Furan-Containing Chiral Spiro-Fused Polycyclic Aromatic Compounds: Synthesis and Photophysical Properties

Spiro-fused polycyclic aromatic compounds (PACs) have received growing interest as rigid chiral scaffolds. However, furan-containing spiro-fused PACs have been quite limited. Here, we design spiro[indeno[1,2-b][1]benzofuran-10,10′-indeno[1,2-b][1]benzothiophene] as a new family of spiro-fused PACs that contains a furan unit. The compound was successfully synthesized in enantiopure form and also transformed to its S,S-dioxide derivative and the pyrrole-containing analog via aromatic metamorphosis. The absorption and emission properties of the obtained furan-containing chiral spiro-fused PACs are apparently different from those of their thiophene analogs that have been reported, owing to the increased electron-richness of furan compared to thiophene. All of the furan-containing chiral spiro-fused PACs were found to be circularly polarized luminescent materials.

When two dissymmetric biaryls are linked by a spiro atom, the resulting spiro compound is chiral. Two different dissymmetric biaryls give a C 1 -symmetric spiro compound, while two identical dissymmetric biaryls afford a C 2 -symmetric one. Although chiral spiro-fused PACs have attracted less attention until recently, there have been several reports on their applications to molecular recognition [17,18], diastereoselective selfassembly [19,20], and asymmetric catalysts [21,22]. In 2016, Kuninobu, Takai, and coworkers reported the first example of a chiral spiro-fused PAC [23] that exhibited circularly polarized luminescence (CPL), which has received significant interest, owing to its potential applications [24][25][26][27][28]. This report has triggered many studies on spiro-fused PACs that exhibit CPL [29][30][31][32][33][34][35][36][37]. We have also developed a series of chiral spiro-fused PACs, such as spiro-SS, -SS(O) 2 , and -SN ( Figure 1) [16,[38][39][40][41][42]. These spiro-fused PACs exhibit CPL In the course of our studies, we have focused on incorporating a furan unit in a chiral spiro-fused PAC skeleton. Furan, the oxygen analog of thiophene, has reduced aromaticity and is more electron-rich compared to thiophene [43]. Therefore, the electronic perturbation of a furan unit to a π-conjugated system would be different from that of a thiophene unit, inducing unique electronic and photophysical properties. To date, a wide range of furan-containing π-conjugated compounds have been reported as organic functional materials [44][45][46][47][48]. However, the synthetic attempt of spiro-fused PACs containing furan unit(s) have been quite limited. In 2010, Ohe and co-workers reported the first examples of furan-containing spiro-fused PACs [49,50]. These compounds were found to be highly emissive. More recently, the chiral spiro-fused PAC with a furan unit has been reported by Nakamura and co-workers, demonstrating CPL properties [35]. Herein, we report the synthesis and photophysical properties of furan-containing chiral spiro-fused PACs 1-3, which are oxygen analogs of spiro-SS, -SS(O)2, and -SN ( Figure 1). The S,S-dioxide derivative 2 and the pyrrole-containing compound 3 can be synthesized from 1 through aromatic metamorphosis. Incorporation of a furan unit in place of a thiophene unit was found to have great impact on photophysical properties.

Results
Our first attempt to prepare racemic 1 (rac-1) is illustrated in Scheme 1. 3-Bromo-2-(bromophenyl)-1-benzothiophene (4) was dilithiated with BuLi, and then treated with the ester 5. The subsequent Friedel-Crafts cyclization of the resulting tertiary alcohol 6 successfully gave the desired compound rac-1 (37% yield from 4). The structure was confirmed by X-ray crystallographic analysis ( Figure 2). Both enantiomers were found to be contained in the unit cell. The two spiro-linked π-conjugated planes are almost completely perpendicular (87.3°). Screening of optical resolution conditions with HPLC on a chiral stationary phase (chiral HPLC) showed that baseline separation of enantiomers cannot be achieved. In the course of our studies, we have focused on incorporating a furan unit in a chiral spiro-fused PAC skeleton. Furan, the oxygen analog of thiophene, has reduced aromaticity and is more electron-rich compared to thiophene [43]. Therefore, the electronic perturbation of a furan unit to a π-conjugated system would be different from that of a thiophene unit, inducing unique electronic and photophysical properties. To date, a wide range of furan-containing π-conjugated compounds have been reported as organic functional materials [44][45][46][47][48]. However, the synthetic attempt of spiro-fused PACs containing furan unit(s) have been quite limited. In 2010, Ohe and co-workers reported the first examples of furan-containing spiro-fused PACs [49,50]. These compounds were found to be highly emissive. More recently, the chiral spiro-fused PAC with a furan unit has been reported by Nakamura and co-workers, demonstrating CPL properties [35]. Herein, we report the synthesis and photophysical properties of furan-containing chiral spiro-fused PACs 1-3, which are oxygen analogs of spiro-SS, -SS(O) 2 , and -SN ( Figure 1). The S,S-dioxide derivative 2 and the pyrrole-containing compound 3 can be synthesized from 1 through aromatic metamorphosis. Incorporation of a furan unit in place of a thiophene unit was found to have great impact on photophysical properties.

