English

• 1.   Introduction

  Cycloalkane-fused dihydrofurans are widely found in many natural products as well as therapeutic agents, such as melicodin C, ^[1] clerodin, ^[2] and hugonianene A, ^[3] whose anti-proliferactive, human immunodeficiency virus (HIV) protease inhibitors, ^[4] or anti-feedant activity have attracted much attention in related biological studies (Figure 1). Thus, various synthetic methods for such compounds have been developed, ^[5] mainly including cyclization of 1, 3- cyclohexanedione and alkenes^[6] or 1, 3-dicarbonyl compounds and cycloalkenes, ^[7] resulting the formation of cyclopentane- or cyclohexane-fused hydrofuran derivatives (Schemes 1a, 1b). Nevertheless, these methods usually could not access to cyclobutane-fused dihydrofurans might due to the strong strain of cyclobutenes. Recently, Yu and co-workers^[8] synthesized cyclobutane-fused dihydrofurans through TfOH-catalyzed cyclopropane ring enlargement/C—C formation/etherify- cation of alkylcyclopropanes and 1, 3-dicarbonyl compounds (Scheme 1c). While the substrates alkylcyclopropanes need to be pre-prepared. Therefore, the development of general methods for various cycloalkane-fused dihydrofuran derivatives starting from easily available materials is highly desirable. Herein, we present copper-catalyzed cyclization of 1-aryl-1-cyclo- alcohols and 1, 3-dicarbonyl compounds, providing a series of cycloalkane-fused dihydrofurans in excellent yields starting from readily available materials (Scheme 1d).

  Figure 1

  

  Figure 1.  Some examples of cycloalkane-fused dihydrofurans skeleton in natural products and therapeutic agents

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  Scheme1

  

  Scheme1.  Synthesis of cycloalkane-fused dihydrofurans

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  2.   Results and discussion

  Initially, 1-phenyl-1-cyclopentanol (1aa) and acetylacetone (2a) were chosed as the model substrates. After the reaction of 1aa (0.2 mmol) and 2a (3 equiv.) was performed in the presence of CuCl (10 mol%) and K₂S₂O₈ (2 equiv.) in CH₃CN (2 mL) at 50 ℃ under nitrogen atmosphere for 17 h, the desired cyclopentane-fused dihydrofuran 3a was obtained in 14% yield, along with the formation of cyclopentene 4a (44%) (Table 1, Entry 1). Other copper salts, such as CuBr, CuI, Cu(CH₃CN)₄PF₆, CuTc, CuCl₂, Cu(OAc)₂ could also promote the reaction (Entries 2~8). Cu(CH₃CN)₄PF₆ gave the best result, affording 3a in 81% yield and no 4a being detected (Entry 4). Other metal salts, such as FeCl₃ and ZnCl₂ could not improve the yield of 3a (Entries 9 and 10). Without the metal salt, 4a became the main product (58%), along with a small amount of 3a (10% yield) (Entry 11). Without the oxidant, 3a could not be formed (Entry 12). When oxidant K₂S₂O₈ was replace by PhI(OAc)₂, tert-butyl hydroperoxid (TBHP), or 3-chloroperbenzoic acid (m-CPBA), only 4a was formed (Entries 13~15). Upon increasing or decreasing the reaction temperature, the yield of 3a decreased to 72% and 64%, respectively (Entries 16 and 17). Using tetrahydrofuran (THF), toluene, dichloroethane (DCE), or dichloromethane (DCM) as solvents, no better results were observed (Entries 18~21).

  Table 1

  

  Table 1.  Optimization of reaction conditions^a

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  Entry	Catalyst	Oxidant	Temp./℃	Solvent	Yieldb/%
  					3a	4a
  1	CuCl	K2S2O8	50	CH3CN	14	44
  2	CuBr	K2S2O8	50	CH3CN	44	13
  3	CuI	K2S2O8	50	CH3CN	23	37
  4	Cu(CH3CN)4PF6	K2S2O8	50	CH3CN	81	0
  5	CuTc	K2S2O8	50	CH3CN	19	48
  7	CuCl2	K2S2O8	50	CH3CN	30	12
  8	Cu(OAc)2	K2S2O8	50	CH3CN	18	41
  9	FeCl3	K2S2O8	50	CH3CN	18	25
  10	ZnCl2	K2S2O8	50	CH3CN	18	51
  11	—	K2S2O8	50	CH3CN	10	58
  12	Cu(CH3CN)4PF6	—	50	CH3CN	0	90
  13	Cu(CH3CN)4PF6	PhI(OAc)2	50	CH3CN	0	86
  14	Cu(CH3CN)4PF6	TBHP	50	CH3CN	0	57
  15	Cu(CH3CN)4PF6	m-CPBA	50	CH3CN	0	47
  16	Cu(CH3CN)4PF6	K2S2O8	30	CH3CN	64	11
  17	Cu(CH3CN)4PF6	K2S2O8	70	CH3CN	72	0
  18	Cu(CH3CN)4PF6	K2S2O8	50	THF	3	47
  19	Cu(CH3CN)4PF6	K2S2O8	50	Toluene	0	89
  20	Cu(CH3CN)4PF6	K2S2O8	50	DCE	6	83
  21	Cu(CH3CN)4PF6	K2S2O8	50	DCM	18	24
  aGeneral reaction conditions: 1aa (0.2 mmol), 2a (3 equiv., 0.6 mmol), catalyst (10 mol%), oxidant (2 equiv.), solvent (2 mL), 17 h, N2 atmosphere. bIsolated yields.

  With these established conditions, the scope of 1-aryl- 1-cyclopentanols (1a) was examined. As shown in Table 2, various aryls containing both electron-donating and withdrawing groups, such as alkyl, alkoxyl, halide, CF₃, and OCF₃, were tolerant, providing the desired cyclopentane-fused dihydrofurans 3a~3l in good to excellent yields. It should be noted that halogen substituents such as Cl (3h and 3j) were well tolerated, which provides the possibility for further transformation. And, the fluorine and trifluoromethyl groups were intact in this novel reaction, which makes the dihydrofurans 3g, 3i and 3k much potential in biological and pharmacological activity study. The naphthyl substituted cyclopentanol (1am) was also suitable substrate, affording the corresponding 3m in excellent yield. Additionally, hetero-aromatic substituent such as thiophenyl (1an) was also suitable for this reaction, albeit the desired product 3n was obtained in a relatively low yield (47%). Unfortunately, furanyl substitutedsubstrate 1ao could not undergo this reaction.

