Lipase-Catalyzed Kinetic Resolution of C₁-Symmetric Heterocyclic Biaryls

Abstract

The highly enantioselective lipase-catalyzed kinetic resolution (KR) of racemic C₁-symmetric biaryl compounds including heterocyclic moieties, such as carbazole and dibenzofuran, has been achieved for the first time. This enzymatic esterification was accelerated by the addition of disodium carbonate while maintaining its high enantioselectivities, and was particularly effective for biaryls having N-substituted carbazole moieties. Furthermore, mesoporous silica-supported oxovanadium-catalyzed cross-dehydrogenative coupling of 3-hydroxycarbazole and 2-naphthol was followed by the lipase-catalyzed KR in one-pot to synthesize the optically active heterocyclic biaryl compounds with high optical purity.

Introduction

Optically active atropisomeric biaryl compounds have played important roles in organic chemistry as organocatalysts, chiral ligands and drug candidates.^1–3) Kinetic resolution (KR) of racemic biaryls is one of the simplest and most straightforward strategies to get such optically active compounds.^4,5) Apart from the KR of racemic biaryls by non-enzymatic routes, lipases have been used for the KR of racemic C₁- and C₂-symmetric atropisomeric 1,1′-biaryl-2,2′diols,^6–15) in which racemic 1,1′-bi-2-naphthol (BINOL) and its derivatives have been resolved via either hydrolysis^6–11) or esterification.^12–15) In contrast, the KR of C₁-symmetric biaryl compounds including heterocyclic moieties has not been reported yet.

Other synthetic methods for optically active biaryls include enantioselective biaryl coupling, central-to-axial chirality transfer, and desymmetrization of σ-symmetrical biaryls.^16,17) Among them, the enantioselective dehydrogenative biaryl coupling reaction by using various transition metal catalysts is an atom-economical route, which does not require specific functionalization of each aromatic precursor.^18–21) In particular, cross-dehydrogenative coupling (CDC) reaction is quite intriguing because it produces C₁-symmetrical biaryls from two different arenes.^22–29) Among a range of dehydrogenative coupling reactions, those of carbazoles have drawn significant attention due to the unique reactivity of the products^30–32) and their potentials as biologically active compounds³³⁾ and functional molecules.³⁴⁾ However, the synthesis of optically active C₁-symmetric biaryl compounds containing carbazoles by CDC reactions still remains challenging, and only one paper has just been reported in 2021.²²⁾

At the same time, we have reported the highly chemoselective CDC reaction of 3-hydroxycarbazoles 1 with 2-naphthol (2) to synthesize racemic C₁-symmetric heterocyclic biaryls 3 by using a mesoporous silica-supported heterogeneous oxovanadium catalyst, V-MPS4.³⁵⁾ In addition, we have found that Na₂CO₃ promotes lipase-catalyzed esterification of both C₁- and C₂-symmetric BINOLs while maintaining high enantioselectivity of the original enzymatic esterification in the absence of the base.^36,37) Building on these findings, we report herein the first example of the lipase-catalyzed KR of C₁-symmetric heterocyclic biaryls rac-3 to give (R)- and (S)-enantiomers with high enantiomeric excesses (Chart 1).

Chart 1. Outline of This Work

Results and Discussion

Initially, we prepared the C₁-symmetric substrates rac-3a–3f (Chart 2). rac-3a–3d were synthesized in good yields by V-MPS4 catalyzed CDC reaction³⁵⁾ of 3-hydroxy-9H-carbazoles 1a–1d and 2-naphthol (2). Contrarily, N-benzoyl-3-hydroxy-9H-carbazole (1e), when reacted with 2, gave the corresponding rac-3e in a low yield (<20%), and an inseparable over-oxidized product was generated under the same reaction conditions. Therefore, rac-3e was prepared from rac-3d via O-silylation followed by N-benzoylation and O-desilylation. We were also interested in the applicability of our lipase-catalyzed KR to other related heterocyclic biaryls, and therefore 3-hydroxy-4-(2-hydroxylnaphthalen-1-yl)dibenzo[b,d]furan (rac-3f) was synthesized by the Suzuki–Miyaura coupling of 1-bromo-2-methoxydibenzo[b,d]furan (8) with 2-methoxynaphthalene-1-boronic acid (9) followed by O-demethylation.

Chart 2. Synthesis of Racemic Substrates rac-3a–f

a) TBSCl, imidazole, CH₂Cl₂, room temperature (r.t.), 93%; b) BzCl, Et₃N, DMAP, DMF, 50 °C, 40%; c) TBAF, AcOH, THF, 0 °C to r.t., 71%; d) 9, Pd(OAc)₂, SPhos, K₂CO₃, toluene/EtOH/H₂O, 80 °C, 71%; e) BBr_3, CH₂Cl₂, 0 °C to r.t., 98%.

With these C₁-symmetric biaryls in hand, we screened several commercially available lipases (Table 1). N-Benzylated compound rac-3a was used as a model substrate of the KR under the following conditions: a mixture of rac-3a (7.0 mg, 0.017 mmol), lipase (1.25 g/mmol), vinyl acetate (10 equivalent (equiv.)) and Na₂CO₃ (1.5 equiv.) in toluene (20 mM) was stirred at 35 °C for 24 h. The crude product was subjected to ¹H-NMR analysis to determine the conversion. As shown in Table 1, only LIP301 (Pseudomonas sp. lipase) catalyzed the resolution with high conversion (42%) to give a mixture of two regioisomeric monoesters (R)-5a and (R)-5a′ along with the recovery of (S)-3a. After separation of a mixture of the monoesters and 3a, the monoesters were treated with acetic anhydride, 4-dimethylaminopyridine (DMAP), and Et₃N to give a single product (R)-4a, whose optical purity was found to be 98% enantiomeric excess (ee) by chiral HPLC analysis. This clearly indicated that both (R)-5a and (R)-5a′ had the same absolute stereochemistry as well as very high optical purity. The optical purity of (S)-3a was 68% ee indicating that the KR proceeded with very high enantioselectivity (E > 200).^38,39) Although PS-IM (Burkholderia cepacia lipase) also catalyzed the esterification, the conversion and E value were low (entry 2). The other screened lipases were not catalytically active at all (entries 3–6).