Results
Our first attempt to prepare racemic 1 (rac-1) is illustrated in Scheme 1. 3-Bromo-2-(bromophenyl)-1-benzothiophene (4) was dilithiated with BuLi, and then treated with the ester 5. The subsequent Friedel-Crafts cyclization of the resulting tertiary alcohol 6 successfully gave the desired compound rac-1 (37% yield from 4). The structure was confirmed by X-ray crystallographic analysis ( Figure 2). Both enantiomers were found to be contained in the unit cell. The two spiro-linked π-conjugated planes are almost completely perpendicular (87.3 • ). Screening of optical resolution conditions with HPLC on a chiral stationary phase (chiral HPLC) showed that baseline separation of enantiomers cannot be achieved.  In order to prepare each enantiomer of 1, we designed the hydroxy-substituted spiro compound 11, which would be converted into 1 via a two-step reaction (Scheme 2). Previously, Lützen and co-workers have reported the efficient optical resolution of 9,9′-spirobi[fluorene]-2,2′-diol and its derivatives with chiral HPLC [51]. We have also demonstrated that the dihydroxylated derivative of spiro-SS can be separated into enantiomers with chiral HPLC more efficiently than its parent compound spiro-SS [39]. Furthermore, Nakamura and co-workers reported the optical resolution of the furan-containing chiral spiro-fused PAC with one hydroxy group by using chiral HPLC [35]. Accordingly, we envisaged that incorporation of a hydroxy group on 1 would make an efficient optical resolution with chiral HPLC possible.
The synthesis of the hydroxy-substituted compound 11 and its transformation to 1 are illustrated in Scheme 2. First, 2-(2-bromo-4-methoxyphenyl)-1-benzothiophene (7) was lithiated with BuLi, and then treated with 10H-indeno[1,2-b] [1]benzofuran-10-one (8). The resulting tertiary alcohol 9 was converted into the methoxy-substituted spiro compound rac-10 via acid-promoted Friedel-Crafts cyclization (66% yield from 8). Finally, demethylation of rac-10 with BBr3 gave the hydroxy-substituted compound 11 (58% yield) in a racemic form. As expected, the optical resolution of rac-11 was achieved by HPLC with a CHIRALPAK ® IA column with hexane/CHCl3 (50/50) as an eluent ( Figure S18). In addition, the hydroxy group of 11 was found to be cleaved off via the transformation to the  In order to prepare each enantiomer of 1, we designed the hydroxy-substituted spiro compound 11, which would be converted into 1 via a two-step reaction (Scheme 2). Previously, Lützen and co-workers have reported the efficient optical resolution of 9,9′-spirobi[fluorene]-2,2′-diol and its derivatives with chiral HPLC [51]. We have also demonstrated that the dihydroxylated derivative of spiro-SS can be separated into enantiomers with chiral HPLC more efficiently than its parent compound spiro-SS [39]. Furthermore, Nakamura and co-workers reported the optical resolution of the furan-containing chiral spiro-fused PAC with one hydroxy group by using chiral HPLC [35]. Accordingly, we envisaged that incorporation of a hydroxy group on 1 would make an efficient optical resolution with chiral HPLC possible.