  Table 2

  

  Table 2.  Variety of 1-aryl-1-cyclopentanols 1a^a

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  Next, the ring size of 1-aryl-1-cycloalcohols 1 was explored under the optimal conditions. The results are summarized in Table 3. Starting from 1-aryl-1-cyclohexanols 1b, the oxidative cyclization reaction could proceed smoothly and give the corresponding cyclohexane-fused dihydrofurans 5a~5d in medium to excellent yields (73%~98%). To our delight, various 1-aryl-1-cyclo- butanols 1c were founded to be well suitable substrates, affording the desired cyclobutane-fused dihydrofurans 6a~6h in good to excellent yields (61%~99%). The structure of 6e was further confirmed by X-ray analysis.^[9] Notably, the medium-sized cycloalcohols could be well-tolerated. Cycloheptanols 1d could efficiently undergo this reaction, and a series of cycloheptane-fused dihydrofurans 7a~7e were obtained in 64%~96% yields. Moreover, using 1-phenylcyclododecanol (1e) as the substrate, the expected product 8 was smoothly formed with an excellent yield (98%). 1-Phenylcyclopropane (1f) was also tested, but no desired product was detected. In all reaction, no obvious electronic effect was observed. Additionally, cyclic 1, 3-diketones 2b~2d were also examined under standard conditions (Scheme 2a). We were pleased to find that 1, 3-cyclopentanedione (2b), 1, 3-cyclo- hexanedione (2c), dimedone (2d) and cyclopentanol (1ak) underwent the oxidative cyclization reaction, forming tricycle compounds 9a~9c in good to excellent yields (79%~99%). Furthermore, unsymmetrical 1, 3-dicarbonyl compounds, such as 1-phenylbutan-1, 3-dione (2e) and hexane-2, 4-dione (2f) could afford the desired products 10a/10aꞌ and 10b/10bꞌ in good yields with a relatively low regioselectivity (Scheme 2b).

  Table 3

  

  Table 3.  Variety of ring-sizes of alicyclic alcohols 1b~1e^a

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  Scheme2

  

  Scheme2.  Reaction of 1ak and 1, 3-diketones 2b~2f

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  In order to probe the reaction mechanism, some control experiments were conducted (Scheme 3). When adding 1.5 equiv. of 2, 2, 6, 6-tetramethyl-1-piperidingloxy (TEMPO) or 1.5 equiv. of 2, 6-di-tert-butyl-4-methylphenol (BHT) to the reaction of 1ak and 2a, the reaction was completely inhibited. These results suggested that the cyclization reaction might involve radical species. Additionally, starting from 1-phenyl-cyclopentene (4a), 3a could be formed in 52% yield under standard conditions. This indicated that the cycloalkene might be intermediate.

  Scheme3

  

  Scheme3.  Control experiments

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  Based on the above experiments and previous works, ^[10] a proposed mechanism is shown in Scheme 4. Initially, 1-phenyl-1-cyclopentanol (1aa) underwent dehydration to form 1-phenyl-1-cyclopentene (4a). Meanwhile, the deprotonation of 1, 3-dicarbonyl compound 2a formed radical A in the presence of K₂S₂O₈, which added to 4a to form benzylic radical B. B was oxidized to give benzylic cation C, which could tautomerize to enol benzylic cation D. Finally, D underwent the intramolecular nucleophilic attack and the loss of proton to produce 3a. For unsymmetrical 1, 3-dicar- bonyl compounds 2e and 2f, the low regioselectivity of oxa-cyclization might result from the low selectivity of ketone-enol tautomerization.

  Scheme4

  

  Scheme4.  Plausible mechanism

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  3.   Conclusions

  In summary, a novel copper-catalyzed cyclization reaction of 1, 3-dicarbonyl compounds and 1-aryl-1-cyclo- alcohols, facially constructing a wide range of cycloalkane-fused dihydrofurans derivatives in good to excellent yields under mild conditions was developed. This reaction would provide a new way toward cycloalkane-fused dihydrofurans.

  4.   Experimental section

  4.1   General information

  All commercially available chemicals were used without further purification. ¹H NMR spectra were recorded at 25 ℃ on a Varian 600 or 500 MHz, ¹³C NMR spectra were recorded at 25 ℃ on a Varian 150 or 125 MHz spectrometer with TMS as internal standard. High resolution mass spectra were recorded on a Bruker microtof spectrometer. Flash column chromatography was performed on silica gel 60 (particle size 300~400 mesh ASTM, purchased from Taizhou, China).

  4.2   Preparation of 1-substituted cycloalcohols

  All glassware were flame- dried before use. Cyclopentanone (13.4 mmol) was dissolved in 25 mL of diethyl ether and purged with N₂. The temperature was reduced to 0 ℃. The appropriate Grignard reagent (14.7 mmol) was added dropwise with stirring. The reaction was allowed to stir for an additional 3 h. Water was added slowly to quench the reaction. The organic layer was removed, and the aqueous layer was extracted three times with diethyl ether (25 mL×3). The organic layers were combined, dried with Na₂SO₄, filtered and the solvent was evaporated under vacuum. The residue was purified by column chromatography (petroleum ether/ ethyl acetate, V:V＝25:1) to give the corresponding product 1-phenyl-1-cyclo- pentanol (1aa).

  4.3   General procedure for cycloalkane-fused dihydrofurans (3 and 5~10)

  Cu(CH₃CN)₄PF₆ (0.02 mmol, 7.5 mg), K₂S₂O₈ (0.4 mmol, 108 mg), 1aa (0.2 mmol) and CH₃CN (2 mL) were added into a screw-cap test tube under N₂ atmosphere in glove-box. The test tube was then stirred at room temperature for 5 min. 2a (60 μL, 0.6 mmol) was added into reaction mixture and the test tube was then sealed off with a screw-cap and the reaction mixture was stirred at 50 ℃ for 17 h. After the reaction finished, the solvent was evaporated under vacuum. The residue was purified by column chromatography (petroleum ether/ethyl ether, V:V＝20:1) to give the corresponding product 3a.

  1-(2-Methyl-6a-phenyl-4, 5, 6, 6a-tetrahydro-3aH-cyclopenta[b]furan-3-yl)ethanone (3a): light yellow oil, 81% yield (39.3 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.38~7.33 (m, 4H), 7.28~7.24 (m, 1H), 3.62 (d, J＝8.4 Hz, 1H), 2.32 (s, 3H), 2.32~2.27 (m, 1H), 2.19 (s, 3H), 2.13~1.98 (m, 2H), 1.95~1.82 (m, 2H), 1.75~1.60 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 194.3, 167.5, 144.2, 128.3, 127.3, 124.2, 116.1, 99.3, 55.3, 42.9, 34.9, 29.1, 24.7, 15.1; HRMS (ESI-TOF) calcd for C₁₆H₁₈O₂Na [M+Na]⁺ 265.1199, found 265.1208.

  1-(2-Methyl-6a-(o-tolyl)-4, 5, 6, 6a-tetrahydro-3aH-cyclopenta[b]furan-3-yl)ethanone (3b): light yellow oil, 83% yield (42.6 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.49 (q, J＝3.0 Hz, 1H), 7.19~7.18 (m, 3H), 3.86 (d, J＝8.4 Hz, 1H), 2.46 (s, 3H), 2.31 (s, 3H), 2.25~2.11 (m, 3H), 2.21 (s, 3H), 1.87 (q, J＝6.0 Hz, 2H), 1.77~1.68 (m, 1H). ¹³C NMR (150 MHz, CDCl₃) δ: 194.2, 166.8, 141.0, 134.7, 132.5, 127.4, 125.8, 125.0, 116.9, 100.5, 53.1, 41.5, 34.3, 29.2, 24.8, 21.3, 15.2; HRMS (ESI-TOF) calcd for C₁₇H₂₀O₂Na [M+Na]⁺ 279.1356, found 279.1358.