Table 1. Screening of Lipases for KR of rac-3a^a)

Entry	Lipaseb)	Conversionc)	Optical purity (% ee)d)		Ee)
			(S)-3a	(R)-4a
1	LIP301	42%	68	98	>200
2	PS IM	<5%	1	86	13
3	AK	No reaction	—	—	—
4	CALB	No reaction	—	—	—
5	PPL	No reaction	—	—	—
6	AY	No reaction	—	—	—

a) Reaction was conducted using rac-3a (7.0 mg, 0.017 mmol), lipase (21 mg, 1.25 g/mmol), Na₂CO₃ (2.7 mg, 0.025 mmol), vinyl acetate (16 µL, 0.17 mmol), and toluene (0.83 mL). b) LIP301 = Pseudomonas sp. lipase (Toyobo), PS IM = Burkholderia cepacia lipase (Amano), AK = Pseudomonas fluorescens lipase (Amano), CALB = Candida antarctica lipase B (Novozyme), PPL = porcine pancreatic lipase (Amano), AY = Candida rugosa lipase (Amano). c) ¹H-NMR ratio of the mixture of two regioisomers (R)-5a and (R)-5a′ out of the total of (R)-5a, (R)-5a′ and (S)-3a. d) After acetylation of a mixture of two regioisomers (R)-5a and (R)-5a′, the optical purity (% ee) of the product (R)-4a was determined by HPLC analysis using a Daicel CHIRALPAK IC-3 column, detection: 254 nm. e) For E value, see refs.^38,39)

Next, we optimized the reaction conditions using LIP301 as a biocatalyst (Table 2). Both conversion and E value were low when MeCN, CH₂Cl₂, and PhCF₃ were used instead of toluene (entries 2–4). While some improvement was observed when CCl₄ and i-Pr₂O were employed (entries 5 and 6), toluene was deemed to be the best solvent in terms of conversion rate and E value. Omission of Na₂CO₃ or the use of organic bases such as Et₃N and Hünig’s base instead of Na₂CO₃ were detrimental to the conversion and optical purities (entries 7–9). Although Na₃PO₄ showed similar results to Na₂CO₃ (entry 10), we encountered reproducibility problems due to its hygroscopicity. The complete conversion (approx. 50%) was achieved within 24 h at 35 °C by using twice the amount of Na₂CO₃ (3.0 equiv.) (entry 11). In the course of screening these bases, the second esterification, leading to 4a, was not observed, which was different from our previous report.³⁷⁾

Table 2. Optimization of the Lipase-Catalyzed KR of rac-3a^a)

Entry	Solvent	Base	Conversionb)	Optical purity (% ee)c)		E
				(S)-3a	(R)-4a
1d)	toluene	Na2CO3	41%	68	98	>200
2	MeCN	Na2CO3	8%	1	11	1
3	CH2Cl2	Na2CO3	2%	2	88	16
4	PhCF3	Na2CO3	3%	3	94	33
5	CCl4	Na2CO3	32%	46	97	104
6	i-Pr2O	Na2CO3	32%	46	97	104
7	toluene	none	13%	15	98	115
8	toluene	Et3N	20%	23	91	27
9	toluene	iPr2NEt	29%	39	95	57
10	toluene	Na3PO4	46%	83	96	130
11e)	toluene	Na2CO3	51%	98	94	150

a) Reaction conditions; 3a (7.0 mg, 0.017 mmol), LIP301 (21 mg, 1.25 g/mmol), base (1.5 equiv), and vinyl acetate (16 µL, 0.17 mmol), and toluene (0.83 mL). b) Calculated from ee of (S)-3a and that of (R)-4a.^38,39) c) Same as footnote d) in Table 1. d) Cited from entry 1 in Table 1. e) Na₂CO₃ (3.0 equiv.) was used.

With the optimized reaction conditions (Table 2, entry 10) in hand, the scope and limitations were investigated using 0.10 mmol of the substrates having a carbazole moiety rac-3a–3e (Table 3). All substrates gave a mixture of regioisomeric monoacetates (R)-5a–5e and (R)-5a′–5e′ similar to previous reports.^37,40) The monoacetates were converted into the diacetates (R)-4a–4e, and their optical purities were in the range of 90–99% ee. The absolute configuration of (S)-3c and 3d was determined by the comparison of their specific optical rotation with those reported,²²⁾ and the others were assigned to be the same because lipases usually react with the same enantiomers owing to their well-documented enantiodiscriminating ability.³⁶⁾ The KR of substrates having a relatively large substituent at the nitrogen, such as rac-3a, 3b, and 3e, proceeded with excellent enantioselectivities (E > 100) (entries 1, 2, and 5), while the KR of rac-3c with a methyl group and rac-3d without any nitrogen substituent showed slightly lower enantioselectivities (E = 85 and 50, respectively) (entries 3 and 4). Nevertheless, it is noteworthy that both (S)-3c and (R)-4d were prepared with an enantiomeric excess of >90% ee, given that the reported enantioselective CDC reaction afforded (R)-3c and (R)-3d in 48% and 88% ee, respectively.²²⁾ The low conversion of 3e is mainly attributable to its poor solubility. KR of other heterocyclic substrates, such as rac-3f having a dibenzo[b,d]furan moiety, was also conducted with good enantioselectivity (E = 125) to give (S)-3f (98% ee) and (R)-4f (93% ee) (entry 6).

Table 3. KR of C₁-Symmetric Biaryl Diols rac-3a–3f^a)

a) Each reaction was conducted by using 0.10 mmol of rac-3. b) Same as footnote d) in Table 1. c) Conducted at 50 °C.

We next combined the above-mentioned KR and the CDC reaction shown in Chart 1 to realize a two-step one-pot synthesis. Toward this end, a crude mixture containing rac-3a, obtained by V-MPS4 catalyzed CDC reaction, was used for the lipase-catalyzed KR in a single flask (Chart 3). The CDC reaction of a 1 : 1 molar ratio of 1a and 2 was conducted with 10 mol% of V-MPS4 in toluene at 30 °C under oxygen atmosphere. After the consumption of 1a, checked by thin layer chromatography, LIP301 (1.25 mmol/g), vinyl acetate (10 equiv.), Na₂CO₃ (3.0 equiv.) and toluene were added to the same flask, and argon was purged. The whole reaction mixture was stirred at 35 °C for 24 h. Then, vinyl acetate (10 equiv.) was added again to the reaction mixture, and the mixture was stirred for another 24 h. After filtration of the mixture through a Celite pad, the resulting crude product was purified by chromatography, followed by acetylation of the mixture of (R)-5a and (R)-5a′ to produce (R)-4a (22% overall yield, 98% ee) and (S)-3a (19% yield, 78% ee) (for a preliminary investigation to analyze the cause of low product yields, and for details, see Supplementary Chart S1 in SM).

Chart 3. One-Pot Reaction for the Preparation of (S)-3a and (R)-4a from 1a and 2

Conclusion

The lipase-catalyzed KR of C₁-symmetric biaryls rac-3 having heterocyclic moieties, such as carbazole and dibenzofuran, was achieved for the first time. The Na₂CO₃-induced rate enhancement of KR was again observed in this class of compounds 3 as in our previous report on the lipase-catalyzed KR of BINOLs.³⁷⁾ The products (S)-3 and (R)-4 were obtained in high enantioselectivities (up to 99% ee). The preparation of such compounds having a range of N-substituted carbazoles is particularly worth noting and can complement the enantioselective CDC reactions.²²⁾ In addition, a one-pot synthesis was achieved by sequentially conducting the V-MPS4-catalyzed CDC reaction of N-benzyl-9H-carbazol-3-ol (1a) with 2-naphthol (2) (1 : 1 molar ratio) followed by a lipase-catalyzed KR to give (S)-3a and (R)-4a. Further research work to expand the substrate scope of the KR and improve of the product yields of the one-pot process is under investigation in our laboratory.

