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Facile synthesis of per(6-O-tert-butyldimethylsilyl)-α-, β-, and γ-cyclodextrin as protected intermediates for the functionalization of the secondary face of the macrocycles

Nature Protocols volume 16, pages 965–987 (2021)Cite this article

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Abstract

Per(6-O-tert-butyldimethylsilyl)-α-, β- and γ-cyclodextrin derivatives are well-known as synthetic intermediates that enable the selective mono-, partial, or perfunctionalization of the secondary face of the macrocycles. Although silylation of the primary rim is readily achieved by treatment with tert-butyldimethylsilyl chloride in the presence of pyridine (either alone or mixed with a co-solvent), the reaction typically results in a mixture containing both under- and oversilylated byproducts that are difficult to remove. To address this challenge in preparing a pure product in high yield, we describe an approach that centers on the addition of a controlled excess of silylating agent to avoid the presence of undersilylated species, followed by the removal of oversilylated species by column chromatography elution with carefully designed solvent mixtures. This methodology works well for 6-, 7-, and 8-member rings (α-, β-, and γ-cyclodextrins, respectively) and has enabled us to repeatedly prepare up to ⁓35 g of ≥98% pure product (as determined by HPLC) in 3 d. We also provide procedures for lower-scale reactions, as well as an example of how the β-cyclodextrin derivative can be used for functionalization of the secondary face of the molecule.

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Fig. 1: Synthesis.
Fig. 2: Glassware setup.
Fig. 3: HPLC chromatograms.
Fig. 4: Glassware setup for silylation.
Fig. 5: Setup for weighing TBDMSCl.
Fig. 6: Monitoring of silylation progress.
Fig. 7: Flash column chromatography setup.

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Data availability

All new data within the protocol are described in the main text and, especially, in the Supplementary Information. We have uploaded data to ChemSpider:

Hexakis(6-O-tert-butyldimethylsilyl)-α-cyclodextrin: http://www.chemspider.com/Chemical-Structure.22906192.html?rid=1005ca4c-3af0-424e-9d66-ce62c6fbd2af

Heptakis(6-O-tert-butyldimethylsilyl)-β-cyclodextrin: http://www.chemspider.com/Chemical-Structure.9117549.html?rid=f58032ed-2a07-41d9-b0a1-e5f96834d59b

Octakis(6-O-tert-butyldimethylsilyl)-γ-cyclodextrin:

http://www.chemspider.com/Chemical-Structure.9161332.html?rid=9f13f13d-2816-437d-8c28-346dfa4e4f3b&page_num=0

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Acknowledgements

We acknowledge the Spanish Ministry of Economy and Competitiveness for funding (CTQ2017-90050-R). S.B. is grateful for financial support from the János Bolyai Research Scholarship of the Hungarian Academy of Sciences and from the Bolyai+ New National Excellence Program (grant no. ÚNKP-19-4-SE-53) of the Ministry of Human Capacities.

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Authors and Affiliations

  1. CycloLab Ltd., Budapest, Hungary

    Gábor Benkovics & Milo Malanga

  2. Department of Chemistry and Physics, University of Almería, Almería, Spain

    Giovanna Cutrone, Antonio Vargas-Berenguel & Juan Manuel Casas-Solvas

  3. Department of Pharmacognosy, Semmelweis University, Budapest, Hungary

    Szabolcs Béni

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  1. Gábor Benkovics
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  2. Milo Malanga
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Contributions

M.M. and J.M.C.-S. designed and optimized the synthesis strategies and the purification steps. G.B., M.M., and G.C. performed the syntheses. S.B., M.M., and J.M.C.-S. performed the NMR experiments and elucidated the spectra. J.M.C.-S. wrote the manuscript. G.B., M.M., and J.M.C.-S. prepared the Supplementary Information. All the authors reviewed the manuscript and added comments and suggestions at all stages. A.V.-B. supervised the project and provided conceptual advice.

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Correspondence to Juan Manuel Casas-Solvas.

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Key references using this protocol

Cutrone, G. et al. Nanomaterials 9, 1103 (2019): https://doi.org/10.3390/nano9081103.

Casas-Solvas, J. M., Vargas-Berenguel, A. & Malanga, M. in Carbohydrate Chemistry: Proven Synthetic Methods Vol. 4 (eds Vogel, C. & Murphy, P.) 26.205–26.211: https://doi.org/10.1201/9781315120300-26.

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Benkovics, G., Malanga, M., Cutrone, G. et al. Facile synthesis of per(6-O-tert-butyldimethylsilyl)-α-, β-, and γ-cyclodextrin as protected intermediates for the functionalization of the secondary face of the macrocycles. Nat Protoc 16, 965–987 (2021). https://doi.org/10.1038/s41596-020-00443-8

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