Synthesis of polyoxygenated dibenzo[a,e]cycloheptatrienes

Accepted Manuscript Synthesis of polyoxygenated dibenzo[a,e]cycloheptatrienes Chieh-Kai Chan, Yi-Ling Chan, Yu-Lin Tsai, Meng-Yang Chang PII:

S0040-4020(17)30202-8

DOI:

10.1016/j.tet.2017.02.054

Reference:

TET 28495

To appear in:

Tetrahedron

Received Date: 23 January 2017 Revised Date:

22 February 2017

Accepted Date: 24 February 2017

Please cite this article as: Chan C-K, Chan Y-L, Tsai Y-L, Chang M-Y, Synthesis of polyoxygenated dibenzo[a,e]cycloheptatrienes, Tetrahedron (2017), doi: 10.1016/j.tet.2017.02.054. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Chieh-Kai Chan, Yi-Ling Chan, Yu-Lin Tsai and Meng-Yang Chang∗

Leave this area blank for abstract info.

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Synthesis of Polyoxygenated Dibenzo[a,e]cycloheptatrienes

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Department of Medicinal and Applied Chemistry, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan

ACCEPTED MANUSCRIPT

Tetrahedron journal homepage: www.elsevier.com

Chieh-Kai Chan, Yi-Ling Chan, Yu-Lin Tsai and Meng-Yang Chang∗

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Synthesis of Polyoxygenated Dibenzo[a,e]cycloheptatrienes

Department of Medicinal and Applied Chemistry, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan

ABSTRACT

Article history: Received Received in revised form Accepted Available online

A successive route for the synthesis of substituted dibenzo[a,e]cycloheptatriene 1 was established by the reduction of 2-allylbenzaldehyde 4, the BF3.OEt2-mediated intermolecular coupling of 2-allylphenylmethanol 5 with oxygenated benzenes 6, the olefinic oxidative cleavage of 7 and the intramolecular ring-closure of 8. Functionalized anthracene 13 were prepared from 2-vinylbenzaldehyde 9. The key structures were confirmed by X-ray single crystal diffraction analysis.

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Keywords: dibenzo[a,e]cycloheptatrienes, anthracenes, 2-allylbenzaldehyde, medium ring, Friedel-Crafts, annulation

——— ∗ Corresponding author. Tel.: +866-7-312-1101x2220; e-mail: [email protected].

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Tetrahedron

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Scheme 3. Synthesis of 5. Table 1. Synthesis of 7.a

entry

5

R1, R2, R3, R4

5a 5a 5a 5b 5b 5b 5c 5c 5c 5d 5d 5d 5e 5e 5e 5f 5f 5a 5a 5a

OMe, H, H, H 6a 1,2-(OMe)2 OMe, H, H, H 6b 1,2,3-(OMe)3 OMe, H, H, H 6c 1,2-CH2O2 OiPr, H, H, H 6a 1,2-(OMe)2 OiPr, H, H, H 6b 1,2,3-(OMe)3 OiPr, H, H, H 6c 1,2-CH2O2 OnBu, H, H, H 6a 1,2-(OMe)2 OnBu, H, H, H 6b 1,2,3-(OMe)3 OnBu, H, H, H 6c 1,2-CH2O2 OC5H9, H, H, H 6a 1,2-(OMe)2 OC5H9, H, H, H 6b 1,2,3-(OMe)3 OC5H9, H, H, H 6c 1,2-CH2O2 OMe, Me, H, H 6a 1,2-(OMe)2 OMe, Me, H, H 6b 1,2,3-(OMe)3 OMe, Me, H, H 6c 1,2-CH2O2 H, H, OMe, Me 6a 1,2-(OMe)2 H, H, OMe, Me 6b 1,2,3-(OMe)3 OMe, H, H, H 6d 1,2-(OiPr)2 OMe, H, H, H 6e 1-OMe-2-OiPr OMe, H, H, H 6f 1-OBn-2-OMe

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Several strategies for the preparation of benzoannulated seven-membered rings have been disclosed. These methods include ring expansion reactions,[5] ring-closing metathesis,[6] intermolecular cyclization,[7] intramolecular cycloadditions,[8] ene reactions,[9] transition metal-mediated hydroacylation,[10] aryne insertion into 1,3-dicarbonyls[11] and Friedel-Crafts reactions.[12] The goal of this research is the development of a facile synthetic route for the synthesis of polyoxygenated dibenzo[a,e]cycloheptatrienes from substituted 2allylbenzaldehydes.

Scheme 2. Synthetic Route of Dibenzo[a,e]cycloheptatriene.

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Medium-sized carbocyclic rings fused with mono- or dibenzoannulated scaffolds are crucial frameworks in many bioactive compounds, natural products, and chiral ligands and represent some versatile intermediates in organic synthesis.[1] Among these compounds, seven-membered dibenzo ring systems are key structural motifs that have appeared in medicinal industry and bioactive natural products with related properties and diverse pharmaceutical activities.[2] As shown in Figure 1, dibenzo[a,e]cycloheptatriene 1 possesses a characteristic tricyclic core scaffold consisting of a doubly benzoannulated cycloheptene ring. The carbocyclic core of 1 with two benzene rings adjacent to a cycloheptene carbocycle has been observed in a number of bioactive molecules and natural products.[3,4] Amurensinine (2a) exhibits CNS activity for the treatment of Parkinson’s and Alzheimer’s diseases,[4a-b] eberconazole (WS-2160, 2b) has been developed as an antifungal agent,[4c-d] and rubialatin (2c) shows cytotoxicity and a synergistic effect with TNF-α for NF-κB activation.[4e] Diptoindonesin D (2d), a resveratrol-based natural product, has potent antifungal activity and is cytotoxic against P388 murine leukemia cells.[4f-g] Compound 2e possesses an acetamide chain resulting in a higher MT2 antagonist activity.[4h]

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1. Introduction

Figure 1. Selected Dibenzo Seven-membered Ring Structures.

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2. Results and discussions

Recently, we became interested in the development of synthetic routes toward benzofused bicyclic skeletons derived from the commercially available isovanillin 3.[13] All of these works were from versatile 2-allylbenzaldehydes 4, which were easily prepared in high yield via a three-step procedure including O-allylation, Claisen-type rearrangement and O-alkylation (Scheme 1). Herein, we describe the synthetic route for the synthesis of oxygenated dibenzo[a,e]cycloheptatriene from 2allylbenzaldehyde and veratrol via BF3.OEt2-mediated intermolecular coupling and intramolecular ring-closure monocouple in a formal [5+2] annulation, as shown in Scheme 2.

Scheme 1. Three-step synthesis of 4.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

6 (OR)n

7 (%)b 7a, 92 7b, 90 7c, 95 7d, 94 7e, 88 7f, 96 7g, 95 7h, 87 7i, 93 7j, 95 7k, 86 7l, 93 7m, 96 7n, 90 7o, 94 7p, 95 7q, 92 7r, 94 7s/7t, 94 7u/7v, 92

a Coupling conditions: 5 (1.0 mmol), 6 (1.3 mmol), BF3.OEt2 (0.5 mmol), CH2Cl2 (8 mL), 25 oC, 2 h. b Isolated yields.

Initially, we used the developed method to create skeleton 7 from a two-step synthetic route including (i) the reduction of benzaldehyde 4 by NaBH4, and (ii) the BF3.OEt2-mediated intermolecular coupling with oxygenated benzene 6.[14] As shown in Scheme 3 and Table 1, the NaBH4-mediated reduction of aldehyde 4 gave 2-allylphenylmethanol 5 in high yields (95%). We believed that BF3.OEt2/CH2Cl2 conditions were appropriate to conduct the intermolecular coupling of 5 with 6. In entry 1, the reaction of 5a (R1 = OMe, R2 = R3 = R4 = H) and veratrol (6a) was employed to afford 7a in 92% yield. Other oxygenated benzenes of 6, such as 1,2,3-trimethoxybenzene (6b) and 1,3benzodioxole (6c), were also suitable for the formation of 7b and

1b, 89%

1c, 90%

O MeO OMe OMe

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MeO

1e, 87%

1f, 90%

1h, 86%

1i, 90%

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7c (entries 2-3). Changing the R1 substituent onACCEPTED 5, 5b (R1 = OiPr),MANUSCRIPT 5c (R1 = OnBu), and 5d (R1 = OC5H9) were reacted with 6a-d to afford 7d-l in yields ranging from 86% to 96% (entries 4-12). In addition, the reaction of 5e (R1 = OMe, R2 = Me, R3 = R4 = H) with 6a-c, and 5f (R1 = R2 = H, R3 = OMe, R4 = Me) with 6a-b, provided 7m-q in excellent yields (90-96%, entries 13-17). Sterically hindered, 1,2-diisopropoxybenzene 6d treated with 5a gave the desired 7r in 94% yield (entry 18). The treatment of unsymmetrical 1-isopropoxy-2-methoxybenzene (6e) with 5a 1a, 88% gave a mixture of 7s and 7t in a ratio of 2:1 and a 94% yield. Likewise, 1-benzyloxy-2-methoxybenzene (6f) with 5a, a mixture of 7u and 7v in a ratio of 1:1 with a 90% yield (entries 19-20). From the electronic effect point of view, the electrondonating oxygenated (RO) group could provide more electron 1d, 92% density for aryl system such that coupling reactions were wellperformed. Attempts to the BF3.OEt2-mediated intermolecular coupling of 5a and benzene failed to isolate the desired product due to no involvement of electron-donating groups. Changing 1g, 91% from electron-donating oxygenated groups (veratrol) to electrondonating nitrogenated groups (N,N-dimethylaniline), attempts to apply other electron-rich nitrogenated benzenes failed to afford desired product in the coupling reaction of 5. For electronwithdrawing aryls, methyl benzoate and nitrobenzene were 1j, 92% examined in the intermolecular coupling reaction of 5. No corresponding product was isolated. However, the substrate scope is limited for the synthetic routes.

1l, 85%

1m, 91%

1n, 82%

1o, 88%

1p, 95%

1q, 91%

1r, 95%

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On the basis of our experience in using a one-pot combination of OsO4/NaIO4 in the synthesis of functionalized isoquinolines,[13c] benzo[g]indazoles,[13d] and 3-benzazepines,[13e] we believed that it was possible to transform benzyl 7 to aldehyde 8 without purification of any intermediates. A successive BF3.OEt2-mediated intramolecular Friedel-Crafts type reaction was then used for the synthesis of substituted dibenzo[a,e]cycloheptatrienes. As expected, this one-pot preparation of 1 from 7 proceeded smoothly via a two-step procedure involving (i) an OsO4/NaIO4-mediated oxidative cleavage of the olefin and (ii) a BF3.OEt2-faciliated intramolecular Friedel-Crafts type cyclization. Substrates with substitution at the R1 position, 7a-l (R1 = OMe, OiPr, OnBu and OC5H9), afforded 1a-l in 84-92% yields. Substituents at R2 or R3 on 7m-q did not affect the results of the two-step procedure and afforded 1m (R2 = Me, R3 = H) and 1q (R2 = H, R3 = OMe) with 82% and 95% yields, respectively. Again, no lowering of yield was observed in the formation of sterically hindered 1r. Unsymmetrical substrates 7s and 7t were utilized as an inseparable mixture, affording 1s and 1t in a ratio of 2:1, with a 93% yield. Although the isomers 1u and 1v were separated from a starting mixture of 7u and 7v, no significant regiocontrol was observed. All product structures and corresponding yields are shown in Table 2.

1s + 1t, 93% (2 : 1)

1u, 44% + 1v, 44% a

Conditions: (i) 7 (0.6 mmol), OsO4 (2.5% in THF, 0.6 mL), NMO (50% in H2O, 1.3 mmol), THF/H2O (v/v = 1/1, 12 mL), 25 oC, 2 h; then NaIO4 (0.7 mmol), 25 oC, 1 h, (ii) BF3.OEt2 (0.5 mmol), CH2Cl2 (8 mL), 25 oC, 2 h. b Isolated yields.

The structures of 1l and 1p were determined by single-crystal X-ray crystallography.[15] For crystal structures of 1l and 1p, we observed that 1l belonged to triclinic crystal system with P -1 space group, and 1p was orthorhombic crystal system with P n m a space group (see Table 3). Single-crystal X-ray diffraction analysis was employed to prove the constitution and relative configuration of dibenzo[a,e]cycloheptatriene. Two ORTEP plots clearly showed that the tricyclic ring system possessed a bowllike configuration. (see Supporting Information). We hypothesized that the migration of the olefin group of 4 to an interna position might allow a intramolecular ring-closure monocouple formal [4+2] annulation for the preparation of anthracene (Scheme 4).

Table 2. Synthesis of 1.a,b

Table 3. Crystal Data for 1l and 1p

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Tetrahedron

1446967 (1l)

Crystal system Space group a (Å) b (Å) c (Å) α (°) β (°) γ (°) 3 Volume (Å ) / Z Temperature (K) 3 Dc (Mg/m ) Absorption coefficient (mm-1) Crystal size (mm) θ range for data collection (°) Reflections collected Independent reflections RF, Rw(F2) (all data)a RF, Rw(F2) (I > 2σ(I))a GOF

triclinic P -1 9.4510(6) 9.7866(6) 11.0042(7) 105.463(3) 102.774(3) 105.821(3) 895.19(10) / 2 296(2) 1.300

orthorhombic Pnma 10.2063(6) 26.4494(15) 6.0198(4) 90 90 90 1625.05(17) / 4 296(2) 1.277

0.089

0.089

0.20 x 0.20 x 0.18

0.25 x 0.20 x 0.18

2.024 to 26.378

1.540 to 26.478

15138

12086

3645(Rint=0.0321)

1712(Rint=0.0348)

0.0600, 0.1408 0.0438, 0.1279 1.074

0.055, 0.1102 0.0406, 0.1005 1.050

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As shown in Scheme 5, NaOH in MeOH was used to transform the terminal double bond to an internal double bond.[13a-b,16] Compounds 9a-c were isolated as the sole (E)isomer form in 91-93% yields. The reduction of aldehyde 9a-c by NaBH4 gave 10a-c in high yields. As in the above results in Table 1, the intermolecular coupling with oxygenated benzene 6 (1.0 equiv) afforded 11a-e in 85-90% yield. Based on the results shown in Table 2, the oxidative cleavage of the internal olefin with the OsO4/NaIO4 system, followed by BF3.OEt2-mediated intramolecular Friedel-Crafts type reaction and aromatization, gave anthracenes 13a-e in good to excellent yields. The structure of 13a was determined by single-crystal X-ray crystallography.[15]

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Scheme 4. Synthetic Route of Anthracene.

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=Σ|Fo-Fc|/Σ|Fo|; RW (F2) = [ΣW|Fo2-Fc2|2/ΣW Fo4]1/2

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Scheme 6. Synthesis of 14a-l.

According to our experience in the synthesis of polyoxygenated dibenzo[a,e]cycloheptatriene 1 and anthracene 13, oxygenated benzene 6 plays important roles in intermolecular and intramolecular Friedel-Crafts type reactions. Therefore, we further explored the reaction of excess phenylmethanol 5 with oxygenated benzene 6 (0.6 equiv). In cases where two oxygenated substituents were present on 6, such as 6a and 6c-f, we changed the equivalents of 6 from 1.3 to 0.6. As shown in Scheme 6, the double intermolecular couplings showed complete conversion under the BF3.OEt2/CH2Cl2 condition, and the 14a-l were isolated in good to excellent yields (83-95%). Disubstituted alkene 10a was also suitable for the double coupling with 6a (0.6 equiv), giving 14m in 88% yield. Using the m-dimethoxy 6g (0.6 equiv) in the double coupling with 5a and 5e gave 14n and 14o, respectively, in high yields (Scheme 7). However, attempts to afford [6,7,6,7,6]-pentacyclic 15 from 14a was unsuccessful due to poor nucleophilicity on the ortho position of methoxy substituent under the optimized conditions (Scheme 8).

Scheme 7. Synthesis of 14m-o. Scheme 5. Synthesis of 13.

4.2.2. 2-Allyl-3-isopropoxy-4-methoxyphenylmethanol ACCEPTED MANUSCRIPT

In summary, we have developed a facile formal [5+2] annulation for the synthesis of polyoxygenated dibenzo[a,e]cycloheptatrienes from 2-allylbenzaldehydes. The synthetic route includes an aldehyde reduction, intermolecular coupling, oxidative olefin cleavage, and an intramolecular Friedel-Crafts reaction and affords the desired products in good to excellent yields. Additionally, a formal [4+2] annulation route toward anthracene 13 was also established. When the amount of oxygenated benzenes 6 was decreased, the corresponding 14 was obtained in modest to good yield. The structures of some products were confirmed by X-ray crystallography. 4. Experimental section 4.1. General

4.2.3. 2-Allyl-3-butoxy-4-methoxyphenylmethanol (5c). According to the general procedure, the reaction was performed in the presence of NaBH4 (76 mg, 2.0 mmol) and 4c (248 mg, 1.0 mmol) in a cosolvent of THF (5 mL) and MeOH (5 mL) at 0 oC for 0.5 h. Purification on silica gel (hexanes/EtOAc = 5/1) afforded 5c (95%, 238 mg). Colorless solid; mp = 37-38 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for C15H22O3Na 273.1460, found 273.1462; 1H NMR (400 MHz, CDCl3): δ 7.02 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.02-5.92 (m, 1H), 4.97 (dq, J = 1.6, 10.4 Hz, 1H), 4.90 (dq, J = 1.6, 17.2 Hz, 1H), 4.53 (s, 2H), 3.91 (t, J = 6.8 Hz, 2H), 3.80 (s, 3H), 3.50 (d, J = 6.0 Hz, 2H), 2.42 (br s, 1H), 1.78-1.71 (m, 2H), 1.54-1.44 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 152.2, 146.4, 137.5, 132.1, 131.6, 123.9, 114.7, 109.9, 72.8, 62.6, 55.4, 32.2, 30.0, 19.0, 13.7.

