Regular Articles
Nucleophilic Addition Reaction with Dearomatization of Naphthalene Ring
2020 Volume 68 Issue 4 Pages 384-391
Details
2020 Volume 68 Issue 4 Pages 384-391
Various aromatic lactones have been synthesized and their regioselectivity (1,2-addition vs. 1,4- or 1,6-addition) investigated in reactions with organolithium species, particularly n-BuLi and sec-BuLi. The regioselectivity varied greatly depending on various factors, such as the bulkiness of both substrates and organolithium species, and types of solvent and cosolvent. In particular, 1,4-addition with dearomatization occurred preferentially using sec-BuLi as the nucleophile in tetrahydrofuran (THF) with hexamethylphosphoramide (HMPA) or N,N′-dimethylpropyleneurea (DMPU) as cosolvent. For sec-BuLi, the reaction was estimated to proceed through a single-electron transfer mechanism.
In the last two decades, organic reactions using dearomatization have attracted much attention as unique methodologies for constructing complex molecules. These reactions are divided into four classes, namely, reduction, oxidation, addition, and cycloaddition reactions, with many examples of each class having been developed.1,2) In particular, nucleophilic addition reactions with dearomatization have been well investigated (Chart 1). For example, in 1964, Dixon et al. reported that t-butyllithium reacted with naphthalene to afford a mixture of t-butyldihydronaphthalenes in 17% yield.3–5) Furthermore, reactions of organometallic species with naphthyl ketones have been reported by Fuson et al. since the late 1950s.6–8) The authors reported the reaction of 1-(1-naphthyl)-2,2,2-triphenyl-ethanone and phenylmagnesium bromide, which predominantly produced the 1,4-adduct, introducing the phenyl group at the 2-position of the naphthalene ring in 93% yield. Furthermore, in the 1980s, Meyers et al. reported pioneering examples of dearomatization reactions using oxazolines as directing and activating groups for aromatic rings.9–12) Several similar reactions have also been reported. Shindo et al. developed a reaction involving collapse of the naphthalene ring possessing a bulky 2,6-bis(t-butyl)-4-methoxyphenyl (BHA) ester.13,14) Miyano and colleagues, and Hattori et al. reported ipso-substitution reactions by combining isopropyl or BHA esters with an alkoxy group at the ortho-position of the naphthalene ring.15,16) In these examples, bulky groups sterically protected the carbonyl group (or carbonyl equivalents), such that nucleophilic addition could not occur at the carbonyl carbon. Nucleophilic attack instead occurred at the β-position of the carbonyl group, causing dearomatization of the naphthalene ring. In contrast, for the sterically smaller methyl ester, the dearomatization reaction did not proceed, with the reaction inevitable occurring at the carbonyl carbon.
We have recently reported unusual 1,4-addition with dearomatization reactions of benzoxanthones 1 and n-butyllithium17) (Chart 2). In these reactions, the selectivity for 1,2- and 1,4-addition varied depending on the reaction conditions, such as the type of solvent and nucleophile. For example, when 2-methyl-tetrahydrofuran (2-Me-THF) was used as solvent, the 1,2-adduct 2 and 1,4-adduct 3 were obtained in 66 and 5% yields, respectively, while in THF/tetramethylethylenediamine (TMEDA), the 1,4-adduct 3 was preferred (47% yield) over the 1,2-adduct 2 (22%).
From these studies, we speculated that the nucleophilic 1,4-addition of organometallic reagents to aromatic carboxylic esters might proceed when the π-face of the aromatic ring and π-face of the carbonyl group are fixed in a coplanar relationship. Accordingly, in this study, we report 1,4-addition reactions accompanied by dearomatization of non-benzoxanthone skeletons. The substrate ester group was fixed as a lactone by connection with an aromatic ring.
Initially, compounds 418) and 519) bearing lactone skeletons were prepared and reactions were conducted using n-BuLi in THF at −78°C for 1 h (Chart 3). Under these reaction conditions, 3 equiv of n-BuLi were required for complete conversion.
Under these conditions, the reaction of compound 4 bearing a benzene ring afforded ketone 620) and alcohol 7, derived from mono- and bis-additions of n-BuLi to the carbonyl group of 4 in 10 and 81% yields, respectively. No formation of compound 8, generated by the 1,4-addition of n-BuLi with dearomatization, was observed. In contrast, under the same reaction conditions, compound 5 bearing a naphthalene ring afforded lactone 11a, derived from the 1,4-addition of n-BuLi, in 41% yield, as well as compounds 9a21) (10%) and 10a22) (32%). Interestingly, Talinli et al. also reported the reaction between compound 5 and n-BuLi in toluene, which afforded compound 10a and its dehydrated derivative in 75 and 5% yields, respectively,22) representing a quite different product distribution to that observed in the present study. These data suggested that the solvent played an important role. Therefore, we next screened solvents and alternative organolithium reagents in the reaction, as shown in Table 1.
 | |||||||
|---|---|---|---|---|---|---|---|
| Entry | Conditions | Yields (%) of | Ratio of 9 + 10:11 | ||||
| RLi | Equiv | Solvent | 9 | 10 | 11 | ||
| 1 | n-BuLi | 3 | THF | 9a:10 | 10a:32 | 11a:41 | 1 : 1 |
| 2 | n-BuLi | 3 | Toluene | 9a:4 | 10a:67 | 11a:10 | 7.1 : 1 |
| 3a) | n-BuLi | 3 | Toluene | 9a:— | 10a:75 | 11a:— | 1 : 0 |
| 4 | n-BuLi | 3 | 2-Me-THF | 9a:2 | 10a:40 | 11a:41 | 1 : 1 |
| 5b) | n-BuLi | 3 | Et2O | 9a:10 | 10a:51 | 11a:24 | 2.5 : 1 |
| 6c) | n-BuLi | 6 | THF:HMPA = 9 : 1 | 9a:4 | 10a:13 | 11a:73 | 1 : 4.3 |
| 7c) | n-BuLi | 6 | THF:DMPU = 9 : 1 | 9a:4 | 10a:16 | 11a:57 | 1 : 2.9 |
| 8 | CH3Li | 3 | THF | 9b:10 | 10b:84 | 11b:— | 1 : 0 |
| 9 | PhLi | 3 | THF | 9c:4 | 10c:82 | 11c:— | 1 : 0 |
| 10 | sec-BuLi | 3 | THF | 9d:8 | 10d:8 | 11d:75 | 1 : 4.7 |
Reaction conditions: Temperature, −78°C; substrate concentration, 44 mM. a) Taken from the results of Talinli.22) Conditions: Substrate concentration, 137 mM. b) Owing to the low solubility of compound 5 in diethyl ether, the substrate concentration was 15 mM. c) 6 equiv of n-BuLi were required for complete conversion.
