Total Synthesis of (−)-Curvulamine

Haelsig, Karl T.; Xuan, Jun; Maimone, Thomas J.

doi:10.1021/jacs.9b12546

Cited by 16 publications

(26 citation statements)

References 32 publications

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“…Their promising bioactivity and challenging structures have inspired organic chemists ever since to develop a successful total synthesis of these MNPs [ 316 , 317 , 318 ]. The group of Maimone published the first successful synthesis of (−)-curvulamine ( 413a ) in 2012, which was only feasible after extensive reconnaissance and several failures ( Scheme 25 ) [ 319 , 320 ]. Starting from commercially available chemicals, they employed a feasible 10 step sequence to (−)-curvulamine ( 413a ).…”

Section: Miscellaneousmentioning

confidence: 99%

“…The desired isomer 422 was reduced by deoxygenation and hydrolysis of the enol ether. The final step involves a diastereoselective reduction of the racemic ketone under CBS reduction conditions, yielding a 1:1 epimeric mixture of alcohols 413a and 413b that was readily separated into the enantiopure MNPs (Scheme 25) [319]. Scheme 25.…”

Section: Miscellaneousmentioning

confidence: 99%

“…It is often disrupted in diseases, including cancer, resulting in the disturbance of the protein balance [325]. Syntheses such as the one shown by Maimone et al play a significant in the development of potential active pharmaceutical ingredients as marine organisms often cannot be easily cultivated for mass production [319]. Further synthetic attempts, e.g., to prepare densanins, were undertaken by Yang and co-workers in 2016, whereas only the BCD tricyclic core could be achieved [321].…”

Section: Pyrroloiminoquinone and Related Analogsmentioning

confidence: 99%

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Marine Pyrrole Alkaloids

2021

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Nitrogen heterocycles are essential parts of the chemical machinery of life and often reveal intriguing structures. They are not only widespread in terrestrial habitats but can also frequently be found as natural products in the marine environment. This review highlights the important class of marine pyrrole alkaloids, well-known for their diverse biological activities. A broad overview of the marine pyrrole alkaloids with a focus on their isolation, biological activities, chemical synthesis, and derivatization covering the decade from 2010 to 2020 is provided. With relevant structural subclasses categorized, this review shall provide a clear and timely synopsis of this area.

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Section: Miscellaneousmentioning

confidence: 99%

Section: Miscellaneousmentioning

confidence: 99%

Section: Pyrroloiminoquinone and Related Analogsmentioning

confidence: 99%

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Marine Pyrrole Alkaloids

2021

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“…Unfortunately, both failed in our case. Eventually, the 1,2-addition was improved by increasing the amount of 27 to 10 equiv., and 28 was prepared in 57% yield. 28 was then subjected to hydrolysis upon the treatment with TsOH, and 17 was obtained in 51% yield from 26 .…”

Section: Resultsmentioning

confidence: 99%

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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“…Eventually, the 1,2-addition was improved by increasing the amount of 27 to 10 equiv. 23 , and 28 was prepared in 57% yield. 28 was then subjected to hydrolysis upon the treatment with p-toluenesulfonic acid and 17 was obtained in 51% yield from 26.…”

mentioning

confidence: 99%

Total Synthesis and Chemoproteomics Connect Curcusone Diterpenes with Oncogenic Protein BRAT1

Dwyer¹,

C²,

Abegg³

et al. 2020

Preprint

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Natural products are an indispensable source of lifesaving medicine, but natural product-based drug discovery often suffers from scarce natural supply and unknown mode of action. The study and development of anticancer curcusone diterpenes fall into such a dilemma. Meanwhile, many biologically-validated disease targets are considered “undruggable” due to the lack of enzymatic activity and/or predicted small molecule binding sites. The oncogenic BRCA1-associated ATM activator 1 (BRAT1) belongs to such an “undruggable” category. Here, we report our synthetic and chemoproteomics studies of the curcusone diterpenes that culminate in an efficient total synthesis and the identification of BRAT1 as a cellular target. We demonstrate for the first time that BRAT1 can be inhibited by a small molecule (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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Total Synthesis of (−)-Curvulamine

Cited by 16 publications

References 32 publications

Marine Pyrrole Alkaloids

Marine Pyrrole Alkaloids

Total Synthesis and Target Identification of the Curcusone Diterpenes

Total Synthesis and Chemoproteomics Connect Curcusone Diterpenes with Oncogenic Protein BRAT1

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