A Two‐Phase Approach to Fusicoccane Synthesis To Uncover a Compound That Reduces Tumourigenesis in Pancreatic Cancer Cells

Chen, Yue; Chen, Bolin; Wu, Qianwei; Xu, Dongdong; Zhang, Xijing; Ding, Ye; Bao, Shiqi; Zhang, Xuemei; Wang, Liang

doi:10.1002/ange.202117476

Cited by 3 publications

(4 citation statements)

References 91 publications

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“…Being allylic, carbocation 34 could also exist in its resonance form 35 . Ring opening of the epoxide by the tethered enol ether , and trapping of the allylic cation 35 by the proximal carboxylate would then afford the observed product 33 .…”

Section: Results and Discussionmentioning

confidence: 99%

Enantioselective Total Synthesis of (−)-Artatrovirenol A

Lavernhe,

Domke,

Wang

et al. 2023

J. Am. Chem. Soc.

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We report herein an enantioselective total synthesis of (−)-artatrovirenol A, a structurally unprecedented cage-like sesquiterpenoid. The synthesis features the following key steps: (a) cationic chiral oxazaborolidinium-catalyzed Diels−Alder reaction between isoprene and ethyl (E)-5-((tert-butyldimethylsilyl)oxy)-4oxopent-2-enoate for the rapid synthesis of an enantioenriched 10carbon bicyclic lactone; (b) union of two enantioenriched fragments by a diastereoselective Mukaiyama−Michael addition for the convergent assembly of an intermediate with all 15 carbons of the natural product; (c) intramolecular de Mayo [2 + 2] cycloaddition/retro-aldol sequence transforming a bicyclic compound to a tetracyclic one with concomitant generation of a five-and a seven-membered ring; (d) Lewis acid-triggered intramolecular ring opening of epoxide generating the norbornane substructure; and (e) Chugaev elimination converting the norbornane to the more strained norbornene.

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Section: Results and Discussionmentioning

confidence: 99%

Enantioselective Total Synthesis of (−)-Artatrovirenol A

Lavernhe,

Domke,

Wang

et al. 2023

J. Am. Chem. Soc.

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“…While the natural product FC-A is a useful tool to validate the ERα/14-3-3 molecular glue concept, its clinical utility is limited by its complex structure which limits diversity via (semi)-synthesis methodologies 23 , by the difficulty in isolating it from natural sources 24 , and by the high micromolecular concentrations needed to achieve a partially effective dose. 13 Therefore, we developed alternative small-molecule stabilizers of the ERα/14-3-3 PPI.…”

Section: Introductionmentioning

confidence: 99%

Estrogen Receptor α/14-3-3 molecular glues as alternative treatment strategy for endocrine resistant breast cancer

Visser,

Collier,

Siefert

et al. 2024

Preprint

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Endocrine resistance in breast cancer treatment is a major clinical hurdle, causing an urgent need for alternative treatment modalities. The suppressive protein-protein interaction (PPI) between Estrogen Receptor alpha ERalpha and the adaptor protein 14-3-3 offers such a strategy. Here, we report the biological impact of small-molecule molecular glues of this ERalpha/14-3-3 PPI by using both fusicoccin-derived semi-synthetic natural products and fully synthetic covalent drug-like molecules. We show that the ERalpha/14-3-3 PPI is stabilized by both the natural- and synthetic glues, resulting in a suppression of ERalpha transcriptional activity and a blockade of breast cancer cell proliferation, both in cell lines and in organoids derived from endocrine therapy resistant breast cancer patients. Importantly, the molecular glues effectively blocked ERalpha action even in case of constitutively active clinical ERalpha mutations, providing the foundations for developing alternative classes of ERalpha targeting compounds to improve treatment of patients with endocrine-therapy resistant breast cancer.

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“…A limited number of natural products with this carbon skeleton have been synthesized in pioneering works by the Kato/Takeshita, 8 Kishi, 9 Boeckman, 10 Paquette, 11 Schreiber, 12 Williams, 13 Nakada, 14 Maimone, 15 and Chen groups. 16 Accordingly, several elegant synthetic strategies for the stepwise construction of [5-8-5] ring systems have been developed, including pinacol coupling, 8a intramolecular ene reaction, 8b NHK reaction, 9 Grob-type fragmentation, 10 Claisen rearrangement, 11 Nicholas reaction, 12 transannular Nazarov reaction, 13 palladium-mediated cyclization. 14b However, there are currently few approaches available for the direct synthesis of [5-8-5] ring systems, excluding Maimone's remarkable radical cyclization cascade.…”

mentioning

confidence: 99%

“…25 Importantly, this classic technique provides a solution for the introduction of αor βstereochemistry for the angular methyl substituent (C11) of natural fusicoccanes. 16 Ketone 14 underwent a diastereoselective reduction with diisobutylaluminium hydride (DIBAL) to give desired allylic alcohol, which underwent diastereoselective Simmons−Smith cyclopropanation to give 15 in 83% overall yield. Subsequently, Ley oxidation of 15 provided 16 in 92% yield.…”

mentioning

confidence: 99%

Asymmetric Total Syntheses of Hypoestin A, Albolic Acid, and Ceroplastol II

Wang

Min

et al. 2022

J. Am. Chem. Soc.

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The first asymmetric total synthesis of bioactive diterpenoid hypoestin A with an unprecedented [5-8-5-3] tetracyclic skeleton is accomplished in 15 steps from commercially available (R)-limonene. Furthermore, the second asymmetric total syntheses of sesterterpenoids albolic acid and ceroplastol II in 21 steps are also reported. The synthetically challenging and highly functionalized [X-8-5] (X = 5 or 7) tricarbocyclic ring systems found in hypoestin A, albolic acid, ceroplastol II, and schindilactone A, as well as other natural products, are efficiently and directly constructed via a unique intramolecular Pauson–Khand reaction of an allene-yne. This work represents the first reported use of the Pauson–Khand reaction to access synthetically challenging eight-membered-ring systems in natural product synthesis.

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A Two‐Phase Approach to Fusicoccane Synthesis To Uncover a Compound That Reduces Tumourigenesis in Pancreatic Cancer Cells

Cited by 3 publications

References 91 publications

Enantioselective Total Synthesis of (−)-Artatrovirenol A

Enantioselective Total Synthesis of (−)-Artatrovirenol A

Estrogen Receptor α/14-3-3 molecular glues as alternative treatment strategy for endocrine resistant breast cancer

Asymmetric Total Syntheses of Hypoestin A, Albolic Acid, and Ceroplastol II

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