The synthesis of the hydroxy-substituted compound 11 and its transformation to 1 are illustrated in Scheme 2. First, 2-(2-bromo-4-methoxyphenyl)-1-benzothiophene (7) was lithiated with BuLi, and then treated with 10H-indeno[1,2-b] [1]benzofuran-10-one (8). The resulting tertiary alcohol 9 was converted into the methoxy-substituted spiro compound rac-10 via acid-promoted Friedel-Crafts cyclization (66% yield from 8). Finally, demethylation of rac-10 with BBr3 gave the hydroxy-substituted compound 11 (58% yield) in a racemic form. As expected, the optical resolution of rac-11 was achieved by HPLC with a CHIRALPAK ® IA column with hexane/CHCl3 (50/50) as an eluent ( Figure S18). In addition, the hydroxy group of 11 was found to be cleaved off via the transformation to the In order to prepare each enantiomer of 1, we designed the hydroxy-substituted spiro compound 11, which would be converted into 1 via a two-step reaction (Scheme 2). Previously, Lützen and co-workers have reported the efficient optical resolution of 9,9spirobi[fluorene]-2,2 -diol and its derivatives with chiral HPLC [51]. We have also demonstrated that the dihydroxylated derivative of spiro-SS can be separated into enantiomers with chiral HPLC more efficiently than its parent compound spiro-SS [39]. Furthermore, Nakamura and co-workers reported the optical resolution of the furan-containing chiral spiro-fused PAC with one hydroxy group by using chiral HPLC [35]. Accordingly, we envisaged that incorporation of a hydroxy group on 1 would make an efficient optical resolution with chiral HPLC possible.

Scheme 2.
Synthesis of the hydroxy-substituted spiro compound 11 and its transformation to 1.
A benzothiophene skeleton can be transformed to an indole one by aromatic metamorphosis, which includes oxidation of a thiophene unit and the inter/intra molecular SNAr reaction of the resulting S,S-dioxide unit with a primary amine [52]. Recently, we applied this transformation to spiro-SS [40]. The resulting spiro-fused compounds with one [spiro-SS(O)2] or two S,S-dioxide units or with one (spiro-SN) or two pyrrole units showed photophysical properties that were quite different from the parent compound spiro-SS. In this context, we investigated the transformation of 1 to the S,S-dioxide derivative 2 and the pyrrole-containing compound 3 (Scheme 3). The oxidation of rac-1 was readily achieved by using an excess amount of 3-chloroperbenzoic acid (mCPBA) as an oxidant, affording rac-2 in high yield (96%). Furthermore, the reaction of rac-2 with aniline in the presence of KHMDS (potassium hexamethyldisilazide) successfully gave rac-3 in a moderate yield (64%). Enantiomers of 2 and 3 were also prepared from enantiopure 1. The oxidation and the inter/intra molecular SNAr reaction should not affect the chiral center. Therefore, these transformations could proceed without racemization to afford enantiopure 2 and 3. A benzothiophene skeleton can be transformed to an indole one by aromatic metamorphosis, which includes oxidation of a thiophene unit and the inter/intra molecular S N Ar reaction of the resulting S,S-dioxide unit with a primary amine [52]. Recently, we applied this transformation to spiro-SS [40]. The resulting spiro-fused compounds with one [spiro-SS(O) 2 ] or two S,S-dioxide units or with one (spiro-SN) or two pyrrole units showed photophysical properties that were quite different from the parent compound spiro-SS. In this context, we investigated the transformation of 1 to the S,S-dioxide derivative 2 and the pyrrole-containing compound 3 (Scheme 3). The oxidation of rac-1 was readily achieved by using an excess amount of 3-chloroperbenzoic acid (mCPBA) as an oxidant, affording rac-2 in high yield (96%). Furthermore, the reaction of rac-2 with aniline in the presence of KHMDS (potassium hexamethyldisilazide) successfully gave rac-3 in a moderate yield (64%). Enantiomers of 2 and 3 were also prepared from enantiopure 1. The oxidation and the inter/intra molecular S N Ar reaction should not affect the chiral center. Therefore, these transformations could proceed without racemization to afford enantiopure 2 and 3.

Scheme 2.
Synthesis of the hydroxy-substituted spiro compound 11 and its transformation to 1.
A benzothiophene skeleton can be transformed to an indole one by aromatic metamorphosis, which includes oxidation of a thiophene unit and the inter/intra molecular SNAr reaction of the resulting S,S-dioxide unit with a primary amine [52]. Recently, we applied this transformation to spiro-SS [40]. The resulting spiro-fused compounds with one [spiro-SS(O)2] or two S,S-dioxide units or with one (spiro-SN) or two pyrrole units showed photophysical properties that were quite different from the parent compound spiro-SS. In this context, we investigated the transformation of 1 to the S,S-dioxide derivative 2 and the pyrrole-containing compound 3 (Scheme 3). The oxidation of rac-1 was readily achieved by using an excess amount of 3-chloroperbenzoic acid (mCPBA) as an oxidant, affording rac-2 in high yield (96%). Furthermore, the reaction of rac-2 with aniline in the presence of KHMDS (potassium hexamethyldisilazide) successfully gave rac-3 in a moderate yield (64%). Enantiomers of 2 and 3 were also prepared from enantiopure 1. The oxidation and the inter/intra molecular SNAr reaction should not affect the chiral center. Therefore, these transformations could proceed without racemization to afford enantiopure 2 and 3. The UV-vis absorption and photoluminescence (PL) spectra of spiro-fused PACs 1-3 are shown in Figure 3. The photophysical data are summarized in Table 1, together with those of the previously reported spiro-SS, spiro-SS(O) 2 , and spiro-SN for comparison.
