Total Synthesis of Dendrochrysanene through a Frame

Article pubs.acs.org/joc

Cite This: J. Org. Chem. 2017, 82, 11573-11584

Total Synthesis of Dendrochrysanene through a Frame Rearrangement Naoki Katsuki,† Shumpei Isshiki,† Daisuke Fukatsu,‡ Juan Okamura,† Kouji Kuramochi,†,§ Takeo Kawabata,‡ and Kazunori Tsubaki*,† †

Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Shimogamo, Sakyo-ku, Kyoto 606-8522, Japan Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan § Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan ‡

S Supporting Information *

ABSTRACT: The first total synthesis of dendrochrysanene (1) was achieved. The key reaction for the construction of dendrochrysanene was an oxidative frame rearrangement reaction from a phenanthrene dimer to a spiro-lactone skeleton, which we serendipitously identified. Owing to the steric hindrance of the substituent on the peri position of the phenanthrene dimer, high-temperature conditions were required for the rearrangement reaction; however, at such temperatures, the substrate decomposed. To address this issue, we added phenylethylamine or benzylamine to the reaction system. We assumed that the amine trapped generated hydrochloric acid and acted as a ligand for iron, helping to maintain an appropriate redox potential. The total synthesis of dendrochrysanene, involving this rearrangement reaction, is an important sequence interlinking phenanthrene derivatives, phenanthrene dimers, and spiro-lactone compounds, which are frequently isolated from plants of Orchidaceae.

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INTRODUCTION Dendrochrysanene (1) is a natural product isolated from the Dendrobium chrysanthum by Wang and co-workers in 2006.1 The structure was determined by X-ray analysis, which revealed a spiro-lactone skeleton composed of two poly oxygenated aromatic (phenanthrene and naphthalene) rings. X-ray analysis showed that the absolute configuration of the quaternary spirocenter in dendrochrysanene (1) is racemic with a space group (C2/c). Three types of compounds, phenanthrenes,2 phenanthrene dimers,3 and spiro-compounds,1,4 are frequently isolated from the Orchidaceae family (Figure 1). Taking into account prospective biosynthetic pathways, the phenanthrene dimers should be accessible by oxidative dimerization of the corresponding phenanthrene monomers.5 However, owing to the large difference of frameworks of spiro-compounds, it is hard to see how the spiro-skeletons are related to phenanthrene monomers and dimers. We previously reported a one-pot construction of spirocompounds through tandem dimerization of 2-naphthols (2) and oxidative rearrangement of binaphthols (3) with FeCl3· 6H2O in dichloromethane (Scheme 1).6,7 Comparing the natural products isolated from the Orchidaceae family shown in Figure 1 with the sequence of reactions shown in Scheme 1, it is assumed that the three types of compounds are closely related and could be made using the same rearrangement reaction. We propose that dendrochrysa© 2017 American Chemical Society

nene (1) could be synthesized by the rearrangement of the corresponding phenanthrene dimer derived from coupling the phenanthrene monomer. We, therefore, investigated the total synthesis of dendrochrysanene (1) using this rearrangement as the key reaction.

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RESULTS AND DISCUSSION

Retrosynthetic Analysis. On the basis of the putative biosynthetic pathway, the synthetic route for dendrochrysanene (1) was envisaged using oxidative dimerization of phenanthrene monomer B followed by rearrangement of A in the final stage (Scheme 2). Direct Route. Initially, we investigated whether the rearrangement would proceed on simple binaphthols possessing methoxy groups in the peri position. The dimerization of compound 6 and the subsequent rearrangement reaction was therefore studied (Scheme 3). The oxidative dimerization was examined using 1-methoxy-7naphthol (6),8 derived from commercially available 1,7dihydroxynaphthalene (5). Although compound 6 decomposed under the our previously reported6 coupling conditions (FeCl3· 6H2O, CH2Cl2, reflux), the desired dimer 7 was obtained in 56% yield using the alternative conditions of Cu(NO3)2·3H2O, 1Received: September 4, 2017 Published: October 2, 2017 11573

DOI: 10.1021/acs.joc.7b02223 J. Org. Chem. 2017, 82, 11573−11584

Article

The Journal of Organic Chemistry

Scheme 3. Oxidative Coupling of 6 and Rearrangement Reaction of 7

desired compound 8 was formed, albeit in a low yield in the model study, and so we proceeded with the synthesis of the phenanthrene skeletons. The target phenanthrene dimer 16 was synthesized following the route outlined in Scheme 4. Compound 10, which was synthesized in two steps from commercially available 2,7Figure 1. Natural products isolated from the Orchidaceae sp.

Scheme 4. Synthesis of Phenanthrene Dimer 16

Scheme 1. Key Rearrangement of 2-Naphthol (2)6

Scheme 2. Retrosynthetic Analysis of Dendrochrysanene (1)

phenylethylamine, and MeOH/CH2Cl2.9 The rearrangement of compound 7 was attempted using the FeCl3·6H2O and CH2Cl2 conditions, but the desired spiro-compound 8 was only afforded in 6% yield at 30 °C at atmospheric pressure and in 9% yield at 30 °C under 9.5 MPa of nitrogen gas using a cylinder. These data indicate that methoxy groups at the peri position act as a significant steric barrier to the rearrangement. Nonetheless, the 11574


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of the bromines in compound C to methoxy groups at the final stage. Compound C would be formed from the rearrangement of D, which is a dimer of phenanthrene E. The bromophenanthrene is synthesized through cyclization of biphenyl bromo-acetylene F. The key bromo-acetylenes 24a−c were constructed as depicted in Scheme 6. Coupling of known compound 1815

dihydroxynaphthalene (9) according to a literature procedure,10 was treated with n-BuLi and trapped with B(OMe)3, followed by 1 M HCl to afford boric acid 11 in 78% yield. Suzuki coupling between boric acid 11 and bromide 1211 (1.3 equiv) with Pd(PPh3)4 and K2CO3 in DME afforded the phenanthrene precursor 13 in 50% yield.12 Compound 13 was converted to the desired phenanthrene 14 through consecutive deprotection of the acetonide group, Friedel−Crafts cyclization in the presence of methanesulfonic acid. The two hydroxy groups in the resulting intermediate were then protected as pivaloyl groups to afford phenanthrene 14 in 34% yield over three steps. The less hindered pivaloyl group of compound 14 was selectively removed by K2CO3 to give coupling precursor 15 in 75% yield.13 The oxidative dimerization of compound 15 proceeded smoothly to afford the desired phenanthrene dimer 16 in a quantitative yield.9 Finally, the key rearrangement reaction using dimer 16 was attempted; however, no desired product 17 was obtained under the following conditions: (1) FeCl3·6H2O (4 equiv), CH2Cl2, reflux, (2) FeCl3·6H2O (4 equiv), CHCl3, reflux, (3) FeCl3·6H2O (4 equiv), toluene, 60 °C, (4) FeCl3·6H2O (2 equiv), CH2Cl2, room temperature. These conditions gave a complicated and/or decomposed mixture, and none of the target compound 17 was observed. These data clearly indicate that the methoxy group at the peri position inhibits the rearrangement, and harsh reaction conditions merely lead to decomposition of 16. Therefore, we reconsidered the synthetic route and swapped the bulky methoxy group to a smaller functional group. Bromo Route. We instead chose bromine as a functional group handle at the peri position. The A-values of a methoxy group and bromine were estimated to be 0.6 and 0.48, respectively.14 The retrosynthetic route is shown in Scheme 5. Dendrochrysanene (1) would be constructed by the conversion

Scheme 6. Synthetic Route for Compounds 24a−c

Scheme 5. Retrosynthetic Analysis of Dendrochrysanene (1) via Bromide C

with resorcinol (19) afforded compound 20 in 68% yield.16 Protecting the hydroxyl group of 20 with a methoxymethyl group and reducing the central lactone part with LiAlH4 gave 21 in a quantitative yield over two steps. The resulting phenolic hydroxyl group was selectively protected with a methyl group, and the benzylic hydroxyl group was oxidized to a formyl group using manganese dioxide to give compound 22 in 91% yield over two steps. The formyl group of compound 22 was converted to an acetylene using the Ohira−Bestmann reagent to afford compound 23 in 97% yield.17 The terminal hydrogen of the acetylene moiety was abstracted by n-BuLi and treated with 1,2-dibromotetrachloroethane to obtain desired bromoacetylene 24a in 91% yield. To attempt the phenanthrene construction, the MOM group of 24a was converted to a pivaloyl group (compound 24b) via the free hydroxy group (compound 24c). There are many examples of the construction of phenanthrenes from biphenyl acetylenes through activation of the triple bond by transition metals such as In and Pt.18 We attempted a range of conditions for the synthesis of phenanthrenes (Table 1). When InCl3 was used as the Lewis acid, a complicated 11575


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The Journal of Organic Chemistry Table 1. Optimization of the Cyclization of 24

entry substrate 1 2 3 4 5 6 a

24a 24a 24b 24b 24c 24c

Scheme 7. Proposed Mechanism of Cyclization of 24

catalyst

phenanthrene yield (%)a

spirocycle 26 yield (%)a

lnCl3 PtCl2 lnCl3 PtCl2 lnCl3 PtCl2

NDb 25a, 9 NDb 25b, 63 NDb NDb

NDb 49 83 NDb 82 72

Isolated yield. bNot detected.

