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DOI: 10.1039/D4NJ03285C (Paper) New J. Chem., 2024, 48, 15846-15855

Synthesis of 3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one and Skeleton construction of a type D spirobisnaphthalene structure via dearomatization by a high-valence iodine reagent and Diels–Alder reaction†

Haoyun Ma , Xinkun An , Tingting Zhang , Xie He , Yiyi Li and Mingan Wang *
Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, People's Republic of China. E-mail: wangma@cau.edu.cn

Received 23rd July 2024 , Accepted 18th August 2024

First published on 22nd August 2024

Abstract

The core skeleton syntheses of 3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one, and their derivatives (3a–3w) of spirobisnaphthalene urnucratins, plecmillins, and lignan kadsulignan, were explored using Suzuki–Miyaura coupling product biphenols as the precursors and intramolecular oxidative dearomatization with high-valence iodine reagent PIFA as the key step in 46–91% yields. A wide range of functional groups were tolerated. Then, using this strategy in combination with the Diels–Alder reaction, two skeleton molecules (5ah and 6d) of the natural products urnucratins and plecmillins were successfully constructed in 78% and 39% overall yields, which provides a potential methodology for the total synthesis of Type D spirobisnaphthalene urnucratins and other natural products with similar structures.

1. Introduction

Spirobisnaphthalene natural products have interesting structures and a variety of biological activities, such as antimicrobial, antifungal, antiparasitic, antitumor, anticancer, anti-inflammatory and cytotoxic activities, which have great potential as potent lead compounds for medicinal chemistry.1–5 Type D spirobisnaphthalenes (such as urnucratins A–C and plecmillin A) are a subfamily of structurally unique spirobisnaphthalene natural products with a core construction of 3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one6–8 (Fig. 1). Plecmillin A exhibited excellent anticancer activity against the human colorectal HCT116 cell line with an IC50 of 2.1 μM. It induced cell cycle arrest and increased the protein levels of p53 and p21, which indicated that plecmillin A can upregulate the tumor-suppressing p53–p21 pathway.8 Kadsulignan A and B have been isolated from the seeds of Kadsura coccinea, and these compounds also contain the 3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one moiety structure9 (Fig. 1).
image file: d4nj03285c-f1.tif
Fig. 1 The typical structures of type D spirobisnaphthalenes and kadsulignans and their core motif.

To the best of our knowledge, there have been no reports describing the total synthesis of the natural products urnucratins, plecmillins, or kadsulignans. Therefore, we attempted to synthesize these compounds after several successes at the total synthesis of type A spirobisnaphthalene natural products in our laboratory.10–14 We attempted to achieve their total synthesis by the strategy of constructing the core motif 3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one. Several groups have reported synthetic approaches for the 3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one ring system (Scheme 1a). Swenton's group15 used aryl lithium reagents to react with 4,4-dimethoxycyclohexa-2,5-dien-1-one to obtain spirocyclohexadienonic ketals 3 and their derivatives. Chiba's group16 reported a Cu-catalyzed aerobic spirocyclization of biaryl-N–H-ketimines, which also was successful in constructing the skeleton of 3.


image file: d4nj03285c-s1.tif
Scheme 1 The strategies used to construct spirocyclic ring system compounds 3 and their derivatives (a and b).

Wang's group17 reported phenyliodine(III) diacetate (PIDA)-promoted/1,1,1,3,3,3-hexafluoroisopropanol-controlled dearomative spirocyclization of phenolic ketones to provide spirocyclohexadienonic ketals and their acetoxylated counterparts. They found that when hexafluoroisopropanol or methanol were used as the solvents, the structures of the products were different. Recently, Phipps's group18 used chiral sulfonated sSPhos as the ligand and electrostatically directed palladium catalysis to realize the dearomatization of arylphenols to form spirocyclohexadienonic ketals in 22–49% yields with 82–93% enantiomeric excess (ee) values. These studies inspired us to synthesize core skeleton 3, but the reaction processes of these strategies are either relatively complex or require the involvement of metals, and the substrate richness is not yet sufficient.

High-valence iodine-mediated oxidative19–22 transformations of phenolic derivatives to construct a highly functionalized cyclohexadienone system of natural products, drug intermediates, and new functional materials have become a versatile and environmentally friendly strategy.23–25 The iodine atom (III or V) acts in an electrophilic attack on the oxygen atom of hydroxyl in phenolic compounds, and completes the dearomatization reaction to produce a cyclohexadienone system.26 In this study, we attempted to construct spirocyclic cyclohexadienone ring system 3 based on an oxidative dearomatization strategy with high-valence iodine reagent, and transfer to the skeleton compounds of natural product urnucratins (Scheme 1b).

Therefore, biphenyl phenolic compounds 2 were designed to construct core structure 3 and its derivatives by intramolecular oxidative dearomatization in the presence of high-valence iodine reagent. Intermediates 2 are easily obtained from commercially available 2-bromobenzenealdehydes and 4-hydroxybenzene boronic acids by Suzuki–Miyaura coupling reaction,27–29 followed by NaBH4 reduction. Then, we successfully prepared the skeleton compounds of spirobisnaphthalene urnucratins by the Diels–Alder reaction30,31 of spirocyclic cyclohexadienone compounds 3 with (E)-1-(t-butyldimethylsiloxy)-1,3-butadiene, followed by oxidative aromatization and deprotection. These approaches provided an effective strategy for the total synthesis of type D spirobisnaphthalene urnucratins and plecmillins, as well as other natural products and medicines containing similar skeletons.

2. Results and discussion

Considering the presence of electron-withdrawing groups such as NO2 and CF3, and the steric hindrance of 2-bromobenzenealdehydes, the conditions of the Suzuki–Miyaura coupling reaction are challenging.32 By changing the solvents for the cross-coupling reaction, and optimizing the catalysts and dosage (Table S1, ESI†), we finally obtained coupling product 1a in 92% yield using K2CO3 as the base and a catalytic amount of Pd (PPh3)2Cl2 (10 mol%) in a mixture of dioxane and H2O (dioxane[thin space (1/6-em)]:[thin space (1/6-em)]H2O = 1[thin space (1/6-em)]:[thin space (1/6-em)]1) at 80 °C, without debromination byproducts (Table S1, entry 15, ESI†). Then, coupling product 1a was reduced by NaBH4 to obtain substrate 2a. Under optimal reaction conditions, the scope of coupling substrates was investigated, and 23 products 2a–2w with different substituents were afforded in 66–85% yields using a similar approach (Table S2, ESI†).

After synthesis of compounds 2a–2w, we examined the feasibility of the envisaged reaction, and we choose compound 2a as a model substrate to optimize the dearomatization reaction conditions with high-valence iodine reagents (Table 1). Initially, the reaction did not take place in the presence of 2-iodobenzoic acid (IBX) with MeCN as the solvent (Table 1, entry 1). When the oxidizing agent was changed to PIDA, the desired product 3a was isolated in 58% yield after 1 h of reaction at ambient temperature (Table 1, entry 2). The more reactive oxidant phenyliodine(III) bis(trifluoroacetate) (PIFA) was then examined, and the yield of 3a was increased to 87% within 15 min at ambient temperature (Table 1, entry 3). Solvent screening (entries 4–9) revealed that DCM, MeCN, and acetone were all useable solvents with high yield, but multiple impurities were produced when DCM was used as the solvent. As the temperature dropped to 0 °C, byproducts were effectively avoided, and the yield of 3a using acetone as a solvent was higher than that with MeCN (Table 1, entries 10 and 11).