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All other reagents and solvents were obtained from commercial sources and used without further purification. Reactions were routinely carried out under an atmosphere of dry nitrogen with magnetic stirring. Products in organic solvents were dried with anhydrous magnesium sulfate before concentration in vacuo. Melting points were determined with a melting apparatus. 1H and 13C NMR spectra were recorded on a spectrometer operating at 400 and at 100 MHz, respectively. Chemical shifts (δ) are reported in parts per million (ppm) and the coupling constants (J) are given in Hertz. High resolution mass spectra (HRMS) were measured with a mass spectrometer microTOF-Q by ESI using a hybrid ion-trap. X-ray crystal structures were obtained with a diffractometer (CAD4, Kappa CCD).

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3. Conclusion

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Scheme 8. Reaction of 14a.

(5b). According to the general procedure, the reaction was performed in the presence of NaBH4 (76 mg, 2.0 mmol) and 4b (234 mg, 1.0 mmol) in a cosolvent of THF (5 mL) and MeOH (5 mL) at 0 oC for 0.5 h. Purification on silica gel (hexanes/EtOAc = 4/1) afforded 5b (95%, 224 mg). Colorless gum; HRMS (ESI, M++Na) calcd for C14H20O3Na 259.1304, found 259.1312; 1H NMR (400 MHz, CDCl3): δ 7.04 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.01-5.91 (m, 1H), 4.98 (dq, J = 1.6, 10.4 Hz, 1H), 4.92 (dq, J = 1.6, 17.2 Hz, 1H), 4.57 (s, 2H), 4.53-4.47 (m, 1H), 3.81 (s, 3H), 3.54 (dt, J = 1.6, 6.0 Hz, 2H), 2.01 (br s, 1H), 1.26 (d, J = 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 152.4, 144.9, 137.6, 132.3, 132.1, 123.7, 114.9, 109.9, 74.5, 63.0, 55.5, 30.5, 22.5 (2x).

4.2. A representative synthetic procedure of skeleton 5 and 10 is as follows:

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NaBH4 (76 mg, 2.0 mmol) was added to a solution of 4a-f or 9a-c (1.0 mmol) in a cosolvent of THF (5 mL) and MeOH (5 mL) at 0 oC. The reaction mixture was stirred for 0.5 h at 0 oC and the solvent was concentrated. The residue was diluted with water (10 mL) and the mixture was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product. Purification on silica gel (hexanes/EtOAc = 5/1~3/1) afforded skeletons 5 and 10. 4.2.1. 2-Allyl-3,4-dimethoxyphenylmethanol (5a). According to the general procedure, the reaction was performed in the presence of NaBH4 (76 mg, 2.0 mmol) and 4a (206 mg, 1.0 mmol) in a cosolvent of THF (5 mL) and MeOH (5 mL) at 0 oC for 0.5 h. Purification on silica gel (hexanes/EtOAc = 4/1) afforded 5a (95%, 198 mg). Colorless gum; HRMS (ESI, M++Na) calcd for C12H16O3Na 231.0992, found 231.0993; 1H NMR (400 MHz, CDCl3): δ 7.07 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.06-5.96 (m, 1H), 5.01 (dq, J = 1.6, 10.0 Hz, 1H), 4.92 (dq, J = 1.6, 17.2 Hz, 1H), 4.58 (s, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 3.52 (dt, J = 1.6, 5.6 Hz, 2H), 1.84 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 152.4, 147.3, 137.7, 132.1, 131.8, 124.4, 115.0, 110.1, 63.0, 60.7, 55.6, 30.0.

4.2.4. 2-Allyl-3-(cyclopentyloxy)-4-methoxyphenylmethanol (5d). According to the general procedure, the reaction was performed in the presence of NaBH4 (76 mg, 2.0 mmol) and 4d (260 mg, 1.0 mmol) in a cosolvent of THF (5 mL) and MeOH (5 mL) at 0 oC for 0.5 h. Purification on silica gel (hexanes/EtOAc = 5/1) afforded 5d (95%, 249 mg). Colorless gum; HRMS (ESI, M++Na) calcd for C16H22O3Na 285.1460, found 285.1463; 1H NMR (400 MHz, CDCl3): δ 7.03 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.00-5.90 (m, 1H), 4.97 (dq, J = 1.6, 10.4 Hz, 1H), 4.91 (dq, J = 1.6, 17.2 Hz, 1H), 4.86-4.82 (m, 1H), 4.56 (s, 2H), 3.81 (s, 3H), 3.50 (dt, J = 1.6, 6.0 Hz, 2H), 2.12 (br s, 1H), 1.891.85 (m, 4H), 1.84-1.77 (m, 2H), 1.59-1.54 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 152.1, 145.3, 137.4, 132.3, 131.9, 123.5, 114.8, 110.1, 84.3, 62.9, 55.5, 32.7 (2x), 30.3, 23.6 (2x).

4.2.5. 2-(But-3-en-2-yl)-3,4-dimethoxyphenylmethanol (5e). According to the general procedure, the reaction was performed in the presence of NaBH4 (76 mg, 2.0 mmol) and 4e (220 mg, 1.0 mmol) in a cosolvent of THF (5 mL) and MeOH (5 mL) at 0 oC for 0.5 h. Purification on silica gel (hexanes/EtOAc = 4/1) afforded 5e (95%, 211 mg). Colorless gum; HRMS (ESI, M++Na) calcd for C13H18O3Na 245.1148, found 245.1150; 1H NMR (400 MHz, CDCl3): δ 7.03 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.26-6.17 (m, 1H), 5.04 (dt, J = 1.6, 8.8 Hz, 1H), 5.01 (q, J = 1.6 Hz, 1H), 4.62 (d, J = 12.4 Hz, 1H), 4.58 (d, J = 12.4 Hz, 1H), 4.04-3.97 (m, 1H), 3.83 (s, 3H), 3.80 (s, 3H), 2.08 (br s, 1H), 1.43 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 152.7, 147.6, 143.2, 137.8, 131.5, 124.9, 112.8, 110.0, 63.2, 60.5, 55.5, 36.3, 19.3. 4.2.6. 2-(But-2-en-1-yl)-4,5-dimethoxyphenylmethanol (5f). According to the general procedure, the reaction was performed in the presence of NaBH4 (76 mg, 2.0 mmol) and 4f (220 mg, 1.0 mmol) in a cosolvent of THF (5 mL) and MeOH (5 mL) at 0 oC for 0.5 h. Purification on silica gel (hexanes/EtOAc = 3/1)

6

Tetrahedron

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(208 mg, 1.0 mmol) and 6a (180 mg, 1.3 mmol) in CH2Cl2 (8 afforded 5f (95%, 211 mg). Colorless gum; HRMS (ESI, MANUSCRIPT ACCEPTED M++Na) calcd for C13H18O3Na 245.1148, found 245.1150; 1H mL) at 25 oC for 2 h. Purification on silica gel (hexanes/EtOAc = NMR (400 MHz, CDCl3): δ 6.89 (s, 1H), 6.66 (s, 1H), 5.58-5.51 4/1) afforded 7a (92%, 302 mg). Colorless gum; HRMS (ESI, (m, 1H), 5.44-5.35 (m, 1H), 4.57 (s, 2H), 3.83 (s, 3H), 3.81 (s, M++Na) calcd for C20H24O4Na 351.1565, found 351.1568; 1H 3H), 3.28 (d, J = 6.0 Hz, 2H), 1.63 (dd, J = 1.2, 6.0 Hz, 3H), 2.21 NMR (400 MHz, CDCl3): δ 6.79-6.73 (m, 3H), 6.66-6.61 (m, 2H), 5.97-5.87 (m, 1H), 5.00 (dq, J = 1.6, 10.0 Hz, 1H), 4.92 (dq, (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 148.1, 147.1, 130.8 (2x), 130.7, 130.1, 126.0, 112.9, 111.8, 62.4, 55.8, 35.1, 17.7. J = 1.6, 17.2 Hz, 1H), 3.88 (s, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 3.82 (s, 3H), 3.81 (s, 3H), 3.42 (dt, J = 1.6, 6.0 Hz, 2H); 13C 4.2.7. 3,4-Dimethoxy-2-(prop-1-en-1-yl)phenylmethanol (10a). NMR (100 MHz, CDCl3): δ 151.2, 148.9, 147.5, 147.3, 136.9, According to the general procedure, the reaction was performed 133.5, 132.5, 132.1, 125.3, 120.7, 114.9, 112.1, 111.1, 110.1, in the presence of NaBH4 (76 mg, 2.0 mmol) and 9a (206 mg, 1.0 60.8, 55.9, 55.8, 55.6, 37.7, 30.6. mmol) in a cosolvent of THF (5 mL) and MeOH (5 mL) at 0 oC for 0.5 h. Purification on silica gel (hexanes/EtOAc = 4/1) 4.3.2. 2-Allyl-3,4-dimethoxy-1-(2,3,4afforded 10a (95%, 198 mg). Colorless gum; HRMS (ESI, trimethoxybenzyl)benzene (7b). According to the general M++Na) calcd for C12H16O3Na 231.0992, found 231.0995; 1H procedure, the reaction was performed in the presence of NMR (400 MHz, CDCl3): δ 7.08 (d, J = 8.4 Hz, 1H), 6.76 (d, J = BF3·OEt2 (71 mg, 0.5 mmol), 5a (208 mg, 1.0 mmol) and 6b 8.4 Hz, 1H), 6.50 (dd, J = 1.6, 16.0 Hz, 1H), 6.24-6.15 (m, 1H), (219 mg, 1.3 mmol) in CH2Cl2 (8 mL) at 25 oC for 2 h. 4.60 (s, 2H), 3.84 (s, 3H), 3.73 (s, 3H), 1.96 (br s, 1H), 1.92 (dd, Purification on silica gel (hexanes/EtOAc = 4/1) afforded 7b (90%, 323 mg). Colorless gum; HRMS (ESI, M++Na) calcd for J = 1.6, 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 152.3, 146.8, 132.1, 131.7, 131.4, 124.5, 123.6, 110.2, 63.3, 60.0, 55.7, C21H26O5Na 381.1670, found 381.1671; 1H NMR (400 MHz, 19.4. CDCl3): δ 6.72 (d, J = 8.8, 10.0 Hz, 2H), 6.62-6.55 (m, 2H), 5.99-5.89 (m, 1H), 4.99 (dq, J = 1.6, 10.0 Hz, 1H), 4.94 (dq, J = 4.2.8. 3-Isopropoxy-4-methoxy-2-(prop-1-en-11.6, 16.8 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 2H), 3.82 (s, 3H), 3.81 (s, yl)phenylmethanol (10b). According to the general procedure, 6H), 3.78 (s, 3H), 3.46 (dt, J = 1.6, 6.0 Hz, 2H); 13C NMR (100 the reaction was performed in the presence of NaBH4 (76 mg, 2.0 MHz, CDCl3): δ 152.0, 151.6, 150.8, 147.2, 142.1, 136.7, 132.2, mmol) and 9b (234 mg, 1.0 mmol) in a cosolvent of THF (5 mL) 131.9, 126.8, 124.8, 124.0, 114.6, 109.9, 106.9, 60.6, 60.5, 60.4, o and MeOH (5 mL) at 0 C for 0.5 h. Purification on silica gel 55.7, 55.4, 31.6, 30.4. (hexanes/EtOAc = 4/1) afforded 10b (95%, 224 mg). Colorless + 4.3.3. 5-(2-Allyl-3,4-dimethoxybenzyl)benzo[d][1,3]dioxole gum; HRMS (ESI, M +Na) calcd for C14H20O3Na 259.1304, found 259.1306; 1H NMR (400 MHz, CDCl3): δ 7.06 (d, J = 8.4 (7c). According to the general procedure, the reaction was Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.49 (dq, J = 1.6, 16.0 Hz, 1H), performed in the presence of BF3·OEt2 (71 mg, 0.5 mmol), 5a 6.14 (dq, J = 6.4, 16.0 Hz, 1H), 4.60 (s, 2H), 4.36-4.30 (m, 1H), (208 mg, 1.0 mmol) and 6c (159 mg, 1.3 mmol) in CH2Cl2 (8 3.81 (s, 3H), 1.91-1.89 (m, 4H), 1.23 (d, J = 6.4 Hz, 6H); 13C mL) at 25 oC for 2 h. Purification on silica gel (hexanes/EtOAc = NMR (100 MHz, CDCl3): δ 152.6, 144.8, 132.7, 131.9, 131.3, 4/1) afforded 7c (95%, 297 mg). Colorless gum; HRMS (ESI, 124.6, 124.0, 110.1, 75.1, 63.5, 55.6, 22.4 (2x), 19.2. M++Na) calcd for C19H20O4Na 335.1253, found 335.1255; 1H NMR (400 MHz, CDCl3): δ 6.80 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 4.2.9. 3-Butoxy-4-methoxy-2-(prop-1-en-1-yl)phenylmethanol 8.4 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.59 (s, 1H), 6.58 (d, J = (10c). According to the general procedure, the reaction was 8.4 Hz, 1H), 5.97-5.87 (m, 1H), 5.91 (s, 2H), 5.00 (dq, J = 1.6, performed in the presence of NaBH4 (76 mg, 2.0 mmol) and 9c 10.0 Hz, 1H), 4.92 (dq, J = 1.6, 17.2 Hz, 1H), 3.86 (s, 2H), 3.85 (248 mg, 1.0 mmol) in a cosolvent of THF (5 mL) and MeOH (5 (s, 3H), 3.82 (s, 3H), 3.40 (dt, J = 2.4, 6.0 Hz, 2H); 13C NMR mL) at 0 oC for 0.5 h. Purification on silica gel (hexanes/EtOAc = (100 MHz, CDCl3): δ 151.2, 147.6, 147.5, 145.7, 145.6, 136.8, 4/1) afforded 10c (95%, 238 mg). Colorless gum; HRMS (ESI, + 1 134.9, 132.3, 125.4, 121.5, 114.8, 110.2, 109.2, 108.0, 100.7, M +Na) calcd for C15H22O3Na 273.1460, found 273.1462; H 60.8, 55.6, 37.8, 30.5. NMR (400 MHz, CDCl3): δ 7.05 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.48 (dq, J = 1.6, 16.0 Hz, 1H), 6.16 (dq, J = 6.4, 4.3.4. 2-Allyl-1-(3,4-dimethoxybenzyl)-3-isopropoxy-416.0 Hz, 1H), 4.59 (s, 2H), 3.84 (t, J = 5.6 Hz, 2H), 3.82 (s, 3H), methoxybenzene (7d). According to the general procedure, the 2.00 (br s, 1H), 1.91 (dd, J = 1.6, 6.4 Hz, 3H), 1.75-1.67 (m, 2H), reaction was performed in the presence of BF3·OEt2 (71 mg, 0.5 1.53-1.44 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, mmol), 5b (236 mg, 1.0 mmol) and 6a (180 mg, 1.3 mmol) in CDCl3): δ 152.4, 146.1, 132.01, 131.95, 131.3, 124.2, 123.8, o CH 2Cl2 (8 mL) at 25 C for 2 h. Purification on silica gel 114.8, 110.2, 72.4, 63.3, 55.7, 32.2, 19.1, 13.8. (hexanes/EtOAc = 4/1) afforded 7d (94%, 335 mg). Colorless gum; HRMS (ESI, M++Na) calcd for C22H28O4Na 379.1877, 4.3. A representative synthetic procedure of skeletons 7 and found 379.1879; 1H NMR (400 MHz, CDCl3): δ 6.79-6.73 (m, 11 is as follows: 3H), 6.64-6.61 (m, 2H), 5.95-5.85 (m, 1H), 4.99 (dq, J = 1.6, BF3·OEt2 (71 mg, 0.5 mmol) was added to a solution of 5a-5f, 10.4 Hz, 1H), 4.93 (dq, J = 1.6, 17.2 Hz, 1H), 4.57-4.51 (m, 1H), 10a-10c (1.0 mmol) and 6a-f (1.3 mmol) in CH2Cl2 (8 mL) at 25 3.90 (s, 2H), 3.85 (s, 3H), 3.81 (s, 3H), 3.79 (s, 3H), 3.44 (dt, J = o C. The reaction mixture was stirred at 25 oC for 2 h. The 1.6, 5.6 Hz, 2H), 1.27 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, reaction mixture was concentrated and the residue was diluted CDCl3): δ 151.2, 148.7, 147.1, 145.0, 136.6, 133.6, 132.43, with water (10 mL) and the mixture was extracted with CH2Cl2 132.35, 124.7, 120.5, 114.7, 111.9, 111.0, 109.9, 74.2, 55.7, 55.6, (3 x 20 mL). The combined organic layers were washed with 55.4, 37.7, 30.9, 22.5 (2x). brine, dried, filtered and evaporated to afford crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc = 4/1) afforded 7a-7v and 11a-11e. 4.3.1. 2-Allyl-1-(3,4-dimethoxybenzyl)-3,4-dimethoxybenzene (7a). According to the general procedure, the reaction was performed in the presence of BF3·OEt2 (71 mg, 0.5 mmol), 5a