Experimental

General Methods

All reactions were monitored by TLC on glass-backed silica gel 60 F₂₅₄, 0.2 mm plates (Merck, Germany), and compounds were visualized under UV light (254 nm). Melting points were determined on a Yanagimoto melting point apparatus and are uncorrected. IR absorption spectra were recorded on a SHIMADZU FTIR-8400S spectrophotometer. ¹H- and ¹³C-NMR spectra were measured on a JEOL JNM-ECA500 (¹H: 500 MHz, ¹³C: 125 MHz) or a JEOL JNM-ECS400 (¹H: 400 MHz, ¹³C: 100 MHz) instrument with chemical shifts reported in δ (ppm) relative to the residual nondeuterated solvent signal for ¹H (CHCl₃: δ = 7.26 ppm, acetone: 2.05 ppm) and relative to the deuterated solvent signal for ¹³C (CDCl₃: δ = 77.0 ppm, acetone-d₆: δ = 29.84 ppm). The MS were measured on a JEOL JMS-S3000 (matrix assisted laser desorption/ionization (MALDI)) with a time of flight (TOF) mass analyzer. HPLC analyses were carried out using a JASCO LC-2000 Plus system (HPLC pump: PU-2080, UV detector: MD-2018) equipped with a Daicel CHIRALPAK IC-3 or IA-3 with a size of 4.6 × 250 mm. Optical rotations were measured on a JASCO P-1020 polarimeter. Vanadium content was measured by inductively coupled plasma-atomic emission spectrometry (ICP-AES, Agilent 720 ICP) analysis.

All reagents and solvents were purchased from FUJIFILM Wako Pure Chemical Corporation (Osaka, Japan), Tokyo Chemical Industry (Tokyo, Japan), Sigma-Aldrich (U.S.A.), Nacalai Tesque (Kyoto, Japan), Kishida Chemical (Osaka, Japan), and Combi Blocks (U.S.A.), and used without further purification. Flash chromatography was performed on silica gel 60N (particle size 40–50 µm) purchased from Kanto Chemical Co., Inc. (Tokyo, Japan). Preparative TLC (PTLC) was performed on glass-backed silica gel 60 F₂₅₄, 0.2 mm plates (Merck). Mesoporous silica (TMPS-4R) was kindly supplied by Taiyo Kagaku Co., Ltd. (Tokyo, Japan). LIP301 (commercial name), the lipase from Pseudomonas sp. (TOYOBO lipoprotein lipase Grade III LPL-311) immobilized on Hyflo Super-Cel, was gifted from TOYOBO CO., LTD. (Osaka, Japan) and used for KR as received. LIP301 was also home-made from LPL-311, whose procedure is shown below.

The compounds 3a–d,³⁵⁾8⁴¹⁾ and 10⁴²⁾ were synthesized according to the reported methods. The other compounds 3e and 3f were synthesized as follows:

3-((tert-Butyldimethylsilyl)oxy)-4-(2-((tert-butyldimethylsilyl)oxy)naphthalen-1-yl)-9H-carbazole (6)

To a solution of rac-3a (0.80 g, 2.6 mmol) and imidazole (0.70 g, 10.4 mmol) in CH₂Cl₂ (26 mL), TBSCl (1.5 g, 10.4 mmol) was added, and then the whole mixture was stirred at room temperature for 18 h. After consumption of 3a, the reaction mixture was filtered through a pad of silica gel to give 6 (1.3 g, 93% yield) as a white solid.

¹H-NMR (500 MHz, CDCl₃) δ: 7.91–7.83 (3H, m), 7.39 (1H, d, J = 8.6 Hz), 7.34–7.28 (2H, m), 7.22–7.16 (3H, m), 7.05 (1H, dd, J = 8.6, 1.2 Hz), 6.71–6.65 (2H, m), 0.50 (9H, s), 0.44 (9H, s), 0.02 (3H, s), −0.06 (3H, s), −0.19 (3H, s), −0.27 (3H, s); ¹³C-NMR (125 MHz, CDCl₃) δ: 150.8, 147.1, 140.3, 134.5, 134.0, 129.1, 128.7, 127.5, 125.9, 125.1, 124.0, 123.8, 123.2, 122.4, 122.3, 121.4, 120.4, 118.6, 117.9, 109.8, 109.5, 25.1, 25.0, 17.61, 17.57, −4.3, −4.58, −4.61, −4.7; mp: 138–142 °C; IR (neat) cm⁻¹: 3420; high resolution (HR)MS (MALDI) m/z: 553.2828 (Calcd for C₃₄H₄₃NO₂Si₂ [M]^+·: 553.2827).

(3-((tert-Butyldimethylsilyl)oxy)-4-(2-((tert-butyldimethylsilyl)oxy)naphthalen-1-yl)-9H-carbazol-9-yl)(phenyl)methanone (7)

To an ice-cold solution of 6 (0.80 g, 1.44 mmol), Et₃N (0.60 mL, 4.3 mmol) and DMAP (53 mg, 0.3 mmol) in N,N-dimethylformamide (DMF) (15 mL), benzoyl chloride (0.56 mL, 4.3 mmol) was added, and then the reaction mixture was stirred at 50 °C for 24 h. Water and EtOAc were added, and the product was extracted with EtOAc three times. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and evaporated in vacuo. The residue was purified by column chromatography to give 7 (0.38 g, 40% yield) as a white solid.

¹H-NMR (500 MHz, CDCl₃) δ: 7.87 (1H, d, J = 8.6 Hz), 7.84 (1H, d, J = 8.0 Hz), 7.73–7.72 (2H, m), 7.64 (1H, t, J = 7.5 Hz), 7.53 (3H, m), 7.36 (2H, m), 7.30 (1H, t, J = 8.2 Hz), 7.22 (2H, m), 7.07 (1H, t, J = 8.0 Hz), 6.91 (1H, d, J = 8.0, 1.2 Hz), 6.80 (1H, t, J = 7.5 Hz), 6.62 (1H, d, J = 7.5 Hz), 0.49 (9H, s), 0.44 (9H, s), 0.06 (3H, s), −0.05 (3H, s), −0.15 (3H, s), −0.16 (3H, s); ¹³C-NMR (100 MHz, CDCl₃) δ: 169.4, 150.8, 150.1, 139.6, 136.2, 133.9, 133.8, 132.1, 129.2, 129.1, 129.0, 128.8, 127.7, 126.8, 126.5, 126.2, 126.0, 125.5, 123.5, 122.9, 122.0, 121.6, 121.4, 120.1, 117.7, 115.2, 115.1, 25.01, 24.97, 17.6, 17.5, −4.2, −4.5, −4.61, −4.62; mp: 116–120 °C; IR (neat) cm⁻¹: 1678, 1622, 1593; HRMS (MALDI) m/z: 657.3083 (Calcd for C₄₁H₄₇NO₃Si₂ [M]^+·: 657.3089).

Synthesis of rac-(3-hydroxy-4-(2-hydroxynaphthalen-1-yl)-9H-carbazol-9-yl)(phenyl)methanone (rac-3e)

To an ice-cold solution of 7 (0.20 g, 0.30 mmol) in tetrahydrofuran (THF) (3.0 mL), acetic acid (34 µL, 0.60 mmol) and tetrabutylammonium fluoride (1.0 M in THF, 0.60 mL, 0.60 mmol) were added, and the reaction mixture was stirred for 30 min at the same temperature. Water and EtOAc were added, and the product was extracted with EtOAc three times. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and evaporated in vacuo. The residue was purified by column chromatography to give rac-3e (92 mg, 71% yield) as a white solid.