Table 1 Reaction optimization for intramolecular oxidative dearomatization of 2a to access 3a

image file: d4nj03285c-u1.tif
Entry Oxidation n/mmol T/°C Solventa Time Yield/%b
a 5 mL of solvent for 1 mmol of raw material. b Isolated yields. c The raw material was recovered. d Solvent participation in the reaction; formaldehyde was obtained.
1 IBX 1.2 eq. rt MeCN 1 h —
2 PIDA 1.2 eq. rt MeCN 1 h 58
3 PIFA 1.2 eq. rt MeCN 15 min 87
4 PIFA 1.2 eq. rt DCM 15 min 84
5 PIFA 1.2 eq. rt THF 15 min 53
6 PIFA 1.2 eq. rt PhMe 15 min 68
7c PIFA 1.2 eq. rt DMF 15 min <10
8d PIFA 1.2 eq. rt MeOH 15 min <10
9 PIFA 1.2 eq. rt Acetone 15 min 89
10 PIFA 1.2 eq. 0 °C MeCN 15 min 88
11 PIFA 1.2 eq. 0 °C Acetone 15 min 90

Under optimal reaction conditions (Table 1 entry 11), the substrate scope of various isobenzofuran spirocyclic cyclohexadienone derivatives (3a–3w) was explored (Scheme 2). First, the generality of biphenol compounds with different substituents R1 was evaluated. These substrates reacted with PIFA to give the corresponding spirocyclohexadienone in yields of 21–93% with no byproducts, but with one exception. When 2u reacted with PIFA, some aldehyde byproduct was obtained due to the oxidation of the CH2OH group. Substituents R1 with electron-donating (3b–3c, 3h) or electron-withdrawing groups (3d–3g, 3i–3j) located at different positions in the A aryl ring were tolerated under the reaction conditions. The strong electrophilicity of the iodine atom coordinated with the hydroxyl oxygen atom in the B ring, as well as with the oxygen atom in the methoxy group in the A ring, which acted as a competing reaction for the former, and this resulted in a lower yield of 3c. Reaction of the bicyclic substrates (3k–3m) also proceeded smoothly under these conditions. Methyl substitution at the α-position of the hydroxyl group of the A-ring branched chain also gave products 3n–3o in high yields. The ortho-chlorine substitution of phenolic hydroxyl on the B ring resulted in lower yields as compared to the meta-position (3qvs.3r, 3tvs.3u), which might be due to the spatial barrier of the chlorine atoms preventing the coordination of the iodine atom with the oxygen atom of phenolic hydroxyl. When there was an electron-withdrawing group on the A ring, the yields were higher as compared to when electron-donating groups were used, regardless of whether the B ring was substituted with methyl or chlorine atoms (3svs.3v, 3uvs.3w). Then, gram-scale reactions of 2a and PIFA were carried out under standard optimal conditions, and product 3a was obtained in 91% yield, which was comparable to smaller-scale reactions (Table 2).


image file: d4nj03285c-s2.tif
Scheme 2 Synthesis of the skeleton of the natural product urnucratin A. Reaction conditions: ① (1) 4-hydroxyphenylboronic acid (1.2 eq.), Pd(PPh3)2Cl2 (0.1 eq.), K2CO3 (2.0 eq.), dioxane/H2O = 1[thin space (1/6-em)]:[thin space (1/6-em)]1, 80 °C for 12 h; (2) NaBH4 (3 eq.), MeOH, 0 °C for 1 h, 74% for two steps. ② PIFA (1.2 eq.), acetone, 0 °C for 15 min, 81%. ③ (1) 4a (10 eq.), 120 °C for 8 h; (2) DDQ, benzene, 80 °C for 8 h; (3) TBAF, THF, rt, 1 h, 65% for three steps.
Table 2 Scope of isobenzofuran spirocyclic cyclohexadienone derivatives (3a–3w)a
a Isolated yields were obtained.
image file: d4nj03285c-u2.tif

Further synthetic transformations were carried out to demonstrate the potential use of these products. As shown in Table 3, the Diels–Alder reaction of 3a with (E)-(buta-1,3-dien-1-yloxy)(tert-butyl)dimethylsilane 4a was attempted to construct the naphthalene ring skeleton of spirobisnaphthalene urnucratins. After the Diels–Alder reaction conditions were optimized (Table S2, ESI†), it was found that the reaction of 3a with an excess of 4a (10 eq.) at 120 °C for 8 h was able to give the target product 4aa in 82% yield. Subsequently, a one-pot method was employed to construct the naphthalene ring skeleton.

Table 3 The spiro-isobenzofuran naphthalene ring derivatives (5aa–5ah) produced by a one-pot method
The isolated yields.
image file: d4nj03285c-u3.tif

First, 4aa was subjected to oxidative aromatization in the presence of DDQ, followed by the removal of the silyl protection group using TBAF, and compound 5aa containing the naphthalene ring skeleton was successfully obtained with a yield of 74%. Inspired by these results, several dearomatization products (3–3f, 3m, and 3j) were then subjected to the Diels–Alder reaction with 4a. DDQ oxidative aromatization and deprotection by TBAF afforded products 5aa–5ah in 49–89% overall yields in similar transformations.

Based on the above reaction exploration, further construction of the functional skeleton of spirobisnaphthalene urnucratins was explored with this strategy. First, Suzuki–Miyaura coupling of substrate 6a with p-hydroxyphenylboronic acid was performed, followed by removal of silyl protection groups to obtain product 6b in 74% yield. Then, 6b was oxidatively dearomatized under optimal conditions (Table 1, entry 11) to obtain product 6c in 81% yield. The chemical structure of 6c was confirmed via X-ray crystal diffraction, and is depicted in Fig. 2. Compound 6c then underwent a similar conversion from 3a to 5aa to produce 6d in 65% yield using a one-pot approach, and it is the core skeleton of spirobisnaphthalene urnucratins and plecmillins (Scheme 2). The chemical structure of compound 6d is clearly very similar to the structure of natural product urnucratin A, which might be obtained by removing the methyl group from the A ring of compound 6d and stereoselectively introducing an epoxy motif into the B ring. The endeavor to complete the transformation from compound 6d and 5ah to the natural product urnucratin A and determine the relative stereochemistry of the products from each step is still under investigation in our laboratory.


image file: d4nj03285c-f2.tif
Fig. 2 The ORTEP drawing of compound 6c.

3. Conclusions

In summary, we have developed a high-valence iodine-mediated intramolecular oxidative dearomatization strategy to rapidly synthesize the key substructure 3 and core skeleton 6d of natural product urnucratin A. The biphenol analogues were easily obtained by Suzuki–Miyaura coupling using commercially available raw materials under mild conditions, followed by oxidative dearomatization in the presence of PIFA to afford 3 and its derivatives in 78–92% yields. Subsequently, the spiro-naphthalene ring skeleton compounds 5aa–5ah were constructed from 3a–3f, 3j, and 3m in 49–89% yields via Diels–Alder reaction, DDQ oxidative aromatization, and deprotection by TBAF. The core skeleton compound 6d of natural product urnucratin A was successfully synthesized in 39% overall yield from 6a in six steps.

