添加剤の検討

第五節添加剤の検討

本反応において、マグネシウム塩 7 のハロゲン原子が臭化マグネシウムとして脱離することが、触媒化の妨げになっていると考えている。そこで、臭化物塩を加えることでハロゲン原子が再生され、触媒化が実現できるのではないか、と考えた(Scheme 11)。

この考えの基、添加剤の検討を行った(Table 11)。20 mol %の配位子3i存在下で、臭化リチウム、臭化マグネシウム・ジエチルエーテル錯体、テトラブチルアンモニウムブロミドをそれぞれ加えて反応を行ったが、改善は見られなかった(entries 2-4)。全体的にエノール化が競合し、化学収率が低下する傾向が見られたため、無機塩の添加には限界があると考えている。

現段階では触媒化は達成できていないが、適切なフェノール系化合物を加えることで、

配位子量の低減が可能になるのではないか、と期待している(Scheme 12)。

結語

以上筆者は、新規BINOL誘導体を不斉配位子として利用することで、アリールGrignard 試薬を直接求核剤としたケトンの不斉1,2−付加反応を開発した。以下にその成果を述べる。

1. 3,3’位に様々なアルキル鎖を有する新規 BINOL 誘導体を合成し、これらをアリール

Grignard試薬とアリールアルキルケトン間の付加反応に適用することで、効果的に不斉

誘起を促す新規配位子を見出すことに成功した。本反応は、アリールGrignard試薬を直接求核剤とした初の不斉反応であり、単純ケトンとGrignard試薬という入手容易な原料から、非常に簡便かつ迅速に多様な光学活性第三級ジアリールアルコールを合成することができる。反応に使用した配位子は、定量的かつ容易に回収、再利用することが可能である。

2. これまで不斉空間の構築に不向きとされていたアルキル鎖によって立体を制御した珍しい反応系である。本研究から、不斉配位子設計における新たな方向性として、嵩高いアルキル鎖を提示することができたと考えている。今後、アルキル鎖を有する不斉配位子の更なるライブラリー構築、ならびにその他の不斉反応への応用が期待できる。

3. 不斉誘起メカニズムの解明に向けた検討の過程で、効果的な不斉誘起にはジマグネシウム塩の形成が不可欠であること、また、配位子は50 mol %まで減量できることを明らかにした。現在のところ、反応後に配位子が生成物から解離することができず、複合体を形成していると考えている。添加剤等加えることで、この解離を促進することが可能となれば、不斉触媒反応への展開が期待できる。

本反応系は、既存のアリール金属試薬を用いた反応と比較し、より調製が容易なGrignard 試薬のみ用いていることが特徴であり、低コスト化、余分な金属廃棄物の低減等につながる。配位子量の更なる低減化を達成することによって、他の追随を許さない画期的な触媒的不斉合成法となり得る。今後より詳細なメカニズムの解明とともに、不斉触媒化、生物活性物質の合成等に応用されることを期待する。

実験の部

Experimental section

General Methods

Melting points (Mp) are uncorrected. ¹H and ¹³C NMR spectra were measured in CDCl3 with JEOL JNM-ECX400 spectrometer. Tetramethylsilane (TMS) (δ = 0 ppm) and CDCl3 (δ = 77.0 ppm) served as internal standards for ¹H and ¹³C NMR, respectively. Infrared spectra were recorded on JEOL JIR 6500-W. Mass spectra were measured with JEOL JMS-DX303HF mass spectrometer.

Optical rotations were recorded on JASCO P-1010 polarimeter. High-pressure liquid chromatography (HPLC) was performed on JASCO P-980 and UV-1575. Thin-layer chromatography (TLC) analysis was carried out using Merck silica gel plates. Visualization was accomplished with UV light and anisaldehyde. Column chromatography was performed using Kanto Chemical Silica Gel 60N (spherical, neutral, 63-210 μm). All reactions were performed under argon atmosphere using glassware equipped with a rubber septum and a magnetic stirring bar.

Solvents and Chemicals

Dry tetrahydrofuran (dehydrated) and phenylmagnesium chloride (2b) was purchased from Kanto Chemical. All other Grignard reagents were prepared under typical procedure. Ligands 3b was purchased as a (R)-isomer and used without purification. Ligands 3a⁴⁹, 3c⁵⁰ and ketone 1f⁵¹, 1h⁵² and styryl bromide⁵³ were prepared by the literature methods. All other chemicals were purified based on standard procedures or used as received otherwise noted.

Typical Procedure for Preparation of Grignard Reagent (2a) in Et2O

Bromobenzene (0.5 mL, 4.75 mmol, 1.0 equiv.) was added dropwise to the mixture of Mg (127 mg, 5.2 mmol, 1.1 equiv.) and Et2O (2.7 mL) under argon atmosphere at room temperature. The reaction was exothermic and maintained at reflux. After the reaction mixture was stirred for 1 h at rt, Ph-MgBr (2a) was generated as approximately 1.48 M Et2O solution. The concentration was determined by neutralization titrated with I2 and Na2S2O3.

All other Grignard reagents 2c-2n were prepared from the corresponding aryl or alkyl bromide and Mg as approximately 1.5 M THF solution. 2o was prepared from ⁿBu-MgBr and phenylacetylene. These reagents were used without titration.

実験の部

Preparation of Ligands 3 Ligand 3d

(R)-2,2'-dihydroxy-1,1'-binaphthyl (10 g, 34.9 mmol, 1.0 equiv.) in THF (50 mL) was added via cannula to the suspension of NaH (4.6 g, 60% in oil, 115 mmol, 3.3 equiv.) in THF (150 mL) under argon atmosphere at 0 °C. The reaction mixture was warmed to room temperature and stirred for 1 h.

After the mixture was re-cooled to 0 °C, chloromethyl methyl ether (8.5 mL, 105 mmol, 3.0 equiv.) was slowly added. The reaction mixture was warmed to room temperature and stirred for 3 h. The reaction was quenched with sat.NH4Cl (20 mL). After evaporation, the aqueous layer was extracted with CH2Cl2 (4 x 20 mL). The combined organic layers were washed with H2O (20 mL), brine (20 mL) and dried over Na2SO4. After filtration and evaporation, the obtained crude product was washed with Hexane to furnish SI-1 as colorless needles (12.3 g, 94%).

n-Butyl lithium (9.4 mL, 15 mmol, 3.0 equiv. 1.6 M in n-hexane) was added to the solution of SI-1 (1.87 g, 5.0 mmol, 1.0 equiv.) in THF (25 mL) under argon atmosphere at 0 °C. The reaction mixture was stirred at the same temperature for 1 h and then acetone (3.7 mL, 50 mmol, 10 equiv.) was added. The reaction mixture was warmed to room temperature and stirred for 10 min. The reaction was quenched with sat.NH4Cl (10 mL) and then the aqueous layer was extracted with EtOAc (4 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4. After filtration and evaporation, the obtained crude product was purified by column chromatography (Hexane/EtOAc = 4/1–1/1, SiO2 50 g) to furnish SI-2 as colorless needles (911 mg).

12 N HCl (10 drops) was added to the solution of SI-2 (911 mg) in MeOH (10 mL) and CH2Cl2

(5 mL) at room temperature. After the reaction mixture was stirred for 3 h, the reaction was quenched with sat.NaHCO3 (10 mL) and H2O (5 mL). The aqueous layer was extracted with CH2Cl2 (4 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4. After filtration and evaporation, the obtained crude product was purified by column chromatography (Hexane/CH2Cl2 = 1/1–0/1, SiO2 20 g) to furnish the BINOL derivative 3d as colorless needles (381 mg, 18% in 3 steps).

実験の部

(R)-3,3'-Bis(1-methoxy-1-methylethyl)-2,2'-dihydroxy-1,1'-binaphthyl (3d) Colorless needles.

Mp: 224.0-226.0 °C.

TLC: Rf 0.38 (Hexane/EtOAc = 4/1, stained blue with anisaldehyde).

[α]D 31 +219.9 (c 1.00, CHCl3).

IR (ATR): 3181, 2979, 1199, 1049, 751, 662 cm^-1.

1H NMR (400 MHz, CDCl3): δ 1.80 (s, 12H), 3.29 (s, 6H), 7.14-7.31 (m, 6H, ArH), 7.72 (s, 2H, ArH), 7.81 (d, J = 8.2 Hz, 2H, ArH), 8.93 (s, 2H, OH).