¹H-NMR (500 MHz, acetone-d₆) δ: 8.00 (1H, d, J = 8.6 Hz), 7.92 (1H, d, J = 8.0 Hz), 7.79–7.73 (3H, m), 7.64 (2H, t, J = 7.4 Hz), 7.51 (1H, d, J = 9.2 Hz), 7.39 (1H, d, J = 9.2 Hz), 7.35 (1H, d, J = 8.6 Hz), 7.30 (1H, ddd, J = 8.0, 6.8, 1.2 Hz), 7.27–7.22 (2H, m), 7.13–7.08 (2H, m), 6.80 (1H, ddd, J = 8.0, 6.8, 1.2 Hz), 6.52 (1H, d, J = 7.4 Hz); ¹³C-NMR (125 MHz, acetone-d₆) δ: 169.7, 154.1, 153.3, 140.6, 137.3, 134.8, 134.2, 133.0, 130.9, 129.91, 129.87, 129.6, 129.0, 127.3, 127.14, 127.07, 126.9, 125.0, 123.9, 123.6, 122.3, 119.5, 116.9, 116.1, 116.0, 115.2; mp: 245–247 °C; IR (neat) cm⁻¹: 3628, 3185, 1662; HRMS (MALDI) m/z: 429.1360 (Calcd for C₂₉H₁₉NO₃ [M]^+·: 429.1359).

1-Bromo-2-methoxydibenzo[b,d]furan (8)

To an ice-cold solution of dibenzo[b,d]furan-2-ol (0.18 g, 1.0 mmol) in EtOH (5 mL), N-bromosuccinimide (0.18 g, 1.0 mmol) was added, and the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was evaporated. Water and EtOAc were added to the residue, and the product was extracted with EtOAc three times. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and evaporated in vacuo. The residue was purified by column chromatography (hexane/CH₂Cl₂ = 1 : 1) to give 8 (0.22 g, 83% yield). Its ¹H-NMR data were in good agreement with those in the previous report.⁴³⁾ To an ice-cold solution of 8 (1.3 g, 5.0 mmol) in dry THF/DMF (10 mL/1.0 mL), NaH (0.24 g, 10 mmol 60% in paraffin liquid) was added. After the reaction mixture was stirred at 0 °C for 30 min, MeI (0.50 mL, 7.5 mmol) was added, and the reaction mixture was stirred at 50 °C for 3 d. Water and hexane/EtOAc (1 : 1) were added, and the product was extracted with hexane/EtOAc (1 : 1) three times. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and evaporated in vacuo. The residue was purified by column chromatography (hexane/CH₂Cl₂ = 10 : 1) to give 9 (0.97 g, 70% yield) as a white solid.

¹H-NMR (500 MHz, CDCl₃) δ: 8.57 (1H, d, J = 8.0 Hz), 7.56–7.47 (3H, m), 7.38 (1H, t, J = 7.4 Hz), 7.07 (1H, d, J = 8.6 Hz), 3.98 (3H, s); ¹³C-NMR (125 MHz, CDCl₃) δ: 156.9, 152.1, 151.0, 127.9, 125.1, 124.3, 122.9, 122.4, 111.5, 111.4, 110.3, 105.0, 57.5; mp: 98–101 °C; HRMS (MALDI) m/z: 275.9778 (Calcd for C₁₃H₉⁷⁹BrO₂ [M]^+·: 275.9780).

rac-1-(2-Hydroxynaphthalen-1-yl)dibenzo[b,d]furan-2-ol (rac-3f)

To a mixture of 8 (0.69 g, 2.1 mmol), 9 (0.65 g, 3.2 mmol), and K₂CO₃ (0.89 g, 6.4 mmol) in toluene/EtOH/H₂O (19.2, 9.6, 3.2 mL, respectively), Pd(OAc)₂ (24 mg, 0.11 mmol) and SPhos (87 mg, 0.21 mmol) were added at room temperature under Ar. The mixture was stirred at 80 °C for 2 h and then was evaporated in vacuo. Water and EtOAc were added to the residue, and the product was extracted with EtOAc three times. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and evaporated in vacuo. The residue was purified by column chromatography (hexane/EtOAc = 9 : 1) to give 11 (0.50 g, 71% yield). To an ice-cold solution of 11 (0.48 g, 1.35 mmol) in dry CH₂Cl₂ (14 mL), BBr₃ (1.0 M in CH₂Cl₂, 1.6 mL, 1.6 mmol) was added. After the mixture was stirred at 0 °C for 2 h, the reaction was quenched with sat. NaHCO₃. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and evaporated in vacuo. The crude product was purified by silica gel column chromatography to give rac-3f (0.32 g, 98% yield).

rac-2-Methoxy-1-(2-methoxynaphthalen-1-yl)dibenzo[b,d]furan (11)

A white solid; ¹H-NMR (500 MHz, CDCl₃) δ: 8.04 (1H, d, J = 9.2 Hz), 7.89 (1H, d, J = 8.0 Hz), 7.61 (1H, d, J = 9.7 Hz), 7.50–7.45 (2H, m), 7.34–7.21 (5H, m), 6.83 (1H, t, J = 7.4 Hz), 6.40 (1H, d, J = 8.0 Hz), 3.77 (3H, s), 3.75 (3H, s); ¹³C-NMR (125 MHz, CDCl₃) δ: 157.0, 154.5, 153.6, 151.0, 133.1, 129.9, 129.1, 128.0, 126.7, 126.6, 124.8, 124.5, 123.7, 122.1, 121.8, 119.5, 118.7, 114.0, 112.0, 111.2, 110.7, 57.4, 56.9; mp: 162–164 °C; IR (neat) cm⁻¹: 1621, 1594, 1508; HRMS (MALDI) m/z: 354.1246 (Calcd for C₂₄H₁₈O₃ [M]^+·: 354.1251).

rac-1-(2-Hydroxynaphthalen-1-yl)dibenzo[b,d]furan-2-ol (rac-3f)

A white solid; ¹H-NMR (500 MHz, CDCl₃) δ: 8.03 (1H, d, J = 8.6 Hz), 7.92 (1H, d, J = 7.4 Hz), 7.66 (1H, dd, J = 8.0, 1.2 Hz), 7.52 (1H, d, J = 8.0 Hz), 7.42-7.36 (2H, m), 7.35–7.31 (3H, m), 7.28 (1H, d, J = 8.0 Hz), 6.91 (1H, t, J = 8.0 Hz), 6.59 (1H, d, J = 8.0 Hz), 5.22 (1H, br s), 4.88 (1H, br s); ¹³C-NMR (125 MHz, CDCl₃) δ: 157.0, 152.2, 150.9, 150.3, 132.6, 131.7, 129.3, 128.5, 127.7, 127.3, 124.2, 123.9, 123.5, 122.6, 121.5, 117.8, 115.7, 113.4, 111.5, 111.4, 110.8; mp: 86–89 °C; IR (neat) cm⁻¹: 3400, 1621; HRMS (MALDI) m/z: 326.0934 (Calcd for C₂₂H₁₄O₃ [M]^+·: 326.0938).