4. Experimental section

All reactions were performed under an air atmosphere with magnetic stirring. Unless otherwise stated, all reagents were purchased from commercial suppliers and used without further purification. Organic solutions were concentrated under reduced pressure using a rotary evaporator or oil pump. Flash column chromatography was performed using Qingdao Haiyang silica gel (200–300 mesh). 1H and 13C spectra were recorded using Bruker DPX 300 MHz and Bruker DPX 500 MHz spectrometers with CDCl3 and DMSO-d6 as the solvent and TMS as the internal standard, operating at 300 MHz or 500 MHz for 1H NMR, and 75 MHz or 126 MHz for 13C NMR. The melting points were determined using a WRX-4 melting point apparatus with a microscope (Shanghai Yice Apparatus & Equipment Co., Ltd, Shanghai, China). HR-ESI-MS was performed using a Bruker APEX II mass spectrometer (Varian, Palo Alto, CA, USA). Mass spectrometry was performed using an Agilent 7890 GC-EI-MS instrument (Agilent, USA). The crystal structure was recorded using an Agilent Gemini E X-ray single-crystal diffractometer.

4.1 Detailed synthesis of intermediates 2a–2w is shown in the ESI† (Tables S1 and S2)

4.2 Synthesis of 3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one 3a–3w

General procedure: using 3a as an example, 2a (0.2 mmol, 1.0 eq.) was placed in a 50-mL round bottom flask, and 10 mL of acetone was added. Then, PIFA (0.24 mmol, 1.2 eq.) was slowly added while the reaction was maintained at 0 °C in an ice-water bath for 15 min. When no raw material was left, as monitored by thin-layer chromatography (TLC), 10 mL of saturated NaHCO3 was added. The liquid was then transferred to a separatory funnel, 30 mL of ethyl acetate was added, and the solution was washed with deionized H2O (3 × 20 mL). The organic phase was washed with saturated NaCl solution and dried over anhydrous Na2SO4, evaporated under reduced pressure, and then, the crude product was purified by silica gel column chromatography (ethyl acetate[thin space (1/6-em)]:[thin space (1/6-em)]petroleum ether = 1[thin space (1/6-em)]:[thin space (1/6-em)]5) to obtain 3a. Compounds 3b–3w were prepared from substrates 2b–2w using a similar process.
4.2.1 3′H-Spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one (3a). Light yellow waxy solid, yield 92%, mp 189–192 °C; 1H NMR (300 MHz, CDCl3) δ 7.43–7.26 (m, 3H), 7.01 (dd, J = 7.3, 1.3 Hz, 1H), 6.91–6.80 (m, 2H), 6.26–6.16 (m, 2H), 5.32 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 185.66, 148.67, 139.95, 137.99, 129.13, 128.33, 127.21, 122.25, 122.00, 83.64, 73.25. HR-MS (ESI), m/z: C13H11O2 [M + H]+ calcd for 199.0754, found: 199.0756.
4.2.2 5′-Methyl-3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one (3b). Light yellow liquid, yield 80%; 1H NMR (300 MHz, CDCl3) δ 7.16–7.05 (m, 2H), 6.88 (d, J = 7.7 Hz, 1H), 6.85–6.76 (m, 2H), 6.26–6.12 (m, 2H), 5.27 (s, 2H), 2.38 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 185.68, 148.87, 140.25, 139.30, 135.01, 129.19, 127.01, 122.47, 121.91, 83.42, 73.07, 21.38. HR-MS (ESI), m/z: C14H13O2 [M + H]+ calcd for 213.0910, found: 213.0913.
4.2.3 5′-Methoxy-3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one (3c). Light yellow solid, yield 46%, mp 79–82 °C; 1H NMR (300 MHz, CDCl3) δ 6.90 (d, J = 9.3 Hz, 1H), 6.86–6.78 (m, 4H), 6.27–6.12 (m, 2H), 5.26 (s, 2H), 3.82 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 185.76, 160.98, 148.96, 141.74, 129.56, 127.01, 123.10, 114.66, 107.16, 83.25, 73.05, 55.78. HR-MS (ESI), m/z: C14H13O3 [M + H]+ calcd for 229.0859, found: 229.0857.
4.2.4 5′-Fluoro-3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one (3d). Light yellow solid, yield 88%, mp 84–86 °C; 1H NMR (300 MHz, CDCl3) δ 7.01–6.92 (m, 3H), 6.81 (d, J = 10.0 Hz, 2H), 6.20 (d, J = 10.0 Hz, 2H), 5.27 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 185.44, 163.63 (d, 1JCF = 247.7 Hz), 148.26, 142.21 (d, 3JCF = 8.9 Hz), 133.53 (d, 4JCF = 2.2 Hz), 127.33, 123.72 (d, 3JCF = 9.2 Hz), 115.77 (d, 2JCF = 23.5 Hz), 109.34 (d, 2JCF = 24.2 Hz), 83.15, 72.71 (d, 4JCF = 2.7 Hz). GC-EI-MS, m/z: 216 (M+), 199, 188, 170, 159, 146, 133, 107, 81, 63. HR-MS (ESI), m/z: C13H10FO2 [M + H]+ calcd for 217.0659, found: 217.0658.
4.2.5 5′-Chloro-3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one (3e). Light yellow solid, yield 82%, mp 82–84 °C; 1H NMR (300 MHz, CDCl3) δ 7.31–7.24 (m, 2H), 6.93 (d, J = 8.0 Hz, 1H), 6.86–6.75 (m, 2H), 6.28–6.15 (m, 2H), 5.27 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 185.35, 147.98, 141.86, 136.71, 135.33, 128.74, 127.51, 123.44, 122.41, 83.28, 72.65. HR-MS (ESI), m/z: C13H10ClO2 [M + H]+ calcd for 233.0364, found: 233.0366.
4.2.6 5′-(Trifluoromethyl)-3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one (3f). Light yellow solid, yield 91%, mp 75–77 °C; 1H NMR (300 MHz, CDCl3) δ 7.58 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 8.0 Hz, 1H), 6.89–6.78 (m, 2H), 6.34–6.19 (m, 2H), 5.36 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 185.19, 147.49, 142.31, 140.80, 131.93 (q, 2JCF = 32.8 Hz), 127.84, 125.80 (q, 3JCF = 3.6 Hz), 123.92 (q, 1JCF = 272.6 Hz), 122.90, 119.36 (q, 3JCF = 3.7 Hz), 83.48, 72.85. GC-EI-MS, m/z: 266 (M+), 247, 238, 223, 209, 183, 169, 158, 141, 133, 115, 82, 63. HR-MS (ESI), m/z: C14H10F3O2 [M + H]+ calcd for 267.0627, found: 267.0628.