We also performed theoretical calculations by density functional theory (DFT) and timedependent (TD) DFT methods at the B3LYP/6-31G(d) level of theory to understand the experimental photophysical properties. The UV-vis absorption and photoluminescence (PL) spectra of spiro-fused PACs 1-3 are shown in Figure 3. The photophysical data are summarized in Table 1, together with those of the previously reported spiro-SS, spiro-SS(O)2, and spiro-SN for comparison. We also performed theoretical calculations by density functional theory (DFT) and timedependent (TD) DFT methods at the B3LYP/6-31G(d) level of theory to understand the experimental photophysical properties.  Compound rac-1 gave a well-resolved absorption spectrum, with the longest absorption maximum (λabs) at 337 nm ( Figure 3a). In contrast, the absorption spectrum of the S,Sdioxide derivative rac-2 exhibited well-resolved absorption bands in the <340 nm range and broad absorption bands in the longer wavelength range. Such a difference in the absorption properties between rac-1 and rac-2 is the same as that observed for spiro-SS and spiro-SS(O)2 [38]. By analogy with the discussion on spiro-SS and spiro-SS(O)2 in our previous report, the well-resolved absorption bands and the broader absorption bands were derived from the indeno[1,2-b] [1]benzofuran subunit and the indeno[1,2-b] [1]benzothiophene S,S-dioxide subunit, respectively. Each of these two subunits works as an almost-independent chromophore, since their perpendicular arrangement through a spiro carbon atom allows a limited orbital interaction between them in the ground state. The absorption spectrum of rac-3 is slightly broader and red-shifted in comparison to that of rac-1, exhibiting a shoulder peak at 353 nm. The absorption spectra of rac-1-3 are almost independent of solvent polarity ( Figure S19a-c). The TD-DFT calculations demonstrated that the spiro-fused PACs rac-1-3 exhibit the calculated longest absorption bands at 352 nm, 428 nm, and 361 nm, respectively, all of which are assigned to the transitions dominated by the HOMO→LUMO transition (Table S5). The obtained calculation results are qualitatively coincident with their experimental absorption spectra. The absorption spectra of rac-1-3 are very similar to those of their thiophene analogs spiro-SS, -SS(O)2, and -  Compound rac-1 gave a well-resolved absorption spectrum, with the longest absorption maximum (λ abs ) at 337 nm ( Figure 3a). In contrast, the absorption spectrum of the S,S-dioxide derivative rac-2 exhibited well-resolved absorption bands in the <340 nm range and broad absorption bands in the longer wavelength range. Such a difference in the absorption properties between rac-1 and rac-2 is the same as that observed for spiro-SS and spiro-SS(O) 2 [38]. By analogy with the discussion on spiro-SS and spiro-SS(O) 2 in our previous report, the well-resolved absorption bands and the broader absorption bands were derived from the indeno[1,2-b] [1]benzofuran subunit and the indeno[1,2b][1]benzothiophene S,S-dioxide subunit, respectively. Each of these two subunits works as an almost-independent chromophore, since their perpendicular arrangement through a spiro carbon atom allows a limited orbital interaction between them in the ground state. The absorption spectrum of rac-3 is slightly broader and red-shifted in comparison to that of rac-1, exhibiting a shoulder peak at 353 nm. The absorption spectra of rac-1-3 are almost independent of solvent polarity ( Figure S19a-c). The TD-DFT calculations demonstrated that the spiro-fused PACs rac-1-3 exhibit the calculated longest absorption bands at 352 nm, 428 nm, and 361 nm, respectively, all of which are assigned to the transitions dominated by the HOMO→LUMO transition (Table S5). The obtained calculation results are qualitatively coincident with their experimental absorption spectra. The absorption spectra of rac-1-3 are very similar to those of their thiophene analogs spiro-SS, -SS(O) 2 , and -SN, respectively [38,40]. Therefore, the replacement of a thiophene unit with a furan unit was found to have little impact on absorption properties.