13C NMR (100 MHz, CDCl3): δ 26.5, 26.8, 51.0, 80.4, 117.3, 123.1, 124.6, 126.4, 128.0, 128.1, 130.6, 133.8, 151.6 (one carbon overlapped).

MS (EI): m/z 430 (M⁺).

HRMS: Calcd for C28H30O4 430.2144, found 430.2133.

Ligand 3e

n-Butyl lithium (5.0 mL, 8.0 mmol, 3.0 equiv. 1.6 M in n-hexane) was added to the solution of SI-1 (1.0 g, 2.7 mmol, 1.0 equiv.) in Et2O (30 mL) under argon atmosphere at 0 °C. The reaction mixture was stirred at the same temperature for 3 h and then benzaldehyde (0.84 mL, 8.0 mmol, 3.0 equiv.) was added. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction was quenched with sat.NH4Cl (10 mL) and then the aqueous layer was extracted with EtOAc (4 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4. After filtration and evaporation, the obtained crude product was purified by column chromatography (Hexane/EtOAc = 6/1–1/1, SiO2 40 g) to furnish SI-3 as a diastereomeric mixture (1.553 g).

12 N HCl (5 drops) was added to the solution of SI-3 (1.553 g) in MeOH (10 mL) and CH2Cl2 (5 mL) at room temperature. After the reaction mixture was stirred for 4 h, the reaction was quenched with sat.NaHCO3 (5 mL) and H2O (5 mL). The aqueous layer was extracted with CH2Cl2 (4 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4. Filtration and evaporation afforded the tetraol (1.33 g) as a diastereomeric mixture. The tetraol was used in the next reaction without further purification.

Triethylsilane (1.6 mL, 10 mmol, 5.0 equiv.) was added to the solution of the above tetraol (1.0 g, 2 mmol, 1.0 equiv.) and boron trifluoride etherate (1.2 mL, 10 mmol, 5.0 equiv.) in CH2Cl2 (5 mL) under argon atmosphere at 0 °C. The reaction mixture was stirred for 1 h, and then the reaction was quenched with sat.NaHCO3 (10 mL). The aqueous layer was extracted with CH2Cl2 (4 x 20 mL).

The combined organic layers were washed with brine (20 mL) and dried over Na2SO4. After

実験の部

filtration and evaporation, the obtained crude product was purified by column chromatography (Hexane/EtOAc = 10/1, SiO2 20 g) to furnish the product 3e as colorless needles (349 mg, 28% in 3 steps).

(R)-3,3'-Dibenzyl-2,2'-dihydroxy-1,1'-binaphthyl (3e) Colorless needles.

Mp: 76.0-77.0 °C.

TLC: Rf 0.54 (Hexane/EtOAc = 4/1, stained blue with anisaldehyde).

[α]D 29 +69.8 (c 1.05, CHCl3).

IR (ATR): 3502, 3026, 748, 696 cm^-1.

1H NMR (400 MHz, CDCl3): δ 4.23 (s, 4H), 5.16 (s, 2H, OH), 7.08 (d, J = 8.2 Hz, 2H, ArH), 7.22-7.28 (m, 4H, ArH), 7.30-7.35 (m, 10H, ArH), 7.69 (s, 2H, ArH), 7.78 (d, J = 8.2 Hz, 2H, ArH).

13C NMR (100 MHz, CDCl3): δ 36.6, 110.9, 123.9, 124.0, 126.2, 126.7, 128.0, 128.5, 129.1, 129.3, 130.1, 130.8, 132.2, 140.0, 151.5.

MS (EI): m/z 466 (M⁺).

HRMS: Calcd for C34H26O2 466.1933, found 466.1917.

Ligand 3f

n-Butyl lithium (26 mL, 42 mmol, 2.6 equiv. 1.6 M in n-hexane) was added to the solution of SI-1 (6.0 g, 16 mmol, 1.0 equiv.) in THF (80 mL) under argon atmosphere at 0 °C. The reaction mixture was stirred at the same temperature for 3 h and then isobutylene oxide (7.1 mL, 80 mmol, 5.0 equiv.) was added. The reaction mixture was warmed to room temperature and stirred for 18 h.

The reaction was quenched with sat.NH4Cl (20 mL). After evaporation, the aqueous layer was extracted with CH2Cl2 (4 x 20 mL). The combined organic layers were washed with H2O (20 mL), brine (20 mL) and dried over Na2SO4. After filtration and evaporation, the obtained crude product was purified by column chromatography (Hexane/EtOAc = 3/1–1/1, SiO2 200 g) to furnish SI-4 as colorless needles (6.3 g, 76%).

SI-4 (6.3 g, 12.1 mmol, 1.0 equiv.) in THF (50 mL) was added to the suspension of NaH (1.46 g, 60% in oil, 36.4 mmol, 3.0 equiv.) in THF (40 mL) under argon atmosphere at 0 °C. The reaction

実験の部

mixture was warmed to room temperature and stirred for 1 h. Methyl iodide (3.0 mL, 48.5 mmol, 4.0 equiv.) was added to the mixture, and then the reaction mixture was stirred for 3 h. The reaction was quenched with sat.NH4Cl (20 mL). After evaporation, the aqueous layer was extracted with CH2Cl2 (4 x 20 mL). The combined organic layers were washed with H2O (20 mL), brine (20 mL) and dried over Na2SO4. After filtration and evaporation, the crude product SI-5 was obtained as colorless needles.

12 N HCl (5 drops) was added to the solution of SI-5 in MeOH (30 mL) and CH2Cl2 (10 mL) at room temperature. After the reaction mixture was stirred for 1 h, the reaction was quenched with sat.NaHCO3 (10 mL) and H2O (5 mL). The aqueous layer was extracted with CH2Cl2 (4 x 20 mL).

The combined organic layers were washed with brine (20 mL) and dried over Na2SO4. After filtration and evaporation, the obtained crude product was purified by column chromatography (Hexane/CH2Cl2 = 1/1–0/1, SiO2 120 g) to furnish the BINOL derivative 3f as colorless needles (5.5 g, 98% in 2 steps).

(R)-3,3'-Bis(2-methoxy-2-methylpropyl)-2,2'-dihydroxy-1,1'-binaphthyl (3f) Colorless needles.

Mp: 148.0-149.5 °C.

TLC: Rf 0.24 (Hexane/EtOAc = 4/1, stained purple with anisaldehyde).

[α]D 31 +132.7 (c 1.00, CHCl3).

IR (ATR): 3152, 2978, 1262, 1061, 748, 633 cm^-1.

1H NMR (400 MHz, CDCl3): δ 1.27 (s, 6H), 1.32 (s, 6H), 3.03 (d, J = 14 Hz, 2H), 3.22 (d, J = 14 Hz, 2H), 3.22 (s, 6H), 7.11-7.19 (m, 4H, ArH), 7.23-7.28 (m, 2H, ArH), 7.64 (s, 2H, ArH), 7.77 (d, J = 7.8 Hz, 2H, ArH), 8.50 (s, 2H, OH).

13C NMR (100 MHz, CDCl3): δ 23.6, 24.3, 46.1, 49.5, 77.7, 117.6, 122.9, 124.9, 125.6, 127.5, 128.6, 131.3, 133.5, 152.1 (one carbon overlapped).

MS (EI): m/z 458 (M⁺).

HRMS: Calcd for C30H34O4 458.2457, found 458.2436.

Ligand 3g

SI-4 (4.43 g, 8.54 mmol, 1.0 equiv.) in THF (30 mL) was added to the suspension of NaH (3.1 g, 60% in oil, 76.9 mmol, 9.0 equiv.) in THF (30 mL) under argon atmosphere at 0 °C. The reaction mixture was warmed to room temperature and stirred for 1 h. Ethyl iodide (2.73 mL, 85.4 mmol, 10 equiv.) was added to the mixture, and then the reaction mixture was stirred for 41 h at reflux. The reaction was quenched with sat.NH4Cl (20 mL). After evaporation, the aqueous layer was extracted with CH2Cl2 (4 x 20 mL). The combined organic layers were washed with H2O (20 mL), brine (20

実験の部

mL) and dried over Na2SO4. After filtration and evaporation, the obtained crude product was purified by column chromatography (Hexane/EtOAc = 6/1–4/1–0/1, SiO2 120 g) to furnish SI-6 as colorless needles (2.78 g).

12 N HCl (5 drops) was added to the solution of SI-6 in MeOH (10 mL) and CH2Cl2 (5 mL) at room temperature. After the reaction mixture was stirred for 2.5 h, the reaction was quenched with sat.NaHCO3 (10 mL) and H2O (5 mL). The aqueous layer was extracted with CH2Cl2 (4 x 20 mL).

