Advances in Supramolecular Host–Mediated Catalysis

Recent progress in supramolecular catalysis brings the field closer to practical applications in synthesis and reveals key promising future directions in which the field can expand.
Advances in Supramolecular Host–Mediated Catalysis

In recent decades, supramolecular host­–guest chemistry has become increasingly viable for practical applications in synthesis. Supramolecular hosts allow chemists to exploit non-covalent macromolecular interactions to render divergent selectivity and rate accelerations rivalling that of enzyme catalysis. Our review covers recent major advances in the study of the unique reactivity promoted by supramolecular hosts.

The confined interior of the supramolecular host has been shown to induce conformational selectivity, as demonstrated by an aza-Prins reaction reported by Raymond and co-workers,1 and tail-to-head terpene cyclization reported by Tiefenbacher and co-workers.2 The electronic charge of the host can also stabilize oppositely charged intermediates, demonstrated both in the case of a 16+ cationic host by Ward and co-workers,3 and that of a 12– anionic host by Raymond and co-workers.4

In cooperation with transition metal catalysts, supramolecular hosts can accelerate basic organometallic steps,5 and pre-organize organometallic compounds to increase reaction rate and turnover, as studied by Reek and co-workers.6 The host scaffold can also improve the performance of metal nanoparticle catalysts, by inducing the formation of more uniform particles and protecting them from degradation and aggregation.7,8

A particularly promising direction for supramolecular hosts is the demonstration of their ability to effect regio- and site-selective transformations either by acting as a macromolecular protecting group9 or by selective encapsulation of desired sites.10 Site-selective encapsulation and functionalization of internal guest moieties enables the targeting of increasingly complex substrates with specificity. This usage of supramolecular catalysis may allow practical applications in late-stage natural product functionalization and modification of biomolecules such as peptides and proteins.

Additionally, examples of supramolecular host–mediated photochemistry include hosts behaving as both photosensitizers11 and conformational frameworks to induce stereo- and enantioselective reactivity.12 While the scope of reactivity with these methods is currently small, the reported phenomena suggest great potential applications in synthesis.

The growing interface between supramolecular catalysis and synthetically relevant fields such as organic, organometallic, and photochemistry evinces its increasing pertinence to synthetic applications. Host-guest chemistry allows control over reactivity in ways that are impossible in bulk solution. Supramolecular chemistry is at the frontier between proof-of-concept type reactivity and synthetic application. Through the study of these supramolecular systems, chemists gain understanding over the mechanistic details of microenvironment catalysis, enabling both a better understanding of more complicated macromolecular systems such as enzymes, and increasingly rational and predictive design of new hosts. The unique reactivity of supramolecular hosts can prove a pivotal addition to the synthetic chemist’s toolbox.

The full review can be found at: Morimoto, M., Bierschenk, S.M., Xia, K.T., Bergman, R.G., Raymond, K.N., Toste, F.D. Advances in supramolecular host-mediated reactivity. Nat Catal (2020).


(1)      Kaphan, D. M.; Toste, F. D.; Bergman, R. G.; Raymond, K. N. Enabling New Modes of Reactivity via Constrictive Binding in a Supramolecular-Assembly-Catalyzed Aza-Prins Cyclization. J. Am. Chem. Soc. 2015, 137 (29), 9202–9205.

(2)      Zhang, Q.; Tiefenbacher, K. Terpene Cyclization Catalysed inside a Self-Assembled Cavity. Nat. Chem. 2015.

(3)      Cullen, W.; Misuraca, M. C.; Hunter, C. A.; Williams, N. H.; Ward, M. D. Highly Efficient Catalysis of the Kemp Elimination in the Cavity of a Cubic Coordination Cage. Nat. Chem. 2016, 8 (3), 231–236.

(4)      Hong, C. M.; Morimoto, M.; Kapustin, E. A.; Alzakhem, N.; Bergman, R. G.; Raymond, K. N.; Toste, F. D. Deconvoluting the Role of Charge in a Supramolecular Catalyst. J. Am. Chem. Soc. 2018, 140 (21), 6591–6595.

(5)      Kaphan, D. M.; Levin, M. D.; Bergman, R. G.; Raymond, K. N.; Toste, F. D. Strategy for Transition Metal Catalysis. Science (80-. ). 2015, 350 (6265), 1235–1238.

(6)      Kuijpers, P. F.; Otte, M.; Dürr, M.; Ivanović-Burmazović, I.; Reek, J. N. H.; De Bruin, B. A Self-Assembled Molecular Cage for Substrate-Selective Epoxidation Reactions in Aqueous Media. ACS Catal. 2016, 6 (5), 3106–3112.

(7)      Wang, S.; Gao, X.; Hang, X.; Zhu, X.; Han, H.; Liao, W.; Chen, W. Ultrafine Pt Nanoclusters Confined in a Calixarene-Based {Ni24} Coordination Cage for High-Efficient Hydrogen Evolution Reaction. J. Am. Chem. Soc.2016, 138 (50), 16236–16239.

(8)      Mondal, B.; Acharyya, K.; Howlader, P.; Mukherjee, P. S. Molecular Cage Impregnated Palladium Nanoparticles: Efficient, Additive-Free Heterogeneous Catalysts for Cyanation of Aryl Halides. J. Am. Chem. Soc. 2016, 138 (5), 1709–1716.

(9)      Takezawa, H.; Kanda, T.; Nanjo, H.; Fujita, M. Site-Selective Functionalization of Linear Diterpenoids through U-Shaped Folding in a Confined Artificial Cavity. J. Am. Chem. Soc. 2019, 141 (13), 5112–5115.

(10)    Bender, T. A.; Bergman, R. G.; Raymond, K. N.; Toste, F. D. A Supramolecular Strategy for Selective Catalytic Hydrogenation Independent of Remote Chain Length. J. Am. Chem. Soc. 2019, 141 (30), 11806–11810.

(11)    Guo, J.; Xu, Y. W.; Li, K.; Xiao, L. M.; Chen, S.; Wu, K.; Chen, X. D.; Fan, Y. Z.; Liu, J. M.; Su, C. Y. Regio- and Enantioselective Photodimerization within the Confined Space of a Homochiral Ruthenium/Palladium Heterometallic Coordination Cage. Angew. Chemie - Int. Ed. 2017, 56 (14), 3852–3856.

(12)    Ji, J.; Wu, W.; Liang, W.; Cheng, G.; Matsushita, R.; Yan, Z.; Wei, X.; Rao, M.; Yuan, D. Q.; Fukuhara, G.; Mori, T.; Inoue, Y.; Yang, C. An Ultimate Stereocontrol in Supramolecular Photochirogenesis: Photocyclodimerization of 2-Anthracenecarboxylate Mediated by Sulfur-Linked β-Cyclodextrin Dimers. J. Am. Chem. Soc. 2019, 141 (23), 9225–9238.

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