Chiral Phosphoric Acid Catalyzed Asymmetric Synthesis of 2-Substituted 2,3-Dihydro-4-Quinolones by Protecting Group-Free Approach

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1 Chiral Phosphoric Acid Catalyzed Asymmetric Synthesis of 2-Substituted 2,3-Dihydro-4-Quinolones by Protecting Group-Free Approach Kodai Saito, Yuka Moriya, and Takahiko Akiyama* Department of Chemistry, Faculty of Science, Gakushuin University, Mejiro, Toshima-ku, Tokyo , Japan Supporting information Table of Contents 1. Syntheses of starting materials 2. General procedure for the phosphoric acid catalyzed aza-michael addition and characterization data of 2-substituted 2,3-dihydro-4-quinolones 3. Derivatization of 2-substituted 2,3-dihydro-4-quinolones 4. Synthesis and reaction of N-acetylated 2-aminochalcone General. NMR spectra were recorded on Unity Inova-400 instrument (Varian Inc., 400 MHz for 1 H, 100 MHz for 13 C) using CDCl 3 as a solvent. Tetramethylsilane (TMS) (δ = 0) or CHCl 3 (δ = 7.26) served as an internal standard for 1 H NMR, and CDCl 3 was used as an internal standard (δ = 77.0) for 13 C NMR. Melting point (mp) determinations were performed by using a AS ONE ATM-01 instrument and are uncorrected. Infrared (IR) spectra were recorded on a FTIR-8600PC instrument (Shimadzu Co.). EI mass spectra were recorded on JEOL GCmate II GC/MS Double-Focusing Mass Spectrometer. Optical rotations were measured on a HORIBA SEPA-500 polarimeter. Purification of the products was performed by column chromatography on silica gel (Fuji sylisia PSQ-60B) or preparative TLC on silica gel (Wako gel B-5F). All solvents were purified according to the standard procedures. S1

2 1. Syntheses and characterization data of starting materials Syntheses of starting materials Starting materials 1a, 1 1b, 2 1c, 3 1d, 2 1e, 4 1f, 5 1g, 3 1h, 5 1i-1k, 1 1l, 6 1m, 2 1n, 5 1o, 2 1p 7 were synthesized by the following procedure. Aldehyde (27.8 mmol) was dissolved in EtOH (20 ml) and NaOH (1 pellet), 2-aminoacetophenone (27.8 mmol) were successively added to the solution at 0 o C. After being stirred for 5 min, the mixture was warmed to room temperature and stirred for 6 h. The mixture was diluted with H 2 O and extracted with Et 2 O three times. The combined organic phase was dried over Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel flash column chromatography. 2. General procedure for the phosphoric acid catalyzed aza-michael addition and characterization data of 2-substitued 2,3-dihydro-4-quinolones A typical procedure for the reaction of 1a is described. A magnetic stirrer bar was placed in a test-tube under nitrogen atmosphere, then dried with a heat gun under reduced pressure and the test-tube was refilled with nitrogen. 1a (22.3 mg, mmol), phosphoric acid (R)-3g (6.8 mg, 10 µmol) were added to the test-tube successively under nitrogen atmosphere at room temperature. Benzene (0.5 ml) and cyclohexane (0.5 ml) was added to the test-tube. After being stirred for 3 days at 70 o C, the volatile materials were removed under reduced pressure, and the residue was purified by preparative thin layer chromatography on silica gel (toluene) to give 21.2 mg ( mmol, 95%) of (S)-2a as yellow solid. Rac-2a was synthesized by following procedure. 1a (23.3 mg, mmol) was dissolved to toluene (1 ml) and H 3 PO 4 (5.80 µl, mmol) was added. After being stirred for 3 h at 70 o C, the reaction was quenched by adding saturated NaHCO 3 aq. The mixture was extracted by CH 2 Cl 2 three times and the combined organic phase was dried over Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (toluene) to give rac-2a (21.0 mg, mmol, 90%). S2

