Total Syntheses of Pepluanols A and B

Euphorbia is a large and diverse genus of flowering plants in the spurge family, comprising more than 2,000 species.^1,2 Many of them have long been used in herbal folk medicine. In 2016 and 2018, Qiu and co-workers isolated five diterpenoids, pepluacetal and pepluanols A–D, from Euphorbia peplus.^3,4 All five compounds show effective inhibitory activity on the K_V1.3 voltage-gated potassium channel. Thus, they are potential candidates for the treatment of autoimmune diseases. To date, only three total syntheses have been published. Ding and co-workers reported the first total synthesis of (±)-pepluanol A in 2017.⁵ They completed the synthesis of this tetracyclic compound using Diels–Alder reaction, reductive annulation and Dauben–Michno reaction. In 2020, She research group published the first total synthesis of pepluanol B in both racemic and enantioenriched forms.⁶ A ring-closing metathesis was employed to construct the eight-member ring. The ring conformation was then controlled by a bromo-epoxidation to facilitate the following methylation with the desired configuration. In 2021, Gaich and co-workers completed a ten-step asymmetric total synthesis of (+)-pepluanol A.⁷ Their strategies included Nozaki–Hiyama–Kishi reaction and the Curtin–Hammett-driven stereo-convergent Diels–Alder reaction. All the chemistry in these three recently published articles will be presented in this seminar.

References:

1. Shi, Q.-W.; Su, X.-H.; Kiyota, H. Chemical and Pharmacological Research of the Plants in Genus Euphorbia. Chem. Rev. 2008, 108, 4295–4327.
2. Vasas, A.; Hohmann, J. Euphorbia Diterpenes: Isolation, Structure, Biological Activity, and Synthesis (2008–2012). Chem. Rev. 2014, 114, 8579–8679.
3. Wan, L.-S.; Nian, Y.; Ye, C.-J.; Shao, L.-D.; Peng, X.-R.; Shao, L.- D.; Geng, C.-A.; Zuo, Z.-L.; Li, X.-N.; Yang, J.; Zhou, M.; Qiu, M.-H. Three Minor Diterpenoids with Three Carbon Skeletons from Euphorbia peplus. Org. Lett. 2016, 18, 2166–2169.
4. Wan, L.-S.; Nian, Y.; Peng, X.-R.; Shao, L.-D.; Li, X.-N.; Yang, J.; Zhou, M.; Qiu, M.-H. Pepluanols C–D, Two Diterpenoids with Two Skeletons from Euphorbia peplus. Org. Lett. 2018, 20, 3074–3078.
5. Xuan, J.; Liu, Z.; Zhu, A.; Rao, P.; Yu, L.; Ding, H. Diastereoselective Total Synthesis of the Euphorbia Diterpenoid Pepluanol A: A Reductive Annulation Approach. Angew. Chem. Int. Ed. 2017, 56, 8898–8901.
6. Zhang, J.; Liu, M.; Wu, C.; Zhao, G.; Chen, P.; Zhou, L.; Xie, X.; Fang, R.; Li, H.; She, X. Total Synthesis of (–)-Pepluanol B: Conformational Control of the Eight-Membered-Ring System. Angew. Chem. Int. Ed. 2020, 59, 3966–3970.
7. Yuan, P.; Gerlinger, C. K. G.; Herberger, J.; Gaich, T. Ten-Step Asymmetric Total Synthesis of (+)-Pepluanol A. J. Am. Chem. Soc. 2021, 143, 11934–11938.