mixture was obtained, at least in part owing to elimination of the MOM group (entry 1). In the case of PtCl2, spiro-compound 26 was obtained via a 5-endo-dig cyclization (49% yield) along with a small amount of phenanthrene 25a through a 6-endo-dig cyclization (9% yield, entry 2). To our surprise, the bromine had migrated from the 10-position to the 9-position.19 To prevent the ipso-cyclization, the MOM group was changed to a pivaloyl group to reduce the electron density at the ipso position. Starting from compound 24b, the two branches of the reaction pathway could be switched by using different types of catalysts. Thus, 25b was preferentially obtained with PtCl2 (63% yield); however, spiro-compound 26 was afforded with InCl3 (83% yield) (entries 3 and 4). Compound 24c, with a free hydroxy group, was transformed to spiro-compound 26 with both InCl3 (82% yield) and PtCl2 (72% yield, entries 5 and 6). The postulated mechanism for this reaction is shown in Scheme 7.19,20 In the case of InCl3, the triple bond was highly activated by the soft, trivalent indium, and 5-endo-dig cyclization from the ipso position of the reactive benzene ring proceeded faster than the other pathways discussed later. As a result, spirocompound 26 was isolated as the main product. However, in the case of PtCl2, the triple bond was only moderately activated by PtCl2. Therefore, if the electron density of the ipso position was sufficient to react (24a and 24c), the 5-endo-dig cyclization predominated, and if not, the other pathways occurred faster to afford the product derived from 6-exo cyclization at the ortho position. The bromine migration may occur via a two-step sequence. The first step involves a 1,2-halide migration to afford intermediate J followed by 6-exo-dig cyclization. The second step involves the bromonium ion M. The usual 6-endo-dig cyclization from the ortho position would take place to form K, and then the proton at the bridgehead position would shift to the vicinal position with rearomatization as the driving force to form L. After the generation of bromonium ion M, compound 25 would be generated by elimination of Pt and bromonium ion opening. Although the position of bromine was incorrect for the target compound, using compound 25b as a model substrate confirmed that the desired dimerization and subsequent rearrangement reaction proceeded (Scheme 8). The pivaloyl

Scheme 8. Synthesis of Spiro-Compound 29

group of compound 25b was removed to afford compound 27 in 92% yield. The oxidative dimerization of 27 proceeded smoothly to afford compound 28 in a quantitative yield. Then, the rearrangement reaction with FeCl3·6H2O at 30 °C afforded the spiro-compound 29 in 92% yield. As described above for the cyclization of bromoacetylene 24, the bromine unexpectedly moved to the vicinal position; therefore, in order to obtain compound E (Scheme 5) with the bromine at the desired position, it was necessary to go via compound N and then introduce a bromo acetylene group to the opposite benzene ring (Scheme 9). Cyclization precursor 35 was synthesized following the synthetic route shown in Scheme 10. According to the procedures described in literature, the coupling partners 3021 and 3122 were obtained from commercially available 4bromophenol and 3,5-dihydroxybenzoic acid in 2 steps (78% overall yield) and 5 steps (in 57% overall yield), respectively. 11576


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The Journal of Organic Chemistry Scheme 9. Retrosynthetic Analysis of Phenanthrene E

Table 2. Coupling and Rearrangement Reaction of 37

Scheme 10. Synthesis of Phenanthrene 37

entry

conditions

solvent

temperature (°C)

yield (%)a

MeOH/CH2Cl2

0 to rt

b

MeOH/CH2Cl2

0 to rt

3 4

Cu(NO3)2·3H2O, 1-phenylethylamine Cu(NO3)2·3H2O, i-PrNH2 CuCl2, i-PrNH2 FeCl3·6H2O

MeOH/CH2Cl2 CH2Cl2

0 to rt rt to reflux

5 6

FeCl3·6H2O FeCl3·6H2O

toluene CHCl3

30−60 30−50

37, 55c b 39, trace 39, 14 39, 38

1 2

a Isolated yield. bA mixture of dimeric compounds. cThe starting material 46 was recovered.

The pivaloyl group of 39 was smoothly deprotected under the K2CO3/MeOH conditions, and the resulting two isopropyl groups were removed with BBr3 (20 equiv) at 0 °C to afford the desired compound 40 in 76% yield over two steps (Scheme 11). Scheme 11. Synthesis of Spiro-Compound 40

Compound 32 was synthesized by Suzuki coupling in a quantitative yield, and the formyl group of 32 was converted to acetylene 33 in 90% yield using the Ohira−Bestmann reagent. The terminal acetylene group was then transformed to bromo acetylene 34 using the NBS/AgNO3 conditions in a quantitative yield. Finally, the two MOM groups of 34 were converted to pivaloyl groups to afford cyclization precursor 35 in 93% yield. The cyclization of compound 35 was then examined. No reaction occurred when InCl3 was used as the catalyst, even at 80 °C. The desired bromine-migrated compound 36 was obtained in 35% yield using PtCl2 as the catalyst. Final selective deprotection of the less-hindered pivaloyl group of 36 afforded compound 37 in 48% yield. Next, the oxidative dimerization of compound 37 was studied (Table 2). The combination of Cu(NO3)2 and amines, the optimal conditions for oxidative coupling through a series of our previous investigations, was not effective in this case (entries 1− 3).9 However, when FeCl3·6H2O was used as the oxidant, both the coupling and the rearrangement reactions proceeded, and spiro-compound 39 was directly obtained in 14% yield in toluene (entry 5) and 38% yield in chloroform (entry 6).

To complete the synthesis of dendrochrysanene (1), all that remained was to convert the two bromines of compound 40 to methoxy groups (Table 3). However, the standard procedure for converting the bromine to a methoxy group using Cu(I) and NaOMe resulted in decomposed products (entries 1 and 2), and a reported method that is applicable to a hindered reaction site was not effective for compound 40 (entries 3 and 4).23,24 Table 3. Attempts to Introduce a Methyl Group to Compound 40 entry

conditions

solvent

temperature (°C)

results

1 2 3 4

CuBr, NaOMe CuCl, NaOMe Pd(PPh3)4, Na2C03 Pd(dba)2, Na2C03

DMF DMF THF/MeOH THF/MeOH

120 120 rt to 50 rt to reflux

decomp decomp NDa NDa

a

Dendrochrysanene (1) could not be detected from the reaction mixture by NMR. 11577


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The Journal of Organic Chemistry Table 4. Optimization of the Synthesis of 17

entry 1 2 3 4 5 6 7 8 9 10 a

additive (equiv)

solvent

temperature (°C)

resultsa

1-phenylethylamine (4.0) 1-phenylethylamine (4.0) 1-phenylethylamine (1.0) 1-phenylethylamine (8.0) 1-phenylethylamine (16.0) 1-phenylethylamine (32.0) benzylamine (4.0) Et3N (4.0) (R)-L-phenylethylamine (4.0)

CHCl3 CHCl3 toluene toluene toluene toluene toluene toluene toluene toluene

rt to 50 rt to reflux rt to 100 rt to 100 rt to 100 rt to 100 rt to 100 80 rt to 100 rt to 100

demethylated substratesb 15/16 = 10:3 17, 26% NDc NDc NRd NRd 17, 17% NRd 17, 24% (9% ee)

Isolated yield. bA mixture of demethylated 15 was obtained. cNot detected. dNo reaction.

Return to the Original Route. As described above, the final step in constructing dendrochrysanene (1) from the key bromoderivative 40 was not successful. Therefore, we reviewed all the synthetic routes again to look for any further opportunities. We realized that the direct transformation from methoxy-phenanthrene monomer 15 to spiro-compound 17 via the methoxyphenanthrene dimer had not yet been attempted. Consecutive coupling and rearrangement reactions from methoxy-phenanthrene monomer 15 to the spiro-compound were thoroughly investigated (Table 4). Initially, phenanthrene monomer 15 was treated with FeCl3·6H2O in chloroform at 50 °C. The NMR of the reaction residue indicated that a compound missing the methoxy group of 15 may be present among the complex signals (entry 1). Because it was thought that the demethylation was caused by the generated hydrochloric acid, 1-phenylethylamine was added to the reaction mixture to trap the acid in situ. In the presence of 1-phenylethylamine (4 equiv), a large portion of starting material 15 was recovered, and the coupled compound 16 was confirmed by NMR (15/16 = 10:3) under refluxing chloroform conditions. The undesired demethylation and degradation products were not detected (entry 2). A high reaction temperature should be necessary to drive the rearrangement, and we know that this rearrangement reaction only proceeds in dichloromethane, chloroform, and toluene; thus, toluene was selected because it has the highest boiling point. When 1-phenylethylamine (4 equiv) was added and the temperature was raised to 100 °C, the rearrangement reaction proceeded to afford desired spiro-compound 17 in 26% yield (entry 3). With regard to the amount of amine, the addition of 1 and 8 equiv of 1-phenylethylamine lead to a complicated mixture and the target spiro-compound was not obtained (entries 4 and 5). Furthermore, in the presence of a large excess amount of 1-phenylethylamine (16 and 32 equiv), no reaction was observed and starting 15 was recovered (entries 6 and 7). The rearrangement reaction was also investigated using amines other than 1-phenylethylamine. When benzylamine was used, the reaction proceeded at 80 °C, and desired spiro-compound