4.3.5. 2-Allyl-3-isopropoxy-4-methoxy-1-(2,3,4trimethoxybenzyl)benzene (7e). According to the general procedure, reaction was performed in the presence of BF3·OEt2 (71 mg, 0.5 mmol), 5b (236 mg, 1.0 mmol) and 6b (219 mg, 1.3 mmol) in CH2Cl2 (8 mL) at 25 oC for 2 h. Purification on silica

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4.3.9. 5-(2-Allyl-3-butoxy-4gel (hexanes/EtOAc = 4/1) afforded 7e (88%, 340 mg). Colorless MANUSCRIPT ACCEPTED methoxybenzyl)benzo[d][1,3]dioxole (7i). According to the gum; HRMS (ESI, M++Na) calcd for C23H30O5Na 409.1982, general procedure, reaction was performed in the presence of found 409.1986; 1H NMR (400 MHz, CDCl3): δ 6.71 (d, J = 8.4 BF3·OEt2 (71 mg, 0.5 mmol), 5c (250 mg, 1.0 mmol) and 6c (159 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 6.59 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 5.96-5.87 (m, 1H), 4.99 (dq, J = 1.6, 10.0 Hz, mg, 1.3 mmol) in CH2Cl2 (8 mL) at 25 oC for 2 h. Purification on 1H), 4.93 (dq, J = 1.6, 17.2 Hz, 1H), 4.57-4.48 (m, 1H), 3.88 (s, silica gel (hexanes/EtOAc = 4/1) afforded 7i (93%, 330 mg). Colorless gum; HRMS (ESI, M++Na) calcd for C22H26O4Na 3H), 3.85 (s, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 3.76 (s, 3H), 3.49 (dt, 13 J = 1.6, 6.0 Hz, 2H), 1.28 (d, J = 6.0 Hz, 6H); C NMR (100 377.1721, found 377.1725; 1H NMR (400 MHz, CDCl3): δ 6.77 MHz, CDCl3): δ 152.0, 151.0, 144.9, 142.2, 136.6, 132.4, 132.3, (d, J = 8.4 Hz, 1H), 6.75 (s, 1H), 6.72 (d, J = 8.4 Hz, 1H), 6.58 (s, 127.1, 124.3, 124.0, 114.6, 109.9, 107.0, 105.1, 74.2, 60.6, 60.5, 2H), 5.96-5.86 (m, 1H), 5.91 (s, 2H), 4.99 (dq, J = 1.6, 10.0 Hz, 55.8, 55.4, 31.8, 30.9, 22.5 (2x). 1H), 4.91 (dq, J = 1.6, 17.2 Hz, 1H), 3.93 (t, J = 6.4 Hz, 2H), 3.85 (s, 2H), 3.83 (s, 3H), 3.40 (dt, J = 1.6, 6.0 Hz, 2H), 1.794.3.6. 5-(2-Allyl-3-isopropoxy-41.72 (m, 2H), 1.55-1.47 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H); 13C methoxybenzyl)benzo[d][1,3]dioxole (7f). NMR (100 MHz, CDCl3): δ 151.4, 147.6, 145.6, 136.9, 135.0, 132.3, 132.2, 125.2, 124.5, 121.5, 114.7, 110.1, 109.2, 108.0, According to the general procedure, reaction was performed in 100.7, 72.9, 55.6, 37.8, 32.4, 30.6, 19.2, 13.9. the presence of BF3·OEt2 (71 mg, 0.5 mmol), 5b (236 mg, 1.0 mmol) and 6c (159 mg, 1.3 mmol) in CH2Cl2 (8 mL) at 25 oC for 4.3.10. 2-Allyl-3-(cyclopentyloxy)-1-(3,4-dimethoxybenzyl)-42 h. Purification on silica gel (hexanes/EtOAc = 4/1) afforded 7f methoxybenzene (7j). According to the general procedure, (96%, 327 mg). Colorless gum; HRMS (ESI, M++Na) calcd for reaction was performed in the presence of BF3·OEt2 (71 mg, 0.5 1 C21H24O4Na 363.1565, found 363.1568; H NMR (400 MHz, mmol), 5d (262 mg, 1.0 mmol) and 6a (180 mg, 1.3 mmol) in CDCl3): δ 6.76 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.72 CH2Cl2 (8 mL) at 25 oC for 2 h. Purification on silica gel (d, J = 7.6 Hz, 1H), 6.58 (s, 1H), 6.56-6.52 (m, 1H), 5.94-5.84 (m, (hexanes/EtOAc = 4/1) afforded 7j (95%, 363 mg). Colorless 1H), 5.91 (s, 2H), 4.99 (dq, J = 1.6, 10.0 Hz, 1H), 4.92 (dq, J = gum; HRMS (ESI, M++Na) calcd for C24H30O4Na 405.2033, 1.6, 17.2 Hz, 1H), 4.56-4.50 (m, 1H), 3.86 (s, 2H), 3.82 (s, 3H), found 405.2037; 1H NMR (400 MHz, CDCl3): δ 6.78 (d, J = 8.8 3.43 (dt, J = 1.6, 6.0 Hz, 2H), 1.28 (d, J = 6.0 Hz, 6H); 13C NMR Hz, 1H), 6.73 (br s, 2H), 6.64-6.62 (m, 2H), 5.94-5.84 (m, 1H), (100 MHz, CDCl3): δ 151.3, 147.6, 145.6, 145.2, 136.7, 135.1, 4.98 (dq, J = 1.6, 10.4 Hz, 1H), 4.91 (dq, J = 1.6, 17.2 Hz, 1H), 132.5, 132.4, 124.9, 121.4, 114.8, 110.0, 109.1, 108.0, 100.7, 4.88-4.85 (m, 1H), 3.89 (s, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.80 (s, 74.4, 55.5, 37.9, 30.9, 22.6 (2x). 3H), 3.40 (dt, J = 1.6, 6.0 Hz, 2H), 1.90-1.78 (m, 4H), 1.76-1.69 (m, 2H), 1.59-1.55 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 4.3.7. 2-Allyl-3-butoxy-1-(3,4-dimethoxybenzyl)-4151.1, 148.8, 147.1, 145.4, 136.6, 133.7, 132.43, 132.38, 124.7, methoxybenzene (7g). According to the general procedure, 120.5, 114.7, 112.0, 111.1, 110.2, 84.2, 55.8, 55.7, 55.5, 37.7, reaction was performed in the presence of BF3·OEt2 (71 mg, 0.5 32.8 (2x), 30.9, 23.7 (2x). mmol), 5c (250 mg, 1.0 mmol) and 6a (180 mg, 1.3 mmol) in CH2Cl2 (8 mL) at 25 oC for 2 h. Purification on silica gel 4.3.11. 2-Allyl-3-(cyclopentyloxy)-4-methoxy-1-(2,3,4(hexanes/EtOAc = 4/1) afforded 7g (95%, 352 mg). Colorless trimethoxybenzyl)benzene (7k). According to the general + gum; HRMS (ESI, M +Na) calcd for C23H30O4Na 393.2033, procedure, reaction was performed in the presence of BF3·OEt2 found 393.2035; 1H NMR (400 MHz, CDCl3): δ 6.78 (d, J = 8.0 (71 mg, 0.5 mmol), 5d (262 mg, 1.0 mmol) and 6b (219 mg, 1.3 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.64 mmol) in CH2Cl2 (8 mL) at 25 oC for 2 h. Purification on silica (s, 1H), 6.63 (d, J = 8.0 Hz, 1H), 5.97-5.87 (m, 1H), 4.99 (dq, J = gel (hexanes/EtOAc = 4/1) afforded 7k (86%, 355 mg). Colorless 1.6, 10.0 Hz, 1H), 4.92 (dq, J = 1.6, 17.2 Hz, 1H), 3.94 (t, J = 6.8 gum; HRMS (ESI, M++Na) calcd for C25H32O5Na 435.2138, Hz, 2H), 3.88 (s, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.80 (s, 3H), found 435.2141; 1H NMR (400 MHz, CDCl3): δ 6.71 (d, J = 8.4 3.42 (dt, J = 1.6, 5.6 Hz, 2H), 1.79-1.72 (m, 2H), 1.55-1.47 (m, Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 6.60-6.55 (m, 2H), 5.94-5.86 2H), 0.97 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ (m, 1H), 4.98 (dq, J = 1.6, 10.4 Hz, 1H), 4.93 (dq, J = 1.6, 17.2 151.3, 148.8, 147.2, 146.7, 136.9, 133.6, 132.4, 132.1, 125.1, Hz, 1H), 4.88-4.84 (m, 1H), 3.89 (s, 2H), 3.86 (s, 3H), 3.83 (s, 120.6, 114.7, 112.1, 111.1, 110.1, 72.9, 55.8, 55.7, 55.6, 37.7, 3H), 3.80 (s, 3H), 3.76 (s, 3H), 3.45 (dt, J = 1.6, 6.0 Hz, 2H), 32.4, 30.6, 19.1, 13.9. 1.92-1.79 (m, 4H), 1.76-1.69 (m, 2H), 1.61-1.55 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 152.0, 151.7, 150.8, 142.2, 136.6, 4.3.8. 2-Allyl-3-butoxy-4-methoxy-1-(2,3,4132.4, 132.3, 127.1, 124.3, 124.0, 114.6, 110.1, 107.0, 105.1, trimethoxybenzyl)benzene (7h). According to the general 84.2, 60.6, 60.5, 55.8, 55.5, 32.7 (2x), 31.8, 30.8, 23.6 (2x). procedure, the reaction was performed in the presence of BF3·OEt2 (71 mg, 0.5 mmol), 5c (250 mg, 1.0 mmol) and 6b 4.3.12. 5-(2-Allyl-3-(cyclopentyloxy)-4(219 mg, 1.3 mmol) in CH2Cl2 (8 mL) at 25 oC for 2 h. methoxybenzyl)benzo[d][1,3]dioxole (7l). According to the Purification on silica gel (hexanes/EtOAc = 4/1) afforded 7h general procedure, the reaction was performed in the presence of (87%, 348 mg). Colorless gum; HRMS (ESI, M++Na) calcd for BF3·OEt2 (71 mg, 0.5 mmol), 5d (262 mg, 1.0 mmol) and 6c 1 C24H32O5Na 423.2138, found 423.2142; H NMR (400 MHz, (159 mg, 1.3 mmol) in CH2Cl2 (8 mL) at 25 oC for 2 h. CDCl3): δ 6.72 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 6.60 Purification on silica gel (hexanes/EtOAc = 4/1) afforded 7l (d, J = 8.8 Hz, 1H), 6.56 (d, J = 8.8 Hz, 1H), 5.98-5.89 (m, 1H), (93%, 341 mg). Colorless gum; HRMS (ESI, M++Na) calcd for 4.99 (dq, J = 1.6, 10.0 Hz, 1H), 4.93 (dq, J = 1.6, 16.8 Hz, 1H), C23H26O4Na 389.1721, found 389.1725; 1H NMR (400 MHz, 3.94 (t, J = 6.4 Hz, 2H), 3.89 (s, 3H), 3.88 (s, 2H), 3.83 (s, 3H), CDCl3): δ 6.75-6.67 (m, 3H), 6.57 (s, 1H), 6.56-6.51 (m, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.46 (dt, J = 1.6, 5.6 Hz, 2H), 1.805.93-5.83 (m, 1H), 5.91 (s, 2H), 4.97 (dq, J = 1.6, 10.0 Hz, 1H), 1.73 (m, 2H), 1.56-1.46 (m, 2H), 0.98 (t, J = 7.6 Hz, 3H); 13C 4.90 (dq, J = 1.6, 17.2 Hz, 1H), 4.87-4.83 (m, 1H), 3.85 (s, 2H), NMR (100 MHz, CDCl3): δ 152.0, 151.7, 151.1, 146.6, 142.2, 3.82 (s, 3H), 3.39 (dt, J = 1.6, 5.6 Hz, 2H), 1.97-1.77 (m, 4H), 136.8, 132.3, 132.1, 127.0, 124.7, 124.1, 114.6, 110.0, 107.0, 1.76-1.69 (m, 2H), 1.59-1.55 (m, 2H); 13C NMR (100 MHz, 72.8, 60.64, 60.55, 55.8, 55.5, 32.4, 31.7, 30.6, 19.1, 13.9. CDCl3): δ 151.2, 147.6, 145.6, 136.6, 135.1, 132.41, 132.38,