4.2.7 5′-Nitro-3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one (3g). White solid, yield 88%, mp 159–160 °C; 1H NMR (300 MHz, CDCl3) δ 8.20–8.17 (m, 2H), 7.17 (d, J = 9.0 Hz, 1H), 6.92–6.77 (m, 2H), 6.38–6.22 (m, 2H), 5.38 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 184.88, 149.23, 146.75, 145.23, 141.69, 128.21, 124.27, 123.27, 117.78, 83.32, 72.47. GC-EI-MS, m/z: 243 (M+), 215, 197, 189, 168, 139, 128, 115, 89, 82, 63. HR-MS (ESI), m/z: C13H10NO4 [M + H]+ calcd for 244.0604, found: 244.0605.
4.2.8 6′-Methyl-3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one (3h). Light yellow solid, yield 83%, mp 49–51 °C; 1H NMR (300 MHz, CDCl3) δ 7.23–7.10 (m, 2H), 6.91–6.75 (m, 3H), 6.26–6.13 (m, 2H), 5.27 (s, 2H), 2.33 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 185.74, 148.88, 138.41, 138.15, 137.09, 130.04, 127.14, 122.63, 121.72, 83.56, 73.17, 21.27. GC-EI-MS, m/z: 212 (M+), 197, 183, 169, 155, 141, 129, 115, 77, 63, 51. HR-MS (ESI), m/z: C14H13O2 [M + H]+ calcd for 213.0910, found: 213.0912.
4.2.9 6′-Fluoro-3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one (3i). Light yellow liquid, yield 67%; 1H NMR (300 MHz, CDCl3) δ 7.26 (dd, 4JHF = 4.9 Hz, 3JHH = 8.5 Hz, 1H), 7.06 (ddd, 3JHF = 8.6 Hz, JHH = 8.6, 2.4 Hz, 1H), 6.89–6.78 (m, 2H), 6.69 (dd, 3JHF = 8.0 Hz, 4JHH = 2.3 Hz, 1H), 6.30–6.18 (m, 2H), 5.27 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 185.30, 163.06 (d, 1JCF = 247.1 Hz), 147.87, 140.56 (d, 3JCF = 8.1 Hz), 135.27 (d, 4JCF = 2.7 Hz), 127.64, 123.30 (d, 3JCF = 8.5 Hz), 116.59 (d, 2JCF = 23.0 Hz), 109.51 (d, 2JCF = 24.2 Hz), 83.36 (d, 4JCF = 2.7 Hz), 72.81. GC-EI-MS, m/z: 216 (M+), 199, 188, 187, 159, 133, 107, 82, 63. HR-MS (ESI), m/z: C13H10FO2 [M + H]+ calcd for 217.0659, found: 217.0657.
4.2.10 6′-Chloro-3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one (3j). Light yellow liquid (84%); 1H NMR (300 MHz, CDCl3) δ 7.33 (dd, J = 8.1, 1.8 Hz, 1H), 7.26–7.22 (m, 1H), 6.98 (d, J = 1.8 Hz, 1H), 6.91–6.76 (m, 2H), 6.33–6.17 (m, 2H), 5.27 (d, J = 1.0 Hz, 2H), 5.27 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 185.25, 147.77, 140.30, 138.32, 134.35, 129.49, 127.68, 123.18, 122.61, 83.31, 72.85. GC-EI-MS, m/z: 234 (M + 2), 232 (M+), 204, 197, 175, 169, 149, 141, 115, 89. HR-MS (ESI), m/z: C13H10ClO2 [M + H]+ calcd for 233.0364, found: 233.0365.
4.2.11 3′H-Spiro[cyclohexane-1,1′-naphtho[1,2-c] furan]-2,5-dien-4-one (3k). White solid, yield 87%, mp 134–136 °C; 1H NMR (300 MHz, CDCl3) δ 7.91 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 7.7 Hz, 1H), 7.54–7.39 (m, 3H), 7.00–6.89 (m, 2H), 6.44–6.31 (m, 2H), 5.46 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 185.71, 148.56, 138.47, 133.64, 131.72, 130.87, 129.09, 128.36, 127.61, 127.49, 126.17, 121.92, 119.42, 83.28, 73.92. HR-MS (ESI), m/z: C17H13O2 [M + H]+ calcd for 249.0910, found: 249.0907.
4.2.12 6′,7′,8′,8a′-Tetrahydrospiro[cyclohexane-1,2′-naphtho[1,8-bc]furan]-2,5-dien-4-one (3l). Light yellow solid, yield 61%, mp 80–81 °C; 1H NMR (300 MHz, CDCl3) δ 7.22 (t, J = 7.5 Hz, 1H), 7.16–7.01 (m, 2H), 6.83 (d, J = 7.4 Hz, 1H), 6.69 (dd, J = 10.1, 2.9 Hz, 1H), 6.30 (dd, J = 10.0, 2.0 Hz, 1H), 6.20 (dd, J = 10.1, 2.0 Hz, 1H), 5.18 (dd, J = 10.9, 5.1 Hz, 1H), 2.92 (dd, J = 17.7, 7.4 Hz, 1H), 2.68 (ddd, J = 17.9, 10.7, 7.2 Hz, 1H), 2.39–2.46 (m, 1H), 2.12–2.22 (m, 1H), 1.76–1.93 (m, 1H), 1.43–1.56 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 185.58, 148.81, 146.58, 141.20, 138.17, 134.50, 128.93, 128.53, 127.63, 126.40, 118.77, 82.66, 79.22, 29.80, 25.28, 20.52. GC-EI-MS, m/z: 238 (M+), 221, 210, 181, 165, 152, 139, 120, 115. HR-MS (ESI), m/z: C16H15O2 [M + H]+ calcd for 239.1067, found: 239.1068.
4.2.13 5′-Methoxy-6′,7′,8′,8a′-tetrahydrospiro[cyclohexane-1,2′-naphtho[1,8-bc]furan]-2,5-dien-4-one (3m). Light yellow solid, yield 78%, mp 122–125 °C; 1H NMR (300 MHz, CDCl3) δ 7.06 (dd, J = 10.0, 3.0 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 6.75–6.62 (m, 2H), 6.27 (dd, J = 10.1, 2.0 Hz, 1H), 6.16 (dd, J = 10.0, 2.0 Hz, 1H), 5.12 (dd, J = 11.0, 5.0 Hz, 1H), 3.82 (s, 3H), 2.76 (dd, J = 18.2, 7.3 Hz, 1H), 2.53 (ddd, J = 18.2, 10.8, 7.2 Hz, 1H), 2.42–2.33 (m, 1H), 2.25–2.13 (m, 1H), 1.88–1.70 (m, 1H), 1.53–1.38 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 185.95, 157.85, 149.20, 147.09, 143.12, 129.73, 128.53, 126.18, 123.03, 119.81, 110.05, 82.30, 79.09, 55.86, 29.67, 21.37, 20.45. HR-MS (ESI), m/z: C17H17O3 [M + H]+ calcd for 269.1172, found: 269.1175.
4.2.14 3′-Methyl-3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one (3n). Light yellow liquid, yield 80%; 1H NMR (300 MHz, CDCl3) δ 7.37 (td, J = 7.4, 1.2 Hz, 1H), 7.33–7.26 (m, 1H), 7.26–7.21 (m, 1H), 7.06–6.95 (m, 1H), 6.88–6.72 (m, 2H), 6.30–6.10 (m, 2H), 5.57 (q, J = 6.4 Hz, 1H), 1.61 (d, J = 6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 185.66, 150.17, 148.88, 144.18, 137.94, 129.24, 128.47, 127.53, 126.72, 122.20, 122.00, 82.85, 80.42, 23.06. HR-MS (ESI), m/z: C14H13O2 [M + H]+ calcd for 213.0910, found: 213.0912.