The result for using THF as solvent (Table 1, entry 1) has already been described above. When toluene was used as solvent (entry 2; the same conditions as reported by Talinli), compound 11a was obtained in 10% yield, along with 9a in 4% yield and 10a in 67% yield. The ratio of 1,2-adduct to 1,4-adduct was 7.1 : 1. The combined yields of compound 9a and 10a were comparable to those reported by Talinli, suggesting that the formation of 1,4-adduct 11a was overlooked previously. In our previous reports, using 2-Me-THF as solvent led predominantly to 1,2-adducts. However, in this study, the ratio of 1,2- and 1,4-adducts, and yields of those compounds, were the same when using 2-Me-THF (entry 4) instead of THF (entry 1). Using diethyl ether as solvent gave 1,4-adduct 11a in a significantly reduced yield of 24%, while compounds 9a and 10a were obtained in 10 and 51% yields, respectively (entry 5). When hexamethylphosphoramide (HMPA) and N,N′-dimethylpropyleneurea (DMPU) were used as cosolvents (10 vol% relative to THF), the ratios of 1,2- and 1,4-adducts were 1 : 4.3 and 1 : 2.9, respectively (entries 6 and 7). Compared with entry 1, these cosolvent additives resulted in improved 1,4-selectivity. These data also indicated that the solvent greatly affected product selectivity, as initially expected. Therefore, the degree of n-BuLi aggregation had a major effect on the product distribution. The selectivity for 1,2- and 1,4-additions changed depending on the type of organolithium species used (entries 8–10). Only 1,2-adducts were obtained in high yields when using MeLi and PhLi (entries 8 and 9), with combined yields of the corresponding ketones (9b23) and 9c24)) and alcohols (10b25) and 10c26)) of 94 and 86%, respectively. Meanwhile, the ratio of 1,2- and 1,4-additions using n-BuLi was about 1 : 1 (entry 1). To our surprise, sec-BuLi showed the reverse selectivity, favoring 1,4-adduct 11d in 75% yield compared with the 1,2-adducts in 16% total yield (entry 10). These results indicated that 1,2-adducts were favored using less bulky or less basic nucleophiles (entries 8 and 9), while 1,4-adducts were preferred when using bulky nucleophiles. The bulkiness and basicity of the nucleophile also affected the product distribution.
Next, with a focus on the ring size and cyclization mode of the lactones, compounds 1226)–17,27) bearing five- to seven-membered rings and the presence or absence of a dimethyl group, were synthesized, and their reactions with n-BuLi and sec-BuLi as nucleophiles were investigated (Table 2).
 |
Reaction conditions: substrate (1 equiv), n-BuLi (3 equiv) or sec-BuLi (3 equiv), THF, −78°C, 1 h.
For five-membered lactone 12, only 1,2-adduct 18a was obtained in 88% yield using n-BuLi as nucleophile (entry 1). In contrast, 1,4-adduct 20d was predominantly afforded in 59% yield over 1,2-adduct 18d in 33% yield when using sec-BuLi (entry 2). As already described above, the 1,2-adducts (9a + 10a) and 1,4-adduct 11a were obtained in 42% combined yield and 41% yield, respectively, using n-BuLi, while 1,4-adduct 11d was the main product in 75% yield using sec-BuLi (entries 3 and 4). The preference of sec-BuLi for 1,4-addition was not observed using substrate 13, which lacked the dimethyl group, affording 1,4-adduct 21d in a significantly reduced 28% yield (entry 6). These results indicated that the bulkiness of both the substrates and organolithium species affected product selectivity. For compound 14, only 1,2-adducts were afforded by both n-BuLi and sec-BuLi (entries 7 and 8). Surprisingly, 1,6-adduct 27d was obtained in 56% yield from the reaction of sec-BuLi with compound 15, representing a different cyclization mode to that of compound 14 (entry 10). In contrast, using n-BuLi predominantly afforded 1,2-adduct 25a in 88% yield (entry 9). The preference of sec-BuLi for 1,4-addition was not observed when using demethylated substrate 16 (entry 12).
Based on DFT calculations, the dihedral angle between the π-face of naphthalene and carbonyl group (shown in bold) in seven-membered lactone 17 was about 32°, which was largely distorted compared with compounds 5 and 12–16, in which the dihedral angles were about 4–6°. Therefore, we initially assumed that the 1,4-addition of organolithium species was suppressed and 1,2-addition would be favored in compound 17 owing to the large dihedral angle. Although n-BuLi selectively afforded 1,2-adducts 29a and 30a in 84% combined yield (entry 13), sec-BuLi afforded 1,4-adduct 31d in 59% yield (entry 14). These data indicated that the dihedral angle between the π-face of naphthalene and carbonyl group had little effect on the regioselectivity. Despite compound 17 lacking the dimethyl group adjacent to the carbonyl group, the 1,4-addition preference of sec-BuLi (31d; 59% yield) suggested that the reaction mechanism of sec-BuLi was different to that of n-BuLi.