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124.8, 124.1, 121.4, 114.8, 110.2, 109.2, 108.0, 100.7, 84.3, MANUSCRIPT J = 1.2, 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 148.7, ACCEPTED 55.6, 37.9, 32.8 (2x), 30.9, 23.7 (2x). 147.2, 147.1, 147.0, 133.5, 131.1, 130.6, 129.6, 125.9, 120.4, 113.5, 112.9, 111.8, 111.0, 55.81, 55.80, 55.76, 55.65, 37.7, 35.6, 4.3.13. 2-(But-3-en-2-yl)-1-(3,4-dimethoxybenzyl)-3,417.8. dimethoxybenzene (7m). According to the general procedure, the reaction was performed in the presence of BF3·OEt2 (71 mg, 4.3.17. 2-(But-2-en-1-yl)-3,4-dimethoxy-1-(2,3,40.5 mmol), 5e (222 mg, 1.0 mmol) and 6a (180 mg, 1.3 mmol) in trimethoxybenzyl)benzene (7q). According to the general CH2Cl2 (8 mL) at 25 oC for 2 h. Purification on silica gel procedure, the reaction was performed in the presence of (hexanes/EtOAc = 4/1) afforded 7m (96%, 329 mg). Colorless BF3·OEt2 (71 mg, 0.5 mmol), 5f (222 mg, 1.0 mmol) and 6b (219 gum; HRMS (ESI, M++Na) calcd for C21H26O4Na 365.1721, mg, 1.3 mmol) in CH2Cl2 (8 mL) at 25 oC for 2 h. Purification on found 365.1724; 1H NMR (400 MHz, CDCl3): δ 6.81-6.73 (m, silica gel (hexanes/EtOAc = 4/1) afforded 7q (92%, 343 mg). 3H), 6.63 (s, 1H), 6.62 (d, J = 8.4 Hz, 1H), 6.20-6.12 (m, 1H), Colorless gum; HRMS (ESI, M++Na) calcd for C22H28O5Na 4.93 (dt, J = 1.6, 10.4 Hz, 1H), 4.84 (dt, J = 1.6, 17.6 Hz, 1H), 395.1826, found 395.1830; 1H NMR (400 MHz, CDCl3): δ 6.69 (s, 1H), 5.59 (s, 1H), 6.55 (br s, 2H), 5.55-5.47 (m, 1H), 5.443.97 (d, J = 16.0 Hz, 1H), 3.92 (d, J = 16.0 Hz, 1H), 3.85 (s, 3H), 5.35 (m, 1H), 3.87 (s, 3H), 3.86 (s, 2H), 3.85 (s, 3H), 3.81 (s, 3H), 3.84 (s, 3H), 3.84-3.83 (m, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 1.32 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 151.6, 148.7, 3.80 (s, 3H), 3.76 (s, 3H), 3.23 (d, J = 6.0 Hz, 2H), 1.64 (d, J = 148.0, 147.1, 143.0, 137.9, 134.0, 131.2, 125.8, 120.5, 112.5, 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 151.9, 151.6, 147.1, 112.0, 111.0, 110.1, 60.5, 55.8, 55.7, 55.5, 38.7, 37.1, 18.9. 146.9, 142.1, 131.1, 130.5, 129.7, 126.9, 125.7, 123.8, 113.5, 112.7, 106.9, 60.6, 60.5, 55.8, 55.74, 55.71, 35.6, 31.7, 17.7. 4.3.14. 2-(But-3-en-2-yl)-3,4-dimethoxy-1-(2,3,4trimethoxybenzyl)benzene (7n). According to the general 4.3.18. 2-Allyl-1-(3,4-diisopropoxybenzyl)-3,4procedure, the reaction was performed in the presence of dimethoxybenzene (7r). According to the general procedure, the BF3·OEt2 (71 mg, 0.5 mmol), 5e (222 mg, 1.0 mmol) and 6b reaction was performed in the presence of BF3·OEt2 (71 mg, 0.5 (219 mg, 1.3 mmol) in CH2Cl2 (8 mL) at 25 oC for 2 h. mmol), 5a (208 mg, 1.0 mmol) and 6d (253 mg, 1.3 mmol) in Purification on silica gel (hexanes/EtOAc = 4/1) afforded 7n CH2Cl2 (8 mL) at 25 oC for 2 h. Purification on silica gel (hexanes/EtOAc = 4/1) afforded 7r (94%, 361 mg). Colorless (90%, 335 mg). Colorless gum; HRMS (ESI, M++Na) calcd for C22H28O5Na 395.1826, found 395.1828; 1H NMR (400 MHz, gum; HRMS (ESI, M++Na) calcd for C24H32O4Na 407.2189, CDCl3): δ 6.75 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 6.55 found 407.2195; 1H NMR (400 MHz, CDCl3): δ 6.82 (d, J = 8.0 (br s, 2H), 6.21-6.13 (m, 1H), 4.93 (dt, J = 1.6, 10.4 Hz, 1H), Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.67 4.87 (dt, J = 1.6, 17.2 Hz, 1H), 3.95 (d, J = 16.0 Hz, 1H), 3.90 (d, (d, J = 2.0 Hz, 1H), 6.63 (dd, J = 2.0, 8.0 Hz, 1H), 5.94-5.85 (m, J = 16.0 Hz, 1H), 3.89 (s, 3H), 3.87-3.85 (m, 1H), 3.83 (br s, 6H), 1H), 4.98 (dq, J = 1.6, 10.0 Hz, 1H), 4.90 (2.0, 17.2 Hz, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 1.33 (d, J = 7.2 Hz, 3H); 13C NMR 4.45-4.38 (m, 2H), 3.85 (br s, 5H), 3.81 (s, 3H), 3.41 (dt, J = 1.6, (100 MHz, CDCl3): δ 151.9, 151.5, 151.4, 143.0, 137.8, 131.2, 6.0 Hz, 2H), 1.32 (d, J = 6.0 Hz, 6H), 1.29 (d, J = 6.0 Hz, 6H); 13 127.3, 125.6, 124.1, 123.5, 112.4, 110.0, 106.9, 105.1, 60.6, C NMR (100 MHz, CDCl3): δ 151.1, 149.0, 147.4, 147.2, 136.8, 134.6, 132.5, 132.1, 125.4, 121.8, 119.0, 118.4, 114.8, 110.1, 60.51, 60.45, 55.8, 55.4, 36.9, 32.5, 18.7. 72.2, 72.0, 60.7, 55.6, 37.7, 30.5, 22.22 (2x), 22.16 (2x). 4.3.15. 5-(2-(But-3-en-2-yl)-3,4dimethoxybenzyl)benzo[d][1,3]dioxole (7o). According to the 4.3.19. 2-Allyl-1-(4-isopropoxy-3-methoxybenzyl)-3,4general procedure, the reaction was performed in the presence of dimethoxybenzene (7s) and 2-Allyl-1-(3-isopropoxy-4methoxybenzyl)-3,4-dimethoxybenzene (7t). According to the BF3·OEt2 (71 mg, 0.5 mmol), 5e (222 mg, 1.0 mmol) and 6c (159 mg, 1.3 mmol) in CH2Cl2 (8 mL) at 25 oC for 2 h. Purification on general procedure, the reaction was performed in the presence of silica gel (hexanes/EtOAc = 4/1) afforded 7o (94%, 307 mg). BF3·OEt2 (71 mg, 0.5 mmol), 5a (208 mg, 1.0 mmol) and 6e (216 Colorless gum; HRMS (ESI, M++Na) calcd for C20H22O4Na mg, 1.3 mmol) in CH2Cl2 (8 mL) at 25 oC for 2 h. Purification on 349.1409, found 349.1412; 1H NMR (400 MHz, CDCl3): δ 6.80 silica gel (hexanes/EtOAc = 4/1) afforded a mixture of 7s and 7t (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 7.6 Hz, (94%, 335 mg) with a ratio of 2:1. HRMS (ESI, M++Na) calcd for C22H28O4Na 379.1877, found 379.1881; 1H NMR (400 MHz, 1H), 6.58 (d, J = 1.2 Hz, 1H), 6.56 (d, J = 7.6 Hz, 1H), 6.18-6.10 (m, 1H), 5.91 (s, 2H), 4.93 (dt, J = 1.6, 10.4 Hz, 1H), 4.84 (dt, J CDCl3): δ 6.82-6.77 (m, 3H), 6.67-6.59 (m, 2H), 5.97-5.87 (m, = 1.6, 17.2 Hz, 1H), 3.94 (d, J = 16.0 Hz, 1H), 3.88 (d, J = 16.0 1H), 5.01-4.90 (m, 2H), 4.51-4.42 (m, 1H), 3.88 (s, 2H), 3.85 (s, Hz, 1H), 3.85 (s, 3H), 3.84-3.82 (m, 1H), 3.81 (s, 3H), 1.30 (d, J 3H), 3.83 (s, 3H), 3.79 (s, 3H), 3.45-3.43 (m, 2H), 1.37-1.32 (m, = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 151.8, 148.1, 6H). 147.6, 145.6, 143.1, 137.9, 135.4, 131.2, 126.0, 121.4, 112.5, 4.3.20. 2-Allyl-1-(4-(benzyloxy)-3-methoxybenzyl)-3,4110.2, 109.1, 108.0, 100.7, 60.6, 55.6, 38.9, 37.1, 18.9. dimethoxybenzene (7u) and 2-Allyl-1-(3-(benzyloxy)-44.3.16. 2-(But-2-en-1-yl)-1-(3,4-dimethoxybenzyl)-3,4methoxybenzyl)-3,4-dimethoxybenzene (7v). According to the dimethoxybenzene (7p). According to the general procedure, the general procedure, the reaction was performed in the presence of reaction was performed in the presence of BF3·OEt2 (71 mg, 0.5 BF3·OEt2 (71 mg, 0.5 mmol), 5a (208 mg, 1.0 mmol) and 6f (279 mmol), 5f (222 mg, 1.0 mmol) and 6a (180 mg, 1.3 mmol) in mg, 1.3 mmol) in CH2Cl2 (8 mL) at 25 oC for 2 h. Purification on o CH2Cl2 (8 mL) at 25 C for 2 h. Purification on silica gel silica gel (hexanes/EtOAc = 4/1) afforded a mixture of 7u and 7v (hexanes/EtOAc = 4/1) afforded 7p (95%, 325 mg). Colorless (92%, 372 mg) with a ratio of 1:1. HRMS (ESI, M++Na) calcd o solid; mp = 71-72 C (recrystallized from hexanes and EtOAc); for C26H28O4Na 427.1877, found 427.1882; 1H NMR (400 MHz, + HRMS (ESI, M +Na) calcd for C21H26O4Na 365.1721, found CDCl3): δ 7.46-7.28 (m, 4H), 6.83-6.75 (m, 3H), 6.70-6.66 (m, 365.1726; 1H NMR (400 MHz, CDCl3): δ 6.77 (d, J = 8.4 Hz, 3H), 5.98-5.84 (m, 1H), 5.14 (s, 1H), 5.10 (s, 1H), 5.03-4.86 (m, 1H), 6.70 (s, 1H), 6.65-6.60 (m, 2H), 6.61 (s, 1H), 5.54-5.46 (m, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 3.83 (s, 2H), 3.44 (dt, 1H), 5.44-5.36 (m, 1H), 3.89 (s, 2H), 3.86 (s, 3H), 3.84 (s, 3H), J = 1.6, 5.6 Hz, 1H), 3.36 (dt, J = 1.6, 5.6 Hz, 1H). 3.80 (s, 3H), 3.78 (s, 3H), 3.21 (dt, J = 1.2, 6.0 Hz, 2H), 1.65 (dq,

4.4. A representative synthetic procedure of skeletons 1 and 13 is as follows:

SC

A solution of 2.5% osmium (OsO4, 0.6 mL, in THF) was added to a solution of skeleton 7, 11 (0.6 mmol) in cosolvent of THF (6 mL) and water (6 mL). N-Methylmorpholine-N-oxide (NMO, 50% in water, 300 mg, 1.3 mmol) was added to the reaction mixture at 25 oC. The reaction mixture was stirred at 25 o C for 2 h. Then, sodium periodate (NaIO4, 150 mg, 0.7 mmol) was added to the reaction mixture at 25 oC. The reaction mixture was stirred at 25 oC for 1 h. The reaction mixture was concentrated and the residue was diluted with water (10 mL) and the mixture was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product under reduced pressure. Next, BF3·OEt2 (71mg, 0.5 mmol) was added to a solution of the crude product 8, 12 without further purification in CH2Cl2 (8 mL) at 25 oC. The reaction mixture was stirred at 25 oC for 2 h. The overall synthetic procedure had to be monitored by TLC until the reaction was completed. The reaction mixture was concentrated and the residue was diluted with water (10 mL) and the mixture was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc = 6/1) afforded 1a-1v and 13a-13e.

M AN U

4.3.22. 1-(3,4-Dimethoxy-2-(prop-1-en-1-yl)benzyl)-2,3,4trimethoxybenzene (11b). According to the general procedure, the reaction was performed in the presence of BF3·OEt2 (71 mg, 0.5 mmol), 10a (208 mg, 1.0 mmol) and 6b (219 mg, 1.3 mmol) in CH2Cl2 (8 mL) at 25 oC for 2 h. Purification on silica gel (hexanes/EtOAc = 4/1) afforded 11b (86%, 308 mg). Colorless gum; HRMS (ESI, M++Na) calcd for C21H26O5Na 381.1670, found 381.1672; 1H NMR (400 MHz, CDCl3): δ 6.74 (d, J = 8.8 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 8.8 Hz, 1H), 638 (dq, J = 1.6, 16.0 Hz, 1H), 6.05 (dq, J = 6.8 Hz, 16.0 Hz, 1H), 3.90 (s, 2H), 3.88 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.75 (s, 3H), 1.86 (dd, J = 1.6, 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 151.9, 151.6, 151.0, 146.9, 142.1, 132.0, 131.5, 131.1, 127.5, 125.3, 124.4, 124.1, 110.2, 107.0, 60.7, 60.5, 59.9, 55.8, 55.7, 32.5, 19.3.

RI PT

4.3.25. 2-Butoxy-1-methoxy-3-(prop-1-en-1-yl)-4-(2,3,44.3.21. 1-(3,4-Dimethoxybenzyl)-3,4-dimethoxy-2-(prop-1-enACCEPTED MANUSCRIPT trimethoxybenzyl)benzene (11e). According to the general 1-yl)benzene (11a). According to the general procedure, the procedure, the reaction was performed in the presence of reaction was performed in the presence of BF3·OEt2 (71 mg, 0.5 BF3·OEt2 (71 mg, 0.5 mmol), 10c (250 mg, 1.0 mmol) and 6b mmol), 10a (208 mg, 1.0 mmol) and 6a (180 mg, 1.3 mmol) in (219 mg, 1.3 mmol) in CH2Cl2 (8 mL) at 25 oC for 2 h. CH2Cl2 (8 mL) at 25 oC for 2 h. Purification on silica gel Purification on silica gel (hexanes/EtOAc = 4/1) afforded 11e (hexanes/EtOAc = 4/1) afforded 11a (90%, 296 mg). Colorless + (85%, 340 mg). Colorless gum; HRMS (ESI, M++Na) calcd for gum; HRMS (ESI, M +Na) calcd for C20H24O4Na 351.1565, C24H32O5Na 423.2138, found 423.2142; 1H NMR (400 MHz, found 351.1566; 1H NMR (400 MHz, CDCl3): δ 6.79 (d, J = 8.4 CDCl3): δ 7.01-6.97 (m, 1H), 6.73-6.66 (m, 2H), 6.59 (s, 1H), Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.66 6.57-6.56 (m, 2H), 6.36 (dq, J = 1.6, 16.0 Hz, 1H), 6.01 (dq, J = (d, J = 2.0 Hz, 1H), 6.62 (dd, J = 2.0, 8.0 Hz, 1H), 6.37 (dq, J = 6.4, 16.0 Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.82 (s, 3H), 3.81 (s, 1.6, 16.0 Hz, 1H), 6.06 (dq, J = 6.8, 16.0 Hz, 1H), 3.92 (s, 2H), 3H), 3.77 (s, 2H), 1.84 (dd, J = 1.6, 6.4 Hz, 3H), 1.74-1.67 (m, 3.84 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H), 3.74 (s, 3H), 1.87 (dd, J = 2H), 1.53-1.45 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H); 13C NMR (100 13 1.6, 6.4 Hz, 3H); C NMR (100 MHz, CDCl3): δ 151.1, 148.7, MHz, CDCl3): δ 153.5, 151.9, 151.2, 146.2, 132.5, 131.4, 131.1, 147.0, 146.9, 133.9, 131.9, 131.6, 131.2, 125.3, 124.3, 120.5, 127.6, 125.0, 124.7, 124.1, 123.6, 110.3, 107.0, 105.1, 72.3, 60.8, 112.0, 111.0, 110.3, 59.8, 55.7, 55.6 (2x), 38.4, 19.2. 60.5, 56.0, 55.9, 32.6, 32.3, 19.2, 13.8.

AC C

EP

TE D

4.3.23. 1-(3,4-Dimethoxybenzyl)-3-isopropoxy-4-methoxy-2(prop-1-en-1-yl)benzene (11c). According to the general procedure, the reaction was performed in the presence of BF3·OEt2 (71 mg, 0.5 mmol), 10b (236 mg, 1.0 mmol) and 6a (180 mg, 1.3 mmol) in CH2Cl2 (8 mL) at 25 oC for 2 h. Purification on silica gel (hexanes/EtOAc = 4/1) afforded 11c (87%, 310 mg). Colorless gum; HRMS (ESI, M++Na) calcd for C22H28O4Na 379.1877, found 379.1880; 1H NMR (400 MHz, CDCl3): δ 6.77 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 6.63 (s, 1H), 6.62 (d, J = 7.6 Hz, 1H), 6.34 (dq, J = 1.6, 16.0 Hz, 1H), 6.01 (dq, J = 6.4, 16.0 Hz, 1H), 4.374.31 (m, 1H), 3.92 (s, 2H), 3.85 (s, 3H), 3.81 (s, 3H), 3.80 (s, 3H), 1.84 (dd, J = 1.6, 6.4 Hz, 3H), 1.23 (d, J = 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 151.6, 148.7, 147.0, 145.0, 134.2, 133.1, 131.5, 131.3, 125.4, 124.9, 120.6, 112.0, 111.1, 110.2, 74.9, 55.8, 55.7 (2x), 38.6, 22.4 (2x), 19.1.

4.3.24. 2-Isopropoxy-1-methoxy-3-(prop-1-en-1-yl)-4-(2,3,4trimethoxybenzyl)benzene (11d). According to the general procedure, the reaction was performed in the presence of BF3·OEt2 (71 mg, 0.5 mmol), 10b (236 mg, 1.0 mmol) and 6b (219 mg, 1.3 mmol) in CH2Cl2 (8 mL) at 25 oC for 2 h. Purification on silica gel (hexanes/EtOAc = 4/1) afforded 11d (88%, 340 mg). Colorless gum; HRMS (ESI, M++Na) calcd for C23H30O5Na 409.1982, found 409.1985; 1H NMR (400 MHz, CDCl3): δ 6.70 (s, 1H), 6.59 (s, 1H), 6.57 (d, J = 8.4 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 6.36 (dd, J = 1.6, 16.0 Hz, 1H), 5.99 (dq, J = 6.4, 16.0 Hz, 1H), 4.37-4.30 (m, 1H), 3.88 (s, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.76 (s, 3H), 1.83 (dd, J = 1.6, 6.4 Hz, 3H), 1.23 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 153.4, 151.9, 151.3, 142.2, 133.1, 131.1, 127.8, 125.4, 124.8, 124.1, 123.6, 110.1, 107.0, 105.1, 74.8, 60.7, 60.5, 56.0, 55.6, 32.6, 22.4 (2x), 19.1.