  1-(2-Methyl-6a-(m-tolyl)-4, 5, 6, 6a-tetrahydro-3aH-cyclopenta[b]furan-3-yl)ethanone (3c): yellow oil, 87% yield (44.6 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.27~7.22 (m, 1H), 7.22~7.13 (m, 2H), 7.08 (d, J＝7.8 Hz, 1H), 3.62 (d, J＝8.4 Hz, 1H), 2.36 (s, 3H), 2.32 (s, 3H), 2.29 (dd, J＝13.8, 6.0 Hz, 1H), 2.20 (s, 3H), 2.15~1.97 (m, 2H), 1.95~1.79 (m, 2H), 1.74~1.67 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 194.4, 167.6, 144.2, 138.0, 128.3, 128.1, 124.9, 121.3, 116.1, 99.4, 55.2, 43.0, 34.9, 29.1, 24.7, 21.5, 15.1; HRMS (ESI-TOF) calcd for C₁₇H₂₁O₂ [M+H]⁺ 257.1536, found 257.1536.

  1-(2-Methyl-6a-(p-tolyl)-4, 5, 6, 6a-tetrahydro-3aH-cyclopenta[b]furan-3-yl)ethanone (3d): light yellow oil, 83% yield (42.6 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.26 (d, J＝7.8 Hz, 2H), 7.16 (d, J＝7.8 Hz, 2H), 3.61 (d, J＝7.8 Hz, 1H), 2.34 (s, 3H), 2.32 (s, 3H), 2.31~2.27 (m, 1H) 2.20 (s, 3H), 2.11~1.97 (m, 2H), 1.89~1.30 (m, 2H), 1.74~1.65 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 194.8, 168.1, 141.1, 137.2, 129.1, 124.3, 116.1, 99.5, 55.1, 42.7, 34.9, 29.0, 24.7, 21.0, 15.2; HRMS (ESI-TOF) calcd for C₁₇H₂₀O₂Na [M+Na]⁺ 279.1356, found 279.1357.

  1-(6a-(4-Methoxyphenyl)-2-methyl-4, 5, 6, 6a-tetrahydro-3aH-cyclopenta[b]furan-3-yl)ethanone (3e): light yellow oil, 96% yield (52.3 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.30 (d, J＝8.4 Hz, 2H), 6.88 (d, J＝9.0 Hz, 2H), 3.80 (s, 3H), 3.60 (d, J＝8.4 Hz, 1H), 2.35~2.25 (m, 4H), 2.20 (s, 3H), 2.07~1.94 (m, 2H), 1.90~1.76 (m, 2H), 1.75~1.61 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 194.5, 167.6, 158.9, 136.2, 125.7, 116.2, 113.7, 99.3, 55.3, 54.9, 42.4, 34.9, 29.2, 24.6, 15.2; HRMS (ESI-TOF) calcd for C₁₇H₂₁O₃ [M+H]⁺ 273.1485, found 273.1485.

  1-(2-Methyl-6a-(4-(trifluoromethoxy)phenyl)-4, 5, 6, 6a-tetrahydro-3aH-cyclopenta[b]furan-3-yl)ethanone (3f): colorless oil, yield 74% (48.3 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.43~7.36 (m, 2H), 7.20 (d, J＝8.4 Hz, 2H), 3.60 (d, J＝8.4 Hz, 1H), 2.37~2.26 (m, 1H), 2.32 (s, 3H), 2.21 (s, 3H), 2.10~2.07 (m, 1H), 2.04~1.96 (m, 1H), 1.91~1.85 (m, 2H), 1.76~1.68 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 194.3, 167.2, 148.4, 143.0, 125.8, 120.9, 120.4 (q, J＝255.3 Hz) 116.2, 98.7, 55.5, 43.1, 34.9, 29.2, 24.7, 15.1; HRMS (ESI-TOF) calcd for C₁₇H₁₈F₃O₃ [M+H]⁺ 327.1203, found 327.1205.

  1-(6a-(4-Fluorophenyl)-2-methyl-4, 5, 6, 6a-tetrahydro-3aH-cyclopenta[b]furan-3-yl)ethanone (3g): colorless oil, yield 92% (47.9 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.39~7.29 (m, 2H), 7.09~6.98 (m, 2H), 3.59 (d, J＝8.4 Hz, 1H), 2.32 (s, 3H), 2.31~2.26 (m, 1H), 2.21 (s, 3H), 2.13~1.94 (m, 2H), 1.93~1.81 (m, 2H), 1.76~1.63 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 194.3, 167.3, 162.0 (d, J＝7.8, 244.5 Hz), 140.0 (d, J＝3.2 Hz), 126.1 (d, J＝8.1 Hz), 116.2, 115.1 (d, J＝21.2 Hz), 98.9, 55.3, 42.9, 34.9, 29.2, 24.7, 15.1; HRMS (ESI-TOF) calcd for C₁₆H₁₇FO₂Na [M+Na]⁺ 283.1105, found 283.1104.

  1-(6a-(4-Chlorophenyl)-2-methyl-4, 5, 6, 6a-tetrahydro-3aH-cyclopenta[b]furan-3-yl)ethanone (3h): colorless oil, yield 93% (51.5 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.34~7.28 (m, 4H), 3.58 (d, J＝8.4 Hz, 1H), 2.31 (s, 3H), 2.31~2.27 (m, 1H), 2.20 (s, 3H), 2.09~2.02 (m, 1H), 2.01~1.92 (m, 1H), 1.93~1.82 (m, 2H), 1.76~1.60 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 194.3, 167.3, 142.8, 133.1, 128.5, 125.8, 116.1, 98.7, 55.4, 43.0, 34.9, 29.2, 24.7, 15.1; HRMS (ESI-TOF) calcd for C₁₆H₁₈ClO₂ [M+H]⁺ 277.0990, found 277.0997.

  1-(6a-(3-Fluorophenyl)-2-methyl-4, 5, 6, 6a-tetrahydro-3aH-cyclopenta[b]furan-3-yl)ethanone (3i): light yellow oil, 97% yield (50.5 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.32 (td, J＝7.8, 6.0 Hz, 1H), 7.13 (d, J＝7.8 Hz, 1H), 7.08 (dt, J＝10.2, 2.4 Hz, 1H), 6.96 (td, J＝7.8, 2.4 Hz, 1H), 3.60 (d, J＝8.4 Hz, 1H), 2.33 (s, 3H), 2.29 (m, 1H), 2.20 (s, 3H), 2.12~2.03 (m, 1H), 2.03~1.95 (m, 1H), 1.93~1.83 (m, 2H), 1.76~1.66 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 194.3, 167.3, 162.8 (d, J＝244.2 Hz), 147.1 (d, J＝244.2 Hz), 130.0 (d, J＝8.2 Hz), 119.8 (d, J＝2.7 Hz), 116.1, 114.0, 111.6 (d, J＝22.7 Hz), 98.7, 55.6, 43.1, 34.9, 29.2, 24.7, 15.1; HRMS (ESI-TOF) calcd for C₁₆H₁₈FO₂ [M+H]⁺ 261.1285, found 261.1283.