In the PL spectra, rac-1 exhibited emission maximum (λ em ) at 369 nm in CH 2 Cl 2 ( Figure 3b). A slight red-shift was observed with an increase in solvent polarity (λ em : 361 nm (hexane), 366 nm (toluene), 366 nm (THF), 369 nm (CH 2 Cl 2 ), and 381 nm (acetonitrile) Figure S19d). The S,S-dioxide derivative rac-2 exhibited emission maximum at 434 nm in non-polar hexane, which is largely red-shifted compared to that of rac-1. With the increase in solvent polarity, a significant positive solvatochromic shift was observed (Figure 4a). In addition, the second emission band clearly appeared at the longer wavelength (519 nm) in CH 2 Cl 2 and became predominant in the most polar acetonitrile (542 nm). According to our previous report [38], the shorter-wavelength emission band reflects the feature of the indeno[1,2-b] [1]benzothiophene S,S-dioxide subunit. On the other hand, the longer-wavelength one could be ascribed to the photo-induced intramolecular charge transfer (ICT), in which the indeno[1,2-b] [1]benzofuran and the indeno[1,2-b] [1]benzothiophene S,S-dioxide subunits work as electron-donating and electron-accepting units, respectively. Indeed, the HOMO and LUMO estimated by DFT calculation are mainly localized in indeno[1,2-b] [1]benzofuran and the indeno[1,2-b] [1]benzothiophene S,S-dioxide subunits, respectively, by reflecting the donor-acceptor-type structure ( Figure 5). The emission band of the pyrrole-containing compound rac-3 is also red-shifted compared to that of rac-1. In addition, the PL spectrum of rac-3 exhibited a stronger dependence on solvent polarity than that of rac-1 (Figure 4b). The HOMO of rac-3 is delocalized both on indeno [ SN, respectively [38,40]. Therefore, the replacement of a thiophene unit with a furan unit was found to have little impact on absorption properties. In the PL spectra, rac-1 exhibited emission maximum (λem) at 369 nm in CH2Cl2 (Figure 3b). A slight red-shift was observed with an increase in solvent polarity (λem: 361 nm (hexane), 366 nm (toluene), 366 nm (THF), 369 nm (CH2Cl2), and 381 nm (acetonitrile) Figure S19d). The S,S-dioxide derivative rac-2 exhibited emission maximum at 434 nm in nonpolar hexane, which is largely red-shifted compared to that of rac-1. With the increase in solvent polarity, a significant positive solvatochromic shift was observed (Figure 4a). In addition, the second emission band clearly appeared at the longer wavelength (519 nm) in CH2Cl2 and became predominant in the most polar acetonitrile (542 nm). According to our previous report [38], the shorter-wavelength emission band reflects the feature of the indeno[1,2-b] [1]benzothiophene S,S-dioxide subunit. On the other hand, the longer-wavelength one could be ascribed to the photo-induced intramolecular charge transfer (ICT), in which the indeno[1,2-b] [1]benzofuran and the indeno[1,2-b] [1]benzothiophene S,S-dioxide subunits work as electron-donating and electron-accepting units, respectively. Indeed, the HOMO and LUMO estimated by DFT calculation are mainly localized in indeno[1,2-b] [1]benzofuran and the indeno[1,2-b] [1]benzothiophene S,S-dioxide subunits, respectively, by reflecting the donor-acceptor-type structure ( Figure 5). The emission band of the pyrrole-containing compound rac-3 is also red-shifted compared to that of rac-1. In addition, the PL spectrum of rac-3 exhibited a stronger dependence on solvent polarity than that of rac-1 (Figure 4b   Next, the effect of the furan unit on the emission properties of rac-1-3 was evaluated through a comparison with those of the thiophene analogs spiro-SS, SS(O)2, and -SN. As described above, the PL spectrum of rac-2 in CH2Cl2 clearly shows the longer-wavelength emission band, owing to a photo-induced ICT, and it is predominant in acetonitrile (Figure 4a). On the other hand, such an emission band is less clear and observed only as a Next, the effect of the furan unit on the emission properties of rac-1-3 was evaluated through a comparison with those of the thiophene analogs spiro-SS, SS(O) 2 , and -SN. As described above, the PL spectrum of rac-2 in CH 2 Cl 2 clearly shows the longerwavelength emission band, owing to a photo-induced ICT, and it is predominant in acetonitrile (Figure 4a). On the other hand, such an emission band is less clear and observed only as a shoulder in the case of spiro-SS(O) 2 [38]. This difference could be attributed to the more electron-rich furan unit, which works as a stronger electron-donating unit and allows more efficient photo-induced ICT. The degree of the solvatochromic shift of rac-3 (λ em : 374 nm (hexane) and 421 (acetonitrile)) ( Figure 4b) is slightly smaller than that of the thiophene analog spiro-SN (λ em : 375 nm (hexane) and 430 (acetonitrile)) [40].  (Table 1), which are much higher than those of spiro-SS (0.06) and spiro-SN (0.02) [38,40]. The S,S-dioxide derivative rac-2 is merely emissive (<0.01), similar to spiro-SS(O) 2 [38].