3 2a (21.2 mg, 95%, 93% ee) 8 Pale yellow solid. 1 H NMR (400MHz, CDCl 3 ): δ 2.77 (dd, J= 16.4, 3.6Hz, 1H), 2.88 (dd, J= 16.4, 13.6Hz, 1H), 4.53 (brs, 1H), 4.75 (dd, J= 13.6, 3.6Hz, 1H), 6.71 (d, J= 8.4Hz, 1H), 6.79 (dd, J= 7.6, 7.2Hz, 1H), (m, 4H), 7.46 (d, J= 7.2Hz, 2H), 7.87 (d, J= 8.0Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 46.4, 58.47, 115.9, 118.4, 119.0, 126.6, 127.6, 128.4, 129.0, 135.4, 141.0, 151.5, HPLC conditions: CHIRALCEL AD-H, hexane/2-propanol = 4/1, flow rate = 0.3 ml min -1, major enantiomer: t R = min; minor enantiomer: t R = min. [α] 24 D (c 2.2, CHCl 3 ) [lit., [α] 20 D (c 0.42, CHCl 3 ) for 98% ee of the (S)-enantiomer] 8 2b (17.1 mg, 71%, 90% ee) 9 Pale yellow solid. 1 H NMR (400MHz, CDCl 3 ): δ (m, 2H), 4.53 (brs, 1H), 5.14 (dd, J= 8.2, 8.8Hz, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 44.3, 50.9, 115.7, 115.9, 116.0, 118.6, 119.1, 124.6, 124.7, 127.5, 127.5, 127.6, 127.9, 128.0, 129.7, 129.8, 135.4, 151.4, 159.0, 161.4, HPLC conditions: CHIRALCEL AD-H, hexane/2-propanol = 4/1, flow rate = 0.3 ml min -1, major enantiomer: t R = min; minor enantiomer: t R = min. [α] 24 D (c 1.7, CHCl 3 ) S3

4 2c (23.3 mg, 90%, 93% ee) 8 Pale yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ (m, 1H), (m, 1H), 4.57 (brs, 1H), 5.25 (dd, J = 12.6, 4.0 Hz, 1H), (m, 2H), (m, 4H), (m, 1H), (m, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 44.0, 54.2, 116.1, 118.6, 119.1, 127.4, 127.5, 127.6, 129.3, 130.0, 132.7, 135.5, 138.3, 151.5, HPLC conditions: CHIRALCEL OD-H, hexane/2-propanol = 4/1, flow rate = 0.5 ml min -1, major enantiomer: t R = min; minor enantiomer: t R = min. 24 [α] D (c 0.3, CHCl 3 ) 2d (27.3 mg, 90%, 94% ee) 10 Pale yellow solid. 1 H NMR (400MHz, CDCl 3 ): δ 2.75 (dd, J=16.2, 12.4Hz, 1H), 2.95 (dd, J=16.4, 4.0Hz, 1H), 4.56 (brs, 1H), 5.22 (dd, J=12.6, 4.0Hz, 1H), 6.74 (d, J=8.0Hz, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 1H), (m, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 44.2, 56.8, 116.1, 118.7, 119.1, 123.0, 127.6, 127.7, 128.2, 129.7, 133.3, 135.5, 139.9, 151.5, HPLC conditions: CHIRALCEL OD-H, hexane/2-propanol = 4/1, flow rate = 0.7 ml min -1, major enantiomer: t R = min; minor enantiomer: t R = min [α] 24 D (c 0.3, CHCl 3 ) S4

5 2e (23.6 mg, 97%, 88% ee) 11 Pale yellow solid. 1 H NMR (400MHz, CDCl 3 ): δ 2.38 (s, 3H), (m, 2H), 4.44 (brs, 1H), 5.02 (dd, J= 13.4, 4.4 Hz, 1H), 6.72 (dd, J= 8.4, 4.0 Hz, 1H), (m, 1H), (m, 4H), 7.67 (dd, J= 7.4, 1.6 Hz), (m, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ -0.09, 26.1, 35.4, 96.8, 99.2, 99.8, 106.7, 107.6, 108.5, 108.9, 111.8, 115.9, 116.2, 119.9, 132.8, HPLC conditions: CHIRALCEL OD-H, hexane/2-propanol = 4/1, flow rate = 0.5 ml min -1, major enantiomer: t R = min; minor enantiomer: t R = min. [α] 24 D (c 0.3, CHCl 3 ) 2f (22.1 mg, 73%, 84% ee, 20 mol% of (R)-3g was used.) 12 Pele yellow solid. 1 H NMR (400MHz, CDCl 3 ): δ (m, 2H), 4.53 (brs, 1H), 4.72 (dd, J=13.2, 4.4 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), 7.64 (dd, J=1.8, 2.0 Hz, 1H), 7.86 (dd, J=8.0, 1.6 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 46.3, 58.0, 116.0, 118.8, 119.0, 123.0, 125.3, 127.6, 129.7, 130.6, 131.6, 135.5, 143.3, 151.3, HPLC conditions: CHIRALCEL OD-H, hexane/2-propanol = 4/1, flow rate = 0.7 ml min -1, major enantiomer: t R = min; minor enantiomer: t R = min. [α] 24 D (c 0.4, CHCl 3 ) S5