  1-(6a-(3-Chlorophenyl)-2-methyl-4, 5, 6, 6a-tetrahydro-3aH-cyclopenta[b]furan-3-yl)ethanone (3j): colorless oil, 92% yield (50.9 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.36 (t, J＝1.8 Hz, 1H), 7.32~7.26 (m, 1H), 7.26~7.19 (m, 2H), 3.60 (d, J＝8.4 Hz, 1H), 2.33 (s, 3H), 2.33~2.27 (m, 1H), 2.21 (s, 3H), 2.12~2.03 (m, 1H), 2.02~1.94 (m, 1H), 1.93~1.80 (m, 2H), 1.80~1.62 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 194.2, 167.2, 146.5, 134.4, 129.7, 127.4, 124.6, 122.5, 116.1, 98.6, 55.5, 43.2, 34.9, 29.2, 24.7, 15.1; HRMS (ESI-TOF) calcd for C₁₇H₁₈ClO₂ [M+H]⁺ 277.0990, found 277.0995.

  1-(2-Methyl-6a-(4-(trifluoromethyl)phenyl)-4, 5, 6, 6a-tetrahydro-3aH-cyclopenta[b]furan-3-yl)ethanone (3k): brown oil, 96% yield (59.6 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.61 (d, J＝7.8 Hz, 2H), 7.49 (d, J＝8.4 Hz, 2H), 3.62 (d, J＝8.4 Hz, 1H), 2.36~2.28 (m, 4H), 2.21 (s, 3H), 2.18~2.05 (m, 1H), 2.05~1.97 (m, 1H), 1.96~1.87 (m, 2H), 1.78~1.69 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 194.4, 167.4, 148.4, 129.6 (q, J＝32.3 Hz), 125.4 (q, J＝3.8 Hz), 124.7, 124.0 (q, J＝270.3 Hz), 116.1, 98.8, 55.7, 43.4, 35.0, 29.1, 24.8, 15.1; HRMS (ESI-TOF) calcd for C₁₇H₁₇F₃O₂Na [M+Na]⁺ 333.1073, found 333.1077.

  1-(6a-(3, 5-Dimethylphenyl)-2-methyl-4, 5, 6, 6a-tetra-hydro-3aH-cyclopenta[b]furan-3-yl)ethanone (3l): colorless oil, 81% yield (43.8 mg). ¹H NMR (600 MHz, CDCl₃) δ: 6.98 (s, 2H), 6.91 (s, 1H), 3.62 (d, J＝7.8 Hz, 1H), 2.34~2.25 (m, 10H), 2.20 (s, 3H), 2.10~1.95 (m, 2H), 1.91~1.81 (m, 2H), 1.73~1.64 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 194.5, 167.6, 144.2, 138.0, 129.0, 122.1, 116.1, 99.4, 55.1, 43.0, 35.0, 29.2, 24.7, 21.4, 15.2; HRMS (ESI-TOF) calcd for C₁₈H₂₃O₂ [M+H]⁺ 271.1693, found 271.1691.

  1-(2-Methyl-6a-(naphthalen-1-yl)-4, 5, 6, 6a-tetrahydro-3aH-cyclopenta[b]furan-3-yl)ethanone (3m): yellow oil, 98% yield (57.3 mg). ¹H NMR (600 MHz, CDCl₃) δ: 8.09 (d, J＝8.4 Hz, 1H), 7.88 (d, J＝7.2, 1H), 7.78 (d, J＝7.8 Hz, 1H), 7.74 (d, J＝7.2 Hz, 1H), 7.52~7.46 (m, 2H), 7.43 (t, J＝7.8 Hz, 1H), 4.12 (d, J＝8.4 Hz, 1H), 2.53~2.45 (m, 2H), 2.37 (s, 3H), 2.35~2.32 (m, 1H), 2.01~1.97 (m, 2H), 1.91~1.83 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 194.3, 166.5, 138.4, 134.7, 129.7, 129.4, 128.7, 125.7, 125.2, 125.0, 124.7, 122.5, 117.1, 100.6, 53.3, 42.4, 34.5, 29.2, 25.0, 15.2; HRMS (ESI-TOF) calcd for C₂₀H₂₀O₂Na [M+Na]⁺ 315.1356, found 315.1352.

  1-(2-Methyl-6a-(thiophen-2-yl)-4, 5, 6, 6a-tetrahydro-3aH-cyclopenta[b]furan-3-yl)ethanone (3n): yellow oil, 47% yield (23.3 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.24 (dd, J＝4.8, 1.2 Hz, 1H), 7.02~6.95 (m, 2H), 3.68 (d, J＝9.0 Hz, 1H), 2.43~2.39 (m, 1H), 2.28 (s, 3H), 2.23 (s, 3H), 2.16~2.01 (m, 2H), 1.88~1.79 (m, 2H), 1.74~1.66 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 194.4, 167.1, 147.8, 126.9, 124.6, 122.7, 116.0, 97.0, 55.5, 42.4, 34.4, 29.3, 24.5, 15.2; HRMS (ESI-TOF) calcd for C₁₄H₁₇O₂S [M+H]⁺ 249.0944, found 249.0949.

  1-(2-Methyl-7a-phenyl-3a, 4, 5, 6, 7, 7a-hexahydrobenzo-furan-3-yl)ethanone (5a): light yellow oil, 87% yield (44.6 mg). ¹H NMR (500 MHz, CDCl₃) δ: 7.37~7.30 (m, 4H), 7.25 (t, J＝7.0 Hz, 1H), 3.31 (t, J＝6.5 Hz, 1H), 2.33 (s, 3H), 2.16 (s, 3H), 2.15~2.01 (m, 2H), 1.90~1.77 (m, 1H), 1.77~1.52 (m, 4H), 1.53~1.34 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ: 194.3, 167.0, 147.1, 128.2, 127.1, 124.2, 119.2, 90.3, 47.0, 34.7, 29.2, 27.6, 19.7, 19.5, 15.6; HRMS (ESI-TOF) calcd for C₁₇H₂₀O₂Na ([M+Na]⁺ 279.1356, found 279.1356.