4.4.1. 1,2,7,8-Tetramethoxy-5H-dibenzo[a,d][7]annulene (1a). According to the general procedure, the reaction was performed in two-step including (i) OsO4 (2.5%, 0.6 mL in THF), NMO (50% in water, 300 mg, 1.3 mmol), NaIO4 (150 mg, 0.7 mmol) and 7a (197 mg, 0.6 mmol) in the cosolvent of THF (6 mL) and water (6 mL) at 25 oC for 3 h, (ii) BF3·OEt2 (71 mg, 0.5 mmol) and in situ-generated 8a without further purification in CH2Cl2 (8 mL) at 25 oC for 2 h. Purification on silica gel (hexanes/EtOAc = 6/1) afforded 1a (88%, 165 mg). Colorless solid; mp = 57-58 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for C19H20O4Na 335.1253, found 335.1254; 1H NMR (400 MHz, CDCl3): δ 7.25 (d, J = 12.0 Hz, 1H), 7.00 (d, J = 12.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.79 (br s, 2H), 3.91 (s, 3H), 3.86 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H), 3.60 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 150.7, 149.5, 147.2, 146.1, 132.8, 131.53, 131.47, 129.4, 127.9, 124.8, 122.6, 112.6, 111.1, 110.8, 60.7, 56.02, 56.00, 55.9, 40.5. 4.4.2. 1,2,6,7,8-Pentamethoxy-5H-dibenzo[a,d][7]annulene (1b). According to the general procedure, the reaction was performed in two-step including (i) OsO4 (2.5%, 0.6 mL in THF), NMO (50% in water, 300 mg, 1.3 mmol), NaIO4 (150 mg, 0.7 mmol) and 7b (215 mg, 0.6 mmol) in the cosolvent of THF (6 mL) and water (6 mL) at 25 oC for 3 h, (ii) BF3·OEt2 (71 mg, 0.5

10

Tetrahedron

AC C

EP

TE D

M AN U

SC

RI PT

6.95 (d, J = 12.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.60 (s, 1H), mmol) and in situ-generated 8b without further purification in MANUSCRIPT ACCEPTED 4.43-4.37 (m, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 3.83 (s, 3H), 3.80 (s, CH2Cl2 (8 mL) at 25 oC for 2 h. Purification on silica gel 3H), 3.66 (br s, 2H), 1.30 (d, J = 6.4 Hz, 6H); 13C NMR (100 (hexanes/EtOAc = 6/1) afforded 1b (89%, 183 mg). Colorless o solid; mp = 119-120 C (recrystallized from hexanes and EtOAc); MHz, CDCl3): δ 151.1, 150.9, 150.0, 144.4, 142.7, 133.2, 131.5, HRMS (ESI, M++Na) calcd for C20H22O5Na 365.1358, found 130.9, 130.6, 127.1, 125.5, 122.5, 112.6, 107.0, 75.5, 61.5, 60.9, 365.1360; 1H NMR (400 MHz, CDCl3): δ 7.28 (d, J = 12.0 Hz, 55.99, 55.97, 31.4, 22.7 (2x). 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 12.0 Hz, 1H), 6.88 (d, 4.4.6. 9-Isopropoxy-8-methoxy-5HJ = 8.4 Hz, 1H), 6.62 (s, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.83 (s, benzo[4',5']cyclohepta[1',2':4,5]benzo[1,2-d][1,3]dioxole (1f). 13 6H), 3.82 (s, 3H), 3.67 (s, 2H); C NMR (100 MHz, CDCl3): δ According to the general procedure, the reaction was performed 151.2, 150.7, 150.0, 146.1, 142.9, 133.1, 131.6, 131.4, 129.7, in two-step including (i) OsO4 (2.5%, 0.6 mL in THF), NMO 125.8, 125.3, 123.0, 112.6, 107.1, 61.5, 60.9, 60.7, 56.0 (2x), (50% in water, 300 mg, 1.3 mmol), NaIO4 (150 mg, 0.7 mmol) 31.3. and 7f (204 mg, 0.6 mmol) in the cosolvent of THF (6 mL) and water (6 mL) at 25 oC for 3 h, (ii) BF3·OEt2 (71 mg, 0.5 mmol) 4.4.3. 8,9-Dimethoxy-5Hand in situ-generated 8f without further purification in CH2Cl2 (8 benzo[4',5']cyclohepta[1',2':4,5]benzo[1,2-d][1,3]dioxole (1c). According to the general procedure, the reaction was performed mL) at 25 oC for 2 h. Purification on silica gel (hexanes/EtOAc = in two-step including (i) OsO4 (2.5%, 0.6 mL in THF), NMO 6/1) afforded 1f (90%, 175 mg). Colorless solid; mp = 86-87 oC (50% in water, 300 mg, 1.3 mmol), NaIO4 (150 mg, 0.7 mmol) (recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) and 7c (187 mg, 0.6 mmol) in the cosolvent of THF (6 mL) and calcd for C20H20O4Na 347.1253, found 347.1255; 1H NMR (400 o water (6 mL) at 25 C for 3 h, (ii) BF3·OEt2 (71 mg, 0.5 mmol) MHz, CDCl3): δ 7.27 (d, J = 12.0 Hz, 1H), 6.93 (d, J = 8.4 Hz, and in situ-generated 8c without further purification in CH2Cl2 (8 1H), 6.91 (d, J = 12.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.78 (s, 1H), 6.74 (s, 1H), 5.91 (s, 2H), 4.43-4.37 (m, 1H), 3.80 (s, 3H), mL) at 25 oC for 2 h. Purification on silica gel (hexanes/EtOAc = 3.55 (s, 2H), 1.29 (d, J = 6.4 Hz, 6H); 13C NMR (100 MHz, 6/1) afforded 1c (90%, 160 mg). Colorless solid; mp = 90-91 oC + (recrystallized from hexanes and EtOAc); HRMS (ESI, M +Na) CDCl3): δ 151.0, 147.9, 145.9, 144.2, 132.9, 132.8, 130.8, 130.2, calcd for C18H16O4Na 319.0941, found 319.0942; 1H NMR (400 129.1, 126.2, 121.9, 112.6, 107.9, 107.7, 101.0, 75.5, 56.0, 40.7, MHz, CDCl3): δ 7.24 (d, J = 12.0 Hz, 1H), 6.96 (d, J = 8.4 Hz, 22.6 (2x). 1H), 6.95 (d, J = 12.0 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.77 (s, 4.4.7. 1-Butoxy-2,7,8-trimethoxy-5H-dibenzo[a,d][7]annulene 1H), 6.75 (s, 1H), 5.91 (s, 2H), 3.83 (s, 3H), 3.81 (s, 3H), 3.55 (s, (1g). According to the general procedure, the reaction was 13 2H); C NMR (100 MHz, CDCl3): δ 150.8, 148.1, 146.04, performed in two-step including (i) OsO4 (2.5%, 0.6 mL in THF), 146.00, 132.8, 132.7, 131.5, 129.3, 129.0, 124.9, 122.5, 112.7, NMO (50% in water, 300 mg, 1.3 mmol), NaIO4 (150 mg, 0.7 108.0, 107.9, 101.0, 60.7, 56.0, 40.6. mmol) and 7g (222 mg, 0.6 mmol) in the cosolvent of THF (6 4.4.4. 1-Isopropoxy-2,7,8-trimethoxy-5HmL) and water (6 mL) at 25 oC for 3 h, (ii) BF3·OEt2 (71 mg, 0.5 dibenzo[a,d][7]annulene (1d). According to the general mmol) and in situ-generated 8g without further purification in procedure, the reaction was performed in two-step including (i) CH2Cl2 (8 mL) at 25 oC for 2 h. Purification on silica gel OsO4 (2.5%, 0.6 mL in THF), NMO (50% in water, 300 mg, 1.3 (hexanes/EtOAc = 6/1) afforded 1g (91%, 194 mg). Colorless mmol), NaIO4 (150 mg, 0.7 mmol) and 7d (214 mg, 0.6 mmol) in solid; mp = 97-98 oC (recrystallized from hexanes and EtOAc); o the cosolvent of THF (6 mL) and water (6 mL) at 25 C for 3 h, HRMS (ESI, M++Na) calcd for C22H26O4Na 377.1721, found (ii) BF3·OEt2 (71 mg, 0.5 mmol) and in situ-generated 8d without 377.1722; 1H NMR (400 MHz, CDCl3): δ 7.28 (d, J = 12.0 Hz, o further purification in CH2Cl2 (8 mL) at 25 C for 2 h. 1H), 6.98 (d, J = 12.0 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.87 (d, Purification on silica gel (hexanes/EtOAc = 6/1) afforded 1d J = 8.0 Hz, 1H), 6.80 (br s, 2H), 3.92 (t, J = 7.2 Hz, 2H), 3.91 (s, (92%, 188 mg). Colorless solid; mp = 98-99 oC (recrystallized 3H), 3.86 (s, 3H), 3.81 (s, 3H), 3.60 (s, 2H), 1.82-1.75 (m, 2H), from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for 1.59-1.49 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, 1 C21H24O4Na 363.1565, found 363.1568; H NMR (400 MHz, CDCl3): δ 150.8, 149.4, 147.1, 145.5, 132.8, 131.5, 131.2, 129.5, CDCl3): δ 7.28 (d, J = 12.0 Hz, 1H), 6.96 (d, J = 12.0 Hz, 1H), 127.9, 125.2, 122.3, 112.7, 111.1, 110.8, 73.1, 56.1, 56.0, 55.9, 6.95 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.80 (s, 1H), 40.5, 32.3, 19.2, 13.9. 6.79 (s, 1H), 4.43-4.37 (m, 1H), 3.91 (s, 3H), 3.85 (s, 3H), 3.80 (s, 4.4.8. 1-Butoxy-2,6,7,8-tetramethoxy-5H3H), 3.59 (s, 2H), 1.29 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, dibenzo[a,d][7]annulene (1h). According to the general CDCl3): δ 151.0, 149.3, 147.1, 144.3, 133.0, 131.6, 130.8, 130.2, procedure, the reaction was performed in two-step including (i) 128.0, 126.0, 122.0, 112.5, 111.1, 110.8, 75.5, 56.0 (2x), 55.9, OsO4 (2.5%, 0.6 mL in THF), NMO (50% in water, 300 mg, 1.3 40.6, 22.6 (2x). mmol), NaIO4 (150 mg, 0.7 mmol) and 7h (240 mg, 0.6 mmol) in 4.4.5. 1-Isopropoxy-2,6,7,8-tetramethoxy-5Hthe cosolvent of THF (6 mL) and water (6 mL) at 25 oC for 3 h, dibenzo[a,d][7]annulene (1e). According to the general (ii) BF3·OEt2 (71 mg, 0.5 mmol) and in situ-generated 8h without procedure, the reaction was performed in two-step including (i) further purification in CH2Cl2 (8 mL) at 25 oC for 2 h. OsO4 (2.5%, 0.6 mL in THF), NMO (50% in water, 300 mg, 1.3 Purification on silica gel (hexanes/EtOAc = 6/1) afforded 1h mmol), NaIO4 (150 mg, 0.7 mmol) and 7e (232 mg, 0.6 mmol) in (86%, 198 mg). Colorless gum; HRMS (ESI, M++Na) calcd for the cosolvent of THF (6 mL) and water (6 mL) at 25 oC for 3 h, C23H28O5Na 407.1826, found 407.1829; 1H NMR (400 MHz, (ii) BF3·OEt2 (71 mg, 0.5 mmol) and in situ-generated 8e without CDCl3): δ 7.29 (d, J = 12.0 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), further purification in CH2Cl2 (8 mL) at 25 oC for 2 h. 6.97 (d, J = 12.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.61 (s, 1H), Purification on silica gel (hexanes/EtOAc = 6/1) afforded 1e 3.92 (t, J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.83 (s, 3H), (87%, 193 mg). Colorless gum; HRMS (ESI, M++Na) calcd for 3.81 (s, 3H), 3.66 (br s, 2H), 1.81-1.74 (m, 2H), 1.58-1.48 (m, C22H26O5Na 393.1670, found 393.1671; 1H NMR (400 MHz, 2H), 0.99 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ CDCl3): δ 7.30 (d, J = 12.0 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 151.1, 150.8, 150.0, 145.6, 142.8, 133.1, 131.5, 131.3, 129.9,

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126.3, 125.4, 122.7, 112.8, 107.0, 73.2, 61.5,ACCEPTED 61.0, 56.1, 56.0, MANUSCRIPT in two-step including (i) OsO4 (2.5%, 0.6 mL in THF), NMO 32.4, 31.4, 19.2, 13.9. (50% in water, 300 mg, 1.3 mmol), NaIO4 (150 mg, 0.7 mmol) and 7l (220 mg, 0.6 mmol) in the cosolvent of THF (6 mL) and 4.4.9. 9-Butoxy-8-methoxy-5Hwater (6 mL) at 25 oC for 3 h, (ii) BF3·OEt2 (71 mg, 0.5 mmol) benzo[4',5']cyclohepta[1',2':4,5]benzo[1,2-d][1,3]dioxole (1i). and in situ-generated 8l without further purification in CH2Cl2 (8 According to the general procedure, the reaction was performed mL) at 25 oC for 2 h. Purification on silica gel (hexanes/EtOAc = in two-step including (i) OsO4 (2.5%, 0.6 mL in THF), NMO 6/1) afforded 1l (85%, 179 mg). Colorless solid; mp = 110-111 (50% in water, 300 mg, 1.3 mmol), NaIO4 (150 mg, 0.7 mmol) o C (recrystallized from hexanes and EtOAc); HRMS (ESI, and 7i (213 mg, 0.6 mmol) in the cosolvent of THF (6 mL) and M++Na) calcd for C22H22O4Na 373.1409, found 373.1412; 1H o water (6 mL) at 25 C for 3 h, (ii) BF3·OEt2 (71 mg, 0.5 mmol) NMR (400 MHz, CDCl3): δ 7.23 (d, J = 12.0 Hz, 1H), 6.92 (d, J and in situ-generated 8i without further purification in CH2Cl2 (8 = 8.4 Hz, 1H), 6.91 (d, J = 12.0 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), o mL) at 25 C for 2 h. Purification on silica gel (hexanes/EtOAc = 6.77 (s, 1H), 6.74 (s, 1H), 5.91 (s, 2H), 4.79-4.76 (m, 1H), 3.80 (s, 6/1) afforded 1i (90%, 183 mg). Colorless gum; HRMS (ESI, 3H), 3.54 (s, 2H), 1.91-1.84 (m, 4H), 1.71-1.54 (m, 4H); 13C M++Na) calcd for C21H22O4Na 361.1409, found 361.1412; 1H NMR (100 MHz, CDCl3): δ 150.9, 147.9, 145.9, 144.4, 132.9, NMR (400 MHz, CDCl3): δ 7.28 (d, J = 12.0 Hz, 1H), 6.95 (d, J 130.8, 130.1, 129.1, 126.1, 121.9, 112.9, 108.0, 107.7, 101.0, = 8.8 Hz, 1H), 6.94 (d, J = 12.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 85.0, 70.5, 56.1, 40.7, 32.8 (2x), 23.7 (2x). Single-crystal X-ray 6.78 (s, 1H), 6.76 (s, 1H), 5.91 (s, 2H), 3.93 (t, J = 6.4 Hz, 2H), diagram: crystal of 1l was grown by slow diffusion of EtOAc 3.82 (s, 3H), 3.55 (s, 2H), 1.82-1.75 (m, 2H), 1.59-1.50 (m, 2H), into a solution of 1l in CH2Cl2 to yield colorless prisms. The 13 1.00 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3): δ 150.8, compound crystallizes in the triclinic crystal system, space group 148.0, 145.9, 145.4, 132.8, 132.7, 131.2, 129.5, 129.0, 125.3, P -1, a = 9.4510(6) Å, b = 9.7866(6) Å, c = 11.0042(7) Å, V = 122.2, 112.8, 107.9, 107.8, 101.0, 73.1, 56.1, 40.6, 32.3, 19.2, 895.19(10) Å3, Z = 2, dcalcd = 1.300 g/cm3, F(000) = 372, 2θ 13.9. range 2.02-26.38o, R indices (all data) R1 = 0.0600, wR2 = 0.1408. 4.4.10. 1-(Cyclopentyloxy)-2,7,8-trimethoxy-5Hdibenzo[a,d][7]annulene (1j). According to the general 4.4.13. 1,2,7,8-Tetramethoxy-11-methyl-5Hprocedure, the reaction was performed in two-step including (i) dibenzo[a,d][7]annulene (1m). According to the general OsO4 (2.5%, 0.6 mL in THF), NMO (50% in water, 300 mg, 1.3 procedure, the reaction was performed in two-step including (i) mmol), NaIO4 (150 mg, 0.7 mmol) and 7j (230 mg, 0.6 mmol) in OsO4 (2.5%, 0.6 mL in THF), NMO (50% in water, 300 mg, 1.3 o the cosolvent of THF (6 mL) and water (6 mL) at 25 C for 3 h, mmol), NaIO4 (150 mg, 0.7 mmol) and 7m (205 mg, 0.6 mmol) (ii) BF3·OEt2 (71 mg, 0.5 mmol) and in situ-generated 8j without in the cosolvent of THF (6 mL) and water (6 mL) at 25 oC for 3 h, o further purification in CH2Cl2 (8 mL) at 25 C for 2 h. (ii) BF3·OEt2 (71 mg, 0.5 mmol) and in situ-generated 8m Purification on silica gel (hexanes/EtOAc = 6/1) afforded 1j without further purification in CH2Cl2 (8 mL) at 25 oC for 2 h. o (92%, 202 mg). Colorless solid; mp = 104-105 C (recrystallized Purification on silica gel (hexanes/EtOAc = 6/1) afforded 1m from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for (91%, 178 mg). Colorless gum; HRMS (ESI, M++Na) calcd for C23H26O4Na 389.1721, found 389.1722; 1H NMR (400 MHz, C20H22O4Na 349.1409, found 349.1412; 1H NMR (400 MHz, CDCl3): δ 7.25 (d, J = 12.0 Hz, 1H), 6.96 (d, J = 12.0 Hz, 1H), CDCl3): δ 6.96 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 1.6 Hz, 1H), 6.83 6.95 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.80 (s, 1H), (d, J = 8.4 Hz, 1H), 6.73 (s, 1H), 6.72 (s, 1H), 3.88 (s, 3H), 3.83 6.79 (s, 1H), 4.80-4.77 (m, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.80 (s, (s, 3H), 3.81 (s, 3H), 3.72 (s, 3H), 3.52 (d, J = 13.2 Hz, 1H), 3.48 13 3H), 3.59 (s, 2H), 1.94-1.86 (m, 4H), 1.71-1.57 (m, 4H); C (d, J = 13.2 Hz, 1H), 2.45 (d, J = 1.6 Hz, 3H); 13C NMR (100 NMR (100 MHz, CDCl3): δ 150.9, 149.3, 147.1, 144.5, 133.0, MHz, CDCl3): δ 151.2, 148.5, 147.04, 146.96, 136.4, 135.7, 131.6, 130.8, 130.1, 128.0, 125.9, 122.0, 112.8, 111.1, 110.8, 133.1, 131.1, 130.0, 127.9, 121.6, 111.8, 110.7, 109.9, 60.2, 56.0, 85.0, 56.05, 56.00, 55.9, 40.6, 32.8 (2x), 23.6 (2x). 55.94, 55.87, 40.3, 24.4. 4.4.11. 1-(Cyclopentyloxy)-2,6,7,8-tetramethoxy-5H4.4.14. 1,2,6,7,8-Pentamethoxy-11-methyl-5Hdibenzo[a,d][7]annulene (1k). According to the general dibenzo[a,d][7]annulene (1n). According to the general procedure, the reaction was performed in two-step including (i) procedure, the reaction was performed in two-step including (i) OsO4 (2.5%, 0.6 mL in THF), NMO (50% in water, 300 mg, 1.3 OsO4 (2.5%, 0.6 mL in THF), NMO (50% in water, 300 mg, 1.3 mmol), NaIO4 (150 mg, 0.7 mmol) and 7k (248 mg, 0.6 mmol) in mmol), NaIO4 (150 mg, 0.7 mmol) and 7n (223 mg, 0.6 mmol) in the cosolvent of THF (6 mL) and water (6 mL) at 25 oC for 3 h, the cosolvent of THF (6 mL) and water (6 mL) at 25 oC for 3 h, (ii) BF3·OEt2 (71 mg, 0.5 mmol) and in situ-generated 8k without (ii) BF3·OEt2 (71 mg, 0.5 mmol) and in situ-generated 8n without further purification in CH2Cl2 (8 mL) at 25 oC for 2 h. further purification in CH2Cl2 (8 mL) at 25 oC for 2 h. Purification on silica gel (hexanes/EtOAc = 6/1) afforded 1k Purification on silica gel (hexanes/EtOAc = 6/1) afforded 1n (84%, 200 mg). Colorless gum; HRMS (ESI, M++Na) calcd for (82%, 175 mg). Colorless gum; HRMS (ESI, M++Na) calcd for 1 C24H28O5Na 419.1826, found 419.1830; H NMR (400 MHz, C21H24O5Na 379.1514, found 379.1515; 1H NMR (400 MHz, CDCl3): δ 7.27 (d, J = 12.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), CDCl3): δ 7.02 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 1.6 Hz, 1H), 6.82 6.95 (d, J = 12.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.60 (s, 1H), (d, J = 8.4 Hz, 1H), 6.54 (s, 1H), 4.12 (d, J = 12.8 Hz, 1H), 3.90 4.80-4.76 (m, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.83 (s, 3H), 3.80 (s, (s, 3H), 3.86 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 3.74 (s, 3H), 3.05 13 3H), 3.65 (br s, 2H), 1.94-1.89 (m, 4H), 1.71-1.56 (m, 4H); C (d, J = 12.8 Hz, 1H), 2.45 (d, J = 1.2 Hz, 3H); 13C NMR (100 NMR (100 MHz, CDCl3): δ 151.1, 150.8, 150.0, 144.6, 142.8, MHz, CDCl3): δ 151.2, 151.0, 149.4, 146.9, 141.8, 137.4, 135.7, 133.3, 131.5, 130.8, 130.5, 127.0, 125.5, 122.4, 112.8, 107.0, 131.4, 130.0, 127.0, 123.7, 122.1, 111.8, 106.6, 61.4, 60.9, 60.3, 85.0, 61.5, 61.0, 56.05, 56.02, 32.9 (2x), 31.5, 23.7 (2x). 55.94, 55.93, 31.5, 24.5. 4.4.12. 9-(Cyclopentyloxy)-8-methoxy-5H4.4.15. 8,9-Dimethoxy-10-methyl-5Hbenzo[4',5']cyclohepta[1',2':4,5]benzo[1,2-d][1,3]dioxole (1l). benzo[4',5']cyclohepta[1',2':4,5]benzo[1,2-d][1,3]dioxole (1o). According to the general procedure, the reaction was performed According to the general procedure, the reaction was performed