Lipase-Catalyzed KR

Preparation of Home-Made LIP301

The immobilized lipase LIP301 used to be the commercially available form from TOYOBO. However, the production of LIP301 stopped, and it is not available now, while non-immobilized lipase (LPL-311) is still commercially available from TOYOBO. Therefore, we made LIP301 by ourselves by immobilizing LPL-311 according to the procedure kindly provided by TOYOBO.

LPL-311 powder (10 mg, 33 U/mg) was added to 5.9 mL of 10 mM Tris–HCl buffer (pH = 8.0, Nacalai). After the lipase powder was dissolved, saccharose (4.2 mg, Nacalai) and diatomite (2.6 g, Nacalai) were added. The mixture was stirred well to make a slurry, and the slurry was left at 4 °C overnight and freeze-dried at <1 mmHg for 10 h. The dried product was crushed and mixed well but not grained, and the product was put in an open plastic bag. To let the lipase absorb moisture, the bag was placed in a 50-mL sealed vial with water (approx. 2 mL) in the bottom and allowed to stand with no water into the bag. The vial was kept in a refrigerator at 4 °C for 8 d. During this time, the powder in the bag was mixed once a day. The product was freeze-dried again at <1 mmHg for 6 h to give home-made LIP301. The amount of protein in home-made LIP301 measured by a BCA assay Kit (TaKaRa Bio, Shiga, Japan) was found to be 1.11 mg per 1 g of the immobilized product, which was almost same as that of commercial LIP301 (1.04 mg/g).

We performed the KR of rac-3a using both commercial and home-made LIP301. The reactivity and enantioselectivity of them were almost the same (for details, see Supplementary Chart S2 in SI).

General Procedure for KR of rac-3

To a 10-mL flask, rac-3a (41.6 mg, 0.10 mmol), LIP301 (125 mg, 1.25 g/mmol), vinyl acetate (93 µL, 1.0 mmol), Na₂CO₃ (32 mg, 0.30 mmol), and anhydrous toluene (5.0 mL, 0.020 M) were added. After being stirred for 24 h at 35 °C, the reaction mixture was filtered through a Celite pad with EtOAc, and the filtrate was evaporated in vacuo. The residue was purified by PTLC (toluene/EtOAc = 10 : 1) to give a mixture of two regioisomeric monoacetates (R)-5a and (R)-5a′ (23.4 mg) in addition to recovered (S)-3a (18.7 mg, 45% yield, 99% ee). The mixture of monoacetates was subjected to acylation as follows: To a stirred solution of a mixture of two resioisomers (R)-5a and (R)-5a′ (23.4 mg, 0.051 mmol) in CH₂Cl₂ (0.50 mL) were added Ac₂O (14 µL, 0.15 mmol), DMAP (1.8 mg, 0.005 mmol), and Et₃N (14 µL, 0.075 mmol). After being stirred for 10 min at room temperature, the reaction mixture was filtered through a silica gel pad with CH₂Cl₂. The filtrate was concentrated in vacuo to give (R)-4a (24.3 mg, 49% yield from rac-3a, 92% ee).

A Mixture of (R)-9-Benzyl-4-(2-hydroxynaphthalen-1-yl)-9H-carbazol-3-yl Acetate ((R)-5a) and (R)-1-(9-Benzyl-3-hydroxy-9H-carbazol-4-yl)naphthalen-2-yl Acetate ((R)-5a′)

¹H-NMR (500 MHz, CDCl₃) δ: 8.13 (0.1H, d, J = 9.2 Hz), 7.99 (0.1H, d, J = 8.6 Hz), 7.97 (0.9H, d, J = 9.2 Hz), 7.88 (0.9H, d, J = 8.6 Hz), 7.53 (0.9H, d, J = 9.2 Hz), 7.51–7.49 (0.1H, m), 7.45–7.17 (13H, m), 6.78 (0.9H, ddd, J = 8.0, 6.3, 1.7 Hz), 6.73 (0.1H, ddd, J = 8.0, 6.3, 1.7 Hz), 6.57 (0.9H, d, J = 8.0 Hz), 6.49 (0.1H, d, J = 8.0 Hz), 5.58 (1.8H, s), 5.54 (0.2H, s), 5.46 (0.9H, s), 5.00 (0.1H, s), 1.87 (0.3H, s), 1.86 (2.7H, s).

(R)-1-(3-Acetoxy-9-benzyl-9H-carbazol-4-yl)naphthalen-2-yl Acetate ((R)-4a)

A white solid; ¹H-NMR (500 MHz, CDCl₃) δ: 8.06 (1H, d, J = 8.6 Hz), 7.96 (1H, d, J = 8.0 Hz), 7.50–7.44 (3H, m), 7.38 (1H, d, J = 8.0 Hz), 7.34–7.22 (9H, m), 6.73–6.70 (1H, m), 6.40 (1H, d, J = 8.0 Hz), 5.57 (2H, s), 1.90 (3H, s), 1.87 (3H, s); ¹³C-NMR (125 MHz, CDCl₃) δ: 170.2, 169.4, 146.2, 142.1, 141.3, 138.3, 137.0, 132.7, 131.5, 129.5, 128.9, 128.0, 127.6, 126.9, 126.5, 126.0, 125.9, 125.8, 123.8, 122.6, 122.3, 122.1, 121.9, 121.6, 120.4, 119.2, 108.9, 108.7, 46.8, 20.7, 20.6; Its optical purity (92% ee) was determined by HPLC analysis at 20 °C using a CHIRALPAK IC-3 column (hexane/2-propanol = 90 : 10; flow rate: 1.0 mL/min; retention times: 11.3 min for (S)-4a, 15.4 min for (R)-4a); mp: 155–158 °C; IR (neat) cm⁻¹: 1759; [α]_D²² −100.3 (c = 0.12, CHCl₃) for (R)-4a with 92% ee; HRMS (MALDI) m/z: 522.1680 (Calcd for C₃₃H₂₅NO₄Na [M + Na]⁺: 522.1676).

(S)-9-Benzyl-4-(2-hydroxynaphthalen-1-yl)-9H-carbazol-3-ol ((S)-3a)

A white solid; ¹H-NMR (500 MHz, CDCl₃) δ: 8.04 (1H, d, J = 9.2 Hz), 7.93 (1H, d, J = 8.0 Hz), 7.46 (1H, d, J = 8.6 Hz), 7.44 (1H, d, J = 9.2 Hz), 7.38 (1H, ddd, J = 8.0, 6.3, 1.7 Hz), 7.35–7.26 (8H, m), 7.24–7.22 (2H, m), 6.78 (1H, ddd, J = 8.0, 6.3, 1.7 Hz), 6.71 (1H, d, J = 7.4 Hz), 5.56 (2H, s), 5.30 (1H, s), 4.73 (1H, s); ¹³C-NMR (125 MHz, CDCl₃) δ: 152.4, 148.1, 141.3, 137.1, 135.9, 132.8, 131.4, 129.4, 128.9, 128.4, 127.6, 127.5, 126.5, 126.0, 124.2, 124.1, 122.1, 121.9, 121.5, 119.1, 117.8, 114.9, 111.8, 110.94, 110.90 108.7, 46.8; Its optical purity (99% ee) was determined by HPLC analysis at 20 °C using a CHIRALPAK IC-3 column (hexane/2-propanol = 80 : 20; flow rate: 1.0 mL/min; retention times: 7.9 min for (R)-3a, 22.0 min for (S)-3a); mp: 168–171 °C; IR (neat) cm⁻¹: 3497, 1618; [α]_D²² +25.2 (c = 0.11, CHCl₃) for (S)-3a with 99% ee; HRMS (MALDI) m/z: 415.1560 (Calcd for C₂₉H₂₁NO₂ [M]^+·: 415.1567).