17 was obtained in 17% yield (entry 8). In the cases of dipropylamine and diisopropylamine, a small amount of compound 17 was observed by TLC analysis (not shown). With triethylamine (4 equiv), the rearrangement reaction did not proceed, even when the temperature was raised to 100 °C. We also studied the transformation in the presence of chiral 1phenylethylamine. Using (R)-1-phenylethylamine, 17 was obtained in a 24% yield with 9% ee. This demonstrated that the amine acted as not only a base for trapping with the generated HCl but also a ligand for Fe, which adjusted the redox potential of the complex. With the optimized conditions for the conversion of monomer 15 to spiro-compound 17 in hand, we applied these conditions to the transformation of dimer 16 to spirocompound 17 (Scheme 12). The dimer 16 was treated with Scheme 12. Synthesis of Dendrochrysanene (1)

FeCl3·6H2O (4 equiv) and 1-phenylethyl amine (4 equiv) in toluene at 100 °C to afford desired spiro-compound 17 in 45% yield. Finally, the two exposed methyl groups as well as the pivaloyl group were removed using BBr3 (20 equiv) to accomplish the first total synthesis of dendrochrysanene (1) in 65% yield. 11578


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(EI+ double-focusing magnetic sector) calcd for C22H16O4 [M]+ 344.1049, found 344.1044. Compound 11. A solution of n-BuLi (1.63 M n-hexane solution; 2.2 mL, 3.59 mmol) was added in a dropwise manner to a solution of compound 10 (800 mg, 3.00 mmol) in dry THF (8 mL) under an atmosphere of N2 at −78 °C. After stirring the mixture for 2 h, B(OMe)3 (840 μL, 7.49 mmol) was added to the reaction mixture in a dropwise manner, and the resulting mixture was stirred at 0 °C for 13.5 h. A 1 M hydrochloric acid solution was added to the solution, and the reaction mixture was stirred for 40 min at room temperature. The resulting mixture was extracted with ethyl acetate. The extract was backextracted with a 1 M sodium hydroxide solution, and the aqueous layer was returned to acidic with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with water and brine. After being dried over sodium sulfate, the solvent was evaporated in vacuo to give compound 11 as a white solid (542 mg 78%). Compound 11: white solid; mp >300 °C; IR (KBr) 3467, 3367, 3005, 2960, 1626, 1473, 1415, 1335, 1213, 1045, 860, 783 cm−1; 1H NMR (270 MHz, CDCl3) δ 8.30 (s, 1H), 7.73 (d, J = 8.9 Hz, 1H), 7.07 (s, 1H), 7.05 (d, J = 2.4 Hz, 1H), 7.02 (dd, J = 8.6, 2.4 Hz, 1H), 5.89 (s, 2H), 4.01 (s, 3H), 3.92 (s, 3H); 13C NMR (68 MHz, DMSO-d6) δ 161.1, 158.1, 136.9, 136.1, 129.5, 123.4, 115.7, 105.0, 103.8, 55.2, 55.1 (one peak overlapped); HRMS (EI+ double-focusing magnetic sector) calcd for C12H13O411B [M]+ 232.0909, found 232.0912. Compound 13. Compound 11 (30.0 mg, 0.13 mmol), compound 12 (37.0 mg, 0.17 mmol), potassium carbonate (31.0 mg, 0.22 mmol), and tetrakis(triphenylphosphine)palladium (13.0 mg, 0.01 mmol) were resolved in DME (2 mL), and the mixture was stirred at 50 °C for 2 days under a N2 atmosphere. The reaction mixture was subsequently quenched by the addition of a 1 M hydrochloric acid solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated to give a residue. The resulting residue was purified by column chromatography (SiO2, n-hexane/ethyl acetate = 5:1) to afford compound 13 (21.2 mg, 50%) as a yellow solid. Compound 13: yellow solid; mp 110−111 °C; IR (KBr) 3008, 2941, 1724, 1635, 1392, 1292, 1230, 1200, 1142, 1111, 1009, 847, 804 cm−1; 1 H NMR (270 MHz, CDCl3) δ 7.61 (d, J = 8.6 Hz, 1H), 7.52 (s, 1H), 7.06 (d, J = 2.5 Hz, 1H), 7.04 (s, 1H), 7.01 (dd, J = 8.6, 2.5 Hz, 1H), 5.11 (s, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 3.62 (s, 2H), 1.63 (s, 6H); 13C NMR (68 MHz, CDCl3) δ 170.7, 161.5, 158.0, 156.1, 135.3, 129.9, 128.7, 123.7, 121.5, 116.3, 106.4, 104.9, 104.6, 93.6, 55.4, 55.3, 34.9, 24.9; HRMS (EI+ double-focusing magnetic sector) calcd for C19H20O5 [M]+ 328.1311, found 328.1311. Compound 14. Compound 13 (941.0 mg, 2.87 mmol) was dissolved in methanesulfonic acid (28 mL). After stirring at room temperature for 3 h, the solution was stirred at 50 °C for 6 h. The reaction mixture was subsequently quenched by the addition of ice water, and a brown precipitate formed that was collected by filtration. The residue was dissolved in CH2Cl2 (28 mL). Triethylamine (0.87 mL, 6.30 mmol) and pivaloyl chloride (0.78 mL, 6.30 mmol) were added to the solution, and the mixture was stirred for 3 h at room temperature. The reaction mixture was subsequently quenched by the addition of a 1 M hydrochloric acid solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated to give a residue. The resulting residue was purified by column chromatography (SiO2, n-hexane/ethyl acetate = 6:1) to afford compound 14 (428 mg, 34%) as a yellow solid. Compound 14: yellow solid; mp 170−171 °C; IR (KBr) 3506, 3496, 2974, 2937, 1753, 1618, 1473, 1390, 1240, 1105, 1039, 868 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.87 (d, J = 9.2 Hz, 1H), 7.98 (d, J = 2.8 Hz, 1H), 7.13 (d, J = 2.8 Hz, 1H), 7.04−7.00 (m, 2H), 6.90 (s, 1H), 4.03 (s, 3H), 3.92 (s, 3H), 1.52 (s, 9H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 176.9, 176.8, 158.2, 153.1, 148.9, 147.8, 135.1, 128.3, 127.9, 122.7, 119.1, 116.7, 113.7, 112.5, 108.3, 103.3, 55.5, 55.3, 39.5, 39.2, 27.3, 27.2; HRMS (ESI+ double-focusing magnetic sector) calcd for C26H30O6Na [M + Na]+ 461.1935, found 461.1938. Compound 15. Potassium carbonate (35.0 mg, 0.253 mmol) was added to a solution of compound 14 (111.0 mg, 0.253 mmol) in a

CONCLUSION We completed the first total synthesis of dendrochrysanene using a key rearrangement reaction from binaphthol to spirocompound that was previously reported by our group.6 Rearrangement reactions of phenanthrene derivatives with bulky substituents required the addition of benzylamine and phenylethylamine as well as high temperatures. The addition of these amines not only prevented the acidic degradation of the substrates but also adjusted the redox potential of the surrounding metal. In addition, chiral phenylethylamine induced some enantioselectivity at the quaternary spiro-carbon. This indicates it should be possible to develop asymmetric rearrangement reactions. Many phenanthrenes and phenanthrene dimers have been reported in natural products isolated from the Orchidaceae family, but as far as we know, the corresponding spiro-skeleton is only found in two compounds (dendrochrysanene and blespirol). We postulate that the synthetic route for dendrochrysanene, that is spiro-compounds from naphthols via dimeric derivatives, mimics the biosynthetic pathways. Therefore, many spiro-compounds related to this rearrangement reaction may be present as structure-undetermined materials in isolated natural products, and we hope that this research may help to identify some of these remaining spiro natural products. We are also investigating the total synthesis of blespirol using this rearrangement as a key reaction, and this will be reported in due course.