To summarize all results above, 1,4-addition reactions with dearomatization of the naphthalene ring depended largely on the nucleophiles, substrates, solvents, and cosolvent additives. The selectivity for 1,4-addition was optimal with sterically bulky organolithium reagents and substrates, THF as solvent, and coordinating HMPA or DMPU as cosolvents. Clearly, as the steric hindrance of the substrate increased, repulsion around the carbonyl group increased, resulting in 1,4-addition being preferred over 1,2-addition. In contrast, coordinative solvent THF increased the selectivity for 1,4-addition, while adding HMPA or DMPU as cosolvent greatly increased the proportion of 1,4-adducts. As the lower-order aggregates derived from coordinative solvents would have a hard character, 1,2-adducts would be expected to be preferred over 1,4-adducts. However, in these experiments, the opposite selectivity occurred. The explanation for this phenomenon has been proposed in previous studies. Accordingly, when using a coordinative solvent, a solvent-separated ion pair is formed, giving the 1,4-adduct.28,29) In contrast, contact ion pairs kinetically give the 1,2-adduct. The different selectivities observed for n-BuLi and sec-BuLi depended not only on steric factors, but on their reaction mechanisms. Therefore, the reaction was assumed to proceed through an ionic mechanism for n-BuLi and a single-electron transfer mechanism for sec-BuLi.
To verify this speculation regarding the reaction systems, the following experiments were conducted (Table 3). First, benzaldehyde was treated with a mixture of n-BuLi (3.0 equiv) and sec-BuLi (3.0 equiv), and the ratio of the generated benzyl alcohols was estimated by 1H-NMR, with compounds possessing n-Bu and sec-Bu side chains obtained in a ratio of about 52 : 48. Therefore, sec-BuLi originally had equal or slightly lower nucleophilicity and higher basicity compared with n-BuLi. Considering these characteristics, a mixed solution of n-BuLi (3 equiv) and sec-BuLi (3 equiv) was added slowly to a THF solution of compound 15 (1 equiv) at −78°C (entry 1). The same reaction was also conducted in the presence of 1 or 3 equiv of galvinoxyl30) as a radical trap reagent, and the ratio of products was estimated from the corresponding integral intensities by 1H-NMR (entries 2 and 3).
 | ||||||
|---|---|---|---|---|---|---|
| Entrya) | Equiv of galvinoxyl | NMR ratio (%) of | ||||
| 25a | 25d | 27d | n-BuLi : sec-BuLi | 1,2- : 1,4- | ||
| 1 | — | 28 | 17 | 55 | 28 : 72 | 45 : 55 |
| 2 | 1 | 47 | 22 | 31 | 47 : 53 | 69 : 31 |
| 3 | 3 | 72 | 15 | 13 | 72 : 28 | 87 : 13 |
a) 26a, 27a, and 26d were not observed.
In the absence of galvinoxyl, compound 27d, resulting from the 1,6-addition of sec-BuLi, was obtained as the major product (entry 1). The ratio of products 25a, 25d, and 27d was estimated by 1H-NMR to be 28 : 17 : 55. The sec-Bu adduct was predominant over the n-Bu adduct, suggesting that sec-BuLi and n-BuLi reacted through different reaction mechanisms. As the amount of galvinoxyl was increased, the formation of sec-Bu adducts markedly decreased and the amount of n-Bu adducts increased (entries 2 and 3). This indicated that the reaction of sec-BuLi mainly occurred through a single-electron transfer pathway.
In conclusion, the regioselectivity of lactones containing naphthalene rings reacting with n-BuLi and sec-BuLi as nucleophiles was investigated. With THF as solvent, HMPA or DMPU as cosolvent, and high steric repulsion in the reaction substrates and nucleophiles, conjugate addition accompanied by dearomatization proceeded readily. Furthermore, conjugate addition of sec-BuLi was strongly suggested to occur through a single-electron transfer pathway. These dearomatization reactions are expected to be developed as a new method for the synthesis of complex compounds from relatively simple starting materials.
All reactions sensitive to air or moisture were carried out under argon atmosphere under anhydrous conditions, unless otherwise noted. Solvents and reagents were used without further purification unless otherwise noted. Oil baths were used to heat reaction mixtures. Analytical TLC was performed using Silica gel 60 F254 plates (0.25 mm, normal phase), Chlomatorex NH TLC plates and Silica gel 60RP-18 F254S plates (0.25 mm, reversed phase). Normal phase flash column chromatography was performed using Silica gel 60 (particle size 40–63 µm; 230–400 mesh ASTM) and Chlomatorex NH-DM1020 (SiO2-NH, average particle size 100 µm). Melting point (mp), determined on a micro melting point apparatus, were uncorrected. IR spectra were recorded using KBr pellets. 1H and proton-decoupled 13C (13C{1H}) NMR spectra (400 and 100 MHz, respectively) were recorded using chloroform-d (CDCl3) and dimethylsulfoxide-d6 (DMSO-d6) as a solvent. Chemical shift values are expressed in δ (ppm) relative to the solvent resonance (CDCl3, δ 7.26 ppm for 1H-NMR and δ 77.0 ppm for 13C-NMR; DMSO-d6, δ 2.54 ppm for 1H-NMR and δ 40.45 ppm for 13C-NMR) or tetramethylsilane (TMS, δ 0.00 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, br = broad, m = multiplet), coupling constants (J; Hz), and integration. Mass spectra were obtained by Fourier transformation ion cyclotron resonance mass spectrometry (FT-ICR-MS) using a spectrometer with electrospray ionization (ESI).
Synthesis of Compounds 6 and 7A hexane solution of n-butyllithium (536 µL, 0.84 mmol, 3 equiv) was added to a THF solution (5 mL) of the 4 (50 mg, 0.28 mmol, 1 equiv) at –78°C. The mixture was stirred for 1 h at –78°C and then quenched with NH4Cl aq. The mixture was allowed to warm up to room temperature (r.t.). The mixture was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, concentrated and purified by chromatography (SiO2, hexane : ethyl acetate = 100 : 3–10 : 1) to give compound 6 (5 mg, 0.03 mmol, 10%) and compound 7 (54 mg, 0.23 mmol, 81%).
