Abstract
For over a century, naturally occurring cyclodextrins (CDs) have been investigated intensively and extensively. CDs possess inherently stable chiralities, which render them versatile players in diverse arenas of technology. Although naturally occurring CDs can be mass-produced by the enzymatic modification of amylose, their mirror-images have, however, remained inaccessible. Here we report the syntheses of three mirror-image CDs—namely, α-, β- and γ-l-CDs, which are composed of six, seven and eight α-1,4-linked l-glucopyranosyl residues, respectively. Hallmarks of their syntheses include the highly diastereoselective installations of multiple contiguous 1,2-cis l-glucopyranosidic linkages, the rapid assembly of linear oligosaccharides employing one-pot glycosylation strategies and three efficient diastereoselective cyclizations. The structures and inherent chiralities of all three synthetic l-CDs have been established unambiguously by single-crystal X-ray diffraction and induced electronic circular dichroism spectroscopy. The availability of l-CDs has enabled the elucidation of an unprecedented chiral self-sorting of a racemic modification of β-CDs in the solid state and an investigation of the chiral recognition of enantiomeric fenchone by α-l-CD. This research identifies a missing piece of the cyclodextrin jigsaw and sets the stage for scientists to explore the mirror-image world of naturally occurring CDs.
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Data availability
All data that support the findings of this study are available in the main text and the Supplementary Information. X-Ray crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition numbers CCDC 2246203 (α-l-CD), 2246204 (β-l-CD), 2246205 (γ-l-CD) and 2266813 (β-d- and β-l-CD cocrystal). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. Source data are provided with this paper.
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Acknowledgements
Northwestern University (NU, J.F.S.), the University of Hong Kong (J.F.S.) and the Robert A. Welch Foundation (Y-0026 to D.W.A.) are acknowledged for financial support. This work made use of the Integrated Molecular Structure Education and Research Center (IMSERC) at NU, which receives support from the NIH (1S10OD012016-01/1S10RR019071-01A1), Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-1542205), the State of Illinois and the International Institute for Nanotechnology (IIN). Use of resources of the Keck Biophysics Facility was supported in part by National Cancer Institute award CCSG-P30-CA060553 to the Robert H. Lurie Comprehensive Cancer Center at NU.
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Y.W. and J.F.S. conceived the study and designed experiments. Y.W. performed research under J.F.S.’s guidance. S.A., G.W. and D.W.A. contributed to the chiral recognition experiments. H.H. conducted density functional theory calculations. C.T. contributed to the IECD spectroscopy and X-ray crystallographic analysis. C.L.S. collected and solved the X-ray diffraction data. X.L., H.W., Q.-H.G., Y.Q., A.X.-Y.C., Y.J., R.Z. and A.H.G.D. commented on the data and all authors contributed to data analysis. Y.W. and J.F.S. wrote the manuscript with input from all authors.
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Y.W. and J.F.S. have filed a patent application with Northwestern University (Innovation and New Ventures Office Reference No. NU 2024-020) based on this research. The other authors declare no competing interests.
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Supplementary information
Supplementary Information
Experimental Details, Supplementary Figs. 1–48 and Schemes 1–17.
Supplementary Data 1
X-ray crystallographic data for α-l-CD, CCDC 2246203.
Supplementary Data 2
X-ray crystallographic data for β-l-CD, CCDC 2246204.
Supplementary Data 3
X-ray crystallographic data for γ-l-CD, CCDC 2246205.
Supplementary Data 4
X-ray crystallographic data for β-d- and β-l-CD cocrystal, CCDC 2266813.
Source data
Source Data Fig. 5
Source data for Fig. 5.
Source Data Fig. 6
Source data for Fig. 6.
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Wu, Y., Aslani, S., Han, H. et al. Mirror-image cyclodextrins. Nat. Synth (2024). https://doi.org/10.1038/s44160-024-00495-8
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DOI: https://doi.org/10.1038/s44160-024-00495-8