6 2g (22.5 mg, 95%, 86% ee) Pale yellow solid. 1 H NMR (400MHz, CDCl 3 ): δ 2.38 (s, 3H), (m, 2H), 4.52 (brs, 1H), 4.70 (dd, J= 14.0, 3.6 Hz, 1H), 6.70 (dd, J= 8.2, 0.80 Hz, 1H), (m, 1H), (m, 5H), 7.87 (dd, J= 8.0, 1.6 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 21.5, 46.4, 58.5, 115.9, 118.4, 119.0, 123.7, 127.3, 127.6, 128.9, 129.2, 135.4, 138.7, 141.0, 151.6, HPLC conditions: CHIRALCEL OD-H, hexane/2-propanol = 4/1, flow rate = 0.5 ml min -1, major enantiomer: t R = min; minor enantiomer: t R = min. [α] 24 D (c 0.4, CHCl 3 ) IR (film): 3321, 2919, 1659, 1610, 1482, 759 cm -1. HRMS (EI) m / z calcd for C 16 H 16 NO (M+H) found m. p o C 2h (23.9 mg, 95%, 92% ee) 8 Pale yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ: (m, 2H), 3.82 (s, 3H), 4.56 (brs, 1H), 4.71 (dd, J = 13.6, 4.0 Hz, 1H), 6.71, (d, J = 8.4 Hz, 1H), (m, 1H), (m, 1H), 7.02 (d, J = 7.6 Hz, 2H) (m, 2H), 7.86 (dd, J = 7.6, 1.2 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 46.4, 55.3, 58.4, 112.2, 113.7, 115.9, 118.4, 118.8, 119.0, 127.6, 130.1, 135.4, 142.7, 151.5, 160.0, HPLC conditions: CHIRALCEL OD-H, hexane/2-propanol = 4/1, flow rate = 0.7 ml min -1, major enantiomer: t R = min; minor enantiomer: t R = min. 24 [α] D (c 1.2, CHCl 3 ) S6

7 2i(24.0 mg, quant, 87% ee) 8 Pale yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ (m, 2H), 4.52 (brs, 1H), 4.73 (dd, J = 13.4, Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), , (m, 1H), (m, 2H), (m, 1H), (m, 2H), 7.86 (dd, J = 7.8, 1.2 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 46.6, 57.9, 115.8, 115.9, 116.0, 118.6, 119.0, 127.6, 128.3, 128.4, 135.5, 136.8, 136.8, 151.4, 161.4, 163.8, HPLC conditions: CHIRALCEL AD-H, hexane/2-propanol = 4/1, flow rate = 1.0 ml min -1, major enantiomer: t R = min; minor enantiomer: t R = 8.11 min. 24 [α] D (c 0.3, CHCl 3 ) 2j (17.2 mg, 67%, 82% ee, 20 mol% of (R)-3g was used.) 8 Pale yellow solid. 1 H NMR (400MHz, CDCl 3 ): δ (m, 2H), 4.50 (brs, 1H), 4.73 (dd, J=13.0, 4.0 Hz, 1H), 6.73 (d, J= 8.4 Hz, 1H), (m, 1H), (m, 5H), 7.86 (dd, J=8.2, 1.6 Hz 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 46.4, 57.9, 116.0, 118.7, 119.1, 127.6, 128.0, 129.2, 134.2, 135.5, 139.5, 151.3, HPLC conditions: CHIRALCEL AD-H, hexane/2-propanol = 4/1, flow rate = 0.3 ml min -1, major enantiomer: t R = min; minor enantiomer: t R = min. [α] 24 D (c 0.3, CHCl 3 ) S7