Compound 6: Known.20)
Compound 7: White solid; mp 88–89°C; IR (KBr) 3333, 2955, 1589, 1468, 1412 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ: 9.94 (br s, 1H), 7.12 (dd, 1H, J = 1.2, 7.6 Hz), 7.00 (ddd, 1H, J = 1.2, 7.6, 7.6 Hz), 6.71 (ddd, 1H, J = 1.2, 7.6, 7.6 Hz), 6.65 (dd, 1H, J = 1.2, 7.6 Hz), 5.52 (s, 1H), 1.99–1.90 (m, 2H), 1.68–1.61 (m, 2H), 1.33–1.11 (m, 6H), 1.00–0.89 (m, 2H), 0.80–0.75 (m, 6H); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 156.2, 130.2, 127.8, 127.8, 118.9, 116.6, 78.9, 41.6, 26.1, 23.2, 14.6; high resolution (HR) MS (ESI/FT-ICR-MS) Calcd for C15H24O2Na [M + Na]+ 259.1669, Found 259.1671.
General Procedure of Reaction of the Organolithium Reagents and Naphthalene 5A solution of the appropriate lithium reagent (3 equiv) was added to a THF solution of 5 (1.0 equiv) at −78°C. The mixture was stirred for 1 h at −78°C and then treated with NH4Cl aq. The mixture was allowed to warm up to r.t. The mixture was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, concentrated and purified by chromatography (SiO2, hexane : ethyl acetate) to give 1,2-adduct 9 and mixture of 1,2-adduct 10 and 1,4-adduct 11. Then the mixture was again purified by chromatography (SiO2–NH, hexane : ethyl acetate) to give corresponding 1,2-adducts 10 and 1,4-adducts 11.
Compound 9a: Known.21) Yield 5 mg (10%) from 50 mg (0.22 mmol) of 5.
Compound 10a: Known.22) Yield 20 mg (32%) from 50 mg (0.22 mmol) of 5.
Compound 11a: Yield 26 mg (41%) from 50 mg (0.22 mmol) of 5; colorless oil; IR (neat) 1726, 1661, 1458, 1417, 1404 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ: 7.30–7.18 (m, 4H), 3.88 (br s, 1H), 3.80 (dd, 1H, J = 2.8, 2J = 22.0 Hz), 3.48 (d, 1H, 2J = 22.0 Hz), 1.73 (s, 3H), 1.67–1.61 (m, 5H), 1.25–0.94 (m, 4H), 0.78 (t, 3H, J = 7.2 Hz); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 164.7, 160.6, 138.4, 131.8, 128.5, 128.4, 127.1, 126.7, 106.4, 104.1, 37.7, 37.4, 32.3, 28.1, 26.8, 23.8, 22.6, 14.4; HRMS (ESI/FT-ICR-MS) Calcd for C18H23O3 [M + H]+ 287.1642, Found 287.1638.
Compound 9b: Known.23) Yield 4 mg (10%) from 50 mg (0.22 mmol) of 5.
Compound 10b: Known.25) Yield 37 mg (84%) from 50 mg (0.22 mmol) of 5.
Compound 9c: Known.24) Yield 2 mg (4%) from 50 mg (0.22 mmol) of 5.
Compound 10c: Known.26) Yield 59 mg (82%) from 50 mg (0.22 mmol) of 5.
Compound 9d: Yield 4 mg (8%) from 50 mg (0.22 mmol) of 5; yellow oil; IR (neat) 3059, 2967, 1645, 1634, 1514, 1454 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ: 8.53 (s, 1H), 7.99 (d, 1H, J = 8.4 Hz), 7.75 (d, 1H, J = 8.4 Hz), 7.54 (dd, 1H, J = 7.2, 7.2 Hz), 7.36 (dd, 1H, J = 7.2, 7.2 Hz), 7.29 (s, 1H), 3.75 (tq, 1H, J = 6.4, 6.4 Hz), 1.78–1.73 (m, 1H), 1.51–1.46 (m, 1H), 1.17–1.11 (m, 3H), 0.93–0.87 (m, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 210.6, 155.8, 137.3, 132.9, 130.0, 129.6, 127.4, 126.3, 124.3, 124.3, 111.5, 43.3, 26.9, 17.1, 11.9; HRMS (ESI/FT-ICR-MS) Calcd for C15H16O2Na [M + Na]+ 251.1043, Found 251.1049.
Compound 10d (Diastereomeric mixture): Yield 5 mg (8%) from 50 mg (0.22 mmol) of 5; colorless oil; IR (neat) 3420, 2967, 1638, 1516, 1508, 1456 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ: 11.53 (br s, 1H), 7.78 (d, 1H, J = 8.0 Hz), 7.63 (d, 1H, J = 8.4 Hz), 7.59 (s, 1H), 7.36 (dd, 1H, J = 6.8, 6.8 Hz), 7.24 (dd, 1H, J = 6.8, 6.8 Hz), 7.05 (s, 1H), 6.42 (br s, 1H), 2.33–2.12 (m, 1H), 1.94–1.84 (m, 1H), 1.53–1.40 (m, 1H), 1.10–0.78 (m, 15H); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 159.0, 157.8, 133.8, 128.4, 127.5, 126.2, 125.5, 122.9, 110.3, 88.0, 87.4, 43.0, 42.6, 24.7, 22.8, 22.6, 14.3, 13.0, 12.7, 12.4 (many peaks overlapped); HRMS (ESI/FT-ICR-MS) Calcd for C19H26O2Na [M + Na]+ 309.1825, Found 309.1832.
Compound 11d (Diastereomeric mixture): Yield 47 mg (75%) from 50 mg (0.22 Mmol) of 5; colorless oil; IR (neat) 2961, 1724, 1651, 1458, 1417, 1404 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ: 7.29–7.23 (m, 4H), 3.92–3.89 (m, 1H), 3.79–3.73 (m, 1H), 3.51–3.44 (m, 1H), 1.77–1.68 (m, 7H), 1.47–1.36 (m, 1H), 1.11–1.04 (m, 0.5H), 0.90–0.85 (m, 3.5H), 0.71–0.65 (m, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 165.6, 165.2, 160.9, 160.7, 138.1, 136.5, 132.9, 132.5, 129.1, 128.8, 128.4, 128.3, 127.0, 126.7, 126.6, 106.3, 106.1, 103.7, 102.5, 44.5, 43.1, 42.8, 42.5, 33.1, 27.4, 27.2, 26.6, 23.4, 23.1, 16.0, 15.6, 12.6, 12.5 (3C overlapped); HRMS (ESI/FT-ICR-MS) Calcd for C18H23O3 [M + H]+ 287.1642, Found 287.1642.
