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Preparative scale and convenient synthesis of a water-soluble, deep cavitand

Nature Protocols volume 11, pages 1371–1387 (2016)Cite this article

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Abstract

Cavitands are established tools of supramolecular chemistry and molecular recognition, and they are finding increasing application in sensing and sequestration of physiologically relevant molecules in aqueous solution. The synthesis of a water-soluble, deep cavitand is described. The route comprises six (linear) steps from commercially available precursors, and it relies on the fourfold oligomeric cyclization reaction of resorcinol with 2,3-dihydrofuran that leads to the formation of a shallow resorcinarene framework; condensation with aromatic panels, which deepens the hydrophobic binding cavity; construction of rigid urea functionalities on the upper rim; and the introduction of the water-solubilizing methylimidazolium groups on the lower rim. Late intermediates of the synthesis can be used in the preparation of congener cavitands with different properties and applications, and a sample of such a synthetic procedure is included in this protocol. Emphasis is placed on scaled-up reactions and on purification procedures that afford materials in high yield and avoid chromatographic purification. This protocol provides improvements over previously described procedures, and it enables the preparation of sizable amounts of deep cavitands: 7 g of a water-soluble cavitand can be prepared from resorcinol in 13 working days.

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Figure 1: Chemical structure of the water-soluble, deep cavitand 6 (ref. 59).
Figure 2: Models of the dynamic conformations of 6.
Figure 3: Synthetic scheme for the preparation of the water-soluble cavitand 6.
Figure 4: Some examples of functional upper rims (top) and water-solubilizing feet (R1, bottom) of congeners of the cavitand 6 prepared in our lab as derivatives of 4.
Figure 5: Typical setup for the synthesis of the tetra(chloropropyl) octaamino cavitand 4.
Figure 6: Part of the 1H-NMR spectrum (25 °C, DMSO-d6, 400 MHz) of the tetra(chloropropyl) octaamino cavitand (4).
Figure 7: 1H-NMR stacked spectra (25 °C, D2O, 600 MHz).

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Acknowledgements

This research was supported by the National Science foundation (CHE 1506266) and a Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme (grant agreement no. PIOF-GA-2013-627403, postdoctoral fellowship to S.M.).

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Authors and Affiliations

  1. The Skaggs Institute for Chemical Biology,

    Simone Mosca, Yang Yu & Julius Rebek Jr

  2. , The Scripps Research Institute, La Jolla, California, USA

    Simone Mosca, Yang Yu & Julius Rebek Jr

  3. Department of Chemistry, The Scripps Research Institute, La Jolla, California, USA

    Simone Mosca, Yang Yu & Julius Rebek Jr

  4. Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano, Italy

    Simone Mosca

  5. Department of Chemistry, Fudan University, Shanghai, China

    Julius Rebek Jr

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  1. Simone Mosca
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Contributions

S.M. and Y.Y. contributed equally to this work. S.M. conceived and optimized the protocol; Y.Y. carried out experiments; and S.M. and J.R. wrote the manuscript.

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Correspondence to Julius Rebek Jr.

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Integrated supplementary information

Supplementary Figure 1 1H NMR spectrum for compound 1

1H-NMR spectrum (25 °C, DMSO-d6, 600 MHz) of the compound 1. The material may contain traces of residual THF, which does not interfere with the next step.

Supplementary Figure 2 1H NMR spectrum for compound 2

1H-NMR spectrum (25 °C, DMSO-d6, 600 MHz) of the compound 2. The characteristic methine peak and the corresponding atoms are marked with the green arrows. The material may contain traces of residual Et2O, which does not interfere with the next step.

Supplementary Figure 3 1H NMR spectrum for compound 3

1H-NMR spectrum (25 °C, DMSO-d6, 600 MHz) of the compound 3. The characteristic methine peak and the corresponding atoms are marked with the green arrows. The material may contain traces of residual Et2O, which does not interfere with the next step.

Supplementary Figure 4 1H NMR spectrum for compound 4

1H-NMR spectrum (25 °C, DMSO-d6, 600 MHz) of the compound 4. The characteristic methine peak and the corresponding atoms are marked with the green arrows. The material usually contains residual solvents and salts that result in extra weighing but do not interfere with the next step.

Supplementary Figure 5 1H NMR spectrum for compound 5

1H-NMR spectrum (25 °C, DMSO-d6, 600 MHz) of the compound 5. The characteristic methine peak and the corresponding atoms are marked with the green arrows. The material may contain traces of residual solvents (AcOEt and ACN), which do not interfere with the next step.

Supplementary Figure 6 1H NMR spectrum for compound 6

1H-NMR spectrum (25 °C, DMSO‑d6, 600 MHz) of the compound 6.23 The characteristic methine peak and the corresponding atoms are marked with the green arrows. The solid usually contains residual acetone (~ 3% w/w by NMR peak integration) that resists removal under high vacuum, as also observed with the previously reported analogue of 6 with pyridinium feet.

Supplementary Figure 7 1H NMR spectrum for compound 6 lyophilized

1H-NMR spectrum (25 °C, DMSO-d6, 600 MHz) of the compound 6 after lyophilization. The characteristic methine peak and the corresponding atoms are marked with the green arrows. Lyophilzation efficiently removes acetone traces.

Supplementary Figure 8 1H NMR spectrum for compound 14

1H-NMR spectrum (25 °C, 5% (vol/vol) D2O in acetone-d6, 600 MHz) of the compound 14.32 The characteristic methine peak and the corresponding atoms are marked with the green arrows. The material may contain traces of residual solvents (AcOEt and ACN), which do not interfere with the next step.

Supplementary Figure 9 1H NMR spectrum for compound 15

1H-NMR spectrum (298 K, 10% (vol/vol) D2O in DMSO-d6, 600 MHz) of the compound 15.32 The characteristic methine peak and the corresponding atoms are marked with the green arrows.

Supplementary Figure 10 1H NMR spectrum for compound 15 in 5% DMSO aqueous solution

1H-NMR spectrum (298 K, 5% (vol/vol) DMSO-d6 in D2O, 600 MHz) of cavitand 15 (1 mM).32 15 features a kinetically stable (on the NMR time scale) vase conformation in aqueous solutions and broadened aryl C−H signals characteristic of kite form (between 6.0 and 6.5 ppm) are not observed either in absence of hydrophobic guests. The characteristic methine peak and the corresponding atoms are marked with the green arrows.

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Supplementary Figures 1–10 (PDF 1193 kb)

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Mosca, S., Yu, Y. & Rebek, J. Preparative scale and convenient synthesis of a water-soluble, deep cavitand. Nat Protoc 11, 1371–1387 (2016). https://doi.org/10.1038/nprot.2016.078

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