(R)-3,3'-Bis(2-ethoxy-2-methylpropyl)-2,2'-dihydroxy-1,1'-binaphtyl (3g) Colorless needles.

Mp: 74.5-76.0 °C.

TLC: Rf 0.44 (Hexane/EtOAc = 4/1, stained purple with anisaldehyde).

[α]D 30 +215.0 (c 1.00, CHCl3).

IR (ATR): 3177, 2973, 1259, 1058, 746, 662 cm^-1.

1H NMR (400 MHz, CDCl3): δ 1.05 (t, J = 6.9 Hz, 6H, (-OCH2CH3)2), 1.29 (s, 6H), 1.33 (s, 6H), 3.00 (d, J = 14 Hz, 2H), 3.19 (d, J = 14 Hz, 2H), 3.45 (q, J = 6.9 Hz, 4H, (-OCH2CH3)2), 7.12-7.17 (m, 4H, ArH), 7.22-7.27 (m, 2H, ArH), 7.63 (s, 2H, ArH), 7.76 (d, J = 8.2 Hz, 2H, ArH), 8.53 (s, 2H, OH).

13C NMR (100 MHz, CDCl3): δ 15.7, 24.1, 25.0, 46.5, 57.4, 77.6, 117.9, 122.8, 125.0, 125.4, 127.4, 127.7, 128.6, 131.1, 133.5, 152.1.

MS (EI): m/z 487 (M+H⁺).

HRMS: Calcd for C32H38O4 486.2770, found 486.2759.

Ligand 3h

The reaction was quenched with sat.NH4Cl (10 mL) and then the aqueous layer was extracted with EtOAc (4 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4. After filtration and evaporation, the obtained crude product was purified by column

実験の部

chromatography (Hexane/CH2Cl2 = 1/1–0/1, SiO2 40 g) to furnish SI-7 as colorless needles (704 mg, 49%).

12 N HCl (5 drops) was added to the solution of SI-7 (704 mg, 1.3 mmol, 1.0 equiv.) in MeOH (10 mL) and CH2Cl2 (5 mL) at room temperature. After the reaction mixture was stirred for 5 h, the reaction was quenched with sat.NaHCO3 (5 mL) and H2O (5 mL). The aqueous layer was extracted with CH2Cl2 (4 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4. Filtration and evaporation afforded the diol (641.3 mg) as colorless needles. The diol was used in the next reaction without further purification.

Triethylsilane (1.1 mL, 6.5 mmol, 5.0 equiv.) was added to the solution of the above diol (641.3 mg, 1.3 mmol, 1.0 equiv.) in TFA (2 mL) under argon atmosphere at room temperature. The reaction mixture was stirred for 2 h, and then the reaction was quenched with sat.NaHCO3 (10 mL).

The aqueous layer was extracted with CH2Cl2 (4 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4. After filtration and evaporation, the obtained crude product was purified by column chromatography (Hexane/CH2Cl2 = 15/1–1/1, SiO2 20 g) to furnish the product 3h as colorless needles (477 mg, 86% in 2 steps).

(R)-3,3'-Bis(2,2-dimethylpropyl)-2,2'-dihydroxy-1,1'-binaphthyl (3h) Colorless needles.

Mp: 79.0-81.0 °C.

TLC: Rf 0.68 (Hexane/EtOAc = 4/1, stained purple with anisaldehyde).

[α]D 32 +70.6 (c 1.00, CHCl3).

IR (ATR): 3521, 2948, 747, 660 cm^-1.

1H NMR (400 MHz, CDCl3): δ 1.01 (s, 18H), 2.77 (d, J = 13 Hz, 2H), 2.88 (d, J = 13 Hz, 2H), 5.09 (s, 2H, OH), 7.07 (d, J = 8.2 Hz, 2H, ArH), 7.21-7.27 (m, 2H, ArH), 7.31-7.37 (m, 2H, ArH), 7.76 (s, 2H, ArH), 7.85 (d, J = 8.2 Hz, 2H, ArH).

13C NMR (100 MHz, CDCl3): δ 29.5, 32.8, 43.1, 110.7, 123.8, 123.9, 126.5, 127.9, 128.7, 129.0, 132.2, 132.7, 152.4.

MS (EI): m/z 426 (M⁺).

HRMS: Calcd for C30H34O2 426.2559, found 426.2547.

実験の部

Ligand 3i and 6

MeI (16 mL, 251 mmol, 9.0 equiv.) was added to the solution of (R)-2,2'-dihydroxy-1,1'-binaphthyl (8 g, 27.9 mmol, 1.0 equiv.) and K2CO3 (17 g, 123 mmol, 4.4 equiv.) in acetone (60 mL) under argon atmosphere at rt. The reaction mixture was warmed to reflux and stirred for 23 h. After filtration through celite and evaporation, the obtained crude product was washed with Hexane to furnish SI-8 as colorless needles (8.3 g, 94%).

n-Butyl lithium (16 mL, 25.4 mmol, 4.0 equiv. 1.6 M in n-hexane) was added to the solution of TMEDA (2.9 mL, 19.1 mmol, 3.0 equiv.) in Et2O (125 mL) under argon atmosphere at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h and then SI-8 (2.0 g, 6.36 mmol, 1.0 equiv.) was added. The mixture was stirred at the same temperature for 3 h and then 3,3-dimethylbutanal (3.7 mL, 29.6 mmol, 4.6 equiv.) was added. The reaction mixture was stirred for 2 h. The reaction was quenched with sat.NH4Cl (10 mL) and then the aqueous layer was extracted with EtOAc (4 x 20 mL). The combined organic layers were washed with 10% HCl (20 mL), H2O (20 mL) and brine (20 mL) and dried over Na2SO4. Filtration and evaporation afforded SI-9 (3.83 g) as a diastereomeric mixture. SI-9 was used in the next reaction without further purification.

Boron trifluoride ethyl ether complex (2.4 mL, 19.1 mmol, 3.0 equiv.) was added to the solution of SI-9 (3.83 g) and triethylsilane (3.1 mL, 19.1 mmol, 3.0 equiv.) in CH2Cl2 (60 mL) under argon atmosphere at 0 °C. The reaction mixture was stirred for 1 h, and then the reaction was quenched with sat.NaHCO3 (10 mL). The aqueous layer was extracted with CH2Cl2 (4 x 20 mL). The combined organic layers were washed with sat.NaHCO3 (20 mL) and brine (20 mL), and dried over Na2SO4. After filtration and evaporation, the obtained crude product was purified by column chromatography (Hexane/CH2Cl2 = 10/1–4/1, SiO2 120 g) to furnish 6 as colorless prisms (2.11 g, 66% in 2 steps).

Boron tribromide (1.25 mL, 13.1 mmol, 3.0 equiv.) was added to the solution of 6 (2.11 g) in CH2Cl2 (45 mL) under argon atmosphere at 0 °C. The reaction mixture was stirred at room temperature for 13 h, and then the reaction was quenched with H2O (20 mL). The aqueous layer was extracted with CH2Cl2 (4 x 20 mL). The combined organic layers were washed with

実験の部

sat.NaHCO3 (20 mL) and brine (20 mL), and dried over Na2SO4. After filtration and evaporation, the obtained crude product was purified by column chromatography (Hexane/CH2Cl2 = 10/1–1/1, SiO2 50 g) to furnish 3i as colorless needles (1.85 g, 93%).

(R)-3,3'-Bis(3,3-dimethylbutyl)-2,2'-dimethoxy-1,1'-binaphthyl (6) Colorless prisms.

Mp: 48.5-50.0 °C.

TLC: Rf 0.69 (Hexane/EtOAc = 9/1, stained white with anisaldehyde).

[α]D 24 –85.2 (c 1.01, CHCl3).

IR (ATR): 2951, 1235, 1012, 748, 674 cm^-1.

1H NMR (400 MHz, CDCl3): δ 1.02 (s, 18H), 1.58-1.76 (m, 4H), 2.78-2.94 (m, 4H), 3.29 (s, 6H), 7.09-7.20 (m, 4H, ArH), 7.35 (t, J = 8.2 Hz, 2H, ArH), 7.79 (s, 2H, ArH), 7.82 (d, J = 8.2 Hz, 2H, ArH).

13C NMR (100 MHz, CDCl3): δ 26.0, 29.4, 30.7, 45.0, 60.7, 124.5, 124.6, 125.3, 125.7, 127.2, 128.5, 130.8, 133.0, 136.9, 155.5.