Synthesis of Compounds 13 and 16K3PO4 (2.7 equiv) was added to a DMF solution (20 v/w) of appropriate naphthoic acid (1 equiv) and CH2I2 (6 equiv). The mixture was stirred for 1 h at 140°C in an oil bath, then the mixture was allowed to cool down to r.t. The mixture was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, concentrated and purified by chromatography (SiO2, hexane : ethyl acetate) to give a corresponding lactone.
Compound 13: Yield 213 mg (40%) from 500 mg (2.66 mmol) of 3-hydroxy-2-naphthoic acid; yellow solid; mp 109–110°C; IR (KBr) 1748, 1641, 1506, 1346 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 8.65 (s, 1H), 7.94 (d, 1H, J = 8.0 Hz), 7.80 (d, 1H, J = 8.0 Hz), 7.61 (ddd, 1H, J = 1.2, 6.8, 6.8 Hz), 7.48 (ddd, 1H, J = 1.2, 6.8, 6.8 Hz), 7.44 (s, 1H), 5.73 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ: 161.8, 153.4, 137.4, 133.1, 129.9, 129.7, 129.5, 127.1, 125.8, 115.2, 112.4, 91.5; HRMS (ESI/FT-ICR-MS) Calcd for C12H9O3 [M + H]+ 201.0546, Found 201.0545.
Compound 16: Yield 319 mg (60%) from 500 mg (2.66 mmol) of 2-hydroxy-1-naphthoic acid; yellow solid; mp 88–89°C; IR (KBr) 1719, 1686, 1520, 1439, 1292 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ: 8.96 (d, 1H, J = 7.6 Hz), 8.29 (d, 1H, J = 9.2 Hz), 8.03 (d, 1H, J = 8.0 Hz), 7.75 (ddd, 1H, J = 1.2, 7.2, 7.2 Hz), 7.58 (ddd, 1H, J = 1.2, 6.8, 6.8 Hz), 7.39 (d, 1H, J = 8.8 Hz), 5.88 (s, 2H); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 161.2, 160.5, 138.6, 131.8, 130.3, 130.0, 129.6, 126.0, 125.5, 117.3, 107.1, 91.0; HRMS (ESI/FT-ICR-MS) Calcd for C12H9O3 [M + H]+ 201.0546, Found 201.0544.
Synthesis of Compounds 14 and 15A mixture of trifluoroacetic acid (0.02 equiv) and trifluoroacetic anhydride (0.01 equiv) was added to an acetone (3 equiv) solution of appropriate naphthoic acid (1 equiv) under ice bath cooling. The mixture was stirred for 24 h at r.t. The organic layer was concentrated and purified by chromatography (SiO2, hexane : ethyl acetate) to give a corresponding lactone.
Compound 14: Yield 286 mg (47%) from 500 mg (2.66 mmol) of 1-hydroxy-2-naphthoic acid; white solid; mp 83–84°C; IR (KBr) 1734, 1719, 1634, 1582, 1508, 1393 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ: 8.18 (d, 1H, J = 7.6 Hz), 8.03 (d, 1H, J = 8.0 Hz), 7.82–7.76 (m, 2H), 7.70–7.67 (m, 2H), 1.81 (s, 6H); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 160.9, 154.1, 137.7, 130.8, 128.8, 127.8, 123.6, 123.5, 122.9, 122.7, 107.7, 107.6, 25.7; HRMS (ESI/FT-ICR-MS) Calcd for C14H12O3Na [M + Na]+ 251.0679, Found 251.0672.
Compound 15: Yield 305 mg (50%) from 500 mg (2.66 mmol) of 2-hydroxy-1-naphthoic acid; white solid; mp 89–90°C; IR (KBr) 1717, 1622, 1518, 1375 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ: 9.06 (d, 1H, J = 8.8 Hz), 8.29 (d, 1H, J = 9.2 Hz), 8.01 (d, 1H, J = 8.0 Hz), 7.72 (ddd, 1H, J = 1.2, 8.4, 8.4 Hz), 7.55 (dd, 1H, J = 7.6, 7.6 Hz), 7.29 (d, 1H, J = 9.2 Hz), 1.76 (s, 6H); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 160.3, 157.8, 139.0, 131.5, 130.1, 130.0, 129.7, 125.8, 125.2, 118.0, 106.1, 105.2, 25.4; HRMS (ESI/FT-ICR-MS) Calcd for C14H12O3Na [M + Na]+ 251.0673, Found 251.0679.
General Procedure of Reaction of n- or sec-Butyllithium and Naphthalenes (Table 2)A hexane solution of n- or sec-butyllithium (3 equiv) was added to a THF solution (100 v/w) of the appropriate naphthalene (1.0 equiv) at −78°C. The mixture was stirred for 1 h at −78°C and then quenched with NH4Cl aq. The mixture was allowed to warm up to r.t. The mixture was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, concentrated and purified by chromatography (SiO2 or SiO2–NH, hexane : ethyl acetate) to give corresponding 1,2-adducts and 1,4-adducts.
Compound 18a: Yield 56 mg (88%) from 50 mg (0.24 mmol) of 12; colorless oil; IR (neat) 3447, 2967, 1751, 1734, 1717, 1506, 1464 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ: 7.99–7.97 (m, 1H), 7.94–7.91 (m, 1H), 7.82 (s, 1H), 7.76 (s, 1H) 7.52–7.46 (m, 2H), 6.18 (s, 1H), 2.00 (tt, 2H, J = 7.2, 7.2 Hz), 1.60 (s, 3H), 1.50 (s, 3H), 1.37–1.21 (m, 3H), 1.05–0.98 (m, 1H), 0.80 (t, 3H, J = 7.2 Hz); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 147.3, 141.7, 134.1, 133.5, 128.8, 128.3, 126.4, 126.0. 121.1, 119.2, 107.1, 83.2, 31.5, 29.8, 27.0, 22.9, 14.5; HRMS (ESI/FT-ICR-MS) Calcd for C18H22O2Na [M + Na]+ 293.1512, Found 293.1513.