4.2.15 5′-Methoxy-3′-methyl-3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one (3o). Light yellow solid, yield 82%, mp 87–88 °C; 1H NMR (300 MHz, CDCl3) δ 6.95–6.66 (m, 5H), 6.20 (dd, J = 9.7, 2.0 Hz, 1H), 6.14 (dd, J = 9.7, 2.0 Hz, 1H), 5.51 (q, J = 6.4 Hz, 1H), 3.82 (s, 3H), 1.59 (d, J = 6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 185.80, 161.08, 150.49, 149.21, 146.00, 129.48, 127.36, 126.51, 123.12, 114.68, 107.27, 82.50, 80.19, 55.79, 23.05. GC-EI-MS, m/z: 242 (M+), 227, 199, 184, 171, 160, 145, 128, 115, 102, 77, 63. HR-MS (ESI), m/z: C15H15O3 [M + H]+ calcd for 243.1016, found: 243.1018.
4.2.16 2-Methyl-3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one (3p). Light yellow liquid, yield 75%; 1H NMR (300 MHz, CDCl3) δ 7.37–7.29 (m, 3H), 6.92 (d, J = 7.5 Hz, 1H), 6.80 (d, J = 9.8 Hz, 1H), 6.27–5.96 (m, 2H), 5.50–5.21 (m, 2H), 1.74 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 186.23, 160.46, 149.18, 139.77, 138.68, 129.08, 128.40, 126.26, 126.18, 121.79, 86.30, 74.31, 18.30. GC-EI-MS, m/z: 212 (M+), 184, 183, 169, 155, 141, 129, 115, 90. HR-MS (ESI), m/z: C14H13O2 [M + H]+ calcd for 213.0910, found: 213.0912.
4.2.17 2-Chloro-3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one (3q). Light yellow solid, yield 78%, mp 79–81 °C; 1H NMR (300 MHz, CDCl3) δ 7.46–7.38 (m, 1H), 7.33 (ddd, J = 8.5, 7.1, 1.2 Hz, 2H), 7.00 (d, J = 7.4 Hz, 1H), 6.85 (d, J = 10.0 Hz, 1H), 6.42 (d, J = 1.8 Hz, 1H), 6.23 (dd, J = 9.9, 1.8 Hz, 1H), 5.48 (d, J = 12.1 Hz, 1H), 5.37 (d, J = 12.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 184.35, 157.70, 148.36, 140.39, 137.21, 129.71, 128.51, 127.44, 126.20, 121.90, 121.85, 86.12, 75.26. GC-EI-MS, m/z: 234 (M + 2), 232 (M+), 204, 197, 169, 139, 115, 89, 63. HR-MS (ESI), m/z: C13H10ClO2 [M + H]+ calcd for 233.0364, found: 233.0365.
4.2.18 3-Chloro-3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one (3r). Light yellow solid, yield 65%, mp 89–90 °C; 1H NMR (300 MHz, CDCl3) δ 7.45–7.28 (m, 3H), 7.03 (d, J = 7.8 Hz, 1H), 7.00 (d, J = 2.8 Hz, 1H), 6.86 (dd, J = 9.9, 2.8 Hz, 1H), 6.31 (d, J = 9.9 Hz, 1H), 5.32 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 178.66, 148.95, 144.55, 139.90, 137.02, 131.42, 129.52, 128.54, 126.26, 122.27, 122.22, 85.19, 73.44. GC-EI-MS, m/z: 234 (M + 2), 232 (M+), 231, 197, 169, 139, 115, 89, 63. HR-MS (ESI), m/z: C13H10ClO2 [M + H]+ calcd for 233.0364, found: 233.0365.
4.2.19 5′-Methoxy-2-methyl-3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one (3s). Light yellow liquid, yield 71%; 1H NMR (300 MHz, CDCl3) δ 6.81 (s, 3H), 6.79 (d, J = 10.8 Hz, 1H), 6.12 (dd, J = 9.9, 2.0 Hz, 1H), 6.08–6.05 (m, 1H), 5.32 (d, J = 20.1, 1H), 5.27 (d, J = 20.1, 1H), 3.81 (s, 3H), 1.75 (d, J = 1.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 186.31, 160.88, 160.68, 149.47, 141.57, 130.35, 126.05, 122.66, 114.78, 106.84, 85.91, 74.10, 55.72, 18.27. GC-EI-MS, m/z: 242 (M+), 227, 213, 199, 171, 146, 115, 102, 77, 63. HR-MS (ESI), m/z: C15H15O3 [M + H]+ calcd for 243.1016, found: 243.1018.
4.2.19 2-Chloro-5′-methoxy-3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one (3t). Light yellow solid, yield 65%, mp 73–77 °C; 1H NMR (300 MHz, CDCl3) δ 6.93–6.78 (m, 4H), 6.39 (d, J = 1.8 Hz, 1H), 6.20 (dd, J = 9.9, 1.9 Hz, 1H), 5.42 (d, J = 12.2 Hz, 1H), 5.31 (d, J = 12.2 Hz, 1H), 3.83 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 184.45, 161.35, 158.05, 148.68, 142.23, 128.79, 127.25, 125.99, 122.71, 114.94, 106.89, 85.70, 75.01, 55.76. GC-EI-MS, m/z: 264 (M + 2), 262 (M+), 247, 234, 227, 199, 184, 171, 155, 145, 128, 115, 102, 89, 77, 63. HR-MS (ESI), m/z: C14H12ClO3 [M + H]+ calcd for 263.0469, found: 263.0470.
4.2.20 3-Chloro-5′-methoxy-3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one (3u). Light yellow liquid, yield 21%; 1H NMR (300 MHz, CDCl3) δ 6.98 (d, J = 2.8 Hz, 1H), 6.92 (d, J = 9.1 Hz, 1H), 6.88–6.78 (m, 3H), 6.27 (d, J = 9.9 Hz, 1H), 5.25 (s, 2H), 3.82 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 178.70, 161.23, 149.24, 144.85, 141.72, 131.09, 128.42, 125.97, 123.08, 114.84, 107.34, 84.78, 73.19, 55.80. GC-EI-MS, m/z: 264 (M + 2), 262 (M+), 247, 234, 227, 199, 184, 171, 155, 145, 128, 115, 102, 89, 77, 63. HR-MS (ESI), m/z: C14H12ClO3 [M + H]+ calcd for 263.0469, found: 263.0470.
4.2.21 5′-Chloro-2-methyl-3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one (3v). White solid, yield 93%, mp 92–93 °C; 1H NMR (300 MHz, CDCl3) δ 7.37–7.22 (m, 2H), 6.86 (d, J = 8.1 Hz, 1H), 6.78 (d, J = 9.9 Hz, 1H), 6.21–6.08 (m, 2H), 5.39–5.25 (m, 2H), 1.76 (d, J = 1.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 185.96, 159.67, 148.47, 141.77, 137.47, 135.28, 128.90, 126.63, 126.52, 123.06, 122.24, 86.01, 73.73, 18.29. GC-EI-MS, m/z: 248 (M + 2), 246 (M+), 231, 218, 211, 203, 178, 165, 152, 139, 128, 115, 89, 63. HR-MS (ESI), m/z: C14H12ClO2 [M + H]+ calcd for 247.0520, found: 247.0521.
4.2.22 3,5′-Dichloro-3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one (3w). Light yellow solid, yield 86%, mp 113–114 °C; 1H NMR (300 MHz, CDCl3) δ 7.34–7.27 (m, 2H), 7.03–6.92 (m, 2H), 6.83 (dd, J = 10.0, 2.9 Hz, 1H), 6.32 (d, J = 9.9 Hz, 1H), 5.27 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 178.37, 148.25, 143.82, 141.82, 135.79, 135.73, 131.81, 128.97, 126.56, 123.45, 122.63, 84.81, 72.81. GC-EI-MS, m/z: 269 (M + 4), 267 (M + 2), 265 (M+), 250, 231, 215, 203, 175, 149, 139, 115, 89, 63. HR-MS (ESI), m/z: C13H9Cl2O2 [M + H]+ calcd for 266.9974, found: 266.9976.

