Total Synthesis of Cephanolide A and Harringtonolide: A Unified Strategy Connecting Benzenoid and Troponoid Cephalotaxus Diterpenoids

Zhang, Zi-An; Gan, Xu-cheng; Tian, Guang; Shi, Xiao-Yu; Qin, Chuanguang; Wang, Jie

doi:10.26434/chemrxiv-2024-rp8s5

2024

DOI: 10.26434/chemrxiv-2024-rp8s5

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Total Synthesis of Cephanolide A and Harringtonolide: A Unified Strategy Connecting Benzenoid and Troponoid Cephalotaxus Diterpenoids

Zi-An Zhang,

Xu-cheng Gan,

Guang Tian

et al.

Abstract: The fascinating benzenoid and troponoid Cephalotaxus diterpenoids are highly related biosynthetically, both of which are popular targets for total synthesis. Herein, we describe a unified strategy for the concise synthesis of cephanolide A and harringtonolide in 14 and 16 steps respectively. Palladium catalyzed Csp2-Csp3 cross-coupling followed by doubly electron-deficient intramolecular Diels-Alder reaction secure the rapid construction of the Cephalotaxus carbon framework. Late-stage benzenoid-to-troponoid r… Show more

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Cited by 3 publications

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Bioinspired Total Synthesis of Cephalotaxus Diterpenoids and Their Structural Analogues

Shao,

Ma,

Cheng

et al. 2024

Angewandte Chemie

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Here, we present a unified chemical synthesis of three subgroups of cephalotaxus diterpenoids for the first time. Key to the success lies in adopting a synthetic strategy that is inspired by biosynthesis but is opposite in nature. By employing selective one‐carbon introduction and ring expansion operations, we have successfully converted cephalotane‐type C18 dinorditerpenoids (using cephanolide B as a starting material) into troponoid‐type C19 norditerpenoids and intact cephalotane‐type C20 diterpenoids. This synthetic approach has enabled us to synthesize cephinoid H, 13‐oxo‐cephinoid H, 7‐oxo‐cephinoid H, fortalpinoid C, 7‐epi‐fortalpinoid C, cephanolide E, and 13‐epi‐cephanolide E. Furthermore, through the development of an intermolecular asymmetric Michael reaction between β‐oxo esters and β‐substituted enones, we have achieved the enantioselective synthesis of advanced intermediates within our synthetic sequence, thus formally realizing the asymmetric total synthesis of the cephalotaxus diterpenoids family.

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Bioinspired Total Synthesis of Cephalotaxus Diterpenoids and Their Structural Analogues

Shao,

Ma,

Cheng

et al. 2024

Angewandte Chemie

View full text Add to dashboard Cite

show abstract

Bioinspired Total Synthesis of Cephalotaxus Diterpenoids and Their Structural Analogues

Shao,

Ma,

Cheng

et al. 2024

Angew Chem Int Ed

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Late-stage benzenoid-to-troponoid skeletal modification of the cephalotanes exemplified by the total synthesis of harringtonolide

Wiesler,

Sennari,

Popescu

et al. 2024

Nat Commun

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Skeletal modifications enable elegant and rapid access to various derivatives of a compound that would otherwise be difficult to prepare. They are therefore a powerful tool, especially in the synthesis of natural products or drug discovery, to explore different natural products or to improve the properties of a drug candidate starting from a common intermediate. Inspired by the biosynthesis of the cephalotane natural products, we report here a single-atom insertion into the framework of the benzenoid subfamily, providing access to the troponoid congeners — representing the reverse of the proposed biosynthesis (i.e., a contra-biosynthesis approach). Computational evaluation of our designed transformation prompted us to investigate a Büchner–Curtius–Schlotterbeck reaction of a p-quinol methylether, which ultimately results in the synthesis of harringtonolide in two steps from cephanolide A, which we had previously prepared. Additional computational studies reveal that unconventional selectivity outcomes are driven by the choice of a Lewis acid and the nucleophile, which should inform further developments of these types of reactions.

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Total Synthesis of Cephanolide A and Harringtonolide: A Unified Strategy Connecting Benzenoid and Troponoid Cephalotaxus Diterpenoids

Cited by 3 publications

References 17 publications

Bioinspired Total Synthesis of Cephalotaxus Diterpenoids and Their Structural Analogues

Bioinspired Total Synthesis of Cephalotaxus Diterpenoids and Their Structural Analogues

Bioinspired Total Synthesis of Cephalotaxus Diterpenoids and Their Structural Analogues

Late-stage benzenoid-to-troponoid skeletal modification of the cephalotanes exemplified by the total synthesis of harringtonolide

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