8 2k (24.4 mg, quant, 83% ee) 8 Pale yellow solid. 1 H NMR (400MHz, CDCl 3 ): δ2.37 (s, 3H), (m, 1H), 2.88 (dd, J=16.4, 14.0 Hz, 1H), 4.47 (brs, 1H), 4.72 (dd, J=13.8, 4.0 Hz, 1H), 6.70 (d, J=8.0 Hz, 1H), (m, 1H), 7.21 (d, J=7.6 Hz, 2H) (m, 3H), 7.87 (dd, J=8.0, 1.6 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 21.1, 46.5, 58.2, 115.9, 118.4, 119.0, 126.5, 127.6, 129.6, 135.4, 138.0, 138.3, 151.6, HPLC conditions: CHIRALCEL AD-H, hexane/2-propanol = 3/2, flow rate = 0.3 ml min -1, major enantiomer: t R = min; minor enantiomer: t R = min. [α] 24 D (c 0.3, CHCl 3 ) 2l (29.8 mg, 95%, 93% ee) 8 Pale yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ: (m, 2H), (m, 9H), (m, 2H), 6.67 (brs, 2H), , (m, 2H), (m, 1H), 7.86 (dd, J = 8.0, 1.2 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 46.7, 56.1, 58.8, 60.8, 103.4, 116.0, 118.5, 119.0, 127.6, 135.4, 136.8, 137.7, 151.6, 153.5, HPLC conditions: CHIRALCEL OD-H, hexane/2-propanol = 7/3, flow rate = 1.0 ml min -1, major enantiomer: t R = min; minor enantiomer: t R = min. 24 [α] D (c 0.5, CHCl 3 ) S8

9 2m (22.4 mg, 82%, 81% ee) 13 Pale yellow solid. 1 H NMR (400MHz, CDCl 3 ): δ (m, 1H), (m, 1H), 2.97 (dd, J= 8.0, 14.0 Hz, 1H), 4.60 (brs, 1H), 4.93 (dd, J= 13.8, 4.0 Hz, 2H), 6.75 (d, J= 8.4 Hz, 1H), (m, 1H), (m, 2H), (m, 5H). 13 C NMR (100 MHz, CDCl 3 ): δ 46.4, 58.6, 116.0, 118.5, 119.1, 124.3, 125.6, 126.4, 126.6, 127.6, 127.8, 127.9, 128.9, 133.3, 133.3, 135.5, 138.4, 151.6, HPLC conditions: CHIRALCEL AD-H, hexane/2-propanol = 4/1, flow rate = 1.0 ml min -1, major enantiomer: t R = min; minor enantiomer: t R = min. [α] 24 D (c 1.0, CHCl 3 ) 2n (23.1 mg, quant, 83% ee) 8 Pale yellow solid. 1 H NMR (400MHz, CDCl 3 ): δ (m, 2H), 4.66 (brs, 1H), 5.05 (dd, J= 10.8, 5.6 Hz, 1H), 6.72 (d, J= 8.4 Hz, 1H), 6.81 (dd, J= 7.6, 7.6 Hz, 1H), 6.99 (dd, J= 4.8, 3.6 Hz, 1H), 7.07 (d, J= 2.8 Hz, 1H), 7.28 (d, J= 4.8 Hz, 1H), 7.35 (dd, J= 7.6, 7.6 Hz, 1H), 7.87 (d, J= 8.0 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 47.0, 53.7, 116.0, 118.8, 119.3, 125.0, 125.2, 126.9, 127.6, 135.5, 144.5, 150.8, HPLC conditions: CHIRALCEL AD-H, hexane/2-propanol = 1/1, flow rate = 0.3 ml min -1, major enantiomer: t R = min; minor enantiomer: t R = min. [α] 24 D (c 0.3, CHCl 3 ) S9

10 2o (21.2 mg, 99%, 91% ee) 8 Pale yellow solid. 1 H NMR (400MHz, CDCl 3 ): δ (m, 2H), 4.74 (brs, 1H), (m, 1H), (m, 1H), 6.33 (dd, J= 3.2, 1.6 Hz, 1H), 6.71 (dd, J= 8.4, 0.40 Hz, 1H), (m, 1H), (m, 1H), 7.39 (dd, J= 1.6, 0.80 Hz, 1H), 7.85 (8.0, 1.6 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 21.6, 30.5, 86.5, 90.1, 95.7, 98.3, 98.9, 107.1, 115.1, 122.2, 130.1, 133.0, HPLC conditions: CHIRALCEL AD-H, hexane/2-propanol = 4/1, flow rate = 0.5 ml min -1, major enantiomer: t R = min; minor enantiomer: t R = min. [α] 24 D (c 0.8, CHCl 3 ) 2p (13.0 mg, 64%, 88% ee) 7 Pale yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ1.02 (s, 9H), 2.51 (dd, J= 15.8, 14.0 Hz, 1H), (m, 1H), 3.33 (dd, J = 14.2, 3.6 Hz, 1H), 4.35, (brs, 1H), (m, 2H), (m, 1H), 7.81 (7.8, 1.6 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 25.9, 33.2, 39.5, 62.2, 115.9, 117.8, 118.7, 127.4, 135.1, 152.0, HPLC conditions: CHIRALCEL OD-H, hexane/2-propanol = 4/1, flow rate = 0.5 ml min -1, major enantiomer: t R = 9.35 min; minor enantiomer: t R = min. 24 [α] D (c 0.4, CHCl 3 ) S10