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EXPERIMENTAL SECTION

Compound 7. To a stirred solution of copper(II) nitrate trihydrate (123 mg, 0.51 mmol) in MeOH (0.5 mL) cooled in an ice bath was added 1-phenylethylamine (158 μL, 1.23 mmol) portionwise under a N2 atmosphere. After 1 h, a solution of compound 6 (35.6 mg, 0.20 mmol) in CH2Cl2 (0.5 mL) was added, and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was subsequently quenched by the addition of a 1 M hydrochloric acid solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate, and evaporated to give a residue. The resulting residue was purified by column chromatography (SiO2, n-hexane/ethyl acetate = 7:1) to afford compound 7 (19.7 mg, 56%) as a green solid. Compound 7: green solid; mp 191−192 °C; IR (KBr) 3479, 1599, 1577, 1518, 1462, 1431, 1340, 1259, 1157, 1107, 829, 756 cm−1; 1H NMR (270 MHz, CDCl3) δ 7.81 (d, J = 8.6 Hz, 2H), 7.44 (dd, J = 8.1, 1.1 Hz, 2H), 7.29 (d, J = 8.6 Hz, 2H), 7.23 (t, J = 8.1 Hz, 2H), 6.67 (dd, J = 8.1, 1.1 Hz, 2H), 5.08 (s, 2H), 3.14 (s, 6H); 13C NMR (68 MHz, CDCl3) δ 156.1, 151.2, 130.9, 130.0, 125.4, 123.4, 121.1, 117.1, 113.3, 107.0, 55.9; HRMS (EI+ double-focusing magnetic sector) calcd for C22H18O4 [M]+ 346.1205, found 346.1201. Compound 8. A mixture of compound 7 (59.3 mg, 0.17 mmol) and iron(III) chloride hexahydrate (370 mg, 1.37 mmol) in CH2Cl2 (30 mL) was heated at 30 °C while stirring in an autoclave under N2 (9.5 MPa) for 14 h. The reaction mixture was subsequently quenched by the addition of water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated to give a residue. The resulting residue was purified by column chromatography (SiO2, n-hexane/ethyl acetate = 6:1) to afford compound 8 (6.7 mg, 9%) as a yellow foam. Compound 8: yellow foam; IR (KBr) 2933, 2839, 1799, 1601, 1525, 1464, 1273, 1109, 993, 964, 825, 756 cm−1; 1H NMR (270 MHz, CDCl3) δ 7.85 (d, J = 8.9 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.40 (dd, J = 8.1, 0.8 Hz, 1H), 7.29 (dd, J = 8.1, 7.6 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 7.13 (dd, J = 7.6, 0.8 Hz, 1H), 7.11 (d, J = 5.4 Hz, 1H), 6.65 (d, J = 8.1 Hz, 1H), 6.60 (dd, J = 8.1, 0.8 Hz, 1H), 6.33 (d, J = 5.4 Hz, 1H), 3.46 (s, 3H), 3.17 (s, 3H); 13C NMR (68 MHz, CDCl3) δ 175.1, 154.8, 154.4, 152.8, 146.7, 137.3, 134.3, 133.2, 132.6, 130.0, 129.5, 124.5, 122.9, 120.8, 117.8, 114.4, 112.2, 109.3, 105.6, 64.2, 55.5, 53.4; HRMS 11579


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Compound SI-1: white solid; mp 70−71 °C; IR (KBr) 3741, 3651, 3084, 2978, 1730, 1620, 1481, 1315, 1277, 1163, 1026, 943 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 2.8 Hz, 1H), 7.35 (dd, J = 8.8, 2.8 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 7.02 (dd, J = 8.8, 2.4 Hz, 1H), 5.24 (s, 2H), 4.72 (sep, J = 6.0 Hz, 1H), 3.51 (s, 3H), 1.40 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 161.6, 158.0, 157.7, 151.4, 128.0, 125.7, 123.1, 123.0, 121.2, 113.4, 112.9, 112.5, 104.7, 94.5, 70.5, 56.3, 21.9; HRMS (ESI+ double-focusing magnetic sector) calcd for C18H18O5Na [M + Na]+ 337.1046, found 337.1055. Compound 21. To a stirred solution of compound SI-1 (2.04 g, 6.49 mmol) in dry THF (60 mL) cooled in ice bath was added lithium aluminum hydride (542 mg, 14.3 mmol) under a N2 atmosphere. After stirring at 0 °C for 2 h, the reaction mixture was subsequently quenched by the addition of ethyl acetate. The organic layer was washed successively with water and brine. After being dried over sodium sulfate, the solvent was evaporated in vacuo to give compound 21 as a yellow solid (2.23 g, quant). Compound 21: yellow solid; mp 91−92 °C; IR (KBr) 3649, 3398, 3192, 2979, 1610, 1491, 1431, 1284, 1254, 995, 847 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 1.6 Hz, 1H), 6.99 (d, J = 9.2 Hz, 1H), 6.88 (dd, J = 8.4, 2.4 Hz, 1H), 6.65−6.63 (m, 2H), 5.16 (s, 2H), 4.59 (sep, J = 6.0 Hz, 1H), 4.42−4.40 (m, 2H), 3.49 (s, 3H), 1.35 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 157.90, 157.87, 154.1, 140.5, 132.3, 131.7, 127.9, 121.1, 116.1, 115.5, 108.6, 104.0, 94.3, 70.0, 63.8, 56.1, 22.1; HRMS (ESI+ double-focusing magnetic sector) calcd for C18H22O5Na [M + Na]+ 341.1359, found 341.1352. Compound SI-2. Compound 21 (2.23 g, 7.01 mmol) was dissolved in DMF (70 mL), and potassium carbonate (1.06 g, 7.71 mmol) and iodomethane (480 μL, 7.71 mmol) were added. The reaction mixture was stirred for 9 h at room temperature. The reaction mixture was subsequently quenched by the addition of a 1 M hydrochloric acid solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate, and evaporated to give compound SI-2 as a brown oil (2.44 g, quant). Compound SI-2: brown oil; IR (neat) 3442, 2976, 2935, 1606, 1487, 1462, 1281, 1157, 1078, 1020, 926, 835 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.09−7.04 (m, 3H), 6.85 (dd, J = 8.4, 2.4 Hz, 1H), 6.70 (dd, J = 8.4, 2.4 Hz, 1H), 6.67 (d, J = 2.4 Hz, 1H), 5.21 (s, 2H), 4.61 (sep, J = 6.0 Hz, 1H), 4.41−4.36 (m, 2H), 3.74 (s, 3H), 3.52 (s, 3H), 2.19 (s, 1H), 1.37 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 158.0, 157.6, 157.4, 140.9, 131.9, 131.6, 129.1, 123.2, 115.1, 114.9, 107.6, 100.3, 94.5, 69.8, 63.8, 56.1, 55.7, 22.2; HRMS (ESI+ double-focusing magnetic sector) calcd for C19H24O5Na [M + Na]+ 355.1516, found 355.1507. Compound 22. To a mixture of compound SI-2 (2.59 g, 7.79 mmol) in CH2Cl2 (75 mL) was added MnO2 (18 g) at room temperature under N2, and the reaction mixture was stirred for 3 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite. The filtrate was evaporated to give a residue. The resulting residue was purified by column chromatography (SiO2, nhexane/ethyl acetate = 4:1) to afford compound 22 (2.35 g, 91%) as a colorless oil. Compound 22: colorless oil; IR (neat) 2978, 2935, 2846, 1691, 1606, 1485, 1417, 1390, 1279, 1157, 1018, 837 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 7.46 (d, J = 2.8 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.17−7.14 (m, 2H), 6.75 (dd, J = 8.4, 2.4 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 5.23 (s, 2H), 4.66 (sep, J = 6.0 Hz, 1H), 3.72 (s, 3H), 3.53 (s, 3H), 1.37 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 192.8, 158.8, 157.7, 157.4, 135.0, 134.1, 132.7, 132.2, 122.7, 120.3, 111.3, 107.7, 100.0, 94.6, 70.2, 56.3, 55.5, 22.1; HRMS (ESI+ doublefocusing magnetic sector) calcd for C19H22O5Na [M + Na]+ 353.1359, found 353.1352. Compound 23. Compound 22 (186 mg, 0.56 mmol) was dissolved in MeOH (5 mL), and potassium carbonate (156 mg, 1.13 mmol) and dimethyl(1-diazo-2-oxopropyl)phosphonate (101 μL, 0.676 mmol) were added. The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was subsequently quenched by the