MS (EI): m/z 482 (M⁺).

HRMS: Calcd for C34H42O2 482.3185, found 482.3161.

(R)-3,3'-Bis(3,3-dimethylbutyl)-2,2'-dihydroxy-1,1'-binaphthyl (3i) Colorless needles.

Mp: 76.0-78.0 °C.

TLC: Rf 0.72 (Hexane/EtOAc = 4/1, stained purple with anisaldehyde).

[α]D 26 +47.6 (c 1.00, CHCl3).

IR (ATR): 3523, 2951, 747, 653 cm^-1.

1H NMR (400 MHz, CDCl3): δ 1.01 (s, 18H), 1.62-1.68 (m, 4H), 2.81-2.88 (m, 4H), 5.12 (s, 2H, OH), 7.07 (d, J = 8.2 Hz, 2H, ArH), 7.21-7.27 (m, 2H, ArH), 7.31-7.36 (m, 2H, ArH), 7.80 (s, 2H, ArH), 7.83 (d, J = 8.2 Hz, 2H, ArH).

13C NMR (100 MHz, CDCl3): δ 26.2, 29.3, 30.7, 44.1, 110.7, 123.8, 124.0, 126.3, 127.6, 129.5, 129.6, 132.0, 132.2, 151.8.

MS (EI): m/z 455 (M+H⁺).

HRMS: Calcd for C32H38O2 454.2872, found 454.2875.

The enantiomeric excess was determined to be >99% ee by chiral HPLC with Daicel Chiralpak AD-H column (0.46 cm φ × 25 cm) [eluent: Hexane/IPA = 49/1; flow rate: 1.0 mL/min; detection:

254 nm; tR: 4.7 min (S), 6.3 min (R)].

実験の部

Ligand 5

MeI (0.19 mL, 3.0 mmol, 2.0 equiv.) was added to the solution of 3i (682 mg, 1.5 mmol, 1.0 equiv.) and K2CO3 (228 mg, 1.65 mmol, 1.1 equiv.) in acetone (10 mL) under argon atmosphere at rt. The reaction mixture was stirred for 18 h. After filtration through celite and evaporation, the obtained crude product was purified by column chromatography (Hexane/CH2Cl2 = 10/1–4/1, SiO2

15 g) to furnish 5 as colorless needles (625 mg, 89%).

(R)-3,3'-Bis(3,3-dimethylbutyl)-2-hydroxy-2'-methoxy-1,1'-binaphthyl (5) Colorless prisms.

TLC: Rf 0.87 (Hexane/EtOAc = 4/1, stained purple with anisaldehyde).

1H NMR (400 MHz, CDCl3): δ 1.01 (s, 9H), 1.03 (s, 9H), 1.60-1.70 (m, 4H), 2.78-2.91 (m, 4H), 3.34 (s, 3H), 5.11 (s, 1 H), 7.04 (d, J = 8.3 Hz, 1H, ArH),

7.10-7.24 (m, 3H, ArH), 7.26-7.31 (m, 1H, ArH), 7.36-7.42 (m, 1H, ArH), 7.75 (s, 1 H, ArH), 7.78-7.86 (m, 3H, ArH).

Ligand 3j

n-Butyl lithium (4.9 mL, 8.0 mmol, 3.0 equiv. 1.63 M in n-hexane) was added to the solution of SI-1 (1.0 g, 2.7 mmol, 1.0 equiv.) in THF (10 mL) under argon atmosphere at 0 °C. The reaction mixture was stirred at the same temperature for 3 h and then 1-bromobutane (1.2 mL, 10.7 mmol, 4.0 equiv.) was added. The reaction mixture was warmed to room temperature and stirred for 13 h.

The reaction was quenched with sat.NH4Cl (10 mL) and then the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4. After filtration and evaporation, the obtained crude product SI-10 (1.4 g) was used in the next reaction without further purification.

12 N HCl (5 drops) was added to the above crude product SI-10 (1.4 g) in MeOH (5 mL) and CH2Cl2 (5 mL) at room temperature. After the reaction mixture was stirred for 6 h, the reaction was quenched with sat.NaHCO3 (5 mL) and H2O (5 mL). The aqueous layer was extracted with CH2Cl2

(3 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4. After filtration and evaporation, the obtained crude product was purified by column

実験の部

chromatography (Hexane/CH2Cl2 = 10/1–5/1–2/1, SiO2 20 g) to furnish the product 3j as colorless oil (751 mg, 71% in 2 steps).

(R)-3,3'-Dibutyl-2,2'-dihydroxy-1,1'-binaphthyl (3j)²⁹ Colorless oil.

TLC: Rf 0.70 (Hexane/EtOAc = 4/1, stained purple with anisaldehyde).

1H NMR (400 MHz, CDCl3): δ 0.99 (t, J = 7.3 Hz, 6H), 1.42-1.52 (m, 4H), 1.71-1.81 (m, 4H), 2.88 (t, J = 7.8 Hz, 4H), 5.11 (s, 2 H), 7.07 (d, J = 8.2 Hz, 2H,

ArH), 7.21-7.27 (m, 2H, ArH), 7.31-7.37 (m, 2H, ArH), 7.80 (s, 2 H, ArH), 7.84 (d, J = 7.8 Hz, 2H, ArH).

実験の部

Section 2

Typical Procedure A: Asymmetric 1,2-Addition of Grignard Reagent to Simple Ketone (Table 2, entry 11).

A solution of Ph-MgBr (2a) in Et2O (1.48 M, 1.18 mL, 1.75 mmol, 3.5 equiv.) was added dropwise to the solution of ligand 3i (228 mg, 0.5 mmol, 1.0 equiv.) and 2’-acetonaphthone (1a) (85.1 mg, 0.5 mmol) in THF (1.0 mL) at –45 °C. After the mixture was stirred for 1 h, the reaction was quenched with sat.NH4Cl (3.0 mL) and stirred for 0.5 h. The aqueous layer was extracted with EtOAc (3 x 20 mL) and the combined organic layers were washed with brine (10 mL), and dried over Na2SO4. After filtration and evaporation, the obtained crude product was purified by column chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4a (117.0 mg, 94%

yield, 93% ee). Ligand 3i could be easily recovered and reused. The quantitative amounts of ligand 3i was recovered after asymmetric 1,2-addition. The Rf values of ligand 3i and product 4a were 0.74 and 0.15 (hexane/CH2Cl2 = 1/1), and the Rf values of all other products 4 were similar to 4a.

(R)-1-(2-Naphthalenyl)-1-phenylethanol (4a)^40b Colorless oil.

TLC: Rf 0.49 (Hexane/EtOAc = 4/1, stained blue with anisaldehyde).

[α]D 17 +17.3 (c 1.1, CH2Cl2) for 93% ee (R). [(lit^40b: [α]D 25 –16.1, c 1.0, CH2Cl2) for 92% ee (S).].

1H NMR (400 MHz, CDCl3): δ 2.06 (s, 3H, CH3), 2.27 (s, 1H, OH), 7.23-7.28 (m, 1H, ArH), 7.29-7.35 (m, 2H, ArH), 7.39-7.51 (m, 5H, ArH), 7.74-7.86 (m, 3H, ArH), 7.98 (s, 1H, ArH).

13C NMR (100 MHz, CDCl3): δ 30.7, 76.3, 123.7, 124.9, 125.9, 126.1, 127.0, 127.5, 127.9, 128.2, 132.3, 132.9, 145.2, 147.7 (two carbons overlapped).

The enantiomeric excess was determined to be 93% ee by chiral HPLC with Daicel Chiralpak OJ column (0.46 cm φ × 25 cm) [eluent: Hexane/IPA = 4/1; flow rate: 1.0 mL/min; detection: 254 nm;

tR: 15.6 min (S), 19.5 min (R)].

Typical Procedure B: Asymmetric 1,2-Addition of Grignard Reagent to Simple Ketone (Table 1, entry 5).

A solution of Ph-MgBr (2a) in Et2O (1.48 M, 1.18 mL, 1.75 mmol, 3.5 equiv.) was added dropwise to the solution of ligand 3a (219.3 mg, 0.5 mmol, 1.0 equiv.) in THF (1.0 mL) at –45 °C.