  1-(2-Methyl-7a-(p-tolyl)-3a, 4, 5, 6, 7, 7a-hexahydrobenzo-furan-3-yl)ethanone (5b): yellow oil, 98% yield (53.0 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.25 (d, J＝7.8 Hz, 2H), 7.13 (d, J＝8.4 Hz, 2H), 3.29 (t, J＝6.6 Hz, 1H), 2.32 (s, 3H), 2.32 (s, 3H), 2.16 (s, 3H), 2.14~2.00 (m, 2H), 1.84~1.75 (m, 1H), 1.67~1.50 (m, 3H), 1.45~1.36 (m, 2H); ¹³C NMR (150 MHz, CDCl₃) δ: 194.3, 166.9, 144.1, 136.7, 128.8, 124.1, 119.2, 90.3, 46.9, 34.7, 29.1, 27.6, 20.9, 19.7, 19.5, 15.5; HRMS (ESI-TOF) calcd for C₁₈H₂₂O₂Na [M+Na]⁺ 293.1512, found 293.1522.

  1-(7a-(4-Fluorophenyl)-2-methyl-3a, 4, 5, 6, 7, 7a-hexahy-drobenzofuran-3-yl)ethanone (5c): colorless oil, 93% yield (51.0 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.36~7.29 (m, 2H), 7.04~6.96 (m, 2H), 3.27 (t, J＝6.6 Hz, 1H), 2.32 (s, 3H), 2.17 (s, 3H), 2.15~2.01 (m, 2H), 1.82~1.75 (m, 1H), 1.68~1.51 (m, 3H), 1.50~1.44 (m, 1H), 1.43~1.36 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 194.2, 166.7, 161.3 (d, J＝244.1 Hz), 142.8 (d, J＝3.0 Hz), 125.9 (d, J＝6.8 Hz), 119.3, 114.9 (d, J＝21.2 Hz), 89.9, 47.0, 34.8, 32.9, 32.8, 29.2, 27.6, 19.6, 19.4, 15.5; HRMS (ESI-TOF) calcd for C₁₇H₁₉FO₂Na [M+Na]⁺ 297.1261, found 297.1265.

  1-(2-Nethyl-7a-(4-(trifluoromethyl)phenyl)-3a, 4, 5, 6, 7, 7a-hexahydrobenzofuran-3-yl)ethanone (5d): colorless oil, 73% yield (47.4 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.58 (d, J＝8.4 Hz, 2H), 7.48 (d, J＝7.8 Hz, 2H), 3.28 (t, J＝6.6 Hz, 1H), 2.34 (s, 3H), 2.19~2.10 (m, 4H), 2.10~2.05 (m, 1H), 1.83~1.75 (m, 1H), 1.69~1.62 (m, 2H), 1.60~1.52 (m, 1H), 1.50~1.38 (m, 2H); ¹³C NMR (150 MHz, CDCl₃) δ: 194.1, 166.6, 151.2, 129.4 (q, J＝2.4 Hz), 126.8, 125.2 (q, J＝3.8 Hz), 123.2 (d, J＝270.2 Hz, 2H), 119.5, 89.8, 46.9, 34.7, 29.2, 27.7, 19.6, 19.5, 15.5; HRMS (ESI-TOF) calcd for C₁₈H₁₉O₂Na [M+Na]⁺ 347.1229, found 347.1223.

  1-(3-Methyl-1-phenyl-2-oxabicyclo[3.2.0]hept-3-en-4-yl)ethanone (6a): colorless oil, 75% yield (34.2 mg). ¹H NMR (500 MHz, CDCl₃) δ: 7.47 (d, J＝7.5 Hz, 2H), 7.42 (t, J＝7.5 Hz, 2H), 7.33 (t, J＝7.5 Hz, 1H), 3.83 (t, J＝3.5, 1H), 2.88~2.67 (m, 2H), 2.57~2.41 (m, 1H), 2.36 (s, 3H), 2.17 (s, 3H), 2.13~1.99 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 194.9, 169.1, 140.8, 128.6, 127.9, 124.7, 117.5, 90.9, 49.3, 35.3, 29.5, 24.6, 15.3; HRMS (ESI-TOF) calcd for C₁₅H₁₇O₂ [M+H]⁺ 229.1223, found 229.1232.

  1-(3-Methyl-1-(o-tolyl)-2-oxabicyclo[3.2.0]hept-3-en-4-yl)ethanone (6b): colorless oil, 97% yield (47.0 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.40 (d, J＝7.2 Hz, 1H), 7.30~7.20 (m, 3H), 4.17 (d, J＝7.2 Hz, 1H), 2.92~2.80 (m, 1H), 2.77~2.67 (m, 1H), 2.40~2.30 (m, 4H), 2.28 (s, 3H), 2.23 (s, 3H), 2.06~1.97 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 194.8, 168.7, 137.7, 136.4, 131.8, 128.7, 125.6, 125.6 117.5, 92.4, 46.2, 35.4, 29.4, 24.2, 20.1, 15.3; HRMS (ESI-TOF) calcd for C₁₆H₁₈O₂Na [M+Na]⁺ 265.1199, found 265.1197.

  1-(3-Methyl-1-(m-tolyl)-2-oxabicyclo[3.2.0]hept-3-en-4-yl)ethanone (6c): yellow oil, 63% yield (30.5 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.30 (t, J＝7.2 Hz, 1H), 7.28~7.24 (m, 2H), 7.15 (d, J＝7.2 Hz, 1H), 3.82 (d, J＝7.2 Hz, 1H), 2.84~2.68 (m, 2H), 2.53~2.41 (m, 1H), 2.39 (s, 3H), 2.35 (s, 3H), 2.17 (s, 3H), 2.11~2.02 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 195.0, 169.1, 140.8, 138.4, 128.8, 128.6, 125.5, 121.8, 117.5, 91.0, 49.3, 35.3, 29.5, 24.7, 21.5, 15.4; HRMS (ESI-TOF) calcd for C₁₆H₁₈O₂Na [M+Na]⁺ 265.1199, found 265.1198.

  1-(3-Methyl-1-(p-tolyl)-2-oxabicyclo[3.2.0]hept-3-en-4-yl)ethanone (6d): yellow oil, 61% yield (29.6 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.35 (d, J＝7.8 Hz, 2H), 7.22 (d, J＝7.8 Hz, 2H), 3.80 (d, J＝7.2 Hz, 1H), 2.84~2.67 (m, 2H), 2.51~2.39 (m, 1H), 2.37 (s, 3H), 2.34 (s, 3H), 2.16 (s, 3H), 2.10~2.02 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 195.0, 169.1, 137.8, 137.8, 129.2, 124.8, 117.5, 90.9, 49.2, 35.2, 29.4, 24.5, 21.1, 15.3; HRMS (ESI-TOF) calcd for C₁₆H₁₈O₂Na [M+Na]⁺ 265.1199, found 265.1201.