mixed solvent of MeOH and CH2Cl2 (10 mL, MeOH/CH2Cl2 = 1:1), and the mixture was stirred at room temperature for 17 h. The reaction mixture was subsequently quenched by the addition of a 1 M hydrochloric acid solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated to give a residue. The resulting residue was purified by column chromatography (SiO2, n-hexane/ethyl acetate = 4:1) to afford compound 15 (66.8 mg, 75%) as a white solid. Compound 15: white solid; mp 191−192 °C; IR (KBr) 3741, 3651, 3367, 2968, 1714, 1622, 1471, 1458, 1279, 1234, 1149, 1041 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 9.2 Hz, 1H), 7.59 (d, J = 2.8 Hz, 1H), 7.13 (d, J = 2.8 Hz, 1H), 7.01 (dd, J = 9.2, 2.8 Hz, 1H), 6.87 (s, 1H), 6.79 (d, J = 2.8 Hz, 1H), 5.16 (br s, 1H), 4.01 (s, 3H), 3.93 (s, 3H), 1.52 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 177.1, 157.6, 152.89, 152.85, 149.6, 134.1, 129.0, 127.3, 119.5, 119.3, 113.5, 112.1, 108.4, 105.1, 103.2, 55.5, 55.3, 39.5, 27.3; HRMS (ESI+ double-focusing magnetic sector) calcd for C21H22O5Na [M + Na]+ 377.1359, found 377.1361. Compound 16. To a stirred solution of copper(II) nitrate trihydrate (446 mg, 1.85 mmol) in MeOH (3.5 mL) cooled in an ice bath was added 1-phenylethylamine (571 μL, 4.43 mmol) portionwise under a N2 atmosphere. After 45 min, a solution of compound 15 (262 mg, 0.74 mmol) in CH2Cl2 (3.5 mL) was added, and the reaction mixture was stirred for 13 h at room temperature. The reaction mixture was subsequently quenched by the addition of a 1 M hydrochloric acid solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated to give compound 16 as a brown solid (277 mg, quant) Compound 16: brown solid; mp 210−211 °C; IR (KBr) 3741, 3649, 3508, 2970, 2937, 1753, 1616, 1468, 1242, 1103, 1039, 787 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.91 (d, J = 9.2 Hz, 2H), 7.06−7.01 (m, 6H), 6.76 (s, 2H), 3.91 (s, 6H), 3.26 (s, 6H), 1.54 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 177.1, 157.7, 154.8, 151.2, 149.9, 134.0, 127.8, 127.3, 120.8, 119.6, 114.7, 113.8, 111.6, 107.4, 105.0, 55.5, 55.3, 39.5, 27.3; HRMS (ESI+ double-focusing magnetic sector) calcd for C42H42O10Na [M + Na]+ 729.2670, found 729.2677. Compound 20. Compound 18 (150 mg, 0.58 mmol), resorcinol (19) (127 mg, 1.16 mmol), sodium hydroxide (46 mg, 1.16 mmol), and copper(II) sulfate pentahydrate (14.5 mg, 0.06 mmol) were resolved in water (0.3 mL), and the mixture was stirred at 80 °C for 2 h under an Ar atmosphere. The reaction mixture was extracted with ethyl acetate. The extract was back-extracted with a saturated sodium hydrogen carbonate solution, and the aqueous layer was returned to acidic with a 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with water and brine. After being dried over sodium sulfate, the solvent was evaporated in vacuo to give compound 20 as a white solid (107 mg, 68%). Compound 20: white solid; mp 195−196 °C; IR (KBr) 3741, 3651, 3275, 2978, 1697, 1616, 1562, 1481, 1306, 1130, 808, 775 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 2.8 Hz, 1H), 7.46 (dd, J = 8.8, 2.8 Hz, 1H), 6.83 (dd, J = 8.8, 2.0 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 4.77 (sep, J = 6.0 Hz, 1H), 1.33 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, DMSO-d6) δ 160.8, 159.1, 156.9, 151.4, 128.4, 125.2, 124.4, 123.9, 120.3, 113.3, 112.9, 109.8, 103.1, 70.2, 21.9; HRMS (ESI+ doublefocusing magnetic sector) calcd for C16H14O4Na [M + Na]+ 293.0784, found 293.0795. Compound SI-1. Compound 20 (618 mg, 2.29 mmol) and potassium carbonate (379 mg, 2.74 mmol) were dissolved in DMF (6 mL), and chloromethyl methyl ether (206 μL, 2.74 mmol) was added to the solution. After stirring at room temperature for 1 h, the solution was stirred at 50 °C for 8.5 h. The reaction mixture was subsequently quenched by the addition of a 1 M hydrochloric acid solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate, and evaporated to give a residue. The resulting residue was purified by column chromatography (SiO2, n-hexane/ethyl acetate = 5:1) to afford compound SI-1 (747 mg, quant) as a white solid. 11580


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116.9, 112.9, 104.9, 79.7, 70.1, 55.8, 50.9, 39.1, 27.2, 22.1; HRMS (ESI+ double-focusing magnetic sector) calcd for C23H2579BrO4Na [M + Na]+ 467.0828, found 467.0827. Compounds 25a and 26. Compound 24a (32.7 mg, 80.7 μmol) was dissolved in toluene (1 mL), and platinum(II) chloride (2.1 mg, 8.07 μmol) was added. The reaction mixture was stirred for 28 h at 80 °C under a N2 atmosphere. The reaction mixture was subsequently quenched by the addition of water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate, and evaporated to give a residue. The resulting residue was purified by column chromatography (SiO2, n-hexane/ethyl acetate = 4:1) to afford compound 25a as a yellow oil (2.9 mg, 9%) and compound 26 as a brown oil (14.3 mg, 49%). Compound 25a: white-yellow solid; mp 104−105 °C; IR (KBr) 3899, 3740, 2924, 1616, 1456, 1265, 1155, 1034, 972, 829 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.49 (d, J = 9.2 Hz, 1H), 7.98 (s, 1H), 7.77 (d, J = 2.8 Hz, 1H), 7.24 (dd, J = 9.6, 2.8 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H), 5.30 (s, 2H), 4.80 (sep, J = 6.0 Hz, 1H), 4.09 (s, 3H), 3.54 (s, 3H), 1.44 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 159.1, 155.8, 155.2, 134.1, 131.5, 131.0, 129.6, 125.6, 122.6, 118.2, 116.0, 111.0, 104.2, 100.6, 94.6, 70.0, 56.2, 55.8, 22.1; HRMS (ESI + double-focusing magnetic sector) calcd for C20H2179BrO4Na [M + Na]+ 427.0515, found 427.0516. Compound 26: brown oil; IR (neat) 3072, 2978, 2935, 1658, 1597, 1466, 1352, 1227, 1115, 866, 756 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.09 (s, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 2.4 Hz, 1H), 6.71 (dd, J = 8.4, 2.4 Hz, 1H), 6.43 (dd, J = 9.6, 1.2 Hz, 1H), 5.99 (d, J = 9.6 Hz, 1H), 5.87 (d, J = 1.2 Hz, 1H), 4.56 (sep, J = 6.0 Hz, 1H), 3.61 (s, 3H), 1.34 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 188.5, 171.8, 158.7, 144.9, 143.2, 136.1, 134.5, 129.9, 128.4, 123.6, 113.7, 109.1, 105.1, 70.3, 62.8, 56.1, 22.1, 22.0; HRMS (ESI+ double-focusing magnetic sector) calcd for C18H1779BrO3Na [M + Na]+ 383.0253, found 383.0239. Compound 25b. Compound 24b (173 mg, 0.388 mmol) was dissolved in toluene (3 mL), and platinum(II) chloride (20.6 mg, 77.5 μmol) was added. The reaction mixture was stirred for 11 h at 80 °C under a N2 atmosphere. The reaction mixture was subsequently quenched by the addition of water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate, and evaporated to give a residue. The resulting residue was purified by column chromatography (SiO2, n-hexane/ethyl acetate = 15:1) to afford compound 25b (109 mg, 63%) as a yellow solid. Compound 25b: yellow solid; mp 97−98 °C; IR (KBr) 3651, 3614, 2974, 1743, 1618, 1531, 1452, 1271, 1149, 1122, 831, 766 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.54 (d, J = 9.6 Hz, 1H), 7.98 (s, 1H), 7.79 (d, J = 2.8 Hz, 1H), 7.26 (d, J = 9.6, 2.8 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.84 (d, J = 2.4 Hz, 1H), 4.81 (sep, J = 6.0 Hz, 1H), 4.10 (s, 3H), 1.45 (d, J = 6.0 Hz, 6H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 177.1, 158.8, 156.4, 148.8, 133.4, 132.2, 130.8, 130.1, 125.3, 122.9, 118.4, 118.3, 111.8, 111.1, 103.5, 70.1, 56.0, 39.2, 27.2, 22.1; HRMS (ESI+ double-focusing magnetic sector) calcd for C23H2579BrO4Na [M + Na]+ 467.0828, found 467.0839. Compound 27. Potassium carbonate (43.9 mg, 0.318 mmol) was added to a solution of compound 25b (109 mg, 0.244 mmol) in a mixed solvent of MeOH and CH2Cl2 (3 mL, MeOH/CH2Cl2 = 1:2), and the mixture was stirred at room temperature for 18 h. The reaction mixture was subsequently quenched by the addition of a 1 M hydrochloric acid solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated to give a residue. The resulting residue was purified by column chromatography (SiO2, n-hexane/ethyl acetate = 4:1) to afford compound 27 (81.4 mg, 92%) as a brown solid. Compound 27: brown solid; mp 75−76 °C; IR (KBr) 3741, 3649, 3402, 2976, 1616, 1452, 1259, 1165, 1138, 1018, 966, 827 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.46 (d, J = 9.6 Hz, 1H), 7.88 (s, 1H), 7.77 (d, J = 2.8 Hz, 1H), 7.24 (d, J = 9.6, 2.8 Hz, 1H), 6.72 (s, 2H), 4.81 (sep, J = 6.0 Hz, 1H), 4.06 (s, 3H), 1.45 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 159.4, 155.6, 153.6, 134.2, 131.2, 130.4, 129.5,