4.3 Synthesis of compounds 5aa–5ahvia Diels–Alder reaction

General procedure: the optimal screening of reaction conditions for the generation of 4aa from compound 3a is demonstrated in the ESI† (Scheme S2). That is, 4a (20 mmol, 3.687 g, 10 eq.) was subjected to Diels–Alder reaction with 3a (2 mmol, 0.396 g) at 120 °C for 8 h. The crude product was directly subjected to column chromatography, and gave 4aa in 82% yield. Then, 4aa (0.627 g, 1.64 mmol) with DDQ (0.558 g, 2.46 mmol) was refluxed under N2 with benzene as the solvent for 8 h. The insoluble material was removed by filtration, and the solvent was spun off. The crude product was re-dissolved with THF, TBAF (1 M, 4.9 mL) was added, and the liquid was then stirred for 1 h at ambient temperature. Deionised H2O (30 mL) was added, and the solution was extracted with ethyl acetate (3 × 30 mL), washed with saturated NaCl, dried over anhydrous Na2SO4, evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate[thin space (1/6-em)]:[thin space (1/6-em)]petroleum = 1[thin space (1/6-em)]:[thin space (1/6-em)]3) to obtain 5aa. The conversion of substrates 3b–3f, 3m, and 3j to 5ab–5ah followed the same reaction process.
4.3.1 5′-Hydroxy-3H,4′H-spiro[isobenzofuran-1,1′-naphthalen]-4′-one (5aa). Light yellow liquid, yield 74%; 1H NMR (300 MHz, CDCl3) δ 12.34 (s, 1H), 7.43–7.30 (m, 3H), 7.24–7.19 (m, 1H), 6.97 (d, J = 10.0 Hz, 1H), 6.90 (dd, J = 8.4, 1.1 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 6.72 (dd, J = 7.7, 1.1 Hz, 1H), 6.33 (d, J = 10.1 Hz, 1H), 5.54 (d, J = 12.4 Hz, 1H), 5.44 (d, J = 12.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 190.31, 162.05, 150.11, 146.70, 141.84, 138.83, 136.09, 128.88, 128.58, 126.25, 122.54, 121.84, 118.92, 117.21, 114.28, 85.10, 73.96. HR-MS (ESI), m/z: C17H13O3 [M + H]+ calcd for 265.0859, found: 265.0860.
4.3.2 5′-Hydroxy-5-methyl-3H,4′H-spiro[isobenzofuran-1,1′-naphthalen]-4′-one (5ab). Light yellow liquid, yield 58%; 1H NMR (300 MHz, CDCl3) δ 12.35 (s, 1H), 7.37 (t, J = 8.1 Hz, 1H), 7.16 (s, 1H), 7.03 (d, J = 7.8 Hz, 1H), 6.96 (d, J = 10.1 Hz, 1H), 6.89 (dd, J = 8.4, 1.1 Hz, 1H), 6.72 (dd, J = 8.4, 1.1 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 6.31 (d, J = 10.1 Hz, 1H), 5.49 (d, J = 12.4 Hz, 1H), 5.39 (d, J = 12.5 Hz, 1H), 2.37 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 190.33, 161.95, 150.37, 146.87, 139.10, 139.01, 138.97, 136.04, 129.47, 126.00, 122.26, 122.17, 118.83, 117.04, 114.22, 84.87, 73.80, 21.42. HR-MS (ESI), m/z: C18H15O3 [M + H]+ calcd for 279.1060, found: 279.1062.
4.3.3 5′-Hydroxy-5-methoxy-3H,4′H-spiro[isobenzofuran-1,1′-naphthalen]-4′-one (5ac). Light yellow liquid, yield 62%; 1H NMR (300 MHz, CDCl3) δ 12.34 (s, 1H), 7.38 (t, J = 8.0 Hz, 1H), 6.95 (d, J = 10.0 Hz, 1H), 6.91–6.83 (m, 2H), 6.80–6.67 (m, 3H), 6.30 (d, J = 10.1 Hz, 1H), 5.47 (d, J = 12.5 Hz, 1H), 5.38 (d, J = 12.5 Hz, 1H), 3.80 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 190.33, 161.95, 160.69, 150.42, 146.88, 140.59, 136.03, 133.62, 125.90, 123.31, 118.86, 117.04, 114.96, 114.22, 106.76, 84.63, 73.70, 55.72. HR-MS (ESI), m/z: C18H15O4 [M + H]+ calcd for 295.0965, found: 295.0967.
4.3.4 5-Fluoro-5′-hydroxy-3H,4′H-spiro[isobenzofuran-1,1′-naphthalen]-4′-one (5ad). Light yellow liquid, yield 77%; 1H NMR (300 MHz, CDCl3) δ 12.31 (s, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.03 (dd, J = 8.2, 2.3 Hz, 1H), 7.00–6.86 (m, 3H), 6.81–6.64 (m, 2H), 6.33 (d, J = 10.1 Hz, 1H), 5.49 (d, J = 12.9 Hz, 1H), 5.39 (d, J = 12.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 190.08, 163.40 (d, 1JCF = 247.7 Hz), 162.01, 149.64, 146.22, 141.07 (d, 3JCF = 8.9 Hz), 137.39 (d, 4JCF = 2.2 Hz), 136.12, 126.33, 123.99 (d, 3JCF = 9.2 Hz), 118.85, 117.35, 116.04 (d, 2JCF = 23.5 Hz), 114.15, 109.04 (d, 2JCF = 24.1 Hz), 84.56, 73.35 (d, 4JCF = 2.8 Hz). HR-MS (ESI), m/z: C17H12FO3 [M + H]+ calcd for 283.0765, found: 283. 0767.
4.3.5 5-Chloro-5′-hydroxy-3H,4′H-spiro[isobenzofuran-1,1′-naphthalen]-4′-one (5ae). Light yellow liquid, yield 49%; 1H NMR (300 MHz, CDCl3) δ 12.30 (s, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.33 (d, J = 1.0 Hz, 1H), 7.19 (ddd, J = 8.2, 1.8, 0.9 Hz, 1H), 6.97–6.89 (m, 2H), 6.73 (d, J = 8.1 Hz, 1H), 6.70 (dd, J = 7.7, 1.1 Hz, 1H), 6.33 (d, J = 10.1 Hz, 1H), 5.48 (d, J = 12.8 Hz, 1H), 5.39 (d, J = 12.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 190.03, 162.06, 149.33, 146.00, 140.74, 140.47, 136.16, 135.02, 128.98, 126.52, 123.70, 122.20, 118.85, 117.46, 114.15, 84.71, 73.30. HR-MS (ESI), m/z: C17H12ClO3 [M + H]+ calcd for 299.0469, found: 299.0470.
4.3.6 5′-Hydroxy-5-(trifluoromethyl)-3H,4′H-spiro[isobenzofuran-1,1′-naphthalen]-4′-one (5af). Light yellow liquid, yield 89%; 1H NMR (300 MHz, CDCl3) δ 12.30 (s, 1H), 7.63 (s, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.40 (t, J = 8.1 Hz, 1H), 7.02–6.84 (m, 3H), 6.70 (dd, J = 7.7, 1.1 Hz, 1H), 6.37 (d, J = 10.1 Hz, 1H), 5.57 (d, J = 12.9 Hz, 1H), 5.47 (d, J = 12.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 189.91, 162.17, 148.79, 145.62, 139.66, 136.24, 131.62 (q, 2JCF = 32.5 Hz), 130.08, 126.89, 126.01 (q, 3JCF = 3.6 Hz), 123.97 (q, 1JCF = 272.6 Hz), 123.16, 119.25 (q, 3JCF = 3.8 Hz), 118.89, 117.69, 114.16, 84.93, 73.49. HR-MS (ESI), m/z: C18H12F3O3 [M + H]+ calcd for 333.0733, found: 333.0735.
4.3.7 6-Chloro-5′-hydroxy-3H,4′H-spiro[isobenzofuran-1,1′-naphthalen]-4′-one (5ag). Light yellow liquid, yield 57%; 1H NMR (300 MHz, CDCl3) δ 12.31 (s, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.35–7.28 (m, 2H), 6.99–6.90 (m, 2H), 6.78 (d, J = 1.1 Hz, 1H), 6.71 (dd, J = 7.7, 1.1 Hz, 1H), 6.35 (d, J = 10.0 Hz, 1H), 5.49 (d, J = 12.6 Hz, 1H), 5.39 (d, J = 12.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 189.96, 162.14, 149.14, 145.80, 143.94, 137.22, 136.21, 134.51, 129.29, 126.72, 123.04, 122.83, 118.89, 117.59, 114.16, 84.76, 73.52. HR-MS (ESI), m/z: C17H12ClO3 [M + H]+ calcd for 299.0469, found: 299.0470.
4.3.8 5-Hydroxy-5′-methoxy-6′,7′,8′,8a′-tetrahydro-4H-spiro[naphthalene-1,2′-naphtho[1,8-bc]furan]-4-one (5ah). Light yellow solid, yield 78%, mp 165–167 °C; 1H NMR (300 MHz, CDCl3) δ 12.40 (s, 1H), 7.39 (t, J = 8.0 Hz, 1H), 6.90 (ddd, J = 8.4, 4.4, 1.1 Hz, 2H), 6.77–6.62 (m, 3H), 6.32 (d, J = 10.0 Hz, 1H), 5.42 (dd, J = 11.0, 4.8 Hz, 1H), 3.82 (s, 3H), 2.80 (dd, J = 18.4, 7.8 Hz, 1H), 2.71–2.51 (m, 1H), 2.44 (dq, J = 11.6, 3.8 Hz, 1H), 2.21 (dddt, J = 11.0, 5.3, 3.9, 2.2 Hz, 1H), 1.99–1.75 (m, 1H), 1.46 (dtd, J = 14.3, 11.2, 3.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 190.51, 162.28, 157.65, 151.67, 146.46, 142.18, 136.02, 132.85, 126.78, 122.99, 119.97, 118.21, 117.18, 113.81, 110.40, 84.17, 81.50, 55.85, 30.48, 21.31, 20.36. HR-MS (ESI), m/z: C21H19O4 [M + H]+ calcd for 335.1278, found: 335.1279.