12

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further purification in CH2Cl2 (8 mL) at 25 oC for 2 h. in two-step including (i) OsO4 (2.5%, 0.6 mL in THF), NMO MANUSCRIPT ACCEPTED (50% in water, 300 mg, 1.3 mmol), NaIO4 (150 mg, 0.7 mmol) Purification on silica gel (hexanes/EtOAc = 6/1) afforded 1r (95%, 210 mg). Colorless solid; mp = 99-100 oC (recrystallized and 7o (196 mg, 0.6 mmol) in the cosolvent of THF (6 mL) and o water (6 mL) at 25 C for 3 h, (ii) BF3·OEt2 (71 mg, 0.5 mmol) from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for and in situ-generated 8o without further purification in CH2Cl2 (8 C23H28O4Na 391.1877, found 391.1880; 1H NMR (400 MHz, o mL) at 25 C for 2 h. Purification on silica gel (hexanes/EtOAc = CDCl3): δ 7.25 (d, J = 12.0 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6/1) afforded 1o (88%, 164 mg). Colorless gum; HRMS (ESI, 6.98 (d, J = 12.0 Hz, 1H), 6.89-6.85 (m, 3H), 4.56-4.50 (m, 1H), M++Na) calcd for C19H18O4Na 333.1097, found 333.1099; 1H 4.44-4.38 (m, 1H), 3.84 (br s, 6H), 3.61 (s, 2H), 1.36 (d, J = 6.4 NMR (400 MHz, CDCl3): δ 6.94 (d, J = 8.4 Hz, 1H), 6.86 (d, J = Hz, 6H), 1.33 (d, J = 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3): 0.8 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.71 (s, 1H), 6.67 (s, 1H), δ 150.7, 149.8, 147.0, 146.0, 132.79, 132.75, 131.6, 129.4, 128.8, 5.91 (d, J = 1.2 Hz, 1H), 5.83 (d, J = 1.2 Hz, 1H), 3.81 (s, 3H), 124.4, 122.6, 118.4, 116.9, 112.3, 72.6, 72.0, 60.6, 55.9, 40.5, 3.71 (s, 3H), 3.49 (d, J = 13.2 Hz, 1H), 3.43 (d, J = 13.2 Hz, 1H), 22.22 (2x), 22.19 (2x). 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 151.3, 147.1, 146.9, 4.4.19. 8-Isopropoxy-1,2,7-trimethoxy-5H145.8, 136.6, 135.6, 134.3, 131.0, 129.9, 129.0, 121.6, 111.9, dibenzo[a,d][7]annulene (1s) and 7-Isopropoxy-1,2,8107.4, 107.1, 100.8, 60.3, 56.0, 40.5, 24.3. trimethoxy-5H-dibenzo[a,d][7]annulene (1t). According to the 4.4.16. 2,3,7,8-Tetramethoxy-5H-dibenzo[a,d][7]annulene general procedure, the reaction was performed in two-step (1p). According to the general procedure, the reaction was including (i) OsO4 (2.5%, 0.6 mL in THF), NMO (50% in water, performed in two-step including (i) OsO4 (2.5%, 0.6 mL in THF), 300 mg, 1.3 mmol), NaIO4 (150 mg, 0.7 mmol), and a mixture of NMO (50% in water, 300 mg, 1.3 mmol), NaIO4 (150 mg, 0.7 7s and 7t (214 mg, 0.6 mmol) in the cosolvent of THF (6 mL) mmol) and 7p (205 mg, 0.6 mmol) in the cosolvent of THF (6 and water (6 mL) at 25 oC for 3 h, (ii) BF3·OEt2 (71 mg, 0.5 mL) and water (6 mL) at 25 oC for 3 h, (ii) BF3·OEt2 (71 mg, 0.5 mmol) and in situ-generated 8s and 8t without further mmol) and in situ-generated 8p without further purification in purification in CH2Cl2 (8 mL) at 25 oC for 2 h. Purification on CH2Cl2 (8 mL) at 25 oC for 2 h. Purification on silica gel silica gel (hexanes/EtOAc = 6/1) afforded a mixture of 1s and 1t (hexanes/EtOAc = 6/1) afforded 1p (95%, 178 mg). Colorless (93%, 190 mg) with a ratio of 2:1. HRMS (ESI, M++Na) calcd o for C21H24O4Na 363.1565, found 363.1568; 1H NMR (400 MHz, solid; mp = 197-198 C (recrystallized from hexanes and EtOAc); + HRMS (ESI, M +Na) calcd for C19H20O4Na 335.1253, found CDCl3): δ 7.28-7.24 (m, 1H), 7.03-6.98 (m, 2H), 6.90-6.82 (m, 335.1255; 1H NMR (400 MHz, CDCl3): δ 6.88 (s, 2H), 6.80 (d, J 3H), 4.60-4.52 (m, 1H), 3.89 (s, 3H), 3.84 (br s, 6H), 3.62 (s, 2H), = 8.4 Hz, 4H), 3.92 (s, 6H), 3.85 (s, 6H), 3.60 (s, 2H); 13C NMR 1.41-1.35 (m, 6H). (100 MHz, CDCl3): δ 149.4 (2x), 147.1 (2x), 130.6 (2x), 129.8 4.4.20. 8-(Benzyloxy)-1,2,7-trimethoxy-5H(2x), 127.9 (2x), 111.0 (2x), 110.8 (2x), 55.95 (2x), 55.92 (2x), dibenzo[a,d][7]annulene (1u). According to the general 40.6. Single-crystal X-ray diagram: crystal of 1p was grown by procedure, the reaction was performed in two-step including (i) slow diffusion of EtOAc into a solution of 1p in CH2Cl2 to yield OsO4 (2.5%, 0.6 mL in THF), NMO (50% in water, 300 mg, 1.3 colorless prisms. The compound crystallizes in the orthorhombic mmol), NaIO4 (150 mg, 0.7 mmol) and 7u (243 mg, 0.6 mmol) in crystal system, space group P n m a, a = 10.2063(6) Å, b = the cosolvent of THF (6 mL) and water (6 mL) at 25 oC for 3 h, 3 26.4494(15) Å, c = 6.0198(4) Å, V = 1625.05(17) Å , Z = 4, dcalcd (ii) BF3·OEt2 (71 mg, 0.5 mmol) and in situ-generated 8u without = 1.277 g/cm3, F(000) = 664, 2θ range 1.54-26.48o, R indices further purification in CH2Cl2 (8 mL) at 25 oC for 2 h. (all data) R1 = 0.0550, wR2 = 0.1102. Purification on silica gel (hexanes/EtOAc = 6/1) afforded 1u 4.4.17. 2,3,4,7,8-Pentamethoxy-5H-dibenzo[a,d][7]annulene (44%, 103 mg). Colorless solid; mp = 117-118 oC (recrystallized (1q). According to the general procedure, the reaction was from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for performed in two-step including (i) OsO4 (2.5%, 0.6 mL in THF), C25H24O4Na 411.1565, found 411.1567; 1H NMR (400 MHz, NMO (50% in water, 300 mg, 1.3 mmol), NaIO4 (150 mg, 0.7 CDCl3): δ 7.47-7.45 (m, 2H), 7.40-7.31 (m, 3H), 7.25 (d, J = 12.0 mmol) and 7q (223 mg, 0.6 mmol) in the cosolvent of THF (6 Hz, 1H), 7.00 (d, J = 12.0 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.86 mL) and water (6 mL) at 25 oC for 3 h, (ii) BF3·OEt2 (71 mg, 0.5 (d, J = 8.4 Hz, 1H), 6.83 (s, 1H), 6.82 (s, 1H), 5.16 (s, 2H), 3.86 mmol) and in situ-generated 8q without further purification in (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H), 3.55 (s, 2H); 13C NMR (100 o MHz, CDCl3): δ 150.7, 148.8, 147.8, 146.1, 137.1, 132.8, 129.3, CH2Cl2 (8 mL) at 25 C for 2 h. Purification on silica gel (hexanes/EtOAc = 6/1) afforded 1q (91%, 187 mg). Colorless 128.52 (2x), 128.49, 127.8, 127.3 (2x), 127.2, 124.9, 122.6, 113.4, solid; mp = 101-102 oC (recrystallized from hexanes and EtOAc); 112.5, 111.8, 71.1, 70.5, 60.7, 56.2, 56.0, 40.4. HRMS (ESI, M++Na) calcd for C20H22O5Na 365.1358, found 4.4.21. 7-(Benzyloxy)-1,2,8-trimethoxy-5H365.1362; 1H NMR (400 MHz, CDCl3): δ 6.90 (s, 1H), 6.87 (d, J dibenzo[a,d][7]annulene (1v). According to the general = 12.0 Hz, 2H), 6.78 (s, 1H), 6.60 (s, 1H), 3.93 (s, 3H), 3.92 (s, procedure, the reaction was performed in two-step including (i) 3H), 3.88 (s, 3H), 3.85 (s, 3H), 3.83 (s, 3H), 3.67 (s, 2H); 13C OsO4 (2.5%, 0.6 mL in THF), NMO (50% in water, 300 mg, 1.3 NMR (100 MHz, CDCl3): δ 151.1, 149.9, 149.6, 147.1, 142.9, mmol), NaIO4 (150 mg, 0.7 mmol) and 7v (243 mg, 0.6 mmol) in 131.4, 131.1, 130.9, 129.9, 128.2, 124.5, 111.2, 111.0, 106.8, the cosolvent of THF (6 mL) and water (6 mL) at 25 oC for 3 h, 61.5, 61.0, 56.0 (3x), 31.5. (ii) BF3·OEt2 (71 mg, 0.5 mmol) and in situ-generated 8v without 4.4.18. 7,8-Diisopropoxy-1,2-dimethoxy-5Hfurther purification in CH2Cl2 (8 mL) at 25 oC for 2 h. dibenzo[a,d][7]annulene (1r). According to the general Purification on silica gel (hexanes/EtOAc = 6/1) afforded 1v procedure, the reaction was performed in two-step including (i) (44%, 103 mg). Colorless solid; mp = 121-122 oC (recrystallized OsO4 (2.5%, 0.6 mL in THF), NMO (50% in water, 300 mg, 1.3 from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for mmol), NaIO4 (150 mg, 0.7 mmol) and 7r (231 mg, 0.6 mmol) in C25H24O4Na 411.1565, found 411.1568; 1H NMR (400 MHz, o the cosolvent of THF (6 mL) and water (6 mL) at 25 C for 3 h, CDCl3): δ 7.45-7.27 (m, 5H), 7.22 (d, J = 12.4 Hz, 1H), 6.99 (d, J (ii) BF3·OEt2 (71 mg, 0.5 mmol) and in situ-generated 8r without = 8.4 Hz, 1H), 6.93 (d, J = 12.0 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H),