After the mixture was stirred for 10 min, a solution of 2’-acetonaphthone (1a) in THF (1.0 M, 0.5 mL, 0.5 mmol, 1.0 equiv.) was added. After the mixture was stirred for 1 h, the reaction was quenched with sat.NH4Cl (3.0 mL) and stirred for 0.5 h. The aqueous layer was extracted with EtOAc (3 x 20 mL) and the combined organic layers were washed with brine (10 mL), and dried

実験の部

over Na2SO4. After filtration and evaporation, the obtained crude product was purified by column chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4a (114.2 mg, 92%

yield, 50% ee).

Asymmetric 1,2-addition between ketone 1a and Grignard reagent 2a at –78 °C (Table 1, entry 1).

The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4a (52.1 mg, 42% yield, 75% ee).

Asymmetric 1,2-addition between ketone 1a and Grignard reagent 2a at –78 °C (Table 1, entry 2).

According to the typical procedure B, a solution of 2’-acetonaphthone (1a) in THF (1.0 M, 0.5 mL, 0.5 mmol, 1.0 equiv.) was added to the mixture of Ph-MgBr (2a) in Et2O (1.48 M, 1.18 mL, 1.75 mmol, 3.5 equiv.) and ligand 3a (219.3 mg, 0.5 mmol, 1.0 equiv.) in THF (4.5 mL) at –78 °C for 3 h. The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4a (74.5 mg, 60% yield, 77% ee).

Asymmetric 1,2-addition between ketone 1a and Grignard reagent 2a at –45 °C (Table 1, entry 3).

The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4a (106.8 mg, 86% yield, 53% ee).

Asymmetric 1,2-addition between ketone 1a and Grignard reagent 2a at –23 °C (Table 1, entry 4).

The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4a (108.0 mg, 87% yield, 47% ee).

Asymmetric 1,2-addition between ketone 1a and Grignard reagent 2a in the presence of ligand 3b (Table 2, entry 2).

実験の部

The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4a (108.0 mg, 87% yield, 18% ee).

Asymmetric 1,2-addition between ketone 1a and Grignard reagent 2a in the presence of ligand 3c (Table 2, entry 3).

The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4a (99.3 mg, 80% yield, 2% ee).

Asymmetric 1,2-addition between ketone 1a and Grignard reagent 2a in the presence of ligand 3d (Table 2, entry 4).

The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product ent-4a (29.9 mg, 24% yield, 25% ee).

Asymmetric 1,2-addition between ketone 1a and Grignard reagent 2a in the presence of ligand 3e (Table 2, entry 5).

The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4a (100.6 mg, 81% yield, 3% ee).

Asymmetric 1,2-addition between ketone 1a and Grignard reagent 2a in the presence of ligand 3f (Table 2, entry 6).

The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4a (119.2 mg, 96% yield, 72% ee).

Asymmetric 1,2-addition between ketone 1a and Grignard reagent 2a in the presence of ligand 3g (Table 2, entry 7).

The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g)

実験の部

to furnish the product 4a (110.5 mg, 89% yield, 72% ee).

Asymmetric 1,2-addition between ketone 1a and Grignard reagent 2a in the presence of ligand 3h (Table 2, entry 8).

The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4a (117.9 mg, 95% yield, 78% ee).

Asymmetric 1,2-addition between ketone 1a and Grignard reagent 2a in the presence of ligand 3i (Table 2, entry 9).

The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4a (114.2 mg, 92% yield, 90% ee).

Asymmetric 1,2-addition between ketone 1a and Grignard reagent 2a in the presence of ligand 3j (Table 2, entry 10).

The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4a (89.7 mg, 72% yield, 2% ee).

Asymmetric 1,2-addition between ketone 1a and Grignard reagent 2a using DME as a solvent (Table 3, entry 2).

According to the typical procedure A, a solution of Ph-MgBr (2a) in Et2O (1.48 M, 1.18 mL, 1.75 mmol, 3.5 equiv.) was added to the mixture of 2’-acetonaphthone (1a) (85.1 mg, 0.5 mmol, 1.0 equiv.) and ligand 3i (227.3 mg, 0.5 mmol, 1.0 equiv.) in DME (1.0 mL) at –45 °C. The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4a (44.1 mg, 36% yield, 1% ee).

Asymmetric 1,2-addition between ketone 1a and Grignard reagent 2a using Et2O as a solvent (Table 3, entry 3).

According to the typical procedure A, a solution of Ph-MgBr (2a) in Et2O (1.48 M, 1.18 mL, 1.75 mmol, 3.5 equiv.) was added to the mixture of 2’-acetonaphthone (1a) (85.1 mg, 0.5 mmol, 1.0 equiv.) and ligand 3i (227.3 mg, 0.5 mmol, 1.0 equiv.) in Et2O (1.0 mL) at –45 °C. The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4a (117.9 mg, 95% yield, 69% ee).

実験の部

Asymmetric 1,2-addition between ketone 1a and Grignard reagent 2a using toluene as a solvent (Table 3, entry 4).

According to the typical procedure A, a solution of Ph-MgBr (2a) in Et2O (1.48 M, 1.18 mL, 1.75 mmol, 3.5 equiv.) was added to the mixture of 2’-acetonaphthone (1a) (85.1 mg, 0.5 mmol, 1.0 equiv.) and ligand 3i (227.3 mg, 0.5 mmol, 1.0 equiv.) in toluene (1.0 mL) at –45 °C. The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4a (115.3 mg, 93% yield, 67% ee).

Asymmetric 1,2-addition between ketone 1a and Grignard reagent 2a in THF (Table 3, entry 5).

According to the typical procedure A, a solution of Ph-MgBr (2a) in THF (1.48 M, 1.18 mL, 1.75 mmol, 3.5 equiv.) was added to the mixture of 2’-acetonaphthone (1a) (85.1 mg, 0.5 mmol, 1.0 equiv.) and ligand 3i (227.3 mg, 0.5 mmol, 1.0 equiv.) in THF (1.0 mL) at –45 °C. The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4a (117.0 mg, 94% yield, 93% ee).

Asymmetric 1,2-addition between ketone 1a and Grignard reagent 2a in THF using toluene as a solvent (Table 3, entry 6).

According to the typical procedure A, a solution of Ph-MgBr (2a) in THF (1.48 M, 1.18 mL, 1.75 mmol, 3.5 equiv.) was added to the mixture of 2’-acetonaphthone (1a) (85.1 mg, 0.5 mmol, 1.0 equiv.) and ligand 3i (227.3 mg, 0.5 mmol, 1.0 equiv.) in toluene (1.0 mL) at –45 °C. The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4a (117.8 mg, 95% yield, 92% ee).

Asymmetric 1,2-addition between ketone 1a and Grignard reagent 2b (Table 4, entry 1).

According to the typical procedure A, a solution of Ph-MgCl (2b) in THF (2.0 M, 0.88 mL, 1.75 mmol, 3.5 equiv.) was added to the mixture of 2’-acetonaphthone (1a) (85.1 mg, 0.5 mmol, 1.0 equiv.) and ligand 3i (227.3 mg, 0.5 mmol, 1.0 equiv.) in THF (1.0 mL) at –45 °C. The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4a (66.5 mg, 54% yield, 85% ee).

Asymmetric 1,2-addition between ketone 1a and Grignard reagent 2c (Table 4, entry 3).

According to the typical procedure A, a solution of Ph-MgI (2c) in Et2O (1.48 M, 1.18 mL, 1.75 mmol, 3.5 equiv.) was added to the mixture of 2’-acetonaphthone (1a) (85.1 mg, 0.5 mmol, 1.0 equiv.) and ligand 3i (227.3 mg, 0.5 mmol, 1.0 equiv.) in THF (1.0 mL) at –45 °C. The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4a (49.3 mg, 40% yield, 77% ee).

実験の部

Section 3

Asymmetric 1,2-addition between ketone 1b and Grignard reagent 2a (Table 5, entry 2).

According to the typical procedure A, a solution of Ph-MgBr (2a) in Et2O (1.48 M, 1.18 mL, 1.75 mmol, 3.5 equiv.) was added to the mixture of 1’-acetonaphthone (1b) in THF (1.0 M, 0.5 mL, 0.5 mmol, 1.0 equiv.) and ligand 3i (227.3 mg, 0.5 mmol, 1.0 equiv.) in THF (0.5 mL) at –45 °C. The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4b (87.5 mg, 70% yield, 96% ee).

(R)-1-(1-Naphthalenyl)-1-phenylethanol (4b)^40b Colorless oil.

TLC: Rf 0.49 (Hexane/EtOAc = 4/1, stained blue with anisaldehyde).

[α]D 19 +87.3 (c 0.97, CH2Cl2) for 96% ee (R). [(lit^40b : [α]D 25 –95.4, c 0.94, CH2Cl2) for 93% ee (S).].