  1-(1-(2, 4-Dimethylphenyl)-3-methyl-2-oxabicyclo[3.2.0]-hept-3-en-4-yl)ethanone (6e): white solid, 62% yield (31.8 mg). m.p. 95~96 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 7.29 (d, J＝7.8 Hz, 1H), 7.07 (s, 1H), 7.03 (d, J＝7.8 Hz, 1H), 4.13 (t, J＝1.8 Hz, 1H), 2.92~2.78 (m, 1H), 2.75~2.67 (m, 1H), 2.40~2.29 (m, 7H), 2.27 (s, 3H), 2.22 (s, 3H), 2.04~1.96 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 194.9, 168.9, 138.6, 137.6, 133.6, 132.7, 126.1, 125.7, 117.5, 92.3, 46.3, 35.4, 29.4, 24.3, 20.9, 20.0, 15.4; HRMS (ESI-TOF) calcd for C₁₇H₂₀O₂Na [M+Na]⁺ 279.1356, found 279.1357.

  1-(1-(4-Fluorophenyl)-3-methyl-2-oxabicyclo[3.2.0]hept-3-en-4-yl)ethanone (6f): light yellow oil, 96% yield (47.3 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.45~7.41 (m, 2H), 7.09 (t, J＝8.4 Hz, 2H), 3.80 (d, J＝7.8 Hz, 1H), 2.83~2.77 (m, 1H), 2.75~2.65 (m, 1H), 2.52~2.41 (m, 1H), 2.35 (s, 3H), 2.17 (s, 3H), 2.11~2.03 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 194.8, 168.9, 162.4 (d, J＝244.5 Hz), 136.8, 126.7 (d, J＝9 Hz), 117.5, 115.5 (d, J＝21.0 Hz), 90.4, 49.4, 35.3, 29.5, 24.5, 15.3; HRMS (ESI-TOF) calcd for C₁₅H₁₆FO₂ [M+H]⁺ 247.1129, found 247.1128.

  1-(1-(4-Chlorophenyl)-3-methyl-2-oxabicyclo[3.2.0]hept-3-en-4-yl)ethanone (6g): yellow oil, yield 98% (51.5 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.40~7.36 (m, 4H), 3.78 (d, J＝7.8 Hz, 1H), 2.82~2.77 (m, 1H), 2.70~2.66 (m, 1H), 2.46~2.43 (m, 1H), 2.35 (s, 3H), 2.17(s, 3H), 2.10~2.05 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 194.9, 169.0, 139.5, 133.8, 128.7, 126.2, 117.6, 90.3, 49.5, 35.4, 29.4, 24.6, 15.3; HRMS (ESI-TOF) calcd for C₁₅H₁₅Cl- O₂Na [M+Na]⁺ 285.0653, found 285.0653.

  1-(3-Methyl-1-(naphthalen-1-yl)-2-oxabicyclo[3.2.0]hept-3-en-4-yl)ethanone (6h): yellow solid, 99% yield (55.1 mg). m.p. 45~46 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 7.99~7.97 (m, 1H), 7.91~7.89 (m, 1H), 7.87 (d, J＝8.4 Hz, 1H), 7.60 (d, J＝7.2 Hz, 1H), 7.54~7.47 (m, 3H), 4.36 (d, J＝6.6 Hz, 1H), 3.12~3.07 (m, 1H), 2.85~2.80 (m, 1H), 2.40~2.34 (m, 1H), 2.32 (s, 1H), 2.28 (s, 3H), 2.13~2.08 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 195.0, 168.9, 134.5, 134.3, 130.8, 129.7, 128.9, 126.2, 125.9, 125.6, 124.7, 124.0, 117.5, 92.2, 46.6, 36.4, 29.5, 24.7, 15.5; HRMS (ESI-TOF) calcd for C₁₉H₁₈O₂Na [M+Na]⁺ 301.1199, found 301.1199.

  1-(2-Methyl-8a-phenyl-4, 5, 6, 7, 8, 8a-hexahydro-3aH-cyclohepta[b]furan-3-yl)ethanone (7a): colorless oil, 96% yield (51.9 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.39 (d, J＝7.2 Hz, 2H), 7.33 (t, J＝7.8 Hz, 2H), 7.27~7.21 (m, 1H), 3.59 (d, J＝5.4 Hz, 1H), 2.34 (s, 3H), 2.19 (s, 3H), 2.14~1.97 (m, 3H), 1.88~1.79 (m, 1H), 1.65~1.58 (m, 2H), 1.56~1.41 (m, 4H); ¹³C NMR (150 MHz, CDCl₃) δ: 193.9, 165.6, 148.3, 128.2, 127.0, 123.8, 116.7, 94.0, 53.3, 40.3, 31.0, 29.8, 29.3, 26.3, 23.9, 15.5; HRMS (ESI-TOF) calcd for C₁₈H₂₂O₂Na [M+Na]⁺ 293.1512, found 293.1506.

  1-(2-Methyl-8a-(o-tolyl)-4, 5, 6, 7, 8, 8a-hexahydro-3aH-cyclohepta[b]furan-3-yl)ethanone (7b): light yellow oil, 83% yield (47.2 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.43~7.34 (m, 1H), 7.18~7.07 (m, 3H), 3.64 (s, 1H), 2.45 (s, 3H), 2.40 (s, 3H), 2.30~2.21 (m, 2H), 2.21 (s, 3H), 2.02~1.95 (m, 1H), 1.88~1.73 (m, 2H), 1.69~1.57 (m, 3H), 1.36~1.17 (m, 2H); ¹³C NMR (150 MHz, CDCl₃) δ: 193.7, 165.1, 146.2, 133.6, 132.6, 126.9, 125.7, 123.5, 116.4, 94.8, 52.0, 37.7, 31.3, 29.7, 29.4, 24.8, 24.5, 21.4, 15.3; HRMS (ESI-TOF) calcd for C₁₉H₂₅O₂ [M+H]⁺ 285.1849, found 285.1851.

  1-(2-Methyl-8a-(p-tolyl)-4, 5, 6, 7, 8, 8a-hexahydro-3aH-cyclohepta[b]furan-3-yl)ethanone (7c): colorless oil, 71% yield (40.4 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.29 (d, J＝8.4 Hz, 2H), 7.14 (d, J＝8.4 Hz, 2H), 3.57 (d, J＝5.4 Hz, 1H), 2.33 (s, 3H), 2.32 (s, 3H), 2.19 (s, 3H), 2.13~1.91 (m, 3H), 1.91~1.78 (m, 1H), 1.64~1.56 (m, 2H), 1.55~1.43 (m, 4H); ¹³C NMR (150 MHz, CDCl₃) δ: 193.9, 165.7, 145.2, 136.7, 128.9, 123.9, 116.8, 94.1, 53.3, 40.3, 31.0, 29.8, 29.3, 26.5, 23.8, 20.9, 15.5; HRMS (ESI-TOF) calcd for C₁₉H₂₅O₂ [M+H]⁺ 285.1849, found 285.1850.