General Procedures
All manipulations that involved air-and/or moisture-sensitive compounds were carried out with the standard Schlenk technique under argon. Analytical thin-layer chromatography was performed on glass plates coated with 0.25-mm 230-400 mesh silica gel that contained a fluorescent indicator. Column chromatography was performed by using silica gel (spherical neutral, particle size 63-210 µm). The recycling preparative HPLC was performed with YMC-GPC T-2000 and T-4000 columns (chloroform as an eluent). Most of the reagents were purchased from commercial suppliers, such as Sigma-Aldrich Co. LLC (St. Louis, MO, USA), Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan), and Kanto Chemical Co., Inc. (Tokyo, Japan), and used without further purification, unless otherwise specified. Commercially available anhydrous solvents were used for air-and/or moisture sensitive reactions. Compound 4 was prepared according to the literature [53].
NMR spectra were recorded in CDCl 3 on a JEOL-ECX400 spectrometer (JEOL Ltd., Tokyo, Japan) ( 1 H 400 MHz; 13 C 101 MHz; 19 F 376 MHz). Chemical shifts were reported in ppm relative to the internal standard signal (0 ppm for Me 4 Si in CDCl 3 and acetoned 6 ) for 1 H and the deuterated solvent signal (77.16 ppm for CDCl 3 and 29.84 ppm for acetone-d 6 ) for 13 C. Data are presented as follows: chemical shift, multiplicity (s = singlet, brs = broad singlet, d = doublet, t = triplet, m = multiplet and/or multiple resonances), coupling constant in hertz (Hz), and signal area integration in natural numbers. Melting points were determined on SRS OptiMelt melting point apparatus (Stanford Research Systems, Sunnyvale, CA, USA). High resolution mass spectra were taken with a Bruker Daltonics micrOTOF-QII mass spectrometer (Bruker Corporation, Billerica, MA, USA) by the atmospheric pressure chemical ionization-time-of-flight (APCI-TOF) method. UV-vis absorption spectra were recorded on a JASCO V-650 spectrophotometer (JASCO Corporation, Tokyo, Japan). Photoluminescence spectra were recorded on a JASCO FP-6500 spectrofluorometer (JASCO Corporation, Tokyo, Japan). Absolute quantum yields were determined by an absolute quantum yield measurement system with a JASCO ILF-533 integrating sphere (JASCO Corporation, Tokyo, Japan). HPLC analyses and optical resolution were carried out using a DAICEL CHIRALPAK ® IA-3 column (4.6 mm × 250 mm) and a DAICEL CHIRALPAK ® IA column (20 mm × 250 mm) (Daicel Corporation, Tokyo, Japan), respectively. Circular dichroism (CD) spectra were recorded on a JASCO J-725 spectrometer (JASCO Corporation, Tokyo, Japan). CPL spectra were measured by using a JASCO CPL-300 spectrometer (JASCO Corporation, Tokyo, Japan). Optical rotations were measured on a JASCO P-2200 polarimeter (JASCO Corporation, Tokyo, Japan) using a 50-mm cell.
The obtained crude residue was dissolved in CH2Cl2 (7 mL). To the solution, trifluoroacetic acid (1.5 mL) was added at ambient temperature, and the reaction mixture was stirred at ambient temperature for 6 h, before being quenched with aqueous saturated NaHCO3. The resulting mixture was extracted with CH2Cl2 (10 mL × 4), and the combined in anhydrous THF (15 mL) was slowly added to the reaction mixture at −78 • C, and the resulting mixture was stirred at −78 • C for 1 h, warmed to ambient temperature, and then stirred for 18 h, before being quenched with water. The resulting mixture was extracted with EtOAc (5 mL × 3), and the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting crude residue containing the tertiary alcohol 6 was used in the following step without purification.