1H NMR (400 MHz, CDCl3): δ 2.08 (s, 3H, CH3), 2.41 (s, 1H, OH), 7.17-7.30 (m, 4H, ArH), 7.33-7.41 (m, 3H, ArH), 7.51 (t, J = 8.2 Hz, 1H, ArH), 7.78-7.93 (m, 4H, ArH).

13C NMR (100 MHz, CDCl3): δ 32.8, 77.1, 124.0, 124.6, 125.2, 125.4, 126.7, 127.2, 128.3, 128.7, 129.0, 130.6, 134.8, 141.9, 148.5 (one carbon overlapped).

The enantiomeric excess was determined to be 96% ee by chiral HPLC with Daicel Chiralpak OJ column (0.46 cm φ × 25 cm) [eluent: Hexane/IPA = 9/1; flow rate: 1.0 mL/min; detection: 254 nm;

tR: 13.8 min (S), 19.3 min (R)].

Asymmetric 1,2-addition between ketone 1c and Grignard reagent 2a (Table 5, entry 3).

According to the typical procedure A, a solution of Ph-MgBr (2a) in Et2O (1.48 M, 1.18 mL, 1.75 mmol, 3.5 equiv.) was added to the mixture of 4’-methoxyacetophenone (1c) (75.1 mg, 0.5 mmol, 1.0 equiv.) and ligand 3i (227.3 mg, 0.5 mmol, 1.0 equiv.) in THF (1.0 mL) at –45 °C. The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2–0/1, SiO2 6 g) to furnish the product 4c (107.9 mg, 95% yield, 91% ee).

(R)-1-(4-Methoxyphenyl)-1-phenylethanol (4c)^40b Colorless oil.

TLC: Rf 0.34 (Hexane/EtOAc = 4/1, stained purple with anisaldehyde).

[α]D 19 +21.6 (c 0.75, CH2Cl2) for 91% ee (R). [(lit^40b: [α]D 25 –14.6 (c 0.71, CH2Cl2) for 90% ee (S).].

1H NMR (400 MHz, CDCl3): δ 1.93 (s, 3H, CH3), 2.12 (s, 1H, OH), 3.79 (s, 3H, OMe), 6.84 (d, J = 8.7 Hz, 2H, ArH), 7.21-7.27 (m, 1H, ArH), 7.29-7.35 (m, 4H, ArH), 7.41 (d, J = 7.8 Hz, 2H, ArH).

13C NMR (100 MHz, CDCl3): δ 30.9, 55.2, 75.9, 113.4, 125.7, 126.8, 127.1, 128.1, 140.2, 148.2, 158.4.

The enantiomeric excess was determined to be 91% ee by chiral HPLC with Daicel Chiralpak OJ column (0.46 cm φ × 25 cm) [eluent: Hexane/IPA = 4/1; flow rate: 1.0 mL/min; detection: 254 nm;

tR: 18.9 min (R), 24.0 min (S)].

実験の部

Asymmetric 1,2-addition between ketone 1d and Grignard reagent 2a (Table 5, entry 4).

According to the typical procedure A, a solution of Ph-MgBr (2a) in Et2O (1.48 M, 1.18 mL, 1.75 mmol, 3.5 equiv.) was added to the mixture of 4’-bromoacetophenone (1d) (99.5 mg, 0.5 mmol, 1.0 equiv.) and ligand 3i (227.3 mg, 0.5 mmol, 1.0 equiv.) in THF (1.0 mL) at –45 °C. The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2–0/1, SiO2 6 g) to furnish the product 4d (127.2 mg, 92% yield, 91% ee).

(R)-1-(4-Bromophenyl)-1-phenylethanol (4d)^38a Colorless oil.

TLC: Rf 0.47 (Hexane/EtOAc = 4/1, stained purple with anisaldehyde).

[α]D 18 –6.67 (c 2.16, CH2Cl2) for 91% ee (R). [(lit^38a: [α]D +9.96, c 2.0, CH2Cl2) for >99% ee (S).].

1H NMR (400 MHz, CDCl3): δ 1.93 (s, 3H, CH3), 2.15 (s, 1H, OH), 7.23-7.36 (m, 5H, ArH), 7.37-7.46 (m, 4H, ArH).

13C NMR (100 MHz, CDCl3): δ 30.7, 75.9, 120.9, 125.7, 127.2, 127.7, 128.3, 131.2, 147.1, 147.3.

The enantiomeric excess was determined to be 91% ee by chiral HPLC with Daicel Chiralpak OD-H column (0.46 cm φ × 25 cm) [eluent: Hexane/IPA = 99/1; flow rate: 1.0 mL/min; detection:

254 nm; tR: 43.8 min (S), 46.6 min (R)].

Asymmetric 1,2-addition between ketone 1e and Grignard reagent 2a (Table 5, entry 5).

According to the typical procedure A, a solution of Ph-MgBr (2a) in Et2O (1.48 M, 1.18 mL, 1.75 mmol, 3.5 equiv.) was added to the mixture of 4’-chloroacetophenone (1e) in THF (1.0 M, 0.5 mL, 0.5 mmol, 1.0 equiv.) and ligand 3i (227.3 mg, 0.5 mmol, 1.0 equiv.) in THF (0.5 mL) at –45 °C.

The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4e (114.0 mg, 98% yield, 86% ee).

(R)-1-(4-Chlorophenyl)-1-phenylethanol (4e)^38a Colorless oil.

TLC: Rf 0.51 (Hexane/EtOAc = 4/1, stained purple with anisaldehyde).

[α]D 18 –9.25 (c 1.01, CHCl3) for 86% ee (R). [(lit^21a: [α]D 22 –11.2, c 1.9, CHCl3) for 92% ee (R).].

1H NMR (400 MHz, CDCl3): δ 1.94 (s, 3H, CH3), 2.17 (s, 1H, OH), 7.23-7.42 (m, 9H, ArH).

13C NMR (100 MHz, CDCl3): δ 30.8, 75.8, 125.7, 127.3, 128.3, 132.7, 146.5, 147.4 (two carbons overlapped).

The enantiomeric excess was determined to be 86% ee by chiral HPLC with Daicel Chiralpak AD-H column (0.46 cm φ × 25 cm) [eluent: Hexane/IPA = 99/1; flow rate: 1.0 mL/min; detection:

254 nm; tR: 37.1 min (R), 41.3 min (S)].

実験の部

Asymmetric 1,2-addition between ketone 1f and Grignard reagent 2a (Table 5, entry 6).

According to the typical procedure A, a solution of Ph-MgBr (2a) in Et2O (1.48 M, 1.18 mL, 1.75 mmol, 3.5 equiv.) was added to the mixture of 2’-naphthyl ethyl ketone (1f) (92.1 mg, 0.5 mmol, 1.0 equiv.) and ligand 3i (227.3 mg, 0.5 mmol, 1.0 equiv.) in THF (1.0 mL) at –45 °C. The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2–0/1, SiO2 6 g) to furnish the product 4f (127.0 mg, 97% yield, 86% ee).

(R)-1-(2-Naphthalenyl)-1-phenylpropanol (4f)³³ Colorless oil.

TLC: Rf 0.52 (Hexane/EtOAc = 4/1, stained purple with anisaldehyde).

[α]D 27 –1.97 (c 1.07, CH2Cl2) for 86% ee (R). [(lit³³ : [α]D 20 +2.5, c 4.9, CH2Cl2) for 86% ee (S).].

IR (ATR): 3460 cm^-1.

1H NMR (400 MHz, CDCl3): δ 0.92 (t, J = 7.3 Hz, 3H, CH2CH3), 2.16 (s, 1H, OH), 2.44 (q, J = 7.3 Hz, 2H, CH2CH3), 7.23 (t, J = 7.8 Hz, 1H, ArH), 7.31 (t, J = 8.2 Hz, 2H, ArH), 7.38-7.50 (m, 5H, ArH), 7.75 (d, J = 8.7 Hz, 1H, ArH), 7.79 (d, J = 9.2 Hz, 1H, ArH), 7.84 (d, J = 9.2 Hz, 1H, ArH), 7.99 (s, 1H, ArH).

13C NMR (100 MHz, CDCl3): δ 8.14, 34.2, 78.5, 124.2, 125.0, 125.8, 126.0, 126.2, 126.9, 127.4, 127.8, 128.1, 128.2, 132.2, 133.0, 144.1, 146.7.

MS (EI): m/z 262 (M⁺).

