α,α‘-Annulation of 2,6-Prenyl-Substituted Cyclohexanone Derivatives with Malonyl Chloride:  Application to a Short Synthesis of (±)-Clusianone. Formation and Rearrangement of a Biogenetic-Like Intermediate

Nuhant, Philippe; David, Marc; Pouplin, Thomas; Delpech, Bernard; Marazano, Christian

doi:10.1021/ol062736s

Cited by 79 publications

(44 citation statements)

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“…9 Syntheses of clusianone (type B) were subsequently reported by several groups 10 including ours. 11 Nemorosone also has been the subject of a total synthesis. 10e Our interest in the field of PPAPs came from the observation that xanthochymol was active in a tubulin disassembly inhibition test.…”

Section: Introductionmentioning

confidence: 99%

“…6 After our work leading to the isolation of oblongifolins A-D, 12 we undertook synthetic studies toward type B PPAPs. 11,13 We previously showed that the boron trifluoride catalyzed Effenberger α,α'-annulation 14 of isomeric 2,4,6-triprenyl-3,3-dimethylcyclohexanones TMS enol ethers 1 with malonyl dichloride allowed the formation of the bicyclo[3.3.1]nonane-2,4,9-trione 2 with an equatorial prenyl group. 11 This led to a short synthesis of (±)-clusianone via C-benzoylation of the enolic β-dicarbonyl moiety of 2 (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

“…11,13 We previously showed that the boron trifluoride catalyzed Effenberger α,α'-annulation 14 of isomeric 2,4,6-triprenyl-3,3-dimethylcyclohexanones TMS enol ethers 1 with malonyl dichloride allowed the formation of the bicyclo[3.3.1]nonane-2,4,9-trione 2 with an equatorial prenyl group. 11 This led to a short synthesis of (±)-clusianone via C-benzoylation of the enolic β-dicarbonyl moiety of 2 (Scheme 1). We also observed the formation of interesting secondary products possessing an additional tetrahydropyran ring, owing to the cyclization of a prenyl group with the oxygen of an enol moiety.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, the amount of ii could also be higher, allowing a second acylation, intramolecular this time and possibly via iii, as in the prenyl series. 11 In the case of the tricyclic product 12, formation of an intermediate (iv) with BF 3 coordinated to the oxygen bound to C-4 (bicyclo[3.3.1]nonane-2,4,9-trione numbering) might favor the participation of the allyl group close to this oxygen. The ring size is the result of an addition following Markovnikov's rule and the advantage of the allyl group, here, is to afford a five membered heterocycle.…”

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confidence: 99%

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A rapid access to the core skeleton of atypic tricyclic polyprenylated acylphloroglucinols

Delpech¹,

Tolón²,

Marazano³

2010

Arkivoc

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A synthesis of (4S*,6S*)-2,4,6-triallyl-3,3-dimethylcyclohexanones, and the treatment of their TMS enol ethers with malonyl dichloride in the presence of BF 3 •Et 2 O, are reported. Formation of a ketoacid, resulting from acylation without cyclization, and of a tricyclic phloroglucinol derivative, involving Effenberger annulation with concomitant O-cyclization, were obtained. The tricyclic compound has the core skeleton of the hyperibones H and I, atypical natural polycyclic polyprenylated acylphloroglucinols. Mechanistic and stereochemical aspects are discussed.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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A rapid access to the core skeleton of atypic tricyclic polyprenylated acylphloroglucinols

Delpech¹,

Tolón²,

Marazano³

2010

Arkivoc

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“…1). In addition, further characterizations of 1-4 were conducted utilizing 1 HNMR and 13 CNMR spectroscopy to characterize both tautomers (a/b) present. Data on clusianone and analogues are available as Supporting Information.…”

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confidence: 99%

Structural Derivatization of Clusianone and In Vitro Cytotoxicity Evaluation Targeting Respiratory Carcinoma Cells

2016

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Abstract! Clusianone (1) was isolated from Garcinia parvifolia and structurally modified using semisynthetic methods to obtain compounds 2-4. The structural derivatization included methylation (2), hydrogenation (3), and the addition of a methylamine group [(4) to (1)]. Cytotoxic effects of these compounds were assessed on MRC5 fibroblasts, A549 lung adenocarcinoma, HK1 squamous nasopharynx carcinoma, and NP69 normal nasopharyngeal epithelial cell lines. Clusianone (1) showed cytotoxic activity against A549 cells with an IC 50 value of 3.06 µM. Compound (4) showed cytotoxic activities against both A549 and HK1 cells with IC 50 values of 4.09 µM and 3.43 µM, respectively. The results of the cytotoxicity assay provide a correlation on the structure activity relationship of clusianone against HK1 and A549 cells, which can be further investigated as a potential antiproliferative compound. Key wordsGarcinia parvifolia · Clusiaceae · clusianone analogues · semisynthetic methods · cytotoxic activity Supporting information available online at http://www.thieme-connect.de/products Natural clusianone belongs to compounds classified as type B polyprenylated polycyclic acylphloroglucines (PPAPs) that are found in plants of the Clusiaceae (Guttiferae) family [1,2]. To date, natural clusianone has been found in various parts of the targeted Clusiaceae plants, including fruits [3], flowers [4,5], leaves [6], roots [7], stems, and bark [8,9]. Naturally occurring 1 has shown potential anticancer activity [9] and further investigations of clusianone-treated HepG2 hepatocarcinoma cells revealed cytotoxic effects by mitochondrial impairment [10]. In the last decade, clusianone (1) has gained substantial interest from the synthetic community leading to a breakthrough in total synthesis of this compound [11][12][13][14]. Synthetic clusianone was tested for cytotoxicity in several cancer cell lines: HeLa (cervix carcinoma), MIAPaCa-2 (pancreatic carcinoma), and MCF7 (breast adenocarcinoma). The IC 50 values ranged from 3.0 µM to 8.3 µM for the three cancer cell lines [15,16]. In our studies, we extracted clusianone using a previously published method [6]. The isolation and abundance of clusianone from the leaves of Garcinia parvifolia (Miq.) Miq. has made chemical modifications readily attainable as compared to clusianone isolated from the dried stem bark of Garcinia assigu [9] and the roots of Hypericum hypericoides (L.) Crantz [7]. X-ray crystallography was identical in previous reports, and a detailed comparison of our and previously reported NMR data [8] was established.This method provided a quantity of over 0.5 g (0.05% yield) of 1 to be used as starting material for synthesizing sufficient quantities of clusianone derivatives (2-4). All products were purified via column chromatography. The products 1-4 exhibited the predicted fragmentation and mass m/z when analyzed by ESI-MS (l " Fig. 1). In addition, further characterizations of 1-4 were conducted utilizing 1 HNMR and 13 CNMR spectroscopy to characterize both tautomers (a/b)...

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Oxidation and Reduction

Mehrotra

2007

Organic Reaction Mechanisms Series

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α,α‘-Annulation of 2,6-Prenyl-Substituted Cyclohexanone Derivatives with Malonyl Chloride: Application to a Short Synthesis of (±)-Clusianone. Formation and Rearrangement of a Biogenetic-Like Intermediate

Cited by 79 publications

References 11 publications

A rapid access to the core skeleton of atypic tricyclic polyprenylated acylphloroglucinols

A rapid access to the core skeleton of atypic tricyclic polyprenylated acylphloroglucinols

Structural Derivatization of Clusianone and In Vitro Cytotoxicity Evaluation Targeting Respiratory Carcinoma Cells

Oxidation and Reduction

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