The obtained crude residue was dissolved in CH 2 Cl 2 (7 mL). To the solution, trifluoroacetic acid (1.5 mL) was added at ambient temperature, and the reaction mixture was stirred at ambient temperature for 6 h, before being quenched with aqueous saturated NaHCO 3 . The resulting mixture was extracted with CH 2 Cl 2 (10 mL × 4), and the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting crude residue was purified by silica-gel column chromatography with hexane (R f = 0.38) as an eluent to give rac-1 as a colorless solid

2-(2-Bromo-4-methoxyphenyl)-1-benzothiophene (7)
A mixture of (1-benzothiophen-2-yl)boronic acid (99 mg, 0.55 mmol), 2-bromo-1-iodo-4-methoxybenzene (0.15 g, 0.49 mmol), Na 2 CO 3 (0.11 g, 1.1 mmol), and Pd(PPh 3 ) 4 (29 mg, 25 µmol) in anhydrous 1,4-dioxane (2.1 mL) and deionized water (0.30 mL) was placed in a 30-mL Schlenk tube and degassed by three freeze-pump-thaw cycles. After stirring at 90 • C for 48 h under argon, the reaction mixture was cooled to room temperature. To the reaction mixture, 1 M aqueous HCl was slowly added, and the resulting mixture was extracted with CH 2 Cl 2 (5 mL × 3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting crude residue was purified by silica-gel column chromatography with hexane/EtOAc (9/1, R f = 0.52) as an eluent and preparative HPLC to give 7 as a colorless solid (0.11 g, 67% yield): mp mg, 25 μmol) in anhydrous 1,4-dioxane (2.1 mL) and deionized water (0.30 mL) was placed in a 30-mL Schlenk tube and degassed by three freeze-pump-thaw cycles. After stirring at 90 °C for 48 h under argon, the reaction mixture was cooled to room temperature. To the reaction mixture, 1 M aqueous HCl was slowly added, and the resulting mixture was extracted with CH2Cl2 (5 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by silica-gel column chromatography with hexane/EtOAc (9/1, Rf = 0.52) as an eluent and preparative HPLC to give 7 as a colorless solid (0.11 g, 67% yield): mp 82. 3 (13) To a solution of 5 (1.75 g, 6.9 mmol) in methanol (20 mL), a mixture of NaOH (1.68 g, 42 mmol) and water (20 mL) was added at room temperature. After stirring at 60 °C for 4.5 h, the reaction mixture was cooled to room temperature and acidified with 1 M aqueous HCl. The resulting mixture was extracted with Et2O (10 mL × 4). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 5 as a colorless solid (1.60 g, 97% yield); mp 132.  (13) To a solution of 5 (1.75 g, 6.9 mmol) in methanol (20 mL), a mixture of NaOH (1.68 g, 42 mmol) and water (20 mL) was added at room temperature. After stirring at 60 • C for 4.5 h, the reaction mixture was cooled to room temperature and acidified with 1 M aqueous HCl. The resulting mixture was extracted with Et 2 O (10 mL × 4). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give 5 as a colorless solid (1.60 g, 97% yield); mp 132.8-135. A mixture of 13 (3.83 g, 16 mmol) and thionyl chloride (1.4 mL, 19 mmol) in anhydrous CH 2 Cl 2 (160 mL) was placed in a 300-mL three-neck flask with a condenser at ambient temperature. To the mixture, anhydrous DMF (100 µL) was added, and the resulting mixture was stirred for 1.5 h at 40 • C. The volatiles were removed under reduced pressure to afford the acid chloride intermediate.
A mixture of AlCl 3 (3.26 g, 24 mmol) and anhydrous CH 2 Cl 2 (180 mL) was charged in a 500-mL three-neck flask with a condenser and a dropping funnel and cooled at 0 • C. To the mixture, a solution of the acid chloride intermediate in anhydrous CH 2 Cl 2 (160 mL) was slowly added via the dropping funnel over 2 h at 0 • C under argon atmosphere. The reaction mixture was stirred for 18 h at 40 • C, cooled to ambient temperature, and then poured into ice-cooled 1 M aqueous HCl. The resulting mixture was extracted with CH 2 Cl 2 (100 mL × 3), and the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting crude residue was purified by silica-gel column chromatography with hexane/EtOAc (9/1, R f = 0.49) as an eluent to give 8 as an orange solid (1.44 g, 41% yield). The 1 H and 13 C NMR data were identical to those reported in the literature [55].
