allows the gliding of one element of the assembly with respect to another, which is of real interest for the design and the actuation of molecular machines with several output signals depending on the locations of the interlocked elements. The first interlocked compounds were synthesized in very low yields via statistical (interlacing of two components that have no affinity for one another) and dynamic covalent bonding strategies using long synthetic routes. In the 80’s, new knowledge on supramolecular interactions gave impetus to the development of various, much more efficient, template-directed syntheses based on coordinative or other noncovalent bonding interactions as the driving force to assemble the elements to be interlocked. Thereby, it provided a better access to interlocked molecules and molecular machines, a field that has just been highlighted by the 2016 Nobel Prize in chemistry. However, efficient synthesis of interlocked molecules lacks generality and remains restricted to structures that bear the recognition features (i.e. templates) used for their fabrication. The necessary presence of the template sites thereafter interferes with subsequent motions, for example by slowing them down, thus limiting their applicative interest. Therefore, interlocked compounds in which the assembled elements have weak or no affinity for each other are scarce. Because interlocked compounds proved to hold very singular properties with respect to their non-interlocked analogues, the generalized synthesis to any kind of interlocked molecules is of the highest interest. In this project, we aim at synthesizing various interlocked molecular architectures devoid of any site of interaction between the assembled elements. The originality of the chemical access relies on the use of two auxiliary species that roughly permit the trapping of a macrocycle around an axle before releasing it efficiently around another axle for which it has no affinity. A so-called auxiliary translocator is designed: (1) to bind efficiently a macrocycle in a first instance thanks to the presence of a template moiety; (2) to be elongated with the targeted axle to be encircled; (3) so that the template can be concealed in order to provide a high degree of freedom to the translation motion of the macrocycle along the entire encircled axle (i.e. a Brownian motion which statistically distributes the macrocycle along the thread depending on the length and the shape of both parts of the elongated axle); (4) the link between the translocator and the axle to be encircled is cleavable to generate the targeted “impossible” interlocked molecule and to recycle the auxiliary translocator. The second auxiliary species is a foldamer, whose role is to bind with a very high affinity the translocator part of the elongated axle, providing a foldarotaxane (i.e. a novel interlaced architecture in which an axle is surrounded by both a foldamer and a macrocycle). The aimed result of the use of the foldamer is a change of the position of the macrocycle through a biased Brownian motion of the macrocycle along the entire axle, even though it has no affinity for any of the two parts of the axle.
Beyond the development of new efficient chemical access to any kinds of interlocked molecules, the project deals with very novel intriguing foldarotaxane architectures whose structures and cooperative actuations of macrocycle and foldamer must be extensively and accurately studied.