Compound 18d (Diastereomeric mixture): Yield 21 mg (33%) from 50 mg (0.24 mmol) of 12; colorless oil; IR (neat) 3460, 2968, 2930, 2876, 1506, 1456 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ: 7.99–7.90 (m, 2H), 7.81–7.80 (m, 1H), 7.75 (s, 1H), 7.51–7.45 (m, 2H), 6.05 (s, 1H), 2.02–1.90 (m, 1H), 1.59 (s, 3H), 1.50–1.49 (m, 3H), 1.35–1.28 (m, 0.5H), 1.14–1.06 (m, 2.5H), 0.92–0.89 (m, 2H), 0.85–0.76 (m, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 147.5, 147.3, 141.7, 141.5, 134.1, 134.1, 133.5, 133.5, 128.8, 128.2, 126.4, 125.9, 121.3, 119.2, 108.9, 83.1, 83.1, 44.4, 43.9, 31.8, 29.4, 29.4, 25.0, 23.2, 15.1, 13.5, 13.0, 12.9 (8C overlapped); HRMS (ESI/FT-ICR-MS) Calcd for C18H22O2Na [M + Na]+ 293.1512, Found 293.1517.
Compound 20d (Diastereomeric mixture): Yield 38 mg (59%) from 50 mg (0.24 mmol) of 12; colorless oil; IR (neat) 3460, 2968, 2930, 2876, 1506, 1456 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ: 7.30–7.29 (m, 4H), 3.78–3.62 (m, 3H), 1.78 (s, 1H), 1.50 (s, 3H), 1.44–1.37 (m, 4H), 1.10–0.99 (m, 1H), 0.92–0.85 (m, 3H), 0.64–0.61 (m, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 171.4, 171.1, 169.7, 168.8, 137.9, 135.9, 134.1, 133.6, 129.9, 129.5, 129.2, 129.0, 127.0, 126.8, 126.7, 125.8, 124.8, 85.5, 44.2, 42.2, 41.5, 41.3, 28.3, 27.2, 26.6, 26.0, 25.8, 24.6, 24.5, 15.7, 15.5, 12.8, 12.7 (3C overlapped); HRMS (ESI/FT-ICR-MS) Calcd for C18H22O2Na [M + Na]+ 293.1512, Found 293.1513.
Compound 21d (Diastereomeric mixture): Yield 18 mg (28%) from 50 mg (0.25 mmol) of 13; yellow oil; IR (neat) 2961, 2930, 1732, 1643, 1414, 1400 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ: 7.31–7.19 (m, 4H), 5.85–5.79 (m, 1H), 5.68–5.65 (m, 1H), 3.95–3.79 (m, 2H), 3.61–3.54 (m, 1H), 1.71–1.62 (m, 1H), 1.50–1.26 (m, 1H), 1.09–0.81 (m, 4H), 0.71–0.63 (m, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 168.6, 168.2, 161.5, 161.4, 137.7, 136.2, 132.1, 131.6, 128.5, 128.2, 127.8, 127.7, 126.5, 126.2, 126.2, 126.1, 105.2, 103.8, 90.1, 89.9, 43.6, 42.4, 42.3, 42.1, 31.9, 31.8, 26.4, 25.1, 15.5, 14.1, 11.9, 11.8; HRMS (ESI/FT-ICR-MS) Calcd for C16H19O3 [M + H]+ 259.1329, Found 259.1329.
Compound 22a: Yield 14 mg (28%) from 50 mg (0.22 mmol) of 14; yellow solid; mp 77–78°C ; IR (KBr) 1626, 1570, 1472, 1408 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ: 8.34 (d, 1H, J = 9.6 Hz), 7.93–7.89 (m, 2H), 7.72 (ddd, 1H, J = 1.2, 6.8, 6.8 Hz), 7.60 (ddd, 1H, J = 1.2, 6.8, 6.8 Hz), 7.42 (d, 1H, J = 8.0 Hz), 3.16 (t, 2H, J = 8.0 Hz), 1.69 (tt, 2H, J = 8.0, 8.0 Hz), 1.45–1.37 (m, 2H), 0.94 (t, 3H, J = 8.0 Hz); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 208.0, 161.6, 137.4, 130.7, 128.1, 126.7, 125.7, 124.9, 124.1, 118.9, 113.3, 38.3, 26.7, 22.3, 14.4; HRMS (ESI/FT-ICR-MS) Calcd for C15H16O2Na [M + Na]+ 251.1043, Found 251.1052.
Compound 23a: Yield 44 mg (70%) from 50 mg (0.22 mmol) of 14; colorless oil; IR (neat) 3435, 3227, 1577, 1466, 1387 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ: 11.4 (s, 1H), 8.12–8.09 (m, 1H), 7.77–7.73 (m, 1H), 7.46–7.40 (m, 2H), 7.28 (d, 1H, J = 8.8 Hz), 7.12 (d, 1H, J = 8.8 Hz), 6.49 (s, 1H), 1.99–1.90 (m, 2H), 1.81–1.72 (m, 2H), 1.48–1.35 (m, 2H), 1.27–1.14 (m, 4H), 1.05–0.93 (m, 2H), 0.78 (t, 6H, J = 7.2 Hz); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 152.8, 133.5, 127.5, 126.3, 125.5, 125.2, 122.4, 120.7, 118.3, 81.7, 43.1, 25.9, 23.0, 14.5 (1C overlapped); HRMS (ESI/FT-ICR-MS) Calcd for C19H27O2 [M + H]+ 287.2006, Found 287.2018.