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4.4.25. 5-Isopropoxy-1,2,3,6-tetramethoxyanthracene (13d). 6.83 (s, 1H), 6.82 (s, 1H), 5.12 (s, 2H), 3.92 (s,ACCEPTED 3H), 3.83 (s, 3H), MANUSCRIPT According to the general procedure, the reaction was performed 3.81 (s, 3H), 3.60 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 150.7, in two-step including (i) OsO4 (2.5%, 0.6 mL in THF), NMO 150.2, 146.4, 146.0, 137.2, 132.7, 132.1, 131.5, 129.4, 128.5 (2x), 127.8, 127.2 (2x), 124.6, 122.6, 114.0, 112.5, 111.3, 71.3, 70.5, (50% in water, 300 mg, 1.3 mmol), NaIO4 (150 mg, 0.7 mmol) 60.7, 56.1, 56.0, 40.5. and 11d (232 mg, 0.6 mmol) in the cosolvent of THF (6 mL) and water (6 mL) at 25 oC for 3 h, (ii) BF3·OEt2 (71 mg, 0.5 mmol) 4.4.22. 1,2,6,7-Tetramethoxyanthracene (13a). According to and in situ-generated 12d without further purification in CH2Cl2 the general procedure, the reaction was performed in two-step (8 mL) at 25 oC for 2 h. Purification on silica gel (hexanes/EtOAc including (i) OsO4 (2.5%, 0.6 mL in THF), NMO (50% in water, = 6/1) afforded 13d (91%, 195 mg). Colorless gum; HRMS (ESI, 300 mg, 1.3 mmol), NaIO4 (150 mg, 0.7 mmol) and 11a (197 mg, M++Na) calcd for C21H24O5Na 379.1514, found 379.1518; 1H 0.6 mmol) in the cosolvent of THF (6 mL) and water (6 mL) at NMR (400 MHz, CDCl3): δ 8.53 (s, 1H), 8.51 (s, 1H), 7.76 (d, J 25 oC for 3 h, (ii) BF3·OEt2 (71 mg, 0.5 mmol) and in situ= 9.2 Hz, 1H), 7.30 (d, J = 9.2 Hz, 1H), 7.05 (s, 1H), 4.79-4.73 generated 12a without further purification in CH2Cl2 (8 mL) at 25 (m, 1H), 4.13 (s, 3H), 4.03 (s, 3H), 4.01 (s, 3H), 4.00 (s, 3H), o C for 2 h. Purification on silica gel (hexanes/EtOAc = 6/1) 1.42 (d, J = 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 153.1, afforded 13a (93%, 166 mg). Colorless solid; mp = 151-152 oC 147.1, 147.0, 140.0, 139.6, 129.5, 129.4, 127.6, 124.6, 123.0, (recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) 120.1, 118.2, 116.0, 101.0, 75.1, 61.3, 61.2, 57.1, 55.8, 22.8 (2x). 1 calcd for C18H18O4Na 321.1097, found 321.1108; H NMR (400 MHz, CDCl3): δ 8.48 (s, 1H), 8.14 (s, 1H), 7.68 (d, J = 9.2 Hz, 4.4.26. 5-Butoxy-1,2,3,6-tetramethoxyanthracene (13e). 1H), 7.27 (d, J = 9.2 Hz, 1H), 7.22 (s, 1H), 7.12 (s, 1H), 4.08 (s, According to the general procedure, the reaction was performed 3H), 4.03 (s, 3H), 4.01 (br s, 6H); 13C NMR (100 MHz, CDCl3): in two-step including (i) OsO4 (2.5%, 0.6 mL in THF), NMO δ 150.1, 149.6, 146.3, 141.9, 128.8, 128.0, 127.3, 126.8, 124.1, (50% in water, 300 mg, 1.3 mmol), NaIO4 (150 mg, 0.7 mmol) 123.9, 117.2, 115.8, 104.9, 104.6, 60.9, 57.2, 55.70, 55.68. and 11e (240 mg, 0.6 mmol) in the cosolvent of THF (6 mL) and Single-crystal X-ray diagram: crystal of 13a was grown by slow water (6 mL) at 25 oC for 3 h, (ii) BF3·OEt2 (71 mg, 0.5 mmol) and in situ-generated 12e without further purification in CH2Cl2 diffusion of EtOAc into a solution of 13a in CH2Cl2 to yield colorless prisms. The compound crystallizes in the triclinic (8 mL) at 25 oC for 2 h. Purification on silica gel (hexanes/EtOAc crystal system, space group P -1, a = 6.8802(3) Å, b = 12.3630(6) = 6/1) afforded 13e (87%, 193 mg). Colorless solid; mp = 45-46 o Å, c = 18.9082(9) Å, V = 1518.82(12) Å3, Z = 4, dcalcd = 1.305 C (recrystallized from hexanes and EtOAc); HRMS (ESI, 3 o g/cm , F(000) = 632, 2θ range 1.14-26.39 , R indices (all data) M++Na) calcd for C22H26O5Na 393.1670, found 393.1673; 1H R1 = 0.0791, wR2 = 0.1623. NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 8.50 (s, 1H), 7.76 (d, J = 9.2 Hz, 1H), 7.29 (d, J = 9.2 Hz, 1H), 7.06 (s, 1H), 4.21 (t, J = 4.4.23. 1,2,3,5,6-Pentamethoxyanthracene (13b). According to 6.4 Hz, 2H), 4.14 (s, 3H), 4.03 (s, 3H), 4.02 (s, 3H), 4.01 (s, 3H), the general procedure, the reaction was performed in two-step 1.99-1.92 (m, 2H), 1.70-1.61 (m, 2H), 1.06 (t, J = 7.6 Hz, 3H); including (i) OsO4 (2.5%, 0.6 mL in THF), NMO (50% in water, 13 C NMR (100 MHz, CDCl3): δ 153.1, 147.0, 146.9, 141.1, 140.0, 300 mg, 1.3 mmol), NaIO4 (150 mg, 0.7 mmol) and 11b (215 mg, 129.6, 128.4, 127.6, 124.7, 123.1, 120.3, 117.5, 116.2, 101.0, 0.6 mmol) in the cosolvent of THF (6 mL) and water (6 mL) at 73.2, 61.3, 61.2, 57.3, 55.7, 32.5, 19.3, 13.9. 25 oC for 3 h, (ii) BF3·OEt2 (71 mg, 0.5 mmol) and in situ4.5. A representative synthetic procedure of skeleton 14 is as generated 12b without further purification in CH2Cl2 (8 mL) at follows: 25 oC for 2 h. Purification on silica gel (hexanes/EtOAc = 6/1) afforded 13b (95%, 187 mg). Colorless solid; mp = 109-110 oC BF3·OEt2 (71 mg, 0.5 mmol) was added to a solution of 5a-5f, (recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) 10a (1.0 mmol) and 6a, 6c-6g (0.6 mmol) in CH2Cl2 (6 mL) at 25 o calcd for C19H20O5Na 351.1202, found 351.1204; 1H NMR (400 C. The reaction mixture was stirred at 25 oC for 3 h. The MHz, CDCl3): δ 8.55 (s, 1H), 8.48 (s, 1H), 7.78 (d, J = 9.2 Hz, reaction mixture was concentrated and the residue was diluted 1H), 7.30 (d, J = 9.2 Hz, 1H), 7.06 (s, 1H), 4.13 (s, 3H), 4.07 (s, with water (10 mL) and the mixture was extracted with CH2Cl2 3H), 4.03 (s, 3H), 4.02 (s, 3H), 4.01 (s, 3H); 13C NMR (100 MHz, (3 x 20 mL). The combined organic layers were washed with CDCl3): δ 153.2, 147.0, 146.9, 141.6, 140.1, 129.7, 127.8, 127.5, brine, dried, filtered and evaporated to afford crude product under 125.1, 123.1, 120.4, 117.3, 115.8, 100.9, 61.3, 61.2, 61.0, 57.2, reduced pressure. Purification on silica gel (hexanes/EtOAc = 55.8. 3/1) afforded 14a-14o. 4.4.24. 1-Isopropoxy-2,6,7-trimethoxyanthracene (13c). According to the general procedure, the reaction was performed in two-step including (i) OsO4 (2.5%, 0.6 mL in THF), NMO (50% in water, 300 mg, 1.3 mmol), NaIO4 (150 mg, 0.7 mmol) and 11c (214 mg, 0.6 mmol) in the cosolvent of THF (6 mL) and water (6 mL) at 25 oC for 3 h, (ii) BF3·OEt2 (71 mg, 0.5 mmol) and in situ-generated 12c without further purification in CH2Cl2 (8 mL) at 25 oC for 2 h. Purification on silica gel (hexanes/EtOAc = 6/1) afforded 13c (86%, 168 mg). Colorless solid; mp = 63-64 o C (recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for C20H22O4Na 349.1409, found 349.1410; 1H NMR (400 MHz, CDCl3): δ 8.50 (s, 1H), 8.14 (s, 1H), 7.67 (d, J = 9.2 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.22 (s, 1H), 7.14 (s, 1H), 4.80-4.74 (m, 1H), 4.05 (s, 3H), 4.02 (s, 3H), 3.99 (s, 3H), 1.43 (d, J = 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 150.1, 149.7, 146.6, 140.0, 128.7, 128.4, 128.2, 127.3, 123.71, 123.65, 118.2, 116.3, 105.2, 104.7, 75.1, 57.3, 55.81, 55.78, 22.8 (2x).

4.5.1. 4,4'-((4,5-Dimethoxy-1,2phenylene)bis(methylene))bis(3-allyl-1,2-dimethoxybenzene) (14a). According to the general procedure, the reaction was performed in the presence of BF3·OEt2 (71 mg, 0.5 mmol), 5a (208 mg, 1.0 mmol) and 6a (83 mg, 0.6 mmol) in CH2Cl2 (6 mL) at 25 oC for 3 h. Purification on silica gel (hexanes/EtOAc = 3/1) afforded 14a (95%, 246 mg). Colorless solid; mp = 104-105 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for C32H38O6Na 541.2555, found 541.2556; 1H NMR (400 MHz, CDCl3): δ 6.71 (d, J = 8.4 Hz, 2H), 6.58 (d, J = 8.4 Hz, 2H), 6.51 (s, 2H), 5.89-5.80 (m, 2H), 4.91 (dq, J = 1.6, 10.0 Hz, 2H), 4.82 (dq, J = 1.6, 17.2 Hz, 2H), 3.83 (s, 6H), 3.81 (s, 6H), 3.76 (s, 4H), 3.74 (s, 6H), 3.36 (dt, J = 1.6, 6.0 Hz, 4H); 13C NMR (100 MHz, CDCl3): δ 150.9 (2x), 147.2 (2x), 147.1 (2x), 136.4 (2x), 131.8 (2x), 131.7 (2x), 130.8 (2x), 124.2 (2x), 114.7 (2x), 113.3 (2x), 110.0 (2x), 60.6 (2x), 55.7 (2x), 55.4 (2x), 34.7 (2x), 30.4 (2x). Single-crystal X-ray diagram: crystal of 14a was

14

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silica gel (hexanes/EtOAc = 3/1) afforded 14e (83%, 244 mg). grown by slow diffusion of EtOAc into a ACCEPTED solution of 14a in MANUSCRIPT Colorless gum; HRMS (ESI, M++Na) calcd for C37H46O6Na CH2Cl2 to yield colorless prisms. The compound crystallizes in the triclinic crystal system, space group P -1, a = 8.4191(8) Å, b 609.3179, found 609.3181; 1H NMR (400 MHz, CDCl3): δ 6.72 3 = 10.7663(10) Å, c = 15.3786(14) Å, V = 1348.2(2) Å , Z = 2, (d, J = 8.4 Hz, 2H), 6.60 (d, J = 8.4 Hz, 2H), 6.42 (s, 2H), 5.89dcalcd = 1.278 g/cm3, F(000) = 556, 2θ range 1.36-27.29o, R 5.80 (m, 2H), 5.88 (s, 2H), 4.90 (dq, J = 1.6, 10.0 Hz, 2H), 4.80 indices (all data) R1 = 0.1167, wR2 = 0.2450. (dq, J = 1.6, 17.2 Hz, 2H), 3.94 (t, 6.4 Hz, 4H), 3.83 (s, 6H), 3.74 (s, 4H), 3.34 (dt, J = 5.6 Hz, 4H), 1.80-1.73 (m, 4H), 1.53-1.48 4.5.2. 5,6-Bis(2-allyl-3,4(m, 4H), 0.98 (t, J = 7.6 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ dimethoxybenzyl)benzo[d][1,3]dioxole (14b). According to the 151.3 (2x), 146.8 (2x), 145.8 (2x), 136.6 (2x), 132.2 (2x), 132.1 general procedure, the reaction was performed in the presence of (2x), 131.6 (2x), 124.4 (2x), 114.7 (2x), 110.2 (2x), 109.8 (2x), BF3·OEt2 (71 mg, 0.5 mmol), 5a (208 mg, 1.0 mmol) and 6c (73 100.6, 72.9 (2x), 55.6 (2x), 35.0 (2x), 32.4 (2x), 30.7 (2x), 19.2 o mg, 0.6 mmol) in CH2Cl2 (6 mL) at 25 C for 3 h. Purification on (2x), 13.9 (2x). silica gel (hexanes/EtOAc = 3/1) afforded 14b (89%, 224 mg). + Colorless gum; HRMS (ESI, M +Na) calcd for C31H34O6Na 4.5.6. 4,4'-((4,5-Dimethoxy-1,2525.2243, found 525.2245; 1H NMR (400 MHz, CDCl3): δ 6.74 phenylene)bis(methylene))bis(3-allyl-2-(cyclopentyloxy)-1(d, J = 8.4 Hz, 2H), 6.63 (d, J = 8.4 Hz, 2H), 6.44 (s, 2H), 5.90methoxybenzene) (14f). According to the general procedure, the 5.82 (m, 2H), 5.88 (s, 2H), 4.93 (dq, J = 1.6, 10.0 Hz, 2H), 4.82 reaction was performed in the presence of BF3·OEt2 (71 mg, 0.5 mmol), 5d (262 mg, 1.0 mmol) and 6a (83 mg, 0.6 mmol) in (dq, J = 1.6, 17.2 Hz, 2H), 3.85 (s, 6H), 3.82 (s, 6H), 3.75 (s, 4H), CH2Cl2 (6 mL) at 25 oC for 3 h. Purification on silica gel 3.34 (dt, J = 1.6, 5.6 Hz, 4H); 13C NMR (100 MHz, CDCl3): δ 151.2 (2x), 147.5 (2x), 145.8 (2x), 136.6 (2x), 132.1 (2x), 132.0 (hexanes/EtOAc = 3/1) afforded 14f (90%, 282 mg). Colorless (2x), 131.6 (2x), 124.6 (2x), 114.8 (2x), 110.2 (2x), 109.8 (2x), gum; HRMS (ESI, M++Na) calcd for C40H50O6Na 649.3491, 100.6, 60.8 (2x), 55.6 (2x), 35.0 (2x), 30.5 (2x). found 649.3492; 1H NMR (400 MHz, CDCl3): δ 6.70 (d, J = 8.8 Hz, 2H), 6.56 (d, J = 8.8 Hz, 2H), 6.47 (s, 2H), 5.86-5.76 (m, 2H), 4.5.3. 4,4'-((4,5-Dimethoxy-1,24.90-4.78 (m, 6H), 3.81 (s, 6H), 3.76 (s, 4H), 3.72 (s, 6H), 3.34 phenylene)bis(methylene))bis(3-allyl-2-isopropoxy-1(d, J = 5.6 Hz, 4H), 1.90-1.78 (m, 8H), 1.75-1.69 (m, 4H), 1.62methoxybenzene) (14c). According to the general procedure, the 1.54 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 151.0 (2x), 147.0 reaction was performed in the presence of BF3·OEt2 (71 mg, 0.5 (2x), 145.3 (2x), 136.3 (2x), 132.4 (2x), 131.9 (2x), 131.1 (2x), mmol), 5b (236 mg, 1.0 mmol) and 6a (83 mg, 0.6 mmol) in 123.9 (2x), 114.7 (2x), 113.1 (2x), 110.2 (2x), 84.1 (2x), 55.7 o CH2Cl2 (6 mL) at 25 C for 3 h. Purification on silica gel (2x), 55.5 (2x), 35.0 (2x), 32.7 (4x), 30.9 (2x), 23.7 (4x). (hexanes/EtOAc = 3/1) afforded 14c (91%, 262 mg). Colorless gum; HRMS (ESI, M++Na) calcd for C36H46O6Na 597.3179, 4.5.7. 4,4'-((4,5-Dimethoxy-1,2found 597.3182; 1H NMR (400 MHz, CDCl3): δ 6.69 (d, J = 8.4 phenylene)bis(methylene))bis(3-(but-3-en-2-yl)-1,2Hz, 2H), 6.56 (d, J = 8.4 Hz, 2H), 6.47 (s, 2H), 5.86-5.76 (m, 2H), dimethoxybenzene) (14g). According to the general procedure, 4.89 (dq, J = 1.6, 10.0 Hz, 2H), 4.81 (dq, J = 2.0, 17.2 Hz, 2H), the reaction was performed in the presence of BF3·OEt2 (71 mg, 4.57-4.51 (m, 2H), 3.81 (s, 6H), 3.76 (s, 4H), 3.72 (s, 6H), 3.38 0.5 mmol), 5e (222 mg, 1.0 mmol) and 6a (83 mg, 0.6 mmol) in (dt, J = 1.6, 6.0 Hz, 4H), 1.27 (d, J = 6.4 Hz, 12H); 13C NMR CH2Cl2 (6 mL) at 25 oC for 3 h. Purification on silica gel (100 MHz, CDCl3): δ 151.2 (2x), 147.1 (2x), 145.0 (2x), 136.4 (hexanes/EtOAc = 3/1) afforded 14g (92%, 251 mg). Colorless (2x), 133.0 (2x), 131.9 (2x), 131.2 (2x), 124.0 (2x), 114.8 (2x), solid; mp = 99-100 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for C34H42O6Na 569.2867, found 113.1 (2x), 110.0 (2x), 74.3 (2x), 55.7 (2x), 55.5 (2x), 35.0 (2x), 31.1 (2x), 22.5 (4x). 569.2869; 1H NMR (400 MHz, CDCl3): δ 6.71 (d, J = 8.4 Hz, 2H), 6.63 (d, J = 8.4 Hz, 2H), 6.44 (d, J = 2.4 Hz, 2H), 6.17-6.08 4.5.4. 4,4'-((4,5-Dimethoxy-1,2(m, 2H), 4.90 (dq, J = 1.6, 10.0 Hz, 2H), 4.82-4.77 (m, 2H), 3.91phenylene)bis(methylene))bis(3-allyl-2-butoxy-13.74 (m, 6H), 3.84 (s, 6H), 3.81 (s, 6H), 3.70 (s, 6H), 1.31 (d, J = methoxybenzene) (14d). According to the general procedure, the 7.2 Hz, 3H), 1.30 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, reaction was performed in the presence of BF3·OEt2 (71 mg, 0.5 CDCl3): δ 151.6 (2x), 147.9 (2x), 147.0 (2x), 142.8 (2x), 137.79, mmol), 5c (250 mg, 1.0 mmol) and 6a (83 mg, 0.6 mmol) in 137.77, 131.1 (2x), 130.7 (2x), 125.24 (2x), 125.20 (2x), 113.4, o CH2Cl2 (6 mL) at 25 C for 3 h. Purification on silica gel 113.3, 112.7 (2x), 110.1 (2x), 60.6 (2x), 55.8 (2x), 55.5 (2x), 35.8 (hexanes/EtOAc = 3/1) afforded 14d (92%, 277 mg). Colorless (2x), 18.8 (2x). + gum; HRMS (ESI, M +Na) calcd for C38H50O6Na 625.3491, 1 4.5.8. 5,6-Bis(2-(but-3-en-2-yl)-3,4found 625.3493; H NMR (400 MHz, CDCl3): δ 6.70 (d, J = 8.4 Hz, 2H), 6.57 (d, J = 8.4 Hz, 2H), 6.49 (s, 2H), 5.89-5.79 (m, 2H), dimethoxybenzyl)benzo[d][1,3]dioxole (14h). According to the 4.90 (dq, J = 1.6, 10.0 Hz, 2H), 4.81 (dq, J = 1.6, 17.2 Hz, 2H), general procedure, the reaction was performed in the presence of 3.93 (t, J = 6.8 Hz, 4H), 3.82 (s, 6H), 3.76 (s, 4H), 3.73 (s, 6H), BF3·OEt2 (71 mg, 0.5 mmol), 5e (222 mg, 1.0 mmol) and 6c (73 3.36 (d, J = 5.6 Hz, 4H), 1.80-1.73 (m, 4H), 1.55-1.46 (m, 4H), mg, 0.6 mmol) in CH2Cl2 (6 mL) at 25 oC for 3 h. Purification on 0.97 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 151.1 silica gel (hexanes/EtOAc = 3/1) afforded 14h (85%, 226 mg). Colorless gum; HRMS (ESI, M++Na) calcd for C33H38O6Na (2x), 147.1 (2x), 146.6 (2x), 136.6 (2x), 132.0 (2x), 131.8 (2x), 131.0 (2x), 124.2 (2x), 114.7 (2x), 113.2 (2x), 110.0 (2x), 72.8 553.2555, found 553.2556; 1H NMR (400 MHz, CDCl3): δ 7.06 (2x), 55.7 (2x), 55.5 (2x), 34.8 (2x), 32.3 (2x), 30.6 (2x), 19.1 (d, J = 8.4 Hz, 2H), 6.76 (d, J = 8.4 Hz, 2H), 6.41 (s, 2H), 6.25(2x), 13.9 (2x). 6.16 (m, 2H), 5.87 (s, 2H), 5.04-4.98 (m, 4H), 4.52 (d, J = 12.0 Hz, 2H), 4.76 (d, J = 12.0 Hz, 2H), 4.03-3.94 (m, 2H), 3.85 (s, 4.5.5. 5,6-Bis(2-allyl-3-butoxy-46H), 3.80 (s, 6H), 1.43 (d, J = 7.2 Hz, 6H); 13C NMR (100 MHz, methoxybenzyl)benzo[d][1,3]dioxole (14e). According to the CDCl3): δ 152.8 (2x), 147.7 (2x), 143.2 (2x), 138.3 (2x), 132.3 general procedure, the reaction was performed in the presence of (2x), 128.9 (2x), 125.6 (2x), 119.1 (2x), 112.6 (2x), 110.2 (2x), BF3·OEt2 (71 mg, 0.5 mmol), 5c (250 mg, 1.0 mmol) and 6c (73 mg, 0.6 mmol) in CH2Cl2 (6 mL) at 25 oC for 3 h. Purification on

