Progress in the Total Synthesis of Cephalotane Diterpenoid Natural Products

doi:10.6023/cjoc202408007

Abstract

Continuous research on Cephalotaxus plants has ultimately led to the US food and drug administration (FDA) approval of homoharringtonine in 2012 for the treatment of chronic myeloid leukemia. Additionally, another important class of natural products from Cephalotaxus plants is cephalotane diterpenoids. Since the discovery of the first member, harringtonolide, in 1978, cephalotane diterpenoids have garnered significant attention from the scientific community due to their remarkable anti-cancer activity. The unique structural features of cephalotane diterpenoids, a 7/6/5/6-fused tetracyclic carbon skeleton and a bridged lactone, make them ideal targets for synthetic chemists. Successfully synthesizing these complex diterpenoids is of great importance for the discovery and development of anti-tumor drugs. To date, ten research groups have completed the total synthesis of 24 cephalotane diterpenoids. The latest progress in the total synthesis of cephalotane diterpenoids is reviewed, showcasing the importance of these innovative synthetic strategies in the efficient synthesis of complex natural products and their potential significance in advancing the field of drug discovery.

Key words: cephalotane diterpenoids, total synthesis, anti-cancer activity, harringtonolide, Cephalotaxus

Cite this article

Yiming Ding, Tingrong Zhang, Jingwei Zhang, Jun Deng. Progress in the Total Synthesis of Cephalotane Diterpenoid Natural Products[J]. Chinese Journal of Organic Chemistry, 2025, 45(6): 2048-2073.

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Fig. & Tab. 27

Figure 1. Representative structures of cephalotane diterpenoids

Scheme 1. Nay, Yue and Cai's proposed biosynthetic proposals for Cephalotaxus troponoids

Scheme 2. Dai's proposed biosynthetic pathway to cephalotene from GGPP

Scheme 3. Yue's proposed biosynthetic pathway to the dimerization of cephalotane-type C19-norditerpenoids

Scheme 4. Total synthesis of (±)-hainanolidol by Mander's group

Scheme 5. Total synthesis of (±)-cephinoid H and (±)-fortalpinoid C by Zhao's group

Scheme 6. Total synthesis of (±)-cephanolide E by Zhao's group

Scheme 7. Synthesis of (±)-harringtonolide by Sarpong's group

Scheme 8. Total synthesis of (±)-cephanolide A and (±)-harringtonolide by Wang's group

Scheme 9. Total synthesis of (±)-hainanolidol and (±)-harringtonolide by Tang's group

Scheme 10. Total synthesis of (＋)-harringtonolide by Zhai's group

Scheme 11. Semi-synthesis of (－)-cephalodiones B~D by Yue's Group

Scheme 12. Total synthesis of (±)-cephanolides A~D by Sarpong's group

Scheme 13. Total synthesis of benzenoid cephalotane-type norditerpenoids by Sarpong's group

Scheme 14. Total synthesis of (－)-cephanolides A and B by Cai's group

Scheme 15. Total synthesis of (＋)-fortalpinoid A, (＋)-cephinoid H, (＋)-3-deoxyfortalpinoid F by Hu's group

Scheme 16. Total synthesis of (±)-cephanolide B by Yang's/Zhang's group

Scheme 17. Total synthesis of (－)-cephanolides B~D and (－)-ceforalide B by Hu's group

Scheme 18. Total synthesis of (－)-cephinoid P, (－)-cephafortoid A, (－)-fortalpinoids M, N, P by Gao's group

Scheme 19. Total synthesis of (－)-cephalotanin B by Hu's group

Scheme 20. Total syntheses of (＋)-3-deoxyfortalpinoid F, (－)-fortapinoids M/N/P, (＋)-harringtonolide by Hu's group

Scheme 21. Total synthesis of (±)-cephanolides B and C by Zhao's group

Scheme 22. Total synthesis of (＋)-mannolide C by Zhai's group

Scheme 23. Total synthesis of (－)-cephanolides A~D by Zhai's group

Scheme 24. Total synthesis of (－)-cephanolides A and B by Gao's group

Scheme 25-1. Key strategies applied for the total syntheses of cephalotane diterpenoids

Scheme 25-2. Key strategies applied for the total syntheses of cephalotane diterpenoids

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