4.4 Synthesis of the core skeleton compound 6d of type D spirobisnaphthalene

4.4.1 The synthesis of intermediate 6a is provided in the ESI† (Schemes S2).
4.4.2 4-Hydroxy-5-(4-hydroxyphenyl)-8-methoxy-3,4-dihydronaphthalen-1(2H)-one (6b). First, 6a (0.771 g, 2 mmol, 1.0 eq.), (4-hydroxyphenyl)boronic acid (0.331 g, 2.4 mmol, 1.2 eq.), Pd(PPh3)2Cl2 (0.140 g, 0.2 mmol, 0.1 eq.), and K2CO3 (0.553 g, 4 mmol, 2 eq.) were sequentially added to a Shrek flask. Then, dioxane (10 mL) and deionized H2O (10 mL) were added, and the reaction was carried out at 80 °C for 8 h in a N2 atmosphere. The reaction was extracted with ethyl acetate (3 × 10 mL), and then, the organic phase was washed with saturated NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtained the crude product. Next, the crude product was dissolved in MeOH (10 mL), and NaBH4 (0.227 g, 6 mmol, 3 eq.) was slowly added while the liquid was maintained at 4 °C in an ice bath. After stirring for 1 h, deionized H2O (10 mL) was added, and the post-processing procedure was the same as that described in the previous step. The crude product was purified by silica gel column chromatography (ethyl acetate[thin space (1/6-em)]:[thin space (1/6-em)]petroleum ether = 1[thin space (1/6-em)]:[thin space (1/6-em)]5) to obtain 0.444 g 6b. Light yellow solid, yield 78%, mp 195–197 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.7 Hz, 1H), 6.82 (d, J = 8.5 Hz, 2H), 5.19 (d, J = 3.2 Hz, 1H), 4.70 (d, J = 2.2 Hz, 1H), 3.79 (s, 3H), 2.74 (ddd, J = 18.3, 11.8, 6.7 Hz, 1H), 2.40 (dd, J = 18.0, 6.8 Hz, 1H), 2.03 (ddd, J = 15.2, 7.6, 4.5 Hz, 1H), 1.94–1.77 (m, 1H); 13C NMR (101 MHz, DMSO-d6) δ 196.69, 157.44, 156.57, 143.68, 135.10, 132.67, 130.50, 130.22, 121.96, 114.87, 112.20, 62.83, 55.76, 33.23, 28.87. HR-MS (ESI), m/z: C17H17O4 [M + H]+ calcd for 285.1121, found: 285.1122.
4.4.3 5′-Methoxy-8′,8a′-dihydrospiro[cyclohexane-1,2′-naphtho[1,8-bc]furan]-2,5-diene-4,6′(7′H)-dione (6c). 6b (0.284 g, 1.0 mmol, 1.0 eq.) was dissolved in 10 mL of acetone. PIFA (0.516 g, 1.2 mmol, 1.2 eq.) was slowly added while the reaction was maintained at 0 °C in an ice bath for 15 min, and then, 2 mL of saturated NaHCO3 was added. Ethyl acetate (3 × 10 mL) was used for extraction, and the organic phase was then washed with saturated NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate[thin space (1/6-em)]:[thin space (1/6-em)]petroleum ether = 1[thin space (1/6-em)]:[thin space (1/6-em)]5) to obtain 0.229 g 6c. Yellow solid, yield 81%, mp 228–229 °C; 1H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 8.4 Hz, 1H), 7.03 (dd, J = 10.0, 3.1 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 6.72 (dd, J = 10.1, 3.0 Hz, 1H), 6.31 (dd, J = 10.0, 2.0 Hz, 1H), 6.20 (dd, J = 10.0, 2.0 Hz, 1H), 5.43 (dd, J = 11.6, 5.0 Hz, 1H), 3.94 (s, 3H), 2.79 (ddd, J = 19.3, 4.6, 2.8 Hz, 1H), 2.67–2.51 (m, 2H), 2.05 (dtd, J = 13.6, 12.2, 11.8, 4.7 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 193.95, 185.36, 159.84, 150.87, 148.14, 146.25, 129.33, 128.94, 128.46, 126.75, 117.22, 112.87, 83.92, 78.44, 77.48, 77.16, 76.84, 56.72, 37.17, 30.99. HR-MS (ESI), m/z: C17H15O4 [M + H]+ calcd for 283.0965, found: 283.0967.

Colorless needle-shaped crystals of compound 6c were obtained by slowly evaporating mixed dichloromethane and methanol solution. A 0.24 × 0.23 × 0.17 mm3 crystal was selected for analysis. The parameters and structural information for compound 6c were deposited at the Cambridge Crystallographic Data Centre. CCDC ID 2362105 contains the supplementary crystallographic data for this paper.