addition of a 1 M hydrochloric acid solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate, and evaporated to give compound 23 as a brown oil (179 mg, 97%). Compound 23: brown oil; IR (neat) 3284, 2976, 2827, 1603, 1483, 1281, 1155, 1018, 926, 835 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 5.2 Hz, 1H), 7.18 (d, J = 5.2 Hz, 1H), 7.09 (d, J = 2.8 Hz, 1H), 6.90 (dd, J = 8.4, 2.4 Hz, 1H), 6.69−6.66 (m, 2H), 5.21 (s, 2H), 4.55 (sep, J = 6.0 Hz, 1H), 3.76 (s, 3H), 3.52 (s, 3H), 2.92 (s, 1H), 1.35 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 158.0, 157.8, 156.5, 133.5, 131.9, 131.7, 123.1, 122.8, 119.4, 116.9, 106.9, 100.4, 94.6, 83.4, 78.7, 70.1, 56.1, 55.5, 22.1; HRMS (ESI+ double-focusing magnetic sector) calcd for C20H22O4Na [M + Na]+ 349.1410, found 349.1409. Compound 24a. A solution of n-BuLi (1.60 M n-hexane solution; 68 mL, 0.109 mmol) was added in a dropwise manner to a solution of compound 23 (29.5 mg, 0.090 mmol) in dry THF (1 mL) under an atmosphere of N2 at −78 °C. After stirring the mixture for 45 min, a solution of 1,2-dibromotetrachloroethane (46 mg, 0.141 mmol) in dry THF (1 mL) was added, and the reaction mixture was stirred for 2 h. The reaction mixture was subsequently quenched by the addition of a 1 M hydrochloric acid solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate, and evaporated to give a residue. The resulting residue was purified by column chromatography (SiO2, nhexane/ethyl acetate = 5:1) to afford compound 24a (33.3 mg, 91%) as a brown oil. Compound 24a: brown oil; IR (neat) 3626, 2976, 2933, 2195, 1601, 1483, 1281, 1155, 1117, 1018, 989, 835 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 8.8 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 2.8 Hz, 1H), 6.89 (dd, J = 8.8, 2.8 Hz, 1H), 6.70−6.66 (m, 2H), 5.22 (s, 2H), 4.54 (sep, J = 6.0 Hz, 1H), 3.78 (s, 3H), 3.53 (s, 3H), 1.35 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 158.0, 157.8, 156.4, 133.6, 131.9, 131.6, 123.3, 122.9, 119.1, 117.0, 107.0, 100.4, 94.6, 79.9, 70.1, 56.2, 55.6, 50.6, 22.1; HRMS (ESI+ double-focusing magnetic sector) calcd for C20H2179BrO4Na [M + Na]+ 427.0515, found 427.0508. Compound 24c. Concentrated hydrochloric acid (0.6 mL) was added in a dropwise manner to a solution of compound 24a (105 mg, 0.259 mmol) in MeOH (3 mL). After stirring at room temperature for 2 h, the reaction mixture was subsequently quenched by the addition of water and ethyl acetate. The organic layer was washed successively with water and brine. After being dried over sodium sulfate, the solvent was evaporated in vacuo to give compound 24c as a yellow-brown solid (97.8 mg, quant). Compound 24c: yellow-brown solid; mp 77−78 °C; IR (KBr) 3741, 3246, 2978, 2933, 1597, 1489, 1462, 1288, 1194, 1119, 953, 827 cm−1; 1 H NMR (400 MHz, CDCl3) δ 7.19 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.90 (dd, J = 8.4, 2.4 Hz, 1H), 6.48 (d, J = 2.4 Hz, 1H), 6.44 (dd, J = 8.4, 2.4 Hz, 1H), 5.37 (br s, 1H), 4.54 (sep, J = 6.0 Hz, 1H), 3.74 (s, 3H), 1.34 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 157.9, 156.3, 133.8, 132.0, 131.7, 123.4, 121.7, 119.1, 117.1, 106.8, 99.2, 79.9, 70.3, 55.6, 50.7, 22.1 (one peak overlapped); HRMS (ESI+ double-focusing magnetic sector) calcd for C18H1779BrO3Na [M + Na]+ 383.0253, found 383.0246. Compound 24b. Compound 24c (42.2 mg, 0.117 mmol) was dissolved in CH2Cl2 (1 mL). Triethylamine (19.5 μL, 0.140 mmol) and pivaloyl chloride (17.0 μL, 0.140 mmol) were added to the solution, and the mixture was stirred for 3 h at room temperature. The reaction mixture was subsequently quenched by the addition of a 1 M hydrochloric acid solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine. After being dried over sodium sulfate, the solvent was evaporated in vacuo to give compound 24b as a brown oil (53.4 mg, quant). Compound 24b: brown oil; IR (neat) 3735, 2976, 2935, 2197, 1751, 1599, 1481, 1273, 1151, 1117, 1036, 758 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 2.8 Hz, 1H), 6.90 (dd, J = 8.4, 2.8 Hz, 1H), 6.71 (dd, J = 8.4, 2.8 Hz, 1H), 6.68 (d, J = 2.4 Hz, 1H), 4.55 (sep, J = 6.0 Hz, 1H), 3.78 (s, 3H), 1.39 (s, 9H), 1.35 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 177.0, 157.5, 156.7, 151.5, 133.1, 131.7, 131.6, 126.4, 123.3, 119.1, 11581


Article

The Journal of Organic Chemistry 125.7, 122.8, 118.2, 115.1, 111.2, 104.0, 99.4, 70.1, 55.8, 22.0; HRMS (ESI+ double-focusing magnetic sector) calcd for C18H1779BrO3Na [M + Na]+ 383.0253, found 383.0259. Compound 28. To a stirred solution of copper(II) nitrate trihydrate (136 mg, 0.563 mmol) in MeOH (1.5 mL) cooled in an ice bath was added 1-phenylethylamine (174 μL, 1.35 mmol) portionwise under a N2 atmosphere. After 45 min, a solution of compound 27 (81.4 mg, 0.225 mmol) in CH2Cl2 (1.5 mL) was added, and the reaction mixture was stirred for 3.5 h at room temperature. The reaction mixture was subsequently quenched by the addition of a 1 M hydrochloric acid solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine. After being dried over sodium sulfate, the solvent was evaporated in vacuo to give compound 28 as a white solid (84.4 mg, quant). Compound 28: white solid; mp >300 °C; IR (KBr) 3899, 3651, 3460, 2976, 1743, 1608, 1525, 1450, 1217, 1173, 972, 831 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.61 (d, J = 9.6 Hz, 2H), 7.74 (d, J = 2.8 Hz, 2H), 7.42 (s, 2H), 7.30 (dd, J = 9.2, 2.8 Hz, 2H), 7.05 (s, 2H), 5.07 (s, 2H), 4.80 (sep, J = 6.0 Hz, 2H), 4.23 (s, 6H), 1.45−1.43 (m, 12H); 13 C NMR (100 MHz, CDCl3) δ 160.5, 155.9, 153.5, 133.6, 131.3, 129.7, 127.3, 125.8, 124.8, 118.8, 116.3, 110.9, 104.3, 99.1, 70.0, 56.0, 22.0, 21.9; HRMS (ESI+ double-focusing magnetic sector) calcd for C36H3279Br81BrO6Na [M + Na]+ 743.0441, found 743.0459. Compound 29. Iron(III) chloride hexahydrate (300 mg, 1.11 mmol) was added to a solution of compound 28 (200 mg, 0.278 mmol) in CH2Cl2 (12 mL), and the mixture was stirred at 30 °C for 21 h. The reaction mixture was subsequently quenched by the addition of water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate, and evaporated to give a residue. The resulting residue was purified by column chromatography (SiO2, n-hexane/ethyl acetate = 4:1) to afford compound 29 (183.3 mg, 92%) as a brown solid. Compound 29: brown solid; mp 120−121 °C; IR (KBr) 3741, 3614, 2976, 2933, 1809, 1711, 1614, 1506, 1450, 1273, 1234, 1111, 1016 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.54 (d, J = 9.6 Hz, 1H), 9.26 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 2.8 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.46 (dd, J = 9.2, 2.8 Hz, 1H), 7.34 (s, 1H), 7.28 (dd, J = 9.2, 2.8 Hz, 1H), 7.24 (s, 1H), 7.15 (s, 1H), 4.82−4.75 (m, 2H), 4.21 (s, 3H), 3.44 (s, 2H), 1.44 (d, J = 6.4 Hz, 6H), 1.42−1.40 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 201.5, 177.6, 160.5, 158.4, 156.4, 151.90, 151.88, 134.2, 131.9, 131.5, 130.4, 129.9, 128.2, 126.5, 125.8, 125.7, 125.4, 124.5, 123.7, 123.5, 119.1, 118.2, 112.3, 111.2, 109.0, 94.0, 70.3, 70.1, 56.4, 52.7, 47.9, 21.9, 21.84, 21.81, 21.79; HRMS (ESI+ double-focusing magnetic sector) calcd for C35H2879Br81BrO6Na [M + Na]+ 727.0128, found 727.0103. Compound 32. Compound 30 (112.0 mg, 0.426 mmol), compound 31 (100.0 mg, 0.328 mmol), potassium carbonate (91.0 mg, 0.655 mmol), and tetrakis(triphenylphosphine)palladium (19.0 mg, 0.016 mmol) were resolved in a mixed solvent of THF and water (4 mL, THF/water = 1:1), and the mixture was stirred at 50 °C for 20 h under a N2 atmosphere. The reaction mixture was subsequently quenched by the addition of a 1 M hydrochloric acid solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated to give a residue. The resulting residue was purified by column chromatography (SiO2, n-hexane/ethyl acetate = 6:1 to chloroform/MeOH = 30:1) to afford compound 32 (124 mg, quant) as a yellow oil. Compound 32: yellow oil; IR (neat) 3651, 2976, 2933, 1689, 1601, 1469, 1242, 1146, 1034, 924, 837 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.22−7.19 (m, 2H), 7.11 (d, J = 2.4 Hz, 1H), 6.95−6.93 (m, 2H), 5.24 (s, 2H), 5.09 (s, 2H), 4.61 (sep, J = 6.0 Hz, 1H), 3.51 (s, 3H), 3.36 (s, 3H), 1.38 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 192.3, 157.6, 157.1, 155.9, 136.1, 132.5, 130.2, 124.6, 115.1, 109.8, 106.3, 95.0, 94.5, 69.8, 56.3, 56.2, 22.1; HRMS (ESI+ double-focusing magnetic sector) calcd for C20H24O6Na [M + Na]+ 383.1465, found 383.1451. Compound 33. Compound 32 (1.24 g, 3.44 mmol) was dissolved in MeOH (22 mL), and potassium carbonate (951 mg, 6.88 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (620 μL, 4.13 mmol)