HRMS: Calcd for C19H18O1 262.1358, found 262.1334.

The enantiomeric excess was determined to be 86% ee by chiral HPLC with Daicel Chiralpak OJ column (0.46 cm φ × 25 cm) [eluent: Hexane/IPA = 4/1; flow rate: 1.0 mL/min; detection: 254 nm;

tR: 12.2 min (S), 15.6 min (R)].

Asymmetric 1,2-addition between ketone 1g and Grignard reagent 2a (Table 5, entry 7).

According to the typical procedure A, a solution of Ph-MgBr (2a) in Et2O (1.48 M, 1.18 mL, 1.75 mmol, 3.5 equiv.) was added to the mixture of cyclohexyl methyl ketone (1g) in THF (1.02 M, 0.49 mL, 0.5 mmol, 1.0 equiv.) and ligand 3i (227.3 mg, 0.5 mmol, 1.0 equiv.) in THF (0.5 mL) at –45 °C. The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4g (94.2 mg, 92% yield, 30% ee).

(S)-1-Cyclohexyl-1-phenylethanol (4g)^40b Colorless oil.

TLC: Rf 0.57 (Hexane/EtOAc = 4/1, stained purple with anisaldehyde).

[α]D 26 –5.39 (c 0.94, CH2Cl2) for 30% ee (S). [(lit^40b : [α]D 25 +18.2, c 0.72, CH2Cl2) for 81% ee (R).].

1H NMR (400 MHz, CDCl3): δ 0.91-1.26 (m, 5H), 1.51-1.79 (m, 10H), 7.23 (t, J = 7.3 Hz, 1H, ArH), 7.33 (t, J = 7.3 Hz, 2H, ArH), 7.40 (d, J = 7.3 Hz, 2H, ArH).

13C NMR (100 MHz, CDCl3): δ 26.3, 26.6, 26.7, 27.1, 27.3, 48.9, 76.6, 125.3, 126.3, 127.8, 147.8 (one carbon overlapped).

The enantiomeric excess was determined to be 30% ee by chiral HPLC with Daicel Chiralpak OJ

実験の部

column (0.46 cm φ × 25 cm) [eluent: Hexane/IPA = 99/1; flow rate: 1.0 mL/min; detection: 254 nm;

tR: 10.1 min (R), 12.1 min (S)].

Asymmetric 1,2-addition between ketone 1h and Grignard reagent 2a (Table 5, entry 8).

According to the typical procedure A, a solution of Ph-MgBr (2a) in Et2O (1.48 M, 1.18 mL, 1.75 mmol, 3.5 equiv.) was added to the mixture of N-benzyl isatin (1h) (118.6 mg, 0.5 mmol, 1.0 equiv.) and ligand 3i (227.3 mg, 0.5 mmol, 1.0 equiv.) in THF (1.0 mL) at –45 °C. The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2–0/1, SiO2 6 g) to furnish the product 4h (132.1 mg, 84% yield, 30% ee).

(R)-1-Benzyl-3-hydroxy-3-phenyl-1,3-dihydroindol-2-one (4h)^43d Colorless needles.

TLC: Rf 0.15 (Hexane/EtOAc = 4/1, stained white with anisaldehyde).

1H NMR (400 MHz, CDCl3): δ 3.22 (brs, 1H, OH), 4.85 (d, J = 16 Hz, 1H), 5.06 (d, J = 16 Hz, 1H), 6.80 (d, J = 7.8 Hz, 1H, ArH), 7.05 (t, J = 7.3 Hz, 1H, ArH), 7.21-7.45 (m, 12H, ArH).

The enantiomeric excess was determined to be 30% ee by chiral HPLC with Daicel Chiralpak OD-H column (0.46 cm φ × 25 cm) [eluent: Hexane/IPA = 4/1; flow rate: 0.5 mL/min; detection:

227 nm; tR: 14.3 min (S), 15.9 min (R)].

Asymmetric 1,2-addition between ketone 1i and Grignard reagent 2d (Table 6, entry 1).

According to the typical procedure A, a solution of 2’-naphthylmagnesium bromide (2d) in THF (1.50 M, 1.16 mL, 1.75 mmol, 3.5 equiv.) was added to the mixture of acetophenone (1i) in THF (1.03 M, 0.49 mL, 0.5 mmol, 1.0 equiv.) and ligand 3i (227.3 mg, 0.5 mmol, 1.0 equiv.) in THF (0.5 mL) at –45 °C. The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product ent-4a (100.4 mg, 80% yield, 94% ee).

(S)-1-(2-Naphthalenyl)-1-phenylethanol (ent-4a)^40b

[α]D 19 –13.4 (c 1.14, CH2Cl2) for 94% ee (S). [(lit^40b: [α]D 25 –16.1, c 1.0, CH2Cl2) for 92% ee (S).].

The enantiomeric excess was determined to be 94% ee by chiral HPLC with

Daicel Chiralpak OJ column (0.46 cm φ × 25 cm) [eluent: Hexane/IPA = 4/1; flow rate: 1.0 mL/min; detection: 254 nm; tR: 15.6 min (S), 20.3 min (R)].

Asymmetric 1,2-addition between ketone 1i and Grignard reagent 2e (Table 6, entry 2).

According to the typical procedure A, a solution of 4-methoxyphenylmagnesium bromide (2e) in THF (1.48 M, 1.18 mL, 1.75 mmol, 3.5 equiv.) was added to the mixture of acetophenone (1i) in THF (1.03 M, 0.49 mL, 0.5 mmol, 1.0 equiv.) and ligand 3i (227.3 mg, 0.5 mmol, 1.0 equiv.) in THF (0.5 mL) at –45 °C. The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product ent-4c (107.7 mg, 94% yield, 84% ee).

実験の部

(S)-1-(4-Methoxyphenyl)-1-phenylethanol (ent-4c)^40b

[α]D 20 –14.1 (c 0.76, CH2Cl2) for 84% ee (S). [(lit^40b: [α]D 25 –14.6 (c 0.71, CH2Cl2) for 90% ee (S).].

The enantiomeric excess was determined to be 84% ee by chiral HPLC with

Daicel Chiralpak OJ column (0.46 cm φ × 25 cm) [eluent: Hexane/IPA = 4/1; flow rate: 1.0 mL/min; detection: 254 nm; tR: 20.0 min (R), 24.2 min (S)].

Asymmetric 1,2-addition between ketone 1i and Grignard reagent 2f (Table 6, entry 3).

According to the typical procedure A, a solution of 3-methoxyphenylmagnesium bromide (2f) in THF (1.48 M, 1.18 mL, 1.75 mmol, 3.5 equiv.) was added to the mixture of acetophenone (1i) in THF (1.03 M, 0.49 mL, 0.5 mmol, 1.0 equiv.) and ligand 3i (227.3 mg, 0.5 mmol, 1.0 equiv.) in THF (0.5 mL) at –45 °C. The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4i (103.0 mg, 90% yield, 87% ee).

(S)-1-(3-Methoxyphenyl)-1-phenylethanol (4i)^40b Yellow oil.

TLC: Rf 0.43 (Hexane/EtOAc = 4/1, stained purple with anisaldehyde).

[α]D 28 +9.25 (c 2.57, CH2Cl2) for 87% ee (S). [(lit^40b : [α]D 25 +9.17 (c 3.0, CH2Cl2) for 92% ee (S).].

1H NMR (400 MHz, CDCl3): δ 1.95 (s, 3H, CH3), 2.18 (s, 1H, OH), 3.78 (s, 3H, OMe), 6.78 (dd, J

= 2.7, 8.2 Hz, 1H, ArH), 6.95-6.98 (m, 1H, ArH), 7.01-7.03 (m, 1H, ArH), 7.21-7.26 (m, 2H, ArH), 7.29-7.35 (m, 2H, ArH), 7.40-7.44 (m, 2H, ArH).

13C NMR (100 MHz, CDCl3): δ 30.7, 55.1, 76.1, 111.89, 111.92, 118.3, 125.7, 126.9, 128.1, 129.1, 147.7, 149.7, 159.3.

The enantiomeric excess was determined to be 87% ee by chiral HPLC with Daicel Chiralpak OD-H column (0.46 cm φ × 25 cm) [eluent: Hexane/IPA = 49/1; flow rate: 1.0 mL/min; detection:

254 nm; tR: 33.3 min (S), 39.5 min (R)].

Asymmetric 1,2-addition between ketone 1i and Grignard reagent 2g (Table 6, entry 4).