4.4.4 5-Hydroxy-5′-methoxy-8′,8a′-dihydro-4H-spiro[naphthalene-1,2′-naphtho[1,8-bc] furan]-4,6′(7′H)-dione (6d). In sequence, 6c (0.141 g, 0.5 mmol, 1.0 eq.) and 4a (5 mmol, 0.922 g, 10 eq.) were added to a 10-mL round bottom flask. After stirring for 2 h at 120 °C, the obtained crude product was dissolved in 10 mL of benzene after rapid column chromatography. Then, DDQ (0.170 g, 0.75 mmol, 1.5 eq.) was added, and the solution was stirred at 80 °C for 8 h in a N2 atmosphere. The insoluble material was removed by filtration, and the solvent was spun off under reduced pressure. The obtained crude product was re-dissolved in THF (5 mL), and then TBAF (1 M, 1.5 mL) was added, and the solution was stirred at ambient temperature for 1 h. Then, deionised H2O (10 mL) was added, and the organic phase was extracted with ethyl acetate (3 × 10 mL), washed with saturated NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate[thin space (1/6-em)]:[thin space (1/6-em)]petroleum ether = 1[thin space (1/6-em)]:[thin space (1/6-em)]3) to obtain 0.145 g 6d. Yellow-brown solid, yield 83%, mp 172–174 °C; 1H NMR (500 MHz, CDCl3) δ 12.32 (s, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.93 (dd, J = 8.4, 1.0 Hz, 1H), 6.88 (t, J = 8.0 Hz, 2H), 6.76 (d, J = 10.0 Hz, 1H), 6.37 (d, J = 10.0 Hz, 1H), 5.75–5.68 (m, 1H), 3.93 (s, 3H), 2.88–2.76 (m, 1H), 2.62 (ddt, J = 15.0, 11.1, 4.9 Hz, 2H), 2.11–1.98 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 193.94, 189.99, 162.33, 159.57, 150.46, 149.77, 145.37, 136.22, 132.37, 128.64, 127.38, 118.04, 117.67, 117.07, 113.60, 113.17, 85.83, 80.57, 56.68, 37.22, 31.71. HR-MS (ESI), m/z: C21H17O5 [M + H]+ calcd for 349.1071, found: 349.1073.

Data availability

The supporting data are included in the article's ESI.†

Conflicts of interest

The authors declare no conflicts of interest.

Acknowledgements

This work was supported by the National Key Research and Development Program of China (2023YFD1700700) and the National Natural Science Foundation of China (21772229).

References

  1. P. Wipf, S. M. Lynch, G. Powis, A. Birmingham and E. E. Englund, Org. Biomol. Chem., 2005, 3880–3882 RSC .
  2. Y. S. Cai, Y. W. Guo and K. Krohn, Nat. Prod. Rep., 2010, 27, 1840–1870 RSC .
  3. L. Zhou, J. Zhao, T. Shan, X. Cai and Y. Peng, Mini. Rev. Med. Chem., 2010, 10, 977–989 CrossRef CAS PubMed .
  4. X. Liu, Y. Zhao, W. Wang, M. Wang and L. Zhou, Chin. J. Org. Chem., 2017, 37, 2883–2894 CrossRef CAS .
  5. L. Xu, H. Ma, X. An and M. Wang, Asian J. Org. Chem., 2023, 12, e202200605 CrossRef CAS .
  6. X. Liu, W. R. Schwan, T. J. Volk, M. Rott, M. Liu, P. Huang, Z. Liu, Y. Wang, N. C. Zitomer, C. Sleger, S. Hartsel, A. Monte and L. Zhang, J. Nat. Prod., 2012, 75, 1534–1538 CrossRef CAS PubMed .
  7. H. Jiang, S. G. Ma, Y. Li, Y. B. Liu, L. Li, J. Qu and S. S. Yu, Bioorg. Med. Chem. Lett., 2016, 26, 4832–4836 CrossRef CAS PubMed .
  8. J. W. Li, R. Ding, H. Gao, L. D. Guo, X. S. Yao, Y. W. Zhang and J. S. Tang, RSC Adv., 2019, 9, 39082–39089 RSC .
  9. J. S. Liu, L. Li and H. G. Yu, Can. J. Chem., 1989, 67, 682–684 CrossRef CAS .
  10. X. Liu, W. Wang, Y. Zhao, D. Lai, L. Zhou, Z. Liu and M. Wang, J. Nat. Prod., 2018, 81, 1803–1809 CrossRef CAS PubMed .
  11. X. Liu, S. Li, X. Wei, Y. Zhao, D. Lai, L. Zhou and M. Wang, RSC Adv., 2020, 10, 1588–1594 RSC .
  12. L. Xu, H. Ma, X. An, Y. Li, Q. Zhang, X. Liu and M. Wang, RSC Adv., 2022, 12, 17629–17636 RSC .
  13. L. Xu, H. Ma, X. An, Y. Li, D. Lai, L. Zhou and M. Wang, ACS Agric. Sci. Technol., 2024, 4, 356–367 CrossRef CAS .
  14. L. Xu, H. Ma, X. An, T. Zhang, D. Lai, L. Zhou and M. Wang, Bioorg. Chem., 2024, 148, 107479 CrossRef CAS PubMed .
  15. G. W. Morrow, S. Wang and J. S. Swenton, Tetrahedron Lett., 1988, 29, 3441–3444 CrossRef CAS .
  16. Y. L. Tnay, G. Y. Ang and S. Chiba, Beilstein J. Org. Chem., 2015, 11, 1933–1943 CrossRef CAS PubMed .
  17. S. Peng, J. He, L. Yang, H. Zhang, H. Li, M. Lang, C. Chen and J. Wang, J. Org. Chem., 2022, 87, 6247–6262 CrossRef CAS PubMed .
  18. M. Kadarauch, D. M. Whalley and R. J. Phipps, J. Am. Chem. Soc., 2023, 145, 25553–25558 CrossRef CAS PubMed .
  19. Y. Tamura, T. Yakura, Y. Shirouchi and J. I. Haruta, Chem. Pharm. Bull., 1986, 34, 1061–1066 CrossRef CAS .
  20. P. Wipf and C. P. Miller, J. Org. Chem., 1993, 58, 1575–1578 CrossRef CAS .
  21. S. Ficht, M. Mülbaier and A. Giannis, Tetrahedron, 2001, 57, 4863–4866 CrossRef CAS .
  22. H. Fujioka, H. Komatsu, T. Nakamura, A. Miyoshi, K. Hata, J. Ganesh, K. Murai and Y. Kita, Chem. Commun., 2010, 46, 4133–4135 RSC .
  23. F. V. Singh, P. B. Kole, S. R. Mangaonkar and S. E. Shetgaonkar, Beilstein J. Org. Chem., 2018, 14, 1778–1805 CrossRef CAS PubMed .
  24. G. Maertens, C. L'Homme and S. Canesi, Front. Chem., 2014, 2, 115 Search PubMed .
  25. L. Pouységu, D. Deffieux and S. Quideau, Tetrahedron, 2010, 66, 2235–2261 CrossRef .
  26. C. Zheng and S.-L. You, ACS Cent. Sci., 2021, 7, 432–444 CrossRef CAS PubMed .
  27. R. Pearce-Higgins, L. N. Hogenhout, P. J. Docherty, D. M. Whalley, P. Chuentragool, N. Lee, N. Y. S. Lam, T. M. McGuire, D. Valette and R. J. Phipps, J. Am. Chem. Soc., 2022, 144, 15026–15032 CrossRef CAS PubMed .
  28. R. B. Bedford, Chem. Commun., 2003, 1787–1796 RSC .
  29. A. Suzuki, J. Organomet., 1999, 576, 147–168 CrossRef CAS .
  30. T. Wang, R. R. Naredla, S. K. Thompson and T. R. Hoye, Nature, 2016, 532, 484–488 CrossRef CAS PubMed .
  31. X. Jiang and R. Wang, Chem. Rev., 2013, 113, 5515–5546 CrossRef CAS PubMed .
  32. X. An, H. Ma, G. Cui, T. Zhang, L. Xu and M. Wang, New J. Chem., 2024, 48, 1741–1756 RSC .

Footnote

† Electronic supplementary information (ESI) available: All 1H and 13C NMR spectra and X-ray data are clarified in the ESI. CCDC 2362105. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4nj03285c
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