Compound 22d: Yield 15 mg (30%) from 50 mg (0.22 mmol) of 14; colorless oil; IR (neat) 3061, 2967, 1622, 1599, 1574, 1470, 1416, 1389 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ: 8.35 (d, 1H, J = 7.6 Hz), 7.96–7.92 (m, 2H), 7.73 (ddd, 1H, J = 1.2, 6.8, 6.8 Hz), 7.61 (ddd, 1H, J = 1.2, 6.8, 6.8 Hz), 7.44 (d, 1H, J = 9.2 Hz), 3.71–3.66 (m, 1H), 1.83–1.74 (m, 1H), 1.56–1.45 (m, 1H), 1.19 (d, 3H, J = 6.4 Hz), 0.90 (t, 3H, J = 7.2 Hz); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 211.5, 162.5, 137.5, 130.9, 128.1, 126.8, 125.4, 125.1, 124.2, 118.9, 112.6, 41.5, 27.0, 17.3, 12.0; HRMS (ESI/FT-ICR-MS) Calcd for C15H16O2Na [M + Na]+ 251.1043, Found 251.1051.
Compound 23d (Diastereomeric mixture): Yield 40 mg (63%) from 50 mg (0.22 mmol) of 14; colorless oil; IR (neat) 3566, 3227, 2967, 2936, 2876, 1636, 1575, 1464 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ: 11.98 (br s, 1H), 8.11 (d, 1H, J = 8.0 Hz), 7.77–7.73 (m, 1H), 7.46–7.38 (m, 2H), 7.23 (d, 1H, J = 8.4 Hz), 7.12–7.08 (m, 1H), 6.29 (br s, 1H), 2.15–1.99 (m, 2H), 1.87–1.80 (m, 1H), 1.50–1.18 (m, 1H), 1.00–0.77 (m, 14H); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 154.4, 154.1, 153.8, 133.4, 133.3, 129.4, 128.7, 127.3, 126.3, 126.0, 125.8, 125.5, 125.0, 122.5, 118.5, 118.3, 118.2, 117.3, 117.2, 42.8, 42.6, 42.2, 41.9, 24.7, 24.6, 22.8, 22.7, 14.3, 14.3, 12.7, 12.6, 12.5 (many peaks overlapped); HRMS (ESI/FT-ICR-MS) Calcd for C19H26O2Na [M + Na]+ 309.1825, Found 309.1828.
Compound 25a: Yield 44 mg (88%) from 50 mg (0.22 mmol) of 15; colorless oil; IR (neat) 3366, 2958, 1624, 1574, 1466 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ: 10.33 (br s, 1H), 7.86–7.82 (m, 2H), 7.58 (d, 1H, J = 8.8 Hz), 7.44 (ddd, 1H, J = 1.2, 8.0, 8.0 Hz), 7.32 (ddd, 1H, J = 1.2, 8.0, 8.0 Hz), 7.21 (d, 1H, J = 8.4 Hz), 2.93 (t, 2H, J = 7.2 Hz), 1.63 (tt, 2H, J = 7.2, 7.2 Hz,), 1.59–1.30 (m, 2H), 0.88 (t, 3H, J = 7.2 Hz); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 207.5, 152.9, 131.6, 131.2, 128.7, 128.2, 127.7, 123.6, 123.5, 122.0, 118.7, 44.4, 26.3, 22.4, 14.4; HRMS (ESI/FT-ICR-MS) Calcd for C15H16O2Na [M + Na]+ 251.1043, Found 251.1054.
Compound 25d: Yield 9 mg (18%) from 50 mg (0.22 mmol) of 15; colorless oil; IR (neat) 3198, 2965, 1684, 1624, 1578, 1508, 1458 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 11.97 (s, 1H), 7.92 (d, 1H, J = 8.4 Hz), 7.87 (d, 1H, J = 8.8 Hz), 7.79 (dd, 1H, J = 1.2, 8.0 Hz), 7.54 (ddd, 1H, J = 1.2, 8.0, 8.0 Hz), 7.39 (ddd, 1H, J = 0.8, 7.2, 7.2 Hz), 7.14 (d, 1H, J = 8.8 Hz), 3.66–3.58 (m, 1H), 1.89–1.78 (m, 1H), 1.61–1.50 (m, 1H), 1.33 (d, 2H, J = 6.4 Hz), 0.84 (t, 3H, J = 7.6 Hz); 13C{1H} NMR (100 MHz, CDCl3) δ: 213.2, 160.9, 136.3, 131.6, 129.3, 128.7, 127.8, 124.4, 123.8, 119.5, 116.3, 46.5, 28.3, 17.3, 11.7; HRMS (ESI/FT-ICR-MS) Calcd for C15H16O2Na [M + Na]+ 251.1043, Found 251.1051.
Compound 27d (Diastereomeric mixture): Yield 35 mg (56%) from 50 mg (0.22 mmol) of 15; colorless oil; IR (neat) 2963, 1732, 1622, 1489, 1404 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ: 7.98–7.96 (m, 1H), 7.24–7.20 (m, 1H), 7.17–7.14 (m, 2H), 2.91–2.73 (m, 2H), 2.51–2.41 (m, 1H), 1.72–1.69 (m, 6H), 1.57–1.53 (m, 1H), 1.49–1.24 (m, 1H), 1.18–1.02 (m, 1H), 0.86–0.73 (m, 6H); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 168.7, 158.8, 136.0, 135.5, 129.7, 129.3, 128.9, 127.0, 126.9, 126.3, 126.2, 125.8, 106.5, 106.5, 101.7, 101.6, 42.0, 41.4, 38.3, 37.8, 30.0, 29.0, 27.0, 26.1, 26.0, 24.5, 24.4, 17.2, 15.8, 12.1, 11.7 (5C overlapped); HRMS (ESI/FT-ICR-MS) Calcd for C18H22O3Na [M + Na]+ 309.1461, Found 309.1470.
