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Synthesis of cyclodextrin derivatives for enantiodifferentiating photocyclodimerization of 2-anthracenecarboxylate

Abstract

Photochemical methods are increasingly being used in organic synthesis. They are especially useful for preparing many compounds that are not readily accessible through thermal or enzymatic reactions. The supramolecular strategy has proved highly promising in recent years for manipulating the stereochemical outcome of chiral photoreactions through relatively strong and long-lasting noncovalent interactions in both ground and excited states. Among the numerous chiral photochemical reactions, photocyclodimerization of 2-anthracenecarboxylate (AC) is the most comprehensively studied supramolecular chiral photoreaction and has essentially become a benchmark reaction for evaluating supramolecular photochirogenesis. Cyclodextrin (CD) derivatives were the earliest and are the most widely applied chiral host for mediating photoreactions. Herein, we use CD-mediated photocyclodimerization of AC as an example to introduce the operation process of supramolecular chiral photoreactions. The protocol includes the following contents: (i) the preparation, purification and characterization of β-CD derivatives; (ii) methods for investigating the host–guest inclusion behavior between AC and β-CD derivatives; (iii) the photochemical reaction operation flow under different solvent and temperature conditions; (iv) chiral high-performance liquid chromatography (HPLC) analyses of the product distribution and enantioselectivity. The protocol is introduced by using representative examples of the synthesis of β-CD derivatives and the manipulation of environmental factors that give excellent regio- and enantioselectivities in the photocyclodimerization of AC. The synthesis and purification of β-CD derivatives require 3–5 d of work. The photoirradiation of AC with β-CD derivatives can be done within 1 h. The product analysis requires 5 h.

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Fig. 1: Photocyclodimerization of AC Mediated by β-CD.
Fig. 2: Instrumental setups for photocyclodimerization of AC mediated by β-CD derivatives.
Fig. 3: Examples.
Fig. 4: Synthesis of cationic β-CDs and sulfur-bridged β-CD dimers.
Fig. 5: Chromatography setup.
Fig. 6: UV-visible spectral titration of AC with 10.
Fig. 7: Photoreaction setup.
Fig. 8: HPLC chromatograms.
Fig. 9: Degassing setup.
Fig. 10: UV-visible spectral changes of AC upon irradiation.
Fig. 11: Manipulation of photocyclodimerization of AC by changing the reaction environment.

Data availability

All relevant data for this protocol can be found in the text and Supplementary Information of this manuscript and/or its supporting primary research papers.

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Acknowledgements

We acknowledge the support of this work by the National Key Research and Development Program of China (2017YFA0505903), the National Natural Science Foundation of China (92056116, 22001046, 21871194, 21971169 and 21572142), the Fundamental Research Funds for the Central Universities (20826041D4117), the Comprehensive Training Platform of Specialized Laboratory (College of Chemistry, Sichuan University), the Department of Education, Science and Technology of Guangxi Zhuang Autonomous Region (2020KY03008, 2020AC19233 and 2021JJB120031) and the Youth Science Foundation of Guangxi Medical University (GXMUYSF201904).

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Contributions

C.Y. and W.W. designed the experiments and supervised the project. X.W. and J.J. contributed equally to this work. They designed and performed the experiments. Y.N. and L.T. performed some of the experiments. M.R., X.W., D.S. and Z.Z. composed the manuscript. All the authors reviewed and approved the manuscript.

Corresponding authors

Correspondence to Wanhua Wu or Cheng Yang.

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Nature Protocols thanks Axel Griesbeck, Yoshihisa Inoue and Yasuhiro Ishida for their contribution to the peer review of this work.

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Related Links

Key references using this protocol

Wei, X. et al. J. Am. Chem. Soc. 140, 3959–3974 (2018): https://doi.org/10.1021/jacs.7b12085

Ji, J. et al. J. Am. Chem. Soc. 141, 9225–9238 (2019): https://doi.org/10.1021/jacs.9b01993

Key data used in this protocol

Ji, J. et al. J. Am. Chem. Soc. 141, 9225–9238 (2019): https://doi.org/10.1021/jacs.9b01993

Extended data

Extended Data Fig. 1 Glassware setup for synthesis of 11 and 12.

a,b, Photographs of the state of the pyridine solution containing 100 mM β-CD before (a) and after the addition of p-toluenesulfonyl chloride dissolved in pyridine for 4 h (b). The reaction mixture was vigorously stirred under Ar protection with an inflated Ar balloon.

Extended Data Fig. 2 Glassware setup and TLC example for synthesis of 13 and 14.

a, Glassware setup for synthesis of 6A,6C-diiodo-β-CD 13 or 6A,6D-diiodo-β-CD 14. b, Iodination for 6A,6C-di-O-tosyl-β-CD 11 monitored by TLC (the TLC Rf values of 6A,6X-di-O-tosyl-β-CD and 6A,6X-diiodo-β-CD are 0.6 and 0.5, respectively, using isopropanol/EtOAc/H2O/NH3∙H2O (5:2:3:1 (vol/vol/vol/vol) as eluent).

Extended Data Fig. 3 Glassware setup.

Glassware setup for synthesis of 6A,6C-TMA2-β-CD 7 or 6A,6D-TMA2-β-CD 8.

Supplementary information

Supplementary Information

Supplementary Figs. 1–33.

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Wei, X., Ji, J., Nie, Y. et al. Synthesis of cyclodextrin derivatives for enantiodifferentiating photocyclodimerization of 2-anthracenecarboxylate. Nat Protoc 17, 2494–2516 (2022). https://doi.org/10.1038/s41596-022-00722-6

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