Total Syntheses of Marine-Derived Polyhalogenated Natural Products

doi:10.6023/cjoc202408037

Abstract

The incorporation of halogens is a unique strategy employed by marine organisms to modify their multifunctional metabolites, often leading to changes in biological activity and the metabolic or degradation processes in vivo. At the same time, the introduction of halogens increases the structural complexity of marine natural products, making their identification more challenging. In recent years, the unique chemical structures and diverse biological functions of polyhalogenated marine-derived natural products have garnered significant interest from organic synthetic chemists. Recent advances in the total synthesis of polyhalogenated marine-derived natural products, focusing on polyhalogenated indole alkaloids (Caulamidines, Perophoramidine, Hinckdentine A, Spiroindimicins, Dictazole B, Securiflustra securifrons, Nortopsentin D), other polyhalogenated alkaloids (Psammaplysins, Massadine, Axinellamine, Discorhabdins), and representative polyhalogenated steroidal natural products (Clionastatins) are summarized.

Key words: marine polyhalogenated natural product, natural product, total synthesis

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Qingxing Yang, Xuan Liu, Shuo Ma, Xinxin Li, Dongxu Ma, Tao Xu. Total Syntheses of Marine-Derived Polyhalogenated Natural Products[J]. Chinese Journal of Organic Chemistry, 2025, 45(3): 764-803.

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Fig. & Tab. 44

Figure 1. Family members of Caulamidines alkaloids

Scheme 1. The first total synthesis of (–)-Caulamidine A by Maimone’s group

Scheme 2. The first enantioselective total synthesis of (–)-Caulamidine D and (–)-Isocaulamidine D by Xu’s group

Scheme 3. Total synthesis of Perophoramidine by Funk’s group

Scheme 4. Total enantioselective synthesis of (+)-Perophoramidine by Qin’s group

Scheme 5. Total enantioselective synthesis of (+)-Perophoramidine by Wang’s group

Scheme 6. Total enantioselective synthesis of (–)-Perophoramidine by Trost’s group

Scheme 7. Formal synthesis of (+)-Perophoramidine by Stoltz’s group

Scheme 8. Total synthesis of (±)-Hinckdentine A by Kawasaki’s group

Scheme 9. Asymmetric total synthesis of (+)-Hinckdentine A by Fukuyama and Kitamura’s group

Scheme 10. Asymmetric total synthesis of (+)-Hinckdentine A by Zhu’s group

Scheme 11. Total synthesis of (±)-Hinckdentine A by Xu’s group

Scheme 12. Total synthesis of (±)-Hinckdentine A by Cheon’s group

Scheme 13. Asymmetric total synthesis of (+)-Hinckdentine A by Hong’s group

Scheme 14. Asymmetric total synthesis of (+)-Hinckdentine A by Rawal’s group

Figure 2. Spiroindimicin alkaloids

Scheme 15. Total synthesis of Spiroindimicin B/C by Sperry’s group

Scheme 16. Total synthesis of Spiroindimicin A by Smith’s group

Scheme 17. Total synthesis of Spiroindimicin A by Xu’s group

Scheme 18. Modular total synthesis of 5/5-Spirocyclic spiroindimicins by Smith’s group

Figure 3. Several representative compounds of Aplysinopsins type alkaloids

Scheme 19. Preparation of precursor for (±)-Dictazole B synthesis

Scheme 20. Solid-state dimerization under irradiation with artificial sunligh

Scheme 21. Rationalization of the DNA-templated [2+2] cycloaddition

Figure 4. Polyhalogenated alkaloids Securiflustra securifrons and Chartelline C

Scheme 22. Synthesis of (±)-Charteline C by Baran’s group

Scheme 23. Synthesis of (±)-Securine A and (±)-Securamine A by Herzon’s group

Scheme 24. Synthesis of other Securiflustra securifrons’ alkaloids by Herzon’s group

Figure 5. Nortopsentin type alkaloids and their synthetic analogues

Scheme 25. Synthesis of Nortopsentin D by Tepe’s group

Scheme 26. Synthesis of (±)-Psammaplysin A by Magauer’s group

Scheme 27. Synthesis of Psammaplysins A, M, O, Q and Ceratinamide A by Smith’s group

Scheme 28. 7?Deoxypsammaplysins K, O and 7?Deoxyceratinamide A by Yang’s group

Scheme 29. Total synthesis of Massadine by Baran

Scheme 30. Total synthesis of Sceptrin by Chuo and Baran

Scheme 31. Total synthesis of Nakamuric acid by Baran

Scheme 32. Total synthesis of Axinellamines by Baran

Scheme 33. Total synthesis of Axinellamines by Chuo

Figure 6. Completely synthesized molecules of the Discorhabdins alkaloid family

Scheme 34. Yamamura’s group on the synthesis of Discorhabdin C

Scheme 35. Synthesis of Discorhabdin C by Kita’s group

Scheme 36. Synthesis of Discorhabdins C and E by Heathcock’s group

Scheme 37. Total synthesis of Clionastatins by Gui’s group

Scheme 38. Total synthesis of Clionastatins by Zhang’s group

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