Compound 28d (Diastereomeric mixture): Yield 18 mg (28%) from 50 mg (0.25 mmol) of 16; colorless oil; IR (neat) 2963, 1736, 1620, 1489, 1450, 1400 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ: 7.76–7.73 (m, 1H), 7.21–7.17 (m, 3H), 5.77–5.75 (m, 1H), 5.65–5.62 (m, 1H), 2.93–2.72 (m, 2H), 2.53–2.45 (m, 1H), 1.54–1.50 (m, 1H), 1.40–1.36 (m, 0.5H), 1.29–1.23 (m, 0.5H), 1.13–0.96 (m, 1H), 0.85–0.68 (m, 6H); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 171.6, 171.6, 160.0, 136.3, 135.7, 129.7, 129.3, 128.9, 127.0, 126.9, 126.7, 126.5, 126.3, 104.6, 104.5, 90.6, 41.9, 41.2, 38.7, 38.1, 29.4, 28.2, 26.9, 25.6, 17.0, 15.6, 12.1, 11.8 (4C overlapped); HRMS (ESI/FT-ICR-MS) Calcd for C16H19O3 [M + H]+ 259.1329, Found 259.1330.
Compound 29a: Yield 10 mg (16%) from 50 mg (0.23 mmol) of 17; colorless oil; IR (neat) 3451, 2954, 2930, 1678, 1626, 1595, 1447 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ: 8.02 (s, 1H), 7.94 (d, 1H, J = 8.0 Hz), 7.84 (d, 1H, J = 8.0 Hz), 7.54 (ddd, 1H, J = 1.2, 8.0, 8.0 Hz), 7.47 (s, 1H), 7.39 (ddd, 1H, J = 1.2, 8.0, 8.0 Hz), 4.91 (t, 1H, J = 4.8 Hz, OH), 4.22–4.19 (m, 2H), 3.84–3.80 (m, 2H), 3.03 (t, 2H, J = 7.2 Hz), 1.62–1.54 (m, 2H), 1.36–1.28 (m, 2H), 0.88 (t, 3H, J = 7.6 Hz); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 203.8, 154.6, 136.0, 131.5, 130.1, 129.3, 128.6, 128.0, 127.0, 124.8, 107.9, 70.7, 60.0, 43.3, 26.7, 22.4, 14.4; HRMS (ESI/FT-ICR-MS) Calcd for C17H20O3Na [M + Na]+ 295.1305, Found 295.1299.
Compound 30a: Yield 52 mg (68%) from 50 mg (0.23 mmol) of 17; colorless oil; IR (neat) 3439, 1633, 1599, 1454 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ: 7.97 (s, 1H), 7.79–7.73 (m, 2H), 7.38 (ddd, 1H, J = 1.2, 8.0, 8.0 Hz), 7.30 (ddd, 1H, J = 1.2, 8.0, 8.0 Hz), 7.23 (s, 1H), 4.84 (t, 1H, J = 4.8 Hz, OH), 4.58 (s, 1H), 4.11–4.08 (m, 2H), 3.82–3.78 (m, 2H), 2.30 (dt, 2H, J = 4.8, 13.2 Hz), 1.67 (dt, 2H, J = 4.8, 13.2 Hz,), 1.29–1.11 (m, 6H), 0.77–0.67 (m, 8H); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 155.0, 136.5, 133.7, 128.5, 128.0, 127.5, 126.4, 126.0, 123.8, 106.5, 78.4, 70.1, 60.2, 40.7, 26.5, 23.2, 14.6; HRMS (ESI/FT-ICR-MS) Calcd for C21H30O3Na [M + Na]+ 353.2087, Found 353.2096.
Compound 31d (Diastereomeric mixture): Yield 30 mg (59%) from 40 mg (0.19 mmol) of 17; colorless oil; IR (neat) 2961, 2926, 1684, 1616, 1584, 1456, 1404 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ: 7.25–7.10 (m, 4H), 4.57–4.50 (m, 2H), 4.47–4.36 (m, 2H), 4.03–4.01 (m, 1H), 3.81 (d, 1H, 2J = 20.4 Hz), 3.43–3.38 (m, 1H), 1.68–1.57 (m, 1H), 1.47–1.24 (m, 1H), 1.16–1.02 (m, 0.5H), 0.90–0.75 (m, 4.5H), 0.60 (d, 2H, J = 6.8 Hz); 13C{1H} NMR (100 MHz, DMSO-d6) δ: 169.1, 168.7, 161.5, 161.2, 139.1, 137.8, 134.2, 134.0, 128.6, 128.4, 127.5, 126.5, 126.4, 126.3, 126.2, 103.8, 103.3, 71.8, 71.7, 66.1, 66.0, 50.0, 49.2, 36.6, 36.5, 27.5, 26.4, 16.8, 16.0, 12.5, 12.0 (3C overlapped); HRMS (ESI/FT-ICR-MS) Calcd for C17H20O3Na [M + Na]+ 295.1305, Found 295.1312.
Reaction of n- or sec-Butyllithium and 15 in the Presence or Absence of Galvinoxyl (Table 3)A mixture of n-butyllithium (3 equiv) and sec-butyllithium (3 equiv) was added to a THF solution (100 v/w) of 15 (1.0 equiv) and galvinoxyl (0 or 1 or 3 equiv) at −78°C. The mixture was stirred for 1 h at −78°C and then quenched with water. The mixture was allowed to warm up to r.t. The mixture was extracted with ethyl acetate, dried over sodium sulfate, and concentrated to give a residue. The ratio of products was estimated from the corresponding integral intensities by 1H-NMR.
The authors are grateful to Ms. Kyohko Ohmine (ICR, Kyoto University) for the NMR measurements and Ms. Akiko Fujihashi (ICR, Kyoto University) for the high resolution mass spectrometry. This study was carried out using the Fourier transform ion cyclotron resonance mass spectrometer and NMR in the Joint Usage/Research Center at the Institute for Chemical Research, Kyoto University. This study was supported in part by KAKENHI (18K19150) and Grant-in-Aid from the Tokyo Biochemical Research Foundation. The authors thank Simon Partridge, Ph.D., for editing a draft of this manuscript.
The authors declare no conflict of interest.
The online version of this article contains supplementary materials.