  1-(8a-(4-Fluorophenyl)-2-methyl-4, 5, 6, 7, 8, 8a-hexahydro-3aH-cyclohepta[b]furan-3-yl)ethanone (7d): colorless oil, 64% yield (36.9 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.36 (dd, J＝8.4, 5.4 Hz, 2H), 7.01 (t, J＝8.4 Hz, 2H), 3.54 (d, J＝5.4 Hz, 1H), 2.33 (s, 3H), 2.21 (s, 3H), 2.09~1.98 (m, 3H), 1.88~1.80 (m, 1H), 1.68~1.54 (m, 2H), 1.55~1.41 (m, 4H); ¹³C NMR (150 MHz, CDCl₃) δ: 193.8, 165.4, 161.7 (d, J＝244.1 Hz), 144.0, 125.6 (d, J＝7.8 Hz), 116.8, 115.0 (d, J＝21.2 Hz), 93.7, 53.4, 40.4, 31.0, 29.7, 29.3, 26.4, 23.8, 15.5; HRMS (ESI-TOF) calcd for C₁₈H₂₂- FO₂ [M+H]⁺ 289.1598, found 289.1597.

  1-(8a-(4-methoxyphenyl)-2-methyl-4, 5, 6, 7, 8, 8a-hexahydro-3aH-cyclohepta[b]furan-3-yl)ethanone (7e): yellow oil, yield 93% (55.9 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.33 (d, J＝8.4 Hz, 2H), 6.86 (d, J＝8.8 Hz, 2H), 3.79 (s, 3H), 3.56 (d, J＝8.4 Hz, 1H), 2.31 (s, 3H), 2.20 (s, 3H), 2.10~1.90 (m, 3H), 1.86~1.82 (m, 1H), 1.63~1.44 (m, 6H); ¹³C NMR (150 MHz, CDCl₃) δ: 193.9, 165.6, 158.6, 140.1, 125.3, 116.9, 113.5, 94.0, 55.2, 53.2, 40.3, 31.0, 29.8, 29.3, 26.7, 23.8, 15.6; HRMS (ESI-TOF) calcd for C₁₉H₂₄O₃Na [M+Na]⁺ 323.1618, found 323.1626.

  1-(2-Methyl-13a-phenyl-3a, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 13a-dodecahydrocyclododeca[b]furan-3-yl)ethanone (8): light yellow oil, 98% yield (66.7 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.35~7.28 (m, 4H), 7.25~7.21 (m, 1H), 3.27 (d, J＝7.8 Hz, 1H), 2.28 (s, 3H), 2.14 (s, 3H), 2.11~2.01 (m, 1H), 2.01~1.91 (m, 1H), 1.91~1.81 (m, 1H), 1.68~1.35 (m, 14H), 1.22~1.14 (m, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 194.0, 165.9, 145.8, 127.8, 127.0, 124.8, 119.2, 93.5, 51.1, 35.6, 29.1, 28.4, 27.1, 26.9, 26.6, 25.5, 24.8, 23.6, 23.5, 22.2, 15.5; HRMS (ESI-TOF) calcd for C₂₃H₃₃O₂ [M+H]⁺ 341.2475., found 341.2476.

  4a-(4-(Trifluoromethyl)phenyl)-2, 3, 5, 6, 7, 7a-hexahydro-dicyclopenta[b, d]furan-1(4aH)-one (9a): black oil, yield 99% (61.0 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.64 (d, J＝7.8 Hz, 2H), 7.50 (d, J＝8.4 Hz, 2H), 3.54 (d, J＝7.8 Hz, 1H), 2.91~2.73 (m, 2H), 2.72~2.56 (m, 2H), 2.51~2.46 (m, 1H), 2.07~1.91 (m 4H), 1.83~1.73 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 196.4, 194.2, 147.1, 130.0 (q, J＝2.4 Hz), 125.6 (q, J＝3.8 Hz), 124.7, 123.8 (q, J＝157.4 Hz), 113.9, 50.4, 43.0, 40.6, 32.5, 25.3, 22.2; HRMS (ESI-TOF) calcd for C₁₇H₁₆F₃O₂ [M+H]⁺ 309.1097, found 309.1090.

  3a-(4-(Trifluoromethyl)phenyl)-3, 3a, 5, 6, 7, 8b-hexahydro-1H-cyclopenta[b]benzofuran-8(2H)-one (9b): colorless oil, 99% yield (63.8 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.61 (d, J＝8.4 Hz, 2H), 7.49 (d, J＝8.4 Hz, 2H), 3.65 (d, J＝7.8 Hz, 1H), 2.50~2.54 (m, 1H), 2.53~2.46 (m, 1H), 2.44~2.26 (m, 3H), 2.12~1.94 (m, 5H), 1.92~1.88 (m, 1H), 1.72~1.63 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 195.3, 176.3, 147.9, 129.7 (q, J＝2.3 Hz), 125.4 (q, J＝3.8 Hz), 124.8, 124.5 (q, J＝270.3 Hz, ), 115.9, 102.5, 52.0, 43.5, 36.6, 33.3, 24.9, 23.8, 21.8; HRMS (ESI-TOF) calcd for C₁₈H₁₈F₃O₂ [M+H]⁺ 323.1253, found 323.1271.

  6, 6-Dimethyl-3a-(4-(trifluoromethyl)phenyl)-3, 3a, 5, 6, 7, 8b-hexahydro-1H-cyclopenta[b]benzofuran-8(2H)-one (9c): yellow solid, 79% yield (55.4 mg). m.p. 117-118 ℃; NMR Spectroscopy: ¹H NMR (600 MHz, CDCl₃) δ: 7.61 (d, J＝8.4 Hz, 2H), 7.48 (d, J＝7.8 Hz, 2H), 3.63 (d, J＝7.8 Hz, 1H), 2.42~2.34 (m, 3H), 2.27~2.17 (m, 2H), 2.10~1.87 (m, 4H), 1.73~1.62 (m, 1H), 1.13 (s, 3H), 1.11 (s, 3H); ¹³C NR (150 MHz, CDCl₃) δ: 194.6, 175.3, 147.9, 129.7 (q, J＝2.3 Hz), 125.5 (q, J＝3.8 Hz), 124.5 (q, J＝270.3 Hz), 124.8, 114.4, 102.7, 52.0, 51.1, 43.3, 37.7, 34.1, 33.3, 29.1, 28.0, 25.0; HRMS (ESI-TOF) calcd for C₂₀H₂₂F₃O₂ [M+H]⁺ 351.1566, found 351.1567.

  (2-Methyl-6a-(4-(trifluoromethyl)phenyl)-4, 5, 6, 6a-tetra-hydro-3aH-cyclopenta[b]furan-3-yl)(phenyl)methanone(10a): colorless oil, 34% yield (25.3 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.63 (d, J＝8.4 Hz, 2H), 7.53 (d, J＝8.4 Hz, 2H), 7.51~7.48 (m, 2H), 7.46 (d, J＝7.2 Hz, 1H), 7.40 (t, J＝7.2 Hz, 2H), 3.90 (d, J＝8.4 Hz, 1H), 2.36 (dd, J＝13.8, 6.0 Hz, 1H), 2.11~1.96 (m, 3H), 1.96~1.88 (m, 1H), 1.87~1.74 (m, 4H); ¹³C NMR (150 MHz, CDCl₃) δ: 193.3, 167.5, 148.6, 141.2, 131.0, 129.5 (q, J＝32.6 Hz), 128.3, 127.7, 125.5 (q, J＝3.6 Hz), 124.8, 124.1 (q, J＝270.8 Hz) 116.3, 98.7, 56.3, 43.7, 34.7, 25.0, 15.5; HRMS (ESI-TOF) calcd for C₂₂H₁₉F₃O₂Na [M+Na]⁺ 395.1229, found 395.1217.