The resulting residue was dissolved in CH 2 Cl 2 (10 mL) and cooled to 0 • C. To the solution, trifluoroacetic acid (0.4 mL) was added at 0 • C, and the reaction mixture was stirred at 0 • C for 1 h, before being quenched with aqueous saturated NaHCO 3 . The resulting mixture was extracted with CH 2 Cl 2 (10 mL × 3), and the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting crude residue was purified by silica-gel column chromatography with hexane/EtOAc (9/1, R f = 0.49) as an eluent to give rac-10 as a colorless solid (0.  To a mixture of rac-10 (1.04 g, 2.4 mmol,) and anhydrous CH 2 Cl 2 (24 mL), BBr 3 (1 M in CH 2 Cl 2 , 4.7 mL, 4.7 mmol) was added dropwise at 0 • C. After stirring at 0 • C for 2.5 h, the reaction was quenched with water. The resulting mixture was extracted with CH 2 Cl 2 (15 mL × 3) and the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting crude residue was purified by silica-gel column chromatography with hexane/EtOAc (3/1, R f = 0.46) as an eluent to give rac-11 as a colorless solid (0.59 g, 58% yield). rac-11 can be separated into enantiopure  A mixture of rac-11 (82 mg, 0.19 mmol) and anhydrous triethylamine (0.14 mL, 1.0 mmol) in anhydrous CH 2 Cl 2 (2 mL) was placed in a 20-mL Schlenk tube and cooled to -78 • C. To the mixture, trifluoromethanesulfonic anhydride (45 µL, 0.27 mmol) was added dropwise, and the resulting mixture was stirred at -78 • C for 30 min. The reaction was quenched with water, and then the resulting mixture was extracted with CH 2 Cl 2 (5 mL × 3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting crude residue was purified by silica-gel column chromatography with hexane/EtOAc (9/1, R f = 0.43) as an eluent to give rac-12 as a colorless solid (92 mg, 85% yield); 1  , 561.0437, found 561.0443. The crude product of (+)-12 was also obtained by using (+)-11 (62 mg, 0.14 mmol), anhydrous triethylamine (0.10 mL, 0.72 mmol), and trifluoromethanesulfonic anhydride (32 µL, 0.20 mmol), according to the procedure for rac-12. Purification by silica-gel column chromatography with hexane/EtOAc (9/1, R f = 0.43) as an eluent gave (+)-12 as a colorless solid (70 mg, 87% yield): [α] D 25 +128 (c 0.158, CH 2 Cl 2 ). The 1 H and 13 C NMR spectra were identical to those of rac-12. , and anhydrous DMF (1.0 mL) was placed in a 20-mL Schlenk tube and degassed by three freeze-pump-thaw cycles. After stirring at 80 • C for 2 h under argon, the reaction mixture was cooled to room temperature. The reaction was quenched by adding 1 M aqueous HCl slowly, and the resulting mixture was extracted with CH 2 Cl 2 (5.0 mL × 3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting crude residue was purified by silica-gel column chromatography with hexane/EtOAc (9/1, R f = 0.70) as an eluent to give rac-1 as a colorless solid (40 mg, 96% yield). The 1 H and 13 C NMR spectra were identical to those of rac-1 described above.

Computational Studies
The DFT and TD-DFT calculations were performed by using the Gaussian 09 program [56] at the B3LYP/6-31G(d) level of theory in the gas phase. The starting molecular models for DFT geometry optimizations were built and optimized with MMFF molecular mechanics by using the Spartan '08 package (Wavefunction, Inc., Irvine, CA, USA). Six singlet states were calculated in the TD-DFT calculations. The visualization of the molecular orbitals was performed using GaussView 5.

X-ray Crystallography
For X-ray crystallographic analysis, a suitable single crystal was selected under ambient conditions, mounted using a nylon loop filled with paraffin oil, and transferred to the goniometer of a RIGAKU R-AXIS RAPID diffractometer (Rigaku Corporation, Tokyo, Japan), with graphite-monochromated Cu-Kα irradiation (λ = 1.54187 Å). The structure was solved by a direct method (SIR 2008 [57]) and refined by full-matrix least-squares techniques against F 2 (SHELXL-2014 [58,59]). The intensities were corrected for Lorentz and polarization effects. All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were placed using AFIX instructions.