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Innovation in protecting-group-free natural product synthesis

Abstract

Many natural products have intriguing medicinal properties that arise from their fascinating chemical structures. This structural complexity means that the total synthesis of natural products often requires the use of protecting-group chemistry, an approach that is neither economical nor biomimetic. However, structurally complicated and bioactive natural products can be accessible through protecting-group-free (PGF) total syntheses, which are usually much more efficient, provided that the individual reactions proceed with high chemoselectivity. In this Review, we present innovations in methodology and strategy that have enabled the PGF construction of sophisticated organic skeletons bearing multiple asymmetric centres and functional groups. We begin by describing the history of PGF synthesis and then focus on illustrative examples of PGF total syntheses of terpenes and alkaloids reported from 2013 to 2017. These advances will enable more concise and efficient syntheses of molecules of structural and biological importance.

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Fig. 1: Classic examples of PGF synthesis.
Fig. 2: Key factors of PGF synthesis and its applications in total synthesis.
Fig. 3: Catalytic construction of carbon frameworks.
Fig. 4: Catalytic construction of asymmetric centres.
Fig. 5: Catalytic construction of asymmetric centres.
Fig. 6: Miscellaneous catalytic methods.
Fig. 7: Synthetic methods in PGF synthesis.
Fig. 8: Synthetic methods in PGF synthesis.
Fig. 9: Miscellaneous synthetic methods.
Fig. 10: [4+2] Cycloadditions in PGF synthesis.
Fig. 11: PGF synthesis using other cycloadditions.
Fig. 12: Cyclization cascades in PGF synthesis.

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Acknowledgements

Financial support from the National Natural Science Foundation of China (NSFC) (21772082), Shenzhen Science and Technology Innovation (SZSTI) Commission (JCYJ20170817110515599 and KQJSCX20170728154233200), Shenzhen Peacock Plan (KQTD20150717103157174), Shenzhen Development and Reform Commission (SZDRC) Discipline Construction Program and Shenzhen Nobel Prize Scientists Laboratory Project (C17783101) is gratefully acknowledged. The authors thank J. Gong (Peking University Shenzhen Graduate School (PKUSZ)), Q. Wan (Huazhong University of Science and Technology (HUST)) and X. Li (University of Hong Kong (HKU)) for helpful discussions during the preparation of this manuscript.

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Hui, C., Chen, F., Pu, F. et al. Innovation in protecting-group-free natural product synthesis. Nat Rev Chem 3, 85–107 (2019). https://doi.org/10.1038/s41570-018-0071-1

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