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Total Syntheses of Pepluanols A and B

Po-Sen Tseng
Po-Sen Tseng
Graduate Student, Department of Chemistry
University of Georgia
Chemistry Building, Room 400
Organic Seminar

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 KV1.3 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.

Pepluanol A and Pepluanol B illustration

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.

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