(R)-1-(3-Acetoxy-9-phenyl-9H-carbazol-4-yl)naphthalen-2-yl Acetate ((R)-4b) and (S)-4-(2-Hydroxynaphthalen-1-yl)-9-phenyl-9H-carbazol-3-ol ((S)-3b)

According to the general procedure, (R)-4b (20.9 mg, 43% yield) and (S)-3b (29.9 mg, 57% yield) were obtained from rac-3b (40.1 mg, 0.10 mmol).

(R)-4b: A pale yellow solid; ¹H-NMR (500 MHz, CDCl₃) δ: 8.07 (1H, d, J = 8.6 Hz), 7.97 (1H, d, J = 8.6 Hz), 7.66–7.62 (4H, m), 7.52–7.45 (4H, m), 7.41 (1H, d, J = 8.6 Hz), 7.33–7.27 (3H, m), 7.22 (1H, ddd, J = 8.0, 6.8, 1.2 Hz), 6.74 (1H, t, J = 8.0 Hz), 6.39 (1H, d, J = 8.0 Hz), 1.96 (3H, s), 1.88 (3H, s); ¹³C-NMR (125 MHz, CDCl₃) δ: 170.2, 169.5, 146.2, 142.5, 141.6, 138.6, 137.4, 132.8, 131.5, 129.9, 129.5, 128.0, 127.8, 127.4, 126.9, 126.0, 125.9, 125.8, 123.8, 122.9, 122.5, 122.02, 121.97, 121.5, 120.4, 119.8, 109.8, 109.6, 20.8, 20.6; Its optical purity (98% ee) was determined by HPLC analysis at 20 °C using a CHIRALPAK IC-3 column (hexane/2-propanol = 90 : 10; flow rate: 1.0 mL/min; retention times: 14.2 min for (S)-4b, 19.6 min for (R)-4b); mp: 110–113 °C; IR (neat) cm⁻¹: 1764, 1596, 1503; [α]_D²² −53.7 (c = 1.0, CHCl₃) for (R)-4b with 98% ee; HRMS (MALDI) m/z: 508.1524 (Calcd for C₃₂H₂₃NO₄Na [M + Na]⁺: 508.1519).

(S)-3b: A pale-yellow solid; ¹H-NMR (500 MHz, CDCl₃) δ: 8.05 (1H, d, J = 9.2 Hz), 7.94 (1H, d, J = 8.6 Hz), 7.66–7.60 (4H, m), 7.51–7.49 (2H, m), 7.45 (1H, dd, J = 8.9, 1.4 Hz), 7.41–7.38 (2H, m), 7.35–7.31 (2H, m), 7.26–7.23 (2H, m), 6.81 (1H, t, J = 7.7 Hz), 6.72 (1H, d, J = 8.0 Hz); ¹³C-NMR (125 MHz, CDCl₃) δ: 152.4, 148.6, 141.5, 137.5, 136.2, 132.8, 131.4, 129.9, 129.4, 128.4, 127.6, 127.2, 126.0, 124.2, 124.1, 122.4, 122.2, 121.4, 119.7, 117.8, 115.0, 111.82, 111.76, 110.7, 109.6; Its optical purity (70% ee) was determined by HPLC analysis at 20 °C using a CHIRALPAK IC-3 column (hexane/2-propanol = 80 : 20; flow rate: 1.0 mL/min; retention times: 9.6 min for (R)-3b, 25.9 min for (S)-3b); mp: 258–260 °C; IR (neat) cm⁻¹: 3506, 3418; [α]_D²² −8.9 (c = 0.23, CHCl₃) for (S)-3c with 70% ee; HRMS (MALDI) m/z: 401.1405 (Calcd for C₂₈H₁₉NO₂ [M]^+·: 401.1410).

(R)-1-(3-Acetoxy-9-methyl-9H-carbazol-4-yl)naphthalen-2-yl Acetate ((R)-4c) and (S)-4-(2-Hydroxynaphthalen-1-yl)-9-methyl-9H-carbazol-3-ol ((S)-3c)

According to the general procedure, (R)-4c (18.6 mg, 43% yield) and (S)-3c (16.1 mg, 47% yield) were obtained from rac-3c (33.9 mg, 0.10 mmol).

(R)-4c: A white solid; ¹H-NMR (500 MHz, CDCl₃) δ: 8.05 (1H, d, J = 8.6 Hz), 7.95 (1H, d, J = 8.0 Hz), 7.52 (1H, d, J = 8.6 Hz), 7.48 (1H, d, J = 9.2 Hz), 7.44 (1H, ddd, J = 8.0, 6.8, 1.2 Hz), 7.39 (1H, d, J = 8.6 Hz), 7.36–7.29 (3H, m), 7.22 (1H, ddd, J = 8.0, 6.8, 1.2 Hz), 6.71 (1H, ddd, J = 8.0, 6.8, 1.2 Hz), 6.36 (1H, d, J = 8.0 Hz), 3.92 (3H, s), 1.90 (3H, s), 1.89 (3H, s); ¹³C-NMR (125 MHz, CDCl₃) δ: 170.3, 169.4, 146.2, 141.8, 141.5, 138.6, 132.8, 131.5, 129.5, 127.9, 126.8, 125.84, 125.75, 123.9, 122.3, 122.0, 121.9, 121.5, 120.2, 118.8, 108.4, 108.3, 29.2, 20.7, 20.6; Its optical purity (90% ee) was determined by HPLC analysis at 20 °C using a CHIRALPAK IC-3 column (hexane/2-propanol = 90 : 10; flow rate: 1.0 mL/min; retention times: 11.7 min for (S)-4c, 16.4 min for (R)-4c); mp: 140–145 °C; IR (neat) cm⁻¹: 1759; [α]_D²² −81.1 (c = 0.10, CHCl₃) for (R)-4e with 90% ee; HRMS (MALDI) m/z: 423.1453 (Calcd for C₂₇H₂₁NO₄ [M]^+·: 423.1465).

(S)-3c: A white solid; ¹H-NMR (500 MHz, CDCl₃) δ: 8.03 (d, J = 9.2 Hz, 1H), 7.93 (d, J = 8.6 Hz, 1H), 7.51 (d, J = 9.2 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.39–7.29 (m, 6H), 6.76 (dd, J = 6.0, 2.0 Hz, 1H), 6.77 (ddd, J = 8.0, 5.7, 2.3 Hz, 1H), 5.26 (s, 1H), 4.71 (s, 1H), 3.91 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ: 152.3, 147.9, 141.5, 136.3, 132.8, 131.3, 129.4, 128.4, 127.5, 125.8, 124.1, 124.0, 121.7, 121.6, 121.4, 118.7, 117.8, 114.8, 111.9, 110.8, 110.4, 108.3, 29.2; Its optical purity (93% ee) was determined by HPLC analysis at 20 °C using a CHIRALPAK IC-3 column (hexane/2-propanol = 95 : 5; flow rate: 1.0 mL/min; retention times: 13.8 min for (R)-3c, 24.9 min for (S)-3c); mp: 153–158 °C; IR (neat) cm⁻¹: 3511; [α]_D²² +9.0 (c 0.33, CHCl₃) for (S)-3c with 93% ee (lit²²⁾: [α]_D¹⁹ −3.30 (c = 0.58, CHCl₃) for (R) configuration with 48% ee); HRMS (MALDI) m/z: 339.1271 (Calcd for C₂₃H₁₇NO₂ [M]^+·: 339.1254).