were added. The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was subsequently quenched by the addition of a 1 M hydrochloric acid solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated to give a residue. The resulting residue was purified by column chromatography (SiO2, n-hexane/ethyl acetate = 5:1) to afford compound 33 (1.11 g, 90%) as a purple oil. Compound 33: purple oil; IR (neat) 3282, 2976, 2827, 1599, 1516, 1466, 1242, 1039, 922, 835, 638 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.32−7.29 (m, 2H), 6.99 (d, J = 2.4 Hz, 1H), 6.92−6.90 (m, 3H), 5.19 (s, 2H), 5.03 (s, 2H), 4.59 (sep, J = 6.0 Hz, 1H), 3.50 (s, 3H), 3.34 (s, 3H), 2.93 (s, 1H), 1.37 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 157.0, 156.5, 155.3, 131.7, 128.8, 127.8, 123.3, 114.7, 113.7, 105.9, 95.0, 94.5, 82.8, 80.0, 69.6, 56.2, 56.1, 22.2; HRMS (ESI+ doublefocusing magnetic sector) calcd for C21H24O5Na [M + Na]+ 379.1516, found 379.1505. Compound 34. To a stirred solution of compound 33 (99 mg, 0.278 mmol) in acetone (1.5 mL) cooled in an ice bath was added silver(I) nitrate (4.7 mg, 0.028 mmol) portionwise under a N2 atmosphere. A solution of N-bromosuccinimide (54.4 mg, 0.306 mmol) in acetone (1.5 mL) was added, and the reaction mixture was stirred for 12 h at room temperature. The reaction mixture was subsequently quenched by the addition of water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated to give compound 34 as a brown oil (123 mg, quant). Compound 34: brown oil; IR (neat) 3674, 3651, 2976, 2933, 2197, 1597, 1466, 1242, 1151, 1034, 955, 835 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.31−7.28 (m, 2H), 6.94−6.89 (m, 4H), 5.17 (s, 2H), 5.02 (s, 2H), 4.60 (sep, J = 6.0 Hz, 1H), 3.50 (s, 3H), 3.34 (s, 3H), 1.37 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 157.0, 156.5, 155.3, 131.7, 128.9, 127.7, 123.9, 114.9, 113.6, 106.0, 95.1, 94.6, 79.5, 69.8, 56.18, 56.15, 52.2, 22.2; HRMS (ESI+ double-focusing magnetic sector) calcd for C21H2379BrO5Na [M + Na]+ 457.0621, found 457.0631. Compound 35. Concentrated hydrochloric acid (12 mL) was added in a dropwise manner to a solution of compound 34 (1.44 g, 3.36 mmol) in MeOH (60 mL). After stirring at 0 °C for 2 h, the solution was stirred at room temperature for 19 h. The reaction mixture was subsequently quenched by the addition of water and ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated to give a residue. The residue was dissolved in CH2Cl2 (40 mL). Triethylamine (1.03 mL, 7.40 mmol) and pivaloyl chloride (0.91 mL, 7.40 mmol) were added to the solution, and the solution was stirred for 12 h at room temperature. The reaction mixture was subsequently quenched by the addition of a 1 M hydrochloric acid solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated to give a residue. The resulting residue was purified by column chromatography (SiO2, n-hexane/ethyl acetate = 15:1) to afford compound 35 (1.61 g, 93%) as a yellow solid. Compound 35: yellow solid; mp 115−116 °C; IR (KBr) 2978, 2935, 2191, 1755, 1604, 1462, 1244, 1119, 1097, 1032, 903 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.21−7.17 (m, 3H), 6.91−6.87 (m, 3H), 4.59 (sep, J = 6.0 Hz, 1H), 1.35−1.34 (m, 15H), 1.03 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 176.6, 176.4, 157.4, 149.7, 149.0, 135.4, 131.1, 126.6, 124.5, 123.4, 117.3, 115.4, 78.1, 69.9, 54.1, 39.2, 38.8, 27.1, 26.8, 22.0; HRMS (ESI+ double-focusing magnetic sector) calcd for C27H3179BrO5Na [M + Na]+ 537.1247, found 537.1246. Compound 36. Compound 35 (1.22 g, 2.37 mmol) was dissolved in toluene (18 mL), and platinum(II) chloride (126 mg, 0.47 mmol) was added. The reaction mixture was stirred for 48 h at 80 °C under a N2 atmosphere. The reaction mixture was subsequently quenched by the addition of water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate, and evaporated to give a residue. The resulting residue was purified by column chromatography (SiO2, n-hexane/ethyl acetate = 10:1) and washed with n-hexane to afford compound 36 (427 mg, 35%) as a white solid. 11582


Article

The Journal of Organic Chemistry Compound 36: white solid; mp 176−177 °C; IR (KBr) 3735, 2974, 1753, 1618, 1479, 1450, 1238, 1136, 1111, 904 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.95 (d, J = 9.2 Hz, 1H), 8.03−8.02 (m, 2H), 7.18 (dd, J = 9.2, 2.8 Hz, 1H), 7.15 (d, J = 2.8 Hz, 1H), 7.05 (d, J = 2.8 Hz, 1H), 4.73 (sep, J = 6.0 Hz, 1H), 1.51 (s, 9H), 1.43−1.40 (m, 15H); 13C NMR (100 MHz, CDCl3) δ 176.8, 176.7, 156.6, 149.0, 148.2, 134.2, 131.93, 131.88, 128.3, 122.9, 122.1, 121.2, 118.2, 118.1, 117.2, 110.3, 70.0, 39.5, 39.2, 27.3, 27.2, 22.0; HRMS (ESI+ double-focusing magnetic sector) calcd for C27H3179BrO5Na [M + Na]+ 537.1247, found 537.1241. Compound 37. Potassium carbonate (35 mg, 0.252 mmol) was added to a solution of compound 36 (129.9 mg, 0.252 mmol) in a mixed solvent of MeOH and CH2Cl2 (4 mL, MeOH/CH2Cl2 = 1:1), and the mixture was stirred at room temperature for 19.5 h. The reaction mixture was subsequently quenched by the addition of a 1 M hydrochloric acid solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated to give a residue. The resulting residue was purified by column chromatography (SiO2, n-hexane/ethyl acetate = 4:1) and preparative gel filtration chromatography (chloroform) to afford compound 37 (52.2 mg, 48%) as a white solid. Compound 37: white solid; mp 220−221 °C; IR (KBr) 3899, 3741, 3383, 2978, 1716, 1622, 1452, 1277, 1240, 1155, 1113, 989 cm−1; 1H NMR (400 MHz, acetone-d6) δ 9.12 (br s, 1H), 8.91 (d, J = 9.2 Hz, 1H), 8.16 (s, 1H), 7.74 (d, J = 2.8 Hz, 1H), 7.40 (d, J = 2.8 Hz, 1H), 7.27 (dd, J = 9.2, 2.8 Hz, 1H), 6.96 (d, J = 2.8 Hz, 1H), 4.82 (sep, J = 6.0 Hz, 1H), 1.52 (s, 9H), 1.38 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, acetone-d6) δ 177.3, 157.0, 156.4, 151.1, 134.2, 133.2, 132.6, 128.2, 123.4, 121.4, 119.5, 119.2, 114.0, 111.5, 111.0, 70.5, 40.1, 27.5, 22.3; HRMS (ESI + double-focusing magnetic sector) calcd for C22H2379BrO4Na [M + Na]+ 453.0672, found 453.0671. Compound 39. Iron(III) chloride hexahydrate (45.4 mg, 0.168 mmol) was added to a solution of compound 37 (18.1 mg, 0.042 mmol) in CHCl3 (3 mL). After stirring at 30 °C for 45 min, the solution was stirred at 50 °C for 4 h. The reaction mixture was subsequently quenched by the addition of water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate, and evaporated to give a residue. The resulting residue was purified by column chromatography (SiO2, n-hexane/ethyl acetate = 7:1) to afford compound 39 (6.2 mg, 38%) as a white solid. The indicated compounds were separated from the reaction crude mixture by flash column chromatography on silica gel but induced a trace amount of inseparable byproduct. The following spectrum data are not complete due to overlapping of some of the peaks. Compound 39: white solid; mp 101−104 °C; IR (KBr) 2976, 2931, 1808, 1759, 1707, 1618, 1502, 1444, 1269, 1190, 1099, 891 cm−1; 1H NMR (400 MHz, acetone-d6) δ 9.12 (d, J = 9.2 Hz, 1H), 8.97 (d, J = 9.6 Hz, 1H), 8.08 (s, 1H), 7.99 (s, 1H), 7.38 (dd, J = 9.2, 2.8 Hz, 1H), 7.28 (s, 1H), 7.18 (dd, J = 9.6, 2.8 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 7.03 (d, J = 2.8 Hz, 1H), 4.75−4.66 (m, 2H), 3.78 (d, J = 18.8 Hz, 1H), 3.33 (d, J = 18.4 Hz, 1H), 1.51 (s, 9H), 1.42 (d, J = 6.0 Hz, 6H), 1.40 (d, J = 6.4 Hz, 6H); 13C NMR (100 MHz, acetone-d6) δ 201.9, 176.5, 176.3, 157.6, 156.8, 153.0, 152.1, 150.6, 137.9, 136.8, 136.3, 134.3, 133.3, 129.8, 128.9, 126.3, 124.7, 123.4, 123.2, 122.4, 119.7, 118.9, 116.9, 114.6, 109.1, 108.1, 107.5, 70.1, 56.1, 51.6, 39.6, 27.2, 21.9 (two peaks overlapped); HRMS (ESI+ double-focusing magnetic sector) calcd for C39H3479Br81BrO7Na [M + Na]+ 797.0547, found 797.0537. Compound 40. Potassium carbonate (4.9 mg, 0.035 mmol) was added to a solution of compound 39 (22.8 mg, 0.029 mmol) in a mixed solvent of MeOH and CH2Cl2 (1 mL, MeOH/CH2Cl2 = 1:1), and the mixture was stirred at room temperature for 1 h. The reaction mixture was subsequently quenched by the addition of a 0.1 M hydrochloric acid solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated to give a residue. The residue was dissolved in CH2Cl2 (5 mL). BBr3 (1.0 M CH2Cl2 solution; 588 μL, 0.588 mmol) was added to the solution, and the solution was stirred for 10 min at 0 °C. The reaction mixture was subsequently quenched by the addition of a 0.1 M hydrochloric acid solution, and the resulting mixture was

extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated to give a residue. The resulting residue was purified by column chromatography (SiO2, nhexane/ethyl acetate = 1:1) to afford compound 40 (13.6 mg, 76%) as a yellow solid. The indicated compounds were separated from the reaction crude mixture by flash column chromatography on silica gel but induced a trace amount of inseparable byproduct. The following spectrum data are not complete due to overlapping of some of the peaks. Compound 40: yellow solid; mp 204−207 °C; IR (KBr) 3375, 2922, 2852, 1778, 1689, 1585, 1214, 1178, 1117, 1028, 893, 829 cm−1; 1H NMR (400 MHz, acetone-d6) δ 9.76 (d, J = 9.6 Hz, 1H), 9.13 (d, J = 9.2 Hz, 1H), 8.27 (s, 1H), 8.10 (s, 1H), 7.47 (dd, J = 9.2, 2.4 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.33 (s, 1H), 7.27 (dd, J = 9.6, 2.4 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 3.75 (d, J = 18.8 Hz, 1H), 3.38 (d, J = 18.8 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 202.6, 177.9, 159.2, 158.1, 156.6, 154.6, 153.3, 138.5, 138.0, 136.9, 135.1, 134.1, 131.3, 130.5, 126.7, 124.8, 123.6, 122.8, 121.2, 118.9, 117.6, 115.4, 113.4, 110.9, 109.9, 100.1, 56.8, 52.5; HRMS (ESI) calcd for C28H1481Br81BrO6Na [M + Na]+ 630.9024, found 630.9008. Compound 17. Compound 16 (170 mg, 0.241 mmol) was dissolved in toluene (50 mL). Iron(III) chloride hexahydrate (260 mg, 0.962 mmol) and 1-phenylethylamine (124 μL, 0.962 mmol) were added to the solution. The reaction mixture temperature was allowed to increase gradually to 100 °C, and the mixture was stirred for 14 h. The reaction mixture was subsequently quenched by the addition of water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a 1 M hydrochloric acid solution, water, and brine. After being dried over sodium sulfate, the solvent was evaporated in vacuo to give a residue. The resulting residue was purified by column chromatography (SiO2, n-hexane/ethyl acetate = 2:1) to afford compound 17 (67.4 mg, 45%) as a yellow solid. Compound 17: yellow solid; 244−247 °C; IR (KBr) 2964, 2935, 1797, 1755, 1705, 1614, 1469, 1240, 1091, 1026, 796, 754 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.12 (d, J = 9.2 Hz, 1H), 8.92 (d, J = 10.0 Hz, 1H), 7.26 (dd, J = 9.2, 2.4 Hz, 1H), 7.21 (s, 1H), 7.13 (s, 1H), 7.11 (d, J = 2.4 Hz, 1H), 7.04−7.01 (m, 2H), 6.73 (s, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 3.58 (s, 3H), 3.41 (d, J = 18.4 Hz, 1H), 3.31 (d, J = 18.4 Hz, 1H), 3.24 (s, 3H), 1.54 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 204.6, 178.8, 176.8, 159.0, 158.4, 154.1, 153.0, 152.1, 150.0, 146.4, 137.2, 134.4, 133.1, 128.3, 125.6, 125.0, 123.4, 120.3, 119.8, 119.5, 118.7, 114.4, 112.0, 107.8, 107.5, 106.1, 105.4, 55.8, 55.4, 54.7, 53.6, 50.0, 39.7, 27.3 (one peak overlapped); HRMS (ESI+ double-focusing magnetic sector) calcd for C37H32O9Na [M + Na]+ 643.1939, found 643.1940. Dendrochrysanene (1). Compound 17 (22.2 mg, 0.036 mmol) was dissolved in CH2Cl2 (1.5 mL). BBr3 (1.0 M CH2Cl2 solution; 715 μL, 0.715 mmol) was added to the solution, and the mixture was stirred for 13 h at room temperature. The reaction mixture was subsequently quenched by the addition of a 1 M hydrochloric acid solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine. After being dried over sodium sulfate, the solvent was evaporated in vacuo to give a residue. The resulting residue was purified by column chromatography (SiO2, n-hexane/ethyl acetate = 1:1) to afford dendrochrysanene (1) (11.8 mg, 65%) as a yellow solid. Compound 1: yellow solid; 265−267 °C; IR (KBr) 3359, 1786, 1693, 1587, 1458, 1394, 1207, 1099, 1024, 866, 827, 687 cm−1; 1H NMR (400 MHz, acetone-d6) δ 9.60 (d, J = 9.6 Hz, 1H), 9.06 (d, J = 9.6 Hz, 1H), 7.33 (s, 1H), 7.30−7.24 (m, 2H), 7.22 (s, 1H), 7.11 (d, J = 2.8 Hz, 1H), 7.03 (dd, J = 9.6, 2.4 Hz, 1H), 6.90 (s, 1H), 3.58 (s, 3H), 3.35 (d, J = 18.4 Hz, 1H), 3.23 (s, 3H), 3.20 (d, J = 18.4 Hz, 1H); 13C NMR (100 MHz, acetone-d6) δ 204.8, 179.5, 157.7, 157.1, 155.9, 154.7, 153.3, 152.9, 147.4, 138.1, 134.8, 133.2, 130.4, 125.5, 125.2, 121.2, 119.4, 118.8, 115.0, 113.7, 112.1, 110.6, 109.8, 105.7, 98.7, 55.8, 54.5, 53.9, 50.5 (one peak overlapped); HRMS (ESI+ double-focusing magnetic sector) calcd for C30H20O8Na [M + Na]+ 531.1050, found 531.1052. 11583


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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02223. 1 H and 13C NMR spectra of new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Kouji Kuramochi: 0000-0003-0571-9703 Takeo Kawabata: 0000-0002-9959-0420 Kazunori Tsubaki: 0000-0001-8181-0854 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are grateful to Professor Hiroaki Ohno (Kyoto University) for the useful discussion and Ms. Kyohko Ohmine (ICR, Kyoto University) for the NMR measurements. This study was carried out using the Fourier transform ion cyclotron resonance mass spectrometer and the NMR in the Joint Usage/ Research Center at the Institute for Chemical Research, Kyoto University. This study was supported in part by KAKENHI (nos. 23659013 and 15K14931), Grant-in-Aid from the Tokyo Biochemical Research Foundation, and the Collaborative Research Program of the Institute for Chemical Research, Kyoto University (Grant no. 2016-33).

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REFERENCES

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