Abstract
Chiral macrocycles are commonly found in nature and have strong binding affinity to their targets. Thus, the development of efficient macrocyclization strategies is an important goal in the synthetic community. However, macrocyclization with chirality induction remains a great challenge because of the large entropic penalty associated with ring closure while maintaining the chiral conformation. Here, we report a highly efficient chiral macrocyclization with controlling enantioselectivity using a chiral confinement strategy. A linear substrate is encapsulated by a host precursor molecule through the formation of chiral capsule structures, which subsequently self-assemble into a robust two-dimensional structure entrapping the substrate with a folded chiral conformation. Then, the reaction under confinement generates an enantiopure macrocycle product. Furthermore, the chirality of the capsule assembly can switch into an opposite form using sonication, capable of controlling enantioselectivity. The substrate-encapsulating process is amenable to a substrate change, thus enabling diverse chirality induction in macrocycle formation. This macrocyclization method works with substrates decorated with a wide range of functional groups at high levels of precision and efficiency.
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Data availability
The data that support the findings of this study are available in the Supplementary Information.
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Acknowledgements
This work was supported by National Natural Science Foundation of China (grant nos. 21971084, 92156023 and 22150710515, to M.L., and 22171052, to M.S.), Science and Technology Commission of Shanghai Municipality (22520712300 and 23WZ2501000, to M.S.) and Fudan University Fund (to M.L. and M.S.). We thank Y. Kim for helpful discussion on simulations.
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L.T., H.W. and J.W. synthesized molecules and performed spectroscopic measurements and TEM experiments. L.T. and M.S. performed HPLC experiments for chiral macrocyclizations to quantify conversion and enantioselectivity. M.S. performed CD experiments, AFM measurements and dynamics simulation. J.K. performed X-ray experiments. M.L. developed the concept, supervised the research and wrote the manuscript with input from all authors.
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Nature Synthesis thanks Niveen Khashab and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Alison Stoddart, in collaboration with the Nature Synthesis team.
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Supplementary Figs. 1–84 and Tables 1 and 2.
Source data
Source Data Fig. 2
Source data for Fig. 2a–e of the calculations of the (P/M)-capsule.
Source Data Fig. 3
Source data for Fig. 3c,d.
Source Data Fig. 4
Source data for Fig. 4b.
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Tan, L., Sun, M., Wang, H. et al. Enantiocontrolled macrocyclization by encapsulation of substrates in chiral capsules. Nat. Synth 2, 1222–1231 (2023). https://doi.org/10.1038/s44160-023-00360-0
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DOI: https://doi.org/10.1038/s44160-023-00360-0