(R)-1-(3-Acetoxy-9H-carbazol-4-yl)naphthalen-2-yl Acetate ((R)-4d) and (S)-4-(2-Hydroxynaphthalen-1-yl)-9H-carbazol-3-ol ((S)-3d)

According to the general procedure, (R)-4d (15.7 mg, 38% yield) and (S)-3d (19.4 mg, 60% yield) were obtained from rac-3d (32.5 mg, 0.10 mmol) with a minor modification; toluene/acetone = 10 : 1 was used as an eluent for the chromatography instead of toluene/EtOAc = 10 : 1.

(R)-4d: A white solid; ¹H-NMR (500 MHz, CDCl₃) δ: 8.23 (1H, s), 8.05 (1H, d, J = 9.2 Hz), 7.95 (1H, d, J = 8.0 Hz), 7.51–7.43 (3H, m), 7.35–7.29 (3H, m), 7.25–7.21 (2H, m), 6.69 (1H, t, J = 7.4 Hz), 6.34 (1H, d, J = 8.0 Hz), 1.91 (3H, s), 1.88 (3H, s); ¹³C-NMR (100 MHz, CDCl₃) δ: 170.3, 169.5, 146.2, 142.2, 140.2, 137.1, 132.7, 131.5, 129.5, 128.0, 126.9, 125.9, 125.84, 125.80, 123.8, 123.1, 122.7, 122.0, 121.9, 121.5, 120.5, 119.4, 110.6, 110.4, 20.7, 20.6; Its optical purity (93% ee) was determined by HPLC analysis at 20 °C using a CHIRALPAK IC-3 column (hexane/2-propanol = 90 : 10; flow rate: 1.0 mL/min; retention times: 8.0 min for (S)-4d, 9.6 min for (R)-4d); mp: 102–105 °C; IR (neat) cm⁻¹: 3393, 1758, 1749; [α]_D²² −101 (c = 0.07, CHCl₃) for (R)-4d with 93% ee; HRMS (MALDI) m/z: 432.1204 (Calcd for C₂₆H₁₉NO₄Na [M + Na]⁺: 432.1206).

(S)-3d: A white solid. ¹H-NMR (400 MHz, CDCl₃) δ: 8.11 (1H, s), 8.04 (1H, d, J = 8.7 Hz), 7.93 (1H, d, J = 8.2 Hz), 7.54 (1H, d, J = 8.7 Hz), 7.43 (1H, d, J = 8.7 Hz), 7.40–7.36 (2H, m), 7.35–7.24 (4H, m), 6.77 (1H, ddd, J = 8.2, 7.3, 0.9 Hz), 6.66 (1H, d, J = 7.3 Hz), 5.25 (1H, s), 4.71 (1H, s); ¹³C-NMR (100 MHz, CDCl₃) δ: 152.3, 148.2, 140.3, 134.6, 132.8, 131.4, 129.4, 128.4, 127.5, 126.0, 124.14, 124.06, 122.6, 122.4, 121.4, 119.4, 117.8, 115.1, 112.6, 111.8, 110.6, 110.5; Its optical purity (58% ee) was determined by HPLC analysis at 20 °C using a CHIRALPAK IC-3 column (hexane/2-propanol = 80 : 20; flow rate: 1.0 mL/min; retention times: 7.4 min for (R)-3d, 10.2 min for (S)-3d); mp: 98–100 °C; IR (neat) cm⁻¹: 3503, 3413; [α]_D²² +12.7 (c = 0.28, CHCl₃) for (S)-3d with 58% ee (lit²²⁾: [α]_D²⁰ −82.90 (c = 0.18, CHCl₃) for (R) configuration with 88% ee); HRMS (MALDI) m/z: 325.1100 (Calcd for C₂₂H₁₅NO₂ [M]^+·: 325.1100).

(R)-1-(3-Acetoxy-9-benzoyl-9H-carbazol-4-yl)naphthalen-2-yl Acetate ((R)-4e) and (S)-(3-Hydroxy-4-(2-hydroxynaphthalen-1-yl)-9H-carbazol-9-yl)(phenyl)methanone ((S)-3e)

According to the general procedure, (R)-4e (7.3 mg, 14% yield) and (S)-3e (35.9 mg, 84% yield) were obtained from rac-3e (42.9 mg, 0.10 mmol) with a minor change; the reaction was conducted at 50 °C.

(R)-4e: A white solid; ¹H-NMR (500 MHz, CDCl₃) δ: 8.07 (1H, d, J = 9.2 Hz), 7.96 (1H, d, J = 8.0 Hz), 7.84–7.78 (3H, m), 7.68 (1H, t, J = 7.5 Hz), 7.57 (2H, t, J = 7.5 Hz), 7.49–7.46 (2H, m), 7.35 (1H, d, J = 8.0 Hz), 7.30–7.26 (3H, m), 7.10 (1H, t, J = 7.7 Hz), 6.77 (1H, t, J = 7.7 Hz), 6.26 (1H, d, J = 8.0 Hz), 1.95 (3H, s), 1.86 (3H, s); ¹³C-NMR (125 MHz, CDCl₃) δ: 169.7, 169.6, 169.3, 146.3, 145.0, 139.6, 136.9, 135.5, 132.64, 132.57, 131.4, 129.9, 129.2, 129.0, 128.1, 127.1, 126.6, 126.00, 125.97, 125.5, 125.0, 123.1, 122.9, 121.9, 121.6, 121.3, 115.9, 115.2, 20.7, 20.5; Its optical purity (99% ee) was determined by HPLC analysis at 20 °C using a CHIRALPAK IA-3 column (hexane/2-propanol = 70 : 30; flow rate: 1.0 mL/min; retention times: 8.0 min for (R)-4e, 17.6 min for (S)-4e); mp: 150–152 °C; IR (neat) cm⁻¹: 1764, 1683; [α]_D²² −36.1 (c = 0.37, CHCl₃) for (R)-4e with 99% ee; HRMS (MALDI) m/z: 536.1468 (Calcd for C₃₃H₂₃NO₅Na [M + Na]⁺: 536.1468).