According to the typical procedure A, a solution of 2-methoxyphenylmagnesium bromide (2g) in THF (1.48 M, 1.18 mL, 1.75 mmol, 3.5 equiv.) was added to the mixture of acetophenone (1i) in THF (1.03 M, 0.49 mL, 0.5 mmol, 1.0 equiv.) and ligand 3i (227.3 mg, 0.5 mmol, 1.0 equiv.) in THF (0.5 mL) at –45 °C. The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4j (111.2 mg, 97% yield, 6% ee).

実験の部

(S)-1-(2-Methoxyphenyl)-1-phenylethanol (4j)^40b Colorless prisms.

Mp: 69.5-71.0 °C for 6% ee (S).

TLC: Rf 0.50 (Hexane/EtOAc = 4/1, stained purple with anisaldehyde).

[α]D 29 –4.46 (c 1.85, CH2Cl2) for 6% ee (S). [(lit^21b : [α]D 23 +78.0 (c 4.8, CH2Cl2) for 99% ee (R).].

1H NMR (400 MHz, CDCl3): δ 1.84 (s, 3H, CH3), 3.59 (s, 3H, OMe), 4.67 (d, J = 1.4 Hz, 1H, OH), 6.89 (dd, J = 0.9, 8.2 Hz, 1H, ArH), 7.03 (dd, J = 0.9, 7.4 Hz, 1H, ArH), 7.16-7.21 (m, 1H, ArH), 7.22-7.33 (m, 5H, ArH), 7.44 (dd, J = 1.4, 7.4 Hz, 1H, ArH).

13C NMR (100 MHz, CDCl3): δ 30.1, 55.5, 76.2, 112.1, 120.8, 124.7, 126.2, 126.9, 127.6, 128.7, 135.1, 149.5, 156.9.

The enantiomeric excess was determined to be 6% ee by chiral HPLC with Daicel Chiralpak OJ column (0.46 cm φ × 25 cm) [eluent: Hexane/IPA = 4/1; flow rate: 1.0 mL/min; detection: 254 nm;

tR: 7.0 min (S), 22.0 min (R)].

Asymmetric 1,2-addition between ketone 1i and Grignard reagent 2h (Table 6, entry 5).

According to the typical procedure A, a solution of 4-methylphenylmagnesium bromide (2h) in THF (1.51 M, 1.16 mL, 1.75 mmol, 3.5 equiv.) was added to the mixture of acetophenone (1i) in THF (1.03 M, 0.49 mL, 0.5 mmol, 1.0 equiv.) and ligand 3i (227.3 mg, 0.5 mmol, 1.0 equiv.) in THF (0.5 mL) at –45 °C. The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4k (101.5 mg, 96% yield, 88% ee).

(S)-1-(4-Methylphenyl)-1-phenylethanol (4k)^38a Colorless oil.

TLC: Rf 0.47 (Hexane/EtOAc = 4/1, stained purple with anisaldehyde).

[α]D 29 –8.64 (c 1.30, CH2Cl2) for 88% ee (S). [(lit^38a : [α]D +16.0 (c 1.20, CH2Cl2) for 96% ee (R).].

1H NMR (400 MHz, CDCl3): δ 1.94 (s, 3H), 2.14 (s, 1H, OH), 2.33 (s, 3H, ArCH3), 7.13 (d, J = 7.8 Hz, 2H, ArH), 7.20-7.34 (m, 5H, ArH), 7.41 (d, J = 7.8 Hz, 2H, ArH).

13C NMR (100 MHz, CDCl3): δ 20.9, 30.8, 76.0, 125.7, 126.8, 128.1, 128.8, 136.5, 145.1, 148.1 (one carbon overlapped).

The enantiomeric excess was determined to be 88% ee by chiral HPLC with Daicel Chiralpak AD-H column (0.46 cm φ × 25 cm) [eluent: Hexane/IPA = 97/3; flow rate: 1.0 mL/min; detection:

254 nm; tR: 16.3 min (R), 17.1 min (S)].

Asymmetric 1,2-addition between ketone 1i and Grignard reagent 2i (Table 6, entry 6).

According to the typical procedure A, a solution of 2-methylphenylmagnesium bromide (2i) in THF (1.48 M, 1.18 mL, 1.75 mmol, 3.5 equiv.) was added to the mixture of acetophenone (1i) in THF (1.03 M, 0.49 mL, 0.5 mmol, 1.0 equiv.) and ligand 3i (227.3 mg, 0.5 mmol, 1.0 equiv.) in THF (0.5 mL) at –45 °C. The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4l (103.8 mg, 98% yield, 90% ee).

実験の部

(S)-1-(2-Methylphenyl)-1-phenylethanol (4l)^40b Colorless oil.

TLC: Rf 0.54 (Hexane/EtOAc = 4/1, stained purple with anisaldehyde).

[α]D 26 –51.1 (c 2.13, CH2Cl2) for 90% ee (S). [(lit^40b : [α]D 25 –60.3 (c 1.8, CH2Cl2) for 96% ee (S).].

1H NMR (400 MHz, CDCl3): δ 1.93 (s, 3H), 1.98 (s, 3H), 2.12 (s, 1H, OH), 7.09-7.14 (m, 1H, ArH), 7.19-7.34 (m, 7H, ArH), 7.67-7.72 (m, 1H, ArH).

13C NMR (100 MHz, CDCl3): δ 21.3, 32.1, 76.7, 125.2, 125.3, 125.9, 126.5, 127.6, 128.1, 132.4, 137.1, 144.5, 147.9.

The enantiomeric excess was determined to be 90% ee by chiral HPLC with Daicel Chiralpak OJ column (0.46 cm φ × 25 cm) [eluent: Hexane/IPA = 19/1; flow rate: 1.0 mL/min; detection: 254 nm;

tR: 12.5 min (S), 18.7 min (R)].

Asymmetric 1,2-addition between ketone 1i and Grignard reagent 2j (Table 6, entry 7).

According to the typical procedure A, a solution of 4-fluorophenylmagnesium bromide (2j) in THF (1.52 M, 1.15 mL, 1.75 mmol, 3.5 equiv.) was added to the mixture of acetophenone (1i) in THF (1.03 M, 0.49 mL, 0.5 mmol, 1.0 equiv.) and ligand 3i (227.3 mg, 0.5 mmol, 1.0 equiv.) in THF (0.5 mL) at –45 °C. The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product 4m (90.0 mg, 83% yield, 94% ee).

(S)-1-(4-Fluorophenyl)-1-phenylethanol (4m)^38a Colorless oil.

TLC: Rf 0.49 (Hexane/EtOAc = 4/1, stained purple with anisaldehyde).

[α]D 28 +6.01 (c 1.09, CHCl3) for 94% ee (S). [(lit^38a : [α]D –4.9 (c 1.06, CHCl3) for 84% ee (R).].

1H NMR (400 MHz, CDCl3) δ: 1.94 (s, 3H, CH3), 2.15 (s, 1H, OH), 6.99 (t, J = 8.7 Hz, 2H, ArH), 7.22-7.28 (m, 1H, ArH), 7.29-7.44 (m, 6H, ArH).

13C NMR (100 MHz, CDCl3) δ: 30.9, 75.8, 114.7, 114.9, 125.7, 127.1, 127.5, 127.6, 128.2, 143.77, 143.8, 147.7, 160.4, 162.9.

The enantiomeric excess was determined to be 94% ee by chiral HPLC with Daicel Chiralpak AD-H column (0.46 cm φ × 25 cm) [eluent: Hexane/IPA = 99/1; flow rate: 0.8 mL/min; detection:

254 nm; tR: 40.7 min (R), 42.0 min (S)].

Asymmetric 1,2-addition between ketone 1i and Grignard reagent 2k (Table 6, entry 8).

According to the typical procedure A, a solution of 4-chlorophenylmagnesium bromide (2k) in THF (1.0 M, 1.75 mL, 1.75 mmol, 3.5 equiv.) was added to the mixture of acetophenone (1i) in THF (1.03 M, 0.49 mL, 0.5 mmol, 1.0 equiv.) and ligand 3i (227.3 mg, 0.5 mmol, 1.0 equiv.) in THF (0.5 mL) at –45 °C. The crude product was purified by columm chromatography (Hexane/CH2Cl2 = 1/1–1/2, SiO2 6 g) to furnish the product ent-4e (81.4 mg, 70% yield, 97% ee).

ドキュメント内本論文において、以下の略語を使用した。 (ページ 37-75)

第五節 添加剤の検討

結語

Experimental section

Section 2

Section 3

第五節添加剤の検討