English

• Dimeric sesquiterpenoids have long been intriguing targets to the synthesis community [1, 2]. Among them, a class of molecules possessing densely substituted 7-norbornenone/7-norbornenol motifs, such as vielanin F [3] and japonicone A [4] (1 and 2, Fig. 1), pose a significant challenge for chemical synthesis. From a strategic perspective, the 7-norbornenone core could be constructed through an intermolecular Diels−Alder reaction of an cyclopentadienone derivative (as a diene) and an electron deficient olefin (as a dienophile). Of note, preparation of aryl-substituted cyclopentadienones is well precedented in the literature [5-10]. In contrast, alkyl-substituted cyclopentadienones have barely been isolated and characterized to our knowledge, presumably due to its strong tendency to dimerize in a [4 + 2] manner [11, 12]. Cyclopentadienone equivalents (e.g., the corresponding ketal [13-15] and fulvalene [16, 17] derivatives) have been employed as dienes in Diels−Alder reactions; however, synthesis of such equivalents bearing multiple alkyl substituents has proved nontrivial [14-16]. Our experience [18-23] with the Diels−Alder reaction in natural product synthesis suggested that a convenient protocol for preparing alkyl-substituted cyclopentadienones in situ would enable expeditious construction of corresponding 7-norbornenones through Diels−Alder cycloaddition. Porco and co-workers reported an elegant synthesis of chamaecypanone C featuring an intermolecular Diels−Alder reaction [24]; a bis-aryl cyclopentadienone was generated in situ from a corresponding cyclopentenone derivative upon treatment with DDQ [25] and used as a dienophile in the Diels−Alder reaction. Inspired by this work, we envisioned a similar strategy for in situ preparation of alkyl-substituted cyclopentadienones which could be exploited to assemble multisubstituted 7-norbornenones (Scheme 1). It is noteworthy that the cyclopentadienone intermediates would serve as dienes rather than dienophiles in the Diels−Alder reactions (Scheme 1). Herein, we describe our endeavors toward synthesis of 7-norbornenone-containing polycyclic compounds based on this strategy.

  Figure 1

  

  Figure 1.  Selected dimeric sesquiterpenoids containing 7-norbornenone/7-norbornenol (highlighted in red) motifs.

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  Scheme 1

  

  Scheme 1.  Diels−Alder strategy for construction of alkyl-substituted 7-norbornenones using cyclopentadienone intermediates generated in situ from corresponding cyclopentenone derivatives. EWG = electron withdrawing group.

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  We first investigated the Diels−Alder reaction of N-phenylmaleimide (3) and cyclopentadienone derivative 4 generated in situ from α, β-unsaturated enone 5. Compound 5 was prepared from cycloheptanone (see Supporting information for details) as a mixture of diastereomers (ca. 1.7:1 dr). Under the Porco conditions (DDQ, 150 ℃, o-dichlorobenzene) [24], no cycloadducts were detected; instead, precursor 5 underwent rapid decomposition. To our delight, lowering the reaction temperature (110 ℃, toluene) led to formation of endo-cycloadduct 6, despite a modest yield. Microwave irradiation (110 ℃, toluene) significantly improved the overall efficiency of this sequence, giving 6 in 97% yield (Scheme 2). A trace amount of a homodimer of 4 was also generated under these conditions. The structure of 6 was verified by X-ray crystallographic analysis (Scheme 2).

  Scheme 2

  

  Scheme 2.  A one-pot dehydrogenation/Diels−Alder cycloaddition sequence for assembly of tetracyclic compound 6. Reagents and conditions: 3 (1 equiv.), 5 (3.0 equiv.), DDQ (4.5 equiv.), toluene, 110 ℃ (microwave irradiation), 12 h.

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  Having established the one-pot dehydrogenation/cycloaddition protocol, we moved forward to prepare a series of polycyclic compounds sharing a 7-norbornenone core (7–14, Table 1) from diene precursor 5 and various dienophiles (15–21). Maleimide (15) and its derivatives (16–18) performed well in the one-pot reactions, and endo-cycloadducts 7–10 were isolated in good to excellent yields (entries 1–4, Table 1). We then examined butyl acrylate (19) as a dienophile. However, the desired product was not observed under the standard conditions, presumably due to insufficient reactivity of the dienophile. Our experience [19, 21, 26] with lanthanide tris(β-diketonate) complexes as Lewis acids in organic synthesis suggested that Er(fod)₃ might serve as an effective promoter for the intermolecular Diels−Alder reaction. To our delight, cycloadduct 11 was obtained in 67% yield in the presence of Er(fod)₃ (entry 5). This modified protocol found more applications in the synthesis of α, β-unsaturated ester/lactone-derived 7-norbornenones (entries 6 and 7). When dimethyl fumarate (20) was employed as a dienophile, an inseparable mixture of 12 and 13 (ca. 1.4:1 ratio) was produced in 64% yield (entry 6). Similarly, we prepared compound 14 representing the congested tetracyclic core of japonicone A (2), through cycloaddition of exocyclic olefin 21 and diene 4 generated in situ.

  Table 1

  

  Table 1.  Preparation of 7-norbornenone-containing polycyclic compounds from diene precursor 5 and various dienophiles.

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  In summary, we developed a convenient protocol for in situ generation of an alkyl-substituted cyclopentadienone from a corresponding cyclopentenone, which enabled an expeditious Diels−Alder approach for assembling multisubstituted 7-norbornenones. The described chemistry is expected to facilitate the synthesis of dimeric sesquiterpenoids containing alkyl-substituted 7-norbornenone/7-norbornenol motifs.

  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  Acknowledgments

  This work was supported by Ministry of Science and Technology (National Key Research and Development Program of China, Nos. 2019YFC1711000 and 2018YFA0901900), National Natural Science Foundation of China (Nos. 21931014, 21525209, 21621002, 21772225, 21761142003 and 82003624), Chinese Academy of Sciences (Strategic Priority Research Program, No. XDB20000000; International Partner Program, No. 121731KYSB20190039; Key Research Program of Frontier Sciences, No. QYZDB-SSW-SLH040), Science and Technology Commission of Shanghai Municipality (Nos. 17XD1404600 and 20YF1458700), State Key Laboratory of Innovative Natural Medicine and Traditional Chinese Medicine Injections (No. QFSKL2017002), and K.C. Wong Education Foundation.

  Supplementary materials

  Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2021.09.030.

  
  
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• 

  Figure 1  Selected dimeric sesquiterpenoids containing 7-norbornenone/7-norbornenol (highlighted in red) motifs.

  下载: 全尺寸图片 幻灯片
  

  Scheme 1  Diels−Alder strategy for construction of alkyl-substituted 7-norbornenones using cyclopentadienone intermediates generated in situ from corresponding cyclopentenone derivatives. EWG = electron withdrawing group.

  下载: 全尺寸图片 幻灯片
  

  Scheme 2  A one-pot dehydrogenation/Diels−Alder cycloaddition sequence for assembly of tetracyclic compound 6. Reagents and conditions: 3 (1 equiv.), 5 (3.0 equiv.), DDQ (4.5 equiv.), toluene, 110 ℃ (microwave irradiation), 12 h.

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  Table 1.  Preparation of 7-norbornenone-containing polycyclic compounds from diene precursor 5 and various dienophiles.

  下载: 导出CSV
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