Synthesis of Racemic β-Chamigrene, a Spiro[5.5]undecane Sesquiterpene

Antonsen, Simen Gjelseth; Skattebøl, Lars; Stenstrøm, Yngve

doi:10.3390/molecules191220664

Cited by 7 publications

(7 citation statements)

References 14 publications

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“…Facile elimination of the acetate to the exocyclic enone 19 occurred in the presence of DBU with mild heating, but attempts at its isolation led to rapid formation of the unusual hetero‐Diels–Alder dimer 20 upon concentration and standing. Circumventing the isolation of this unstable intermediate, we generated enone 19 in situ and treated it with dimethylaluminum chloride and excess isoprene . In this way, the desired Diels–Alder adduct was readily obtained as a 4.3:1 (52 % 21 + 12 % 22 ) mixture of separable epimers.…”

Section: Methodsmentioning

confidence: 99%

A Unified Approach for the Enantioselective Synthesis of the Brominated Chamigrene Sesquiterpenes

2016

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The brominated chamigrene sesquiterpenes constitute a large subclass of bromocyclohexane containing natural products, yet no general enantioselective strategy for the synthesis of these small molecules exists. Herein we report a general strategy for accessing this family of secondary metabolites including the enantioselective synthesis of (−)-α-and (−)-ent-β-bromochamigrene, (−)-dactylone, and (+)-aplydactone. Access to these molecules is enabled by a stereospecific bromopolyene cyclization initiated by the solvolysis of an enantioenriched vicinal bromochloride. Dihalides Light the WayA highly general approach to the brominated chamigrene sesquiterpenes has been realized via a stereospecific bromopolyene cyclization of an enantioenriched bromochloride. The total synthesis of (+)-aplydactone has been accomplished for the first time via an intramolecular [2+2] cycloaddition.Keywords asymmetric synthesis; halogenation; natural products; solvolysis; terpenes Of the roughly 300 natural products that have been isolated and structurally characterized containing a bromocyclohexane motif (1, Figure 1a), [1a-c] more than 50 are represented by the brominated chamigrene sesquiterpenes (2, Figure 1a). Most members of this family differ in their level of saturation, halogenation, and oxygenation (3-8, Figure 1b). The structural variety within the halogenated chamigrenes is complemented by diverse biological * nburns@stanford.edu.Supporting information for this article is given via a link at the end of the document. HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript activities, with noteworthy examples including antibacterial, [2] antifungal, [3] antiviral, [4] anthelmintic, [5] and anticancer [6] effects. To date, the total synthesis of (+)-elatol 6 by Stoltz and Grubbs [7a] constitutes the only enantioselective synthesis of a member of the halogenated chamigrene sesquiterpenes. A general enantioselective approach for the synthesis of this class of molecules has yet to be reported. [7b-e] Along these lines, we set out to develop a strategy that would enable rapid construction of the spirocyclic core and thus facilitate elaboration to structurally disparate members of this family of small molecules for further chemical and biological investigations.We were particularly intrigued by the cancer preventive agent dactylone (7) [8] and a related congener, aplydactone (8). [9] Dactylone has been shown to suppress phenotype expression at non-cytotoxic doses in human lung, colon, and skin tumor cell lines and therefore holds promise as a molecular tool for anticancer studies. [8c] Dactylone and aplydactone were originally isolated from the sea hare Aplysia dactylomela in 1987, however the structure of aplydactone was not disclosed until 2001 with the assistance of X-ray crystallography. [9] In that report, it was suggested that 8 may arise from an intramolecular [2 + 2] cycloaddition of 7. Accordingly, we selected dactylone 7 as a synthetic target with the objective of also interrog...

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Section: Methodsmentioning

confidence: 99%

A Unified Approach for the Enantioselective Synthesis of the Brominated Chamigrene Sesquiterpenes

2016

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“…Facile elimination of the acetate to the exocyclic enone 19 occurred in the presence of DBU with mild heating, but attempts at its isolation led to rapid formation of unusual hetero-Diels–Alder dimer 20 upon concentration and standing. Circumventing isolation of this unstable intermediate, enone 19 was generated in situ and treated with dimethylaluminum chloride and excess isoprene, [18] and the desired Diels–Alder adduct was easily obtained as a 4.3:1 (52% 21 + 12% 22 ) mixture of separable epimers. Access to these diastereomeric spiroketones served as a convenient diversification point in our synthesis providing access to the doubly unsaturated, isomeric α- and ent -β-bromochamigrenes ( 4 and 3 , respectively).…”

mentioning

confidence: 99%

A Unified Approach for the Enantioselective Synthesis of the Brominated Chamigrene Sesquiterpenes

2016

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“…With a reliable route to 14 in hand, we turned our attention to the key Diels–Alder reaction to introduce the spiroundecane scaffold. 29 Unfortunately, 14 was found to be either unreactive toward isoprene or unstable in the presence of several Lewis acids. Reacting 14 with 4 equiv of isoprene and 1.5 equiv of BCl 3 converted 14 into the desired spirocyclic ketone 15 in moderate yield but as a single diastereoisomer.…”

Section: Synthesis Of Dactylone and 10- Epi -Dactymentioning

confidence: 99%

Unravelling Photochemical Relationships Among Natural Products from Aplysia dactylomela

et al. 2016

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Aplydactone (1) is a brominated ladderane sesquiterpenoid that was isolated from the sea hare Aplysia dactylomela together with the chamigranes dactylone (2) and 10-epi-dactylone (3). Given the habitat of A. dactylomela, it seems likely that 1 is formed from 2 through a photochemical [2 + 2] cycloaddition. Here, we disclose a concise synthesis of 1, 2, and 3 that was guided by excited state theory and relied on several highly stereoselective transformations. Our experiments and calculations confirm the photochemical origin of 1 and explain why it is formed as the sole isomer. Irradiation of 3 with long wavelength UV light resulted in a [2 + 2] cycloaddition that proceeded with opposite regioselectivity. On the basis of this finding, it seems likely that the resulting regioisomer, termed “8-epi-isoaplydactone”, could also be found in A. dactylomela.

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Synthesis of Racemic β-Chamigrene, a Spiro[5.5]undecane Sesquiterpene

Cited by 7 publications

References 14 publications

A Unified Approach for the Enantioselective Synthesis of the Brominated Chamigrene Sesquiterpenes

A Unified Approach for the Enantioselective Synthesis of the Brominated Chamigrene Sesquiterpenes

A Unified Approach for the Enantioselective Synthesis of the Brominated Chamigrene Sesquiterpenes

Unravelling Photochemical Relationships Among Natural Products from Aplysia dactylomela

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