  1-(2-Phenyl-6a-(4-(trifluoromethyl)phenyl)-4, 5, 6, 6a-tetrahydro-3aH-cyclopenta[b]furan-3-yl)ethanone (10aꞌ): white solid, yield 34% (25.3 mg). m.p.119~120 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 7.64 (d, J＝8.4 Hz, 2H), 7.62~7.54 (m, 4H), 7.54~7.46 (m, 3H), 3.85 (d, J＝8.4 Hz, 1H), 2.42 (dd, J＝13.8, 6.0 Hz, 1H), 2.24~2.13 (m, 1H), 2.13~2.00 (m, 2H), 2.00~1.93 (m, 1H), 1.92~1.81 (m, 4H); ¹³C NMR (150 MHz, CDCl₃) δ: 194.3, 166.1, 148.5, 131.0, 130.7, 129.7 (q, J＝32.4 Hz), 129.1, 128.5, 125.5 (q, J＝3.6 Hz), 124.8, 124.1 (q, J＝270.8 Hz), 118.5, 98.7, 56.3, 44.0, 35.1, 29.0, 25.1; HRMS (ESI-TOF) calcd for C₂₂H₁₉F₃O₂Na [M+Na]⁺ 395.1229, found 395.1229.

  1-(2-Methyl-6a-(4-(trifluoromethyl)phenyl)-4, 5, 6, 6a-tetrahydro-3aH-cyclopenta[b]furan-3-yl)propan-1-one(10b): colorless oil, 56% yield (36.3 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.61 (d, J＝8.4 Hz, 2H), 7.50 (d, J＝8.4 Hz, 2H), 3.62 (d, J＝8.4 Hz, 1H), 2.48 (q, J＝7.2 Hz, 2H), 2.35 (s, 3H), 2.32 (dd, J＝13.8, 6.0 Hz, 1H), 2.16~2.06 (m, 1H), 2.05~1.97 (m, 1H), 1.94~1.87 (m, 2H), 1.80~1.69 (m, 1H), 1.07 (t, J＝7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 197.4, 166.7, 148.5, 129.5 (q, J＝32.1 Hz), 125.3 (q, J＝3.6 Hz), 124.0 (q, J＝270.3 Hz), 124.7, 115.3, 98.6, 55.6, 43.2, 35.2, 34.0, 24.9, 15.0, 7.9; HRMS (ESI-TOF) calcd for C₁₈H₁₉F₃O₂Na [M+Na]⁺ 347.1229, found 347.1227.

  1-(2-Ethyl-6a-(4-(trifluoromethyl)phenyl)-4, 5, 6, 6a-tetrahydro-3aH-cyclopenta[b]furan-3-yl)ethanone (10bꞌ): colorless oil, 42% yield (27.2 mg). ¹H NMR (600 MHz, CDCl₃) δ: 7.54 (d, J＝8.4 Hz, 2H), 7.42 (d, J＝7.8 Hz, 2H), 3.53 (d, J＝8.4 Hz, 1H), 2.78~2.59 (m, 2H), 2.24 (dd, J＝13.8, 6.0 Hz, 1H), 2.12 (s, 3H), 2.08~1.98 (m, 1H), 1.95~1.89 (m, 1H), 1.87~1.77 (m, 2H), 2.78~2.59 (m, 1H), 1.17 (t, J＝7.6 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 194.1, 172.1, 148.6, 129.5 (q, J＝32.4 Hz), 125.3 (q, J＝3.6 Hz), 124.6, 129.5 (q, J＝124.01 Hz), 114.9, 98.3, 55.9, 43.5, 35.1, 29.1, 24.7, 22.0, 11.5; HRMS (ESI-TOF) calcd for C₁₈H₁₉F₃O₂Na [M+Na]⁺ 347.1229, found 347.1233.

  Supporting Information     Crystal structures of 6e, and ¹H NMR and ¹³C NMR spectra of new compounds 3, 5~10. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn.

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• 

  Figure 1  Some examples of cycloalkane-fused dihydrofurans skeleton in natural products and therapeutic agents

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  Scheme1  Synthesis of cycloalkane-fused dihydrofurans

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  Scheme2  Reaction of 1ak and 1, 3-diketones 2b~2f

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  Scheme3  Control experiments

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  Scheme4  Plausible mechanism

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  Table 1.  Optimization of reaction conditions^a

  Entry	Catalyst	Oxidant	Temp./℃	Solvent	Yieldb/%
  					3a	4a
  1	CuCl	K2S2O8	50	CH3CN	14	44
  2	CuBr	K2S2O8	50	CH3CN	44	13
  3	CuI	K2S2O8	50	CH3CN	23	37
  4	Cu(CH3CN)4PF6	K2S2O8	50	CH3CN	81	0
  5	CuTc	K2S2O8	50	CH3CN	19	48
  7	CuCl2	K2S2O8	50	CH3CN	30	12
  8	Cu(OAc)2	K2S2O8	50	CH3CN	18	41
  9	FeCl3	K2S2O8	50	CH3CN	18	25
  10	ZnCl2	K2S2O8	50	CH3CN	18	51
  11	—	K2S2O8	50	CH3CN	10	58
  12	Cu(CH3CN)4PF6	—	50	CH3CN	0	90
  13	Cu(CH3CN)4PF6	PhI(OAc)2	50	CH3CN	0	86
  14	Cu(CH3CN)4PF6	TBHP	50	CH3CN	0	57
  15	Cu(CH3CN)4PF6	m-CPBA	50	CH3CN	0	47
  16	Cu(CH3CN)4PF6	K2S2O8	30	CH3CN	64	11
  17	Cu(CH3CN)4PF6	K2S2O8	70	CH3CN	72	0
  18	Cu(CH3CN)4PF6	K2S2O8	50	THF	3	47
  19	Cu(CH3CN)4PF6	K2S2O8	50	Toluene	0	89
  20	Cu(CH3CN)4PF6	K2S2O8	50	DCE	6	83
  21	Cu(CH3CN)4PF6	K2S2O8	50	DCM	18	24
  aGeneral reaction conditions: 1aa (0.2 mmol), 2a (3 equiv., 0.6 mmol), catalyst (10 mol%), oxidant (2 equiv.), solvent (2 mL), 17 h, N2 atmosphere. bIsolated yields.

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  Table 2.  Variety of 1-aryl-1-cyclopentanols 1a^a

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  Table 3.  Variety of ring-sizes of alicyclic alcohols 1b~1e^a

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•