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calcd for C38H42O6Na 617.2867, found 617.2869; 1H NMR (400 109.9 (2x), 100.6, 70.3 (2x), 60.6 (2x), 55.6 (2x), 36.5 (2x), 19.2 MANUSCRIPT ACCEPTED (2x). MHz, CDCl3): δ 7.34-7.25 (m, 4H), 6.72 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H), 6.55 (d, J = 8.4 Hz, 4.5.9. 5,5'-((4,5-Dimethoxy-1,21H), 6.53 (s, 1H), 6.49 (s, 1H), 5.91-5.74 (m, 2H), 5.01 (s, 2H), phenylene)bis(methylene))bis(4-but-2-en-1-yl)-1,25.94.94 (dq, J = 1.6, 10.0 Hz, 1H), 4.89 (dq, J = 1.6, 10.0 Hz, dimethoxybenzene) (14i). According to the general procedure, 1H), 4.86 (dq, J = 2.0, 17.2 Hz, 1H), 4.77 (dq, J = 1.6, 17.2 Hz, the reaction was performed in the presence of BF3·OEt2 (71 mg, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3H), 3.81 (s, 3H), 3.77 (s, 0.5 mmol), 5f (222 mg, 1.0 mmol) and 6a (83 mg, 0.6 mmol) in 2H), 3.76 (s, 3H), 3.69 (s, 3H), 3.38 (dt, J = 1.6, 6.0 Hz, 2H), o CH2Cl2 (6 mL) at 25 C for 3 h. Purification on silica gel 3.27 (dt, J = 1.6, 6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ (hexanes/EtOAc = 3/1) afforded 14i (95%, 260 mg). Colorless 151.0 (2x), 147.8, 147.34, 147.32, 146.2, 137.2, 136.6, 136.5, solid; mp = 90-91 oC (recrystallized from hexanes and EtOAc); 132.0, 131.9, 131.7, 131.6, 131.4, 131.1, 128.3 (2x), 127.6, 127.4 + HRMS (ESI, M +Na) calcd for C34H42O6Na 569.2867, found (2x), 124.7, 124.3, 116.0, 114.8, 114.7, 113.9, 111.0, 110.1, 71.0, 1 569.2868; H NMR (400 MHz, CDCl3): δ 6.69 (s, 2H), 6.47 (s, 60.8 (2x), 56.0, 55.57, 55.55, 34.8, 34.6, 30.50, 30.46. 2H), 6.44 (s, 2H), 5.48-5.41 (m, 2H), 5.35-5.28 (m, 2H), 3.85 (s, 6H), 3.78 (s, 4H), 3.71 (s, 6H), 3.69 (s, 6H), 3.14 (d, J = 6.4 Hz, 4.5.13. 4,4'-((4,5-Dimethoxy-1,24H), 1.59 (d, J = 1.2, 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3): phenylene)bis(methylene))bis(1,2-dimethoxy-3-prop-1-en-1δ 147.1 (2x), 147.0 (2x), 146.9 (2x), 131.0 (2x), 130.8 (2x), 129.9 ylbenzene) (14m). According to the general procedure, the (2x), 129.3 (2x), 125.8 (2x), 112.9 (2x), 112.7 (4x), 55.7 (2x), reaction was performed in the presence of BF3·OEt2 (71 mg, 0.5 55.6 (4x), 35.6 (2x), 34.8 (2x), 17.6 (2x). mmol), 10a (208 mg, 1.0 mmol) and 6a (83 mg, 0.6 mmol) in CH2Cl2 (6 mL) at 25 oC for 3 h. Purification on silica gel 4.5.10. 4,4'-((4,5-Diisopropoxy-1,2(hexanes/EtOAc = 3/1) afforded 14m (88%, 228 mg). Colorless phenylene)bis(methylene))bis(3-allyl-1,2-dimethoxybenzene) solid; mp = 100-101 oC (recrystallized from hexanes and EtOAc); (14j). According to the general procedure, the reaction was HRMS (ESI, M++Na) calcd for C32H38O6Na 541.2555, found performed in the presence of BF3·OEt2 (71 mg, 0.5 mmol), 5a 541.2558; 1H NMR (400 MHz, CDCl3): δ 6.68 (d, J = 8.8 Hz, (208 mg, 1.0 mmol) and 6d (117 mg, 0.6 mmol) in CH2Cl2 (6 2H), 6.59 (d, J = 8.8 Hz, 2H), 6.53 (s, 2H), 6.30 (dq, J = 1.6, 16.0 mL) at 25 oC for 3 h. Purification on silica gel (hexanes/EtOAc = Hz, 2H), 6.04 (dq, J = 6.4, 16.0 Hz, 2H), 3.83 (s, 6H), 3.81 (s, 3/1) afforded 14j (92%, 264 mg). Colorless gum; HRMS (ESI, 4H), 3.75 (s, 6H), 3.74 (s, 6H), 1.84 (dd, J = 1.6, 6.4 Hz, 6H); 13C M++Na) calcd for C36H46O6Na 597.3179, found 597.3180; 1H NMR (100 MHz, CDCl3): δ 151.0 (2x), 147.0 (2x), 146.8 (2x), NMR (400 MHz, CDCl3): δ 6.71 (d, J = 8.4 Hz, 2H), 6.60 (d, J = 131.9 (2x), 131.3 (2x), 131.2 (2x), 131.1 (2x), 124.6 (2x), 124.2 8.4 Hz, 2H), 6.49 (s, 2H), 5.86-5.77 (m, 2H), 4.89 (dq, J = 1.6, (2x), 113.4 (2x), 110.3 (2x), 59.9 (2x), 55.8 (2x), 55.7 (2x), 35.8 10.4 Hz, 2H), 4.80 (dq, J = 1.6, 17.2 Hz, 2H), 4.34-4.28 (m, 2H), (2x), 19.3 (2x). Single-crystal X-ray diagram: crystal of 14m was 3.84 (s, 6H), 3.80 (s, 6H), 3.71 (s, 4H), 3.32 (dt, J = 1.6, 4.4 Hz, grown by slow diffusion of EtOAc into a solution of 14m in 13 4H), 1.24 (d, J = 6.0 Hz, 12H); C NMR (100 MHz, CDCl3): δ CH2Cl2 to yield colorless prisms. The compound crystallizes in 151.1 (2x), 147.4 (2x), 147.2 (2x), 136.6 (2x), 132.14 (2x), the triclinic crystal system, space group C 2/c, a = 26.873(11) Å, 132.09 (2x), 131.8 (2x), 124.6 (2x), 120.2 (2x), 114.8 (2x), 110.2 b = 8.423(3) Å, c = 13.594(6) Å, V = 2864(2) Å3, Z = 4, dcalcd = (2x), 72.1 (2x), 60.8 (2x), 55.6 (2x), 34.8 (2x), 30.6 (2x), 22.2 1.203 g/cm3, F(000) = 1112, 2θ range 1.63-25.55o, R indices (all (4x). data) R1 = 0.0984, wR2 = 0.1249. 4.5.11. 4,4'-((4-Isopropoxy-5-methoxy-1,24.5.14. 4,4'-((4,6-Dimethoxy-1,3phenylene)bis(methylene))bis(3-allyl-1,2-dimethoxybenzene) phenylene)bis(methylene))bis(3-allyl-1,2-dimethoxybenzene) (14k). According to the general procedure, the reaction was (14n). According to the general procedure, the reaction was performed in the presence of BF3·OEt2 (71 mg, 0.5 mmol), 5a performed in the presence of BF3·OEt2 (71 mg, 0.5 mmol), 5a (208 mg, 1.0 mmol) and 6e (100 mg, 0.6 mmol) in CH2Cl2 (6 (208 mg, 1.0 mmol) and 6g (83 mg, 0.6 mmol) in CH2Cl2 (6 mL) o mL) at 25 C for 3 h. Purification on silica gel (hexanes/EtOAc = at 25 oC for 3 h. Purification on silica gel (hexanes/EtOAc = 3/1) o 3/1) afforded 14k (94%, 257 mg). Colorless solid; mp = 78-79 C afforded 14n (95%, 246 mg). Colorless gum; HRMS (ESI, (recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) M++Na) calcd for C32H38O6Na 541.2555, found 541.2556; 1H 1 calcd for C34H42O6Na 569.2867, found 569.2868; H NMR (400 NMR (400 MHz, CDCl3): δ 6.69 (dd, J = 8.4, 11.6 Hz, 4H), 6.51 MHz, CDCl3): δ 6.72 (d, J = 8.4 Hz, 2H), 6.61 (d, J = 8.4 Hz, (s, 1H), 6.48 (s, 1H), 5.97-5.87 (m, 2H), 4.98 (dq, J = 1.6, 10.0 1H), 6.60 (d, J = 8.4 Hz, 1H), 6.51 (s, 1H), 6.50 (s, 1H), 5.90Hz, 2H), 4.93 (dq, J = 1.6, 16.8 Hz, 2H), 3.85 (s, 12H), 3.81 (s, 5.78 (m, 2H), 4.93-4.89 (m, 2H), 4.85-4.79 (m, 2H), 4.38-4.32 6H), 3.80 (s, 4H), 3.41 (dt, J = 1.6, 5.6 Hz, 4H); 13C NMR (100 (m, 1H), 3.84 (br s, 6H), 3.82 (s, 3H), 3.81 (s, 3H), 3.76 (s, 2H), MHz, CDCl3): δ 156.4 (2x), 150.7 (2x), 147.2 (2x), 136.9 (2x), 3.73 (s, 2H), 3.72 (s, 3H), 3.37-3.33 (m, 4H), 1.28 (d, J = 6.0 Hz, 132.4 (2x), 131.9 (2x), 131.5 (2x), 124.7 (2x), 120.6, 114.6 (2x), 13 6H); C NMR (100 MHz, CDCl3): δ 151.0 (2x), 148.6, 147.3, 110.0 (2x), 95.1, 60.6 (2x), 55.6 (2x), 55.5 (2x), 31.2 (2x), 30.4 147.2, 145.2, 136.5 (2x), 131.9, 131.8, 131.7, 131.4, 130.9, 124.5 (2x). (2x), 124.3 (2x), 118.0, 114.73, 114.70, 114.0, 110.04, 109.99, 71.2, 60.7, 55.9, 55.49, 55.47, 34.8, 34.6, 30.5, 30.4, 21.9 (2x). 4.5.15. 4,4'-((4,6-Dimethoxy-1,3phenylene)bis(methylene))bis(3-(but-3-en-2-yl)-1,24.5.12. 4,4'-((4-(Benzyloxy)-5-methoxy-1,2dimethoxybenzene) (14o). According to the general procedure, phenylene)bis(methylene))bis(3-allyl-1,2-dimethoxybenzene) the reaction was performed in the presence of BF3·OEt2 (71 mg, (14l). According to the general procedure, the reaction was 0.5 mmol), 5e (222 mg, 1.0 mmol) and 6g (83 mg, 0.6 mmol) in performed in the presence of BF3·OEt2 (71 mg, 0.5 mmol), 5a CH2Cl2 (6 mL) at 25 oC for 3 h. Purification on silica gel (208 mg, 1.0 mmol) and 6f (129 mg, 0.6 mmol) in CH2Cl2 (6 (hexanes/EtOAc = 3/1) afforded 14o (94%, 257 mg). Colorless mL) at 25 oC for 3 h. Purification on silica gel (hexanes/EtOAc = gum; HRMS (ESI, M++Na) calcd for C34H42O6Na 569.2867, o 3/1) afforded 14l (91%, 271 mg). Colorless solid; mp = 79-80 C found 569.2868; 1H NMR (400 MHz, CDCl3): δ 6.63 (br s, 4H), (recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na) 6.48 (s, 1H), 6.31 (s, 1H), 6.09-6.00 (m, 2H), 4.89-4.81 (m, 4H),

16

Tetrahedron

(6) (a) Furstner, A.; Thiel, O. R. J. Org. Chem. 2000, 65, 1738-1742. (b) 3.84 (s, 6H), 3.80 (s, 6H), 3.79-3.76 (m, 6H), 3.75 (s, 6H), MANUSCRIPT ACCEPTED Michaut, A.; Rodriguez, J. Angew. Chem., Int. Ed. 2006, 45, 5740-5750. 1.23 (d, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 156.0 (c) Arican, D.; Bruckner, R. Org. Lett. 2013, 15, 2582-2585. (2x), 151.3 (2x), 147.8 (2x), 143.3 (2x), 137.7 (2x), 131.5 (2x), (7) (a) Tietze, L. F.; Hungerland, T.; Depken, C.; Maab, C.; Stalkeb, D. 131.4 (2x), 125.6 (2x), 121.1, 112.2 (2x), 110.1 (2x), 94.9, 60.5 Synlett 2012, 23, 2516-2520. (b) Julia-Hernandez, F.; Ziadi, A.; (2x), 55.7 (2x), 55.5 (2x), 36.8 (2x), 32.0 (2x), 18.7 (2x). Nishimura, A.; Martin, R. Angew. Chem., Int. Ed. 2015, 54, 9537-9541.

We thank for the Ministry of Science and Technology of the Republic of China for financial support (MOST 105-2113-M037-001). (9)

References and notes

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Supplementary Material Scanned photocopies of spectral data and crystallographic data of compounds 1l, 1p, 13a, 14a and 14m were supported.

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