Total synthesis of crotophorbolone

Yu, Tianzi; Sun, Ying; Tu, Canhui; Chen, Ting; Fu, Shaomin; Liu, Bo

doi:10.1039/d0sc02829k

Cited by 24 publications

(7 citation statements)

References 73 publications

(12 reference statements)

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“…In the time span of 2013–2020, four total 5/7/6-based Euphorbia diterpenoids were synthesized–phorbol (5/7/6/3, tigliane) by Baran's group in 2016, 382 crotophorbolone (5/7/6, rhamnofolane) and resiniferatoxin (5/7/6, daphnane) by Inoue's group in 2015 and 2017, respectively, 383,384 crotophorbolone by Liu's group in 2020, 385 and prostratin (5/7/6/3, tigliane) by Li's group in 2020. 386 The detailed information of these syntheses was summarized in a recent NPR review, which covered the synthetic achievements of this biogenetically related class up to 2020.…”

Section: Synthesismentioning

confidence: 99%

Euphorbiaditerpenoids: isolation, structure, bioactivity, biosynthesis, and synthesis (2013–2021)

et al. 2022

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Section: Synthesismentioning

confidence: 99%

Euphorbiaditerpenoids: isolation, structure, bioactivity, biosynthesis, and synthesis (2013–2021)

et al. 2022

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“…While the closely related daphnane and tigliane diterpenes have attracted a significant amount of synthetic interest, the curcusone molecules have surprisingly received little attention despite their therapeutic potential. In 2017, we reported the first total syntheses of the putative structures of curcusones I and J ( 1i and 1j ) in 21 steps (Figure B), ultimately leading to the conclusion that the originally proposed structures of both 1i and 1j were incorrect .…”

Section: Introductionmentioning

confidence: 97%

Total Synthesis and Target Identification of the Curcusone Diterpenes

et al. 2021

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The curcusone natural products are complex diterpenes featuring a characteristic [6−7−5] tricyclic carbon skeleton similar to the daphnane and tigliane diterpenes. Among them, curcusones A−D demonstrated potent anticancer activity against a broad spectrum of human cancer cell lines. Prior to this study, no total synthesis of the curcusones was achieved and their anticancer mode of action remained unknown. Herein, we report our synthetic and chemoproteomics studies of the curcusone diterpenes which culminate in the first total synthesis of several curcusone natural products and identification of BRCA1-associated ATM activator 1 (BRAT1) as a cellular target. Our efficient synthesis is highly convergent, builds upon cheap and abundant starting materials, features a thermal [3,3]-sigmatropic rearrangement and a novel FeCl 3 -promoted cascade reaction to rapidly construct the critical cycloheptadienone core of the curcusones, and led us to complete the first total synthesis of curcusones A and B in only 9 steps, C and D in 10 steps, and dimericursone A in 12 steps. The chemical synthesis of dimericursone A from curcusones C and D provided direct evidence to support the proposed Diels−Alder dimerization and cheletropic elimination biosynthetic pathway. Using an alkyne-tagged probe molecule, BRAT1, an important but previously "undruggable" oncoprotein, was identified as a key cellular target via chemoproteomics. We further demonstrate for the first time that BRAT1 can be inhibited by curcusone D, resulting in impaired DNA damage response, reduced cancer cell migration, potentiated activity of the DNA damaging drug etoposide, and other phenotypes similar to BRAT1 knockdown.

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“…The remarkable biological activities and architecturally complex structures, rhamnofolane, tigliane, and daphnane diterpenoids, have drawn considerable attention from organic chemists. , Numerous laboratories over several decades have together provided many creative strategies for constructing the unique 5/7/6-ring system. To date, the groups of Wender, Cha, Baran, Li, Liu, and Inoue have reported successful total syntheses of these molecules by applying a series of powerful and selective transformations. The Wender group synthesized tigliane phorbol as a racemate in 1989 (52 steps from the starting material) and as an enantiopure phorbol in 1997 (35 steps).…”

Section: Introductionmentioning

confidence: 99%

Unified Total Syntheses of Rhamnofolane, Tigliane, and Daphnane Diterpenoids

et al. 2021

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Rhamnofolane, tigliane, and daphnane diterpenoids are structurally complex natural products with multiple oxygen functionalities, making them synthetically challenging. While these diterpenoids share a 5/7/6-trans-fused ring system (ABC-ring), the three-carbon substitutions at the C13- and C14-positions on the C-ring and appending oxygen functional groups differ among them, accounting for the disparate biological activities of these natural products. Here, we developed a new, unified strategy for expeditious total syntheses of five representative members of these three families, crotophorbolone (1), langduin A (2), prostratin (3), resiniferatoxin (4), and tinyatoxin (5). Retrosynthetically, 1–5 were simplified into their common ABC-ring 6 by detaching the three-carbon units and the oxygen-appended groups. Intermediate 6 with six stereocenters was assembled from four achiral fragments in 12 steps by integrating three powerful transformations, as follows: (i) asymmetric Diels–Alder reaction to induce formation of the C-ring; (ii) π-allyl Stille coupling reaction to set the trisubstituted E-olefin of the B-ring; and (iii) Eu(fod)3-promoted 7-endo cyclization of the B-ring via the generation of a bridgehead radical. Then 6 was diversified into 1–5 by selective installation of the different functional groups. Attachment of the C14-β-isopropenyl and isopropyl groups led to 1 and 2, respectively, while oxidative acetoxylation and C13,14-β-dimethylcyclopropane formation gave rise to 3. Finally, formation of an α-oriented caged orthoester by C13-stereochemical inversion and esterification with two different homovanillic acids delivered 4 and 5 with a C13-β-isopropenyl group. This unified synthetic route to 1–5 required only 16–20 total steps, demonstrating the exceptional efficiency of the present strategy.

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Total synthesis of crotophorbolone

Abstract: Convergent total synthesis of crotophorbolone was accomplished in 18 longest linear steps. Observation of unexpected thermodynamic stability of a cis,trans-5/7/6 tricycle would benefit synthetic design of tigliane- and daphnane-related diterpenoids.

Cited by 24 publications

References 73 publications

Euphorbiaditerpenoids: isolation, structure, bioactivity, biosynthesis, and synthesis (2013–2021)

Euphorbiaditerpenoids: isolation, structure, bioactivity, biosynthesis, and synthesis (2013–2021)

Total Synthesis and Target Identification of the Curcusone Diterpenes

Unified Total Syntheses of Rhamnofolane, Tigliane, and Daphnane Diterpenoids

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