(S)-3e: A white solid; ¹H-NMR (500 MHz, acetone-d₆) δ: 8.04–7.91 (2H, br s), 8.00 (1H, d, J = 9.2 Hz), 7.92 (1H, d, J = 8.0 Hz), 7.80–7.72 (3H, m), 7.65–7.62 (2H, m), 7.52 (1H, d, J = 8.6 Hz), 7.40 (1H, d, J = 8.6 Hz), 7.36 (1H, d, J = 8.0 Hz), 7.32–7.22 (3H, m), 7.13–7.09 (2H, m), 6.80 (1H, ddd, J = 8.0, 6.8, 1.2 Hz), 6.53 (1H, d, J = 8.0 Hz); ¹³C-NMR (125 MHz, CDCl₃) δ: 169.7, 154.1, 153.3, 140.6, 137.3, 134.8, 134.2, 133.0, 130.9, 129.9, 129.6, 129.0, 127.3, 127.14, 127.06, 126.9, 125.0, 123.9, 123.6, 122.2, 119.5, 116.9, 116.1, 116.0, 115.1; Its optical purity (22% ee) was determined by HPLC analysis at 20 °C using a CHIRALPAK IC-3 column (hexane/2-propanol = 70 : 30; flow rate: 1.0 mL/min; retention times: 11.9 min for (R)-3e, 21.2 min for (S)-3e); mp: 245–247 °C; IR (neat) cm⁻¹: 3628, 3184, 1662; [α]_D²² +0.32 (c = 0.33, CHCl₃) for (S)-3e with 22% ee; HRMS (MALDI) m/z: 429.1356 (Calcd for C₂₉H₁₉NO₃ [M]^+·: 429.1356).

(R)-1-(2-Acetoxydibenzo[b,d]furan-1-yl)naphthalen-2-yl Acetate ((R)-4f) and (S)-1-(2-Hydroxynaphthalen-1-yl)dibenzo[b,d]furan-2-ol ((S)-3f)

According to the general procedure, (R)-4f (20.0 mg, 49% yield) and (S)-3f (15.0 mg, 46% yield) were obtained from rac-3f (32.6 mg, 0.10 mmol).

(R)-4f: A white solid; ¹H-NMR (500 MHz, CDCl₃) δ: 8.06 (1H, d, J = 9.2 Hz), 7.97 (1H, d, J = 8.0 Hz), 7.69 (1H, d, J = 8.6 Hz), 7.52 (1H, d, J = 8.6 Hz), 7.49–7.46 (2H, m), 7.38–7.36 (2H, m), 7.32–7.27 (2H, m), 6.85 (1H, ddd, J = 8.0, 6.8, 1.2 Hz), 6.29 (1H, d, J = 7.4 Hz), 1.94 (3H, s), 1.90 (3H, s); ¹³C-NMR (125 MHz, CDCl₃) δ: 169.7, 169.3, 156.9, 153.3, 146.2, 144.4, 132.4, 131.4, 129.9, 128.1, 127.3, 127.1, 125.9, 125.5, 124.7, 123.5, 122.7, 122.6, 122.1, 122.0, 121.8, 121.6, 111.7, 111.4, 20.6, 20.5; Its optical purity (93% ee) was determined by HPLC analysis at 20 °C using a CHIRALPAK IC-3 column (hexane/2-propanol = 95 : 5; flow rate: 1.0 mL/min; retention times: 8.3 min for (S)-4f, 9.6 min for (R)-4f); mp: 112–116 °C; IR (neat) cm⁻¹: 1763; [α]_D²³ −139.4 (c = 0.32, CHCl₃) for (R)-4f with 93% ee; HRMS (MALDI) m/z: 433.1043 (Calcd for C₂₆H₁₈O₅Na [M + Na]⁺: 433.1046).

(S)-3f: A white solid; ¹H-NMR (500 MHz, CDCl₃) δ: 8.03 (1H, d, J = 8.6 Hz), 7.92 (1H, d, J = 7.4 Hz), 7.66–7.64 (1H, d, J = 8.0, 1.2 Hz), 7.52 (1H, d, J = 8.0 Hz), 7.42–7.36 (2H, m), 7.35–7.31 (3H, m), 7.28 (1H, d, J = 8.0 Hz), 6.91 (1H, t, J = 8.0 Hz), 6.59 (1H, d, J = 8.0 Hz), 5.22 (1H, br s), 4.88 (1H, br s); ¹³C-NMR (125 MHz, CDCl₃) δ: 157.0, 152.2, 150.9, 150.3, 132.6, 131.7, 129.3, 128.5, 127.7, 127.3, 124.2, 123.9, 123.5, 122.6, 121.5, 117.8, 115.7, 113.4, 111.5, 111.4, 110.8; Its optical purity (98% ee) was determined by HPLC analysis at 20 °C using a CHIRALPAK IC-3 column (hexane/2-propanol = 90 : 10; flow rate: 1.0 mL/min; retention times: 8.9 min for (R)-3f, 13.0 min for (S)-3f); mp: 85–89 °C; IR (neat) cm⁻¹: 3400, 1621; [α]_D²³ +71.5 (c = 0.55, CHCl₃) for (S)-3f with 98% ee; HRMS (MALDI) m/z: 326.0937 (Calcd for C₂₂H₁₄O₃ [M]^+·: 326.0934).

One-Pot Reaction for the Preparation of (S)-3a and (R)-4a from 1a and 2

A 5-mL sealed tube was charged with 3-hydroxycarbazole (1a) (18.3 mg, 0.10 mmol), 2-naphthol (2) (14.4 mg, 0.10 mmol), V-MPS4 (58.5 mg, 10 mol% based on vanadium content), and toluene (1.0 mL, 0.10 M). After oxygen was purged to the tube, the reaction mixture was stirred at 30 °C for 17 h in a sealed condition. After the complete consumption of 1a was confirmed by TLC analysis, LIP301 (125 mg, 1.25 g/mmol), vinyl acetate (93 µL, 1.0 mmol), Na₂CO₃ (32 mg, 0.30 mmol), and toluene (4.0 mL) were added to the mixture. After argon was purged to the tube, the reaction mixture was stirred at 35 °C for 24 h. The additional vinyl acetate (93 µL, 1.0 mmol) was added into the mixture before stirring for another 24 h. After that, the reaction mixture was filtered through a Celite pad. The Celite pad was washed with EtOAc, and the combined filtrate was evaporated in vacuo. The residue was purified by PTLC (toluene/EtOAc = 10 : 1) to give a mixture of two regioisomeric esters (R)-5a and (S)-3a (7.7 mg, 19% yield from 1a, 78% ee). The mixture of regioisomers (R)-5a was subjected to acylation according to the above-mentioned general procedure to give (R)-4a (11.0 mg, 22% yield from 1a, 98% ee).

Acknowledgments

We thank Professor Hiroaki Sasai, Professor Shinobu Takizawa, and Professor Makoto Sako for their useful suggestions. This work was supported by JSPS KAKENHI (Grant Numbers 21H02605 and 18KK0154) and Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED under Grant Number 21am0101084. K. Kasama would like to thank Nagai Memorial Research Scholarship from the Pharmaceutical Society of Japan, the Tokyo Biochemical Research Foundation, and JST SPRING, Grant Number JPMJSP2138 for financial support. We acknowledge TOYOBO Co., Ltd. (Osaka, Japan) for kindly supplying lipases (LIP301 and LPL-311) and the immobilization procedure, Amano Enzyme Inc. (Nagoya, Japan) for lipases and Taiyo Kagaku Co., Ltd. (Tokyo, Japan) for mesoporous silica (TMPS-4R).

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

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