11 3. Derivatization of 2-substituted 2,3-dihydro-4-quinolones Br O N H (S)-2a NaBH 4 MeOH OH N H (n-bu) 3 P DEAD 4-BrC 6 H 4 SH THF S N H (S,S)-4a Synthesis of (S,S)-4a (S)-2a (22.2 mg, mmol, 93% ee) was dissolved in MeOH (2 ml) and NaBH 4 (13.3 mg, mmol) was added to the solution at room temperature. After being stirred for 20 min, the reaction was quenched by adding H 2 O. The mixture was extracted with CH 2 Cl 2 four times and the combined organic phase was dried over Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure and dried in vacuo. The corresponding product was slightly decomposed by silica-gel column chromatography to give 2-phenylquinoline. Therefore, the crude was directly used for next step without further purification (Disatereomer ratio was determined by 1 H NMR; trans/cis = ca. 15/1). The crude was dissolved to THF (2 ml), and (n-bu) 3 P (65 µl, mmol), 4-bromobenzenethiol (49.7 mg, mmol) was added to the solution. DEAD (118 µl, mmol, 2.2 M solution in toluene) was slowly added to the solution at 0 o C. After being stirred for 5 min, the solution was warmed to room temperature. After being stirred for 60 min, the solution was poured into Et 2 O. The organic phase was washed with saturated NaHCO 3 aq three times and the resulting organic phase was dried over Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica-gel thin layer chromatography (AcOEt/hexanes = 1/10) to give 35.0 mg ( mmol, 89% (2 steps), 93% ee) as pale yellow oil) S11

12 (S,S)-4a (89%, 93% ee) Pale yellow oil. 1 H NMR (400 MHz, CDCl 3 )δ: (m, 2H), 4.16 (brs, 1H), (m, 1H), 4.85 (dd, J = 10.4, 3.6 Hz, 1H), 6.56, (d, J = 8.0 Hz, 1H), 6.68 (dd, J = 7.4, 7.2 Hz, 1H), (m, 1H), (m, 1H), (m, 9H). 13 C NMR (100 MHz, CDCl 3 ): δ 36.0, 46.1, 51.7, 114.7, 117.4, 118.2, 121.5, 126.8, 127.8, 128.7, 128.8, 130.8, 132.2, 133.8, 134.2, 143.4, HPLC conditions: CHIRALCEL OD-H, hexane/2-propanol = 7/3, flow rate = 1.0 ml min -1, major enantiomer: t R = 6.12 min; minor enantiomer: t R = 9.36 min. 24 [α] D (c 3.0, CHCl 3 ) IR (film): 3386, 3026, 2918, 2851, 1718, 1607, 1584, 1484, 1472, 1454, 1427, 1385, 1341, 1317, 1258, 1224, 1156, 1113, 1090, 1068, 1035, 1009, 984, 900, 817, 750, 701, 609 cm -1. HRMS (EI) m / z calcd for C 21 H 18 NSBr (M) found O N H (S)-2a LiAlH 4, THF then AlCl 3 N H (S)-5a Synthesis of (S)-5a (S)-2a (10.0 mg, mmol) was dissolved to THF (1 ml) and LiAlH 4 (12.0 mg, mmol) was added to the solution at 0 o C. After being stirred for 1 h, the reaction mixture was warmed to room temperature. After being stirred for 30 min at room temperature, AlCl 3 (finely crushed under N 2 atmosphere, 13.0 mg, mmol) was added at room temperature. After being stirred for 10 min, the reaction was quenched by adding H 2 O. The mixture was extracted with CH 2 Cl 2 three times and the combined organic phase was dried over Na 2 SO 4. After filtration, the filtrate was concentrated S12

13 under reduced pressure. The residue was purified by silica-gel thin layer chromatography (AcOEt/hexanes = 1/10) to give (S)-5a (7.9 mg, mmol, 84%, 93% ee) N H (S)-5a (84%, 93% ee) 14 Colorless oil. 1 H NMR (400 MHz, CDCl 3 )δ: (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 4H). 13 C NMR (100 MHz, CDCl 3 ): δ 26.3, 30.9, 56.2, 113.9, 117.1, 120.8, 126.5, 126.8, 127.4, 128.5, 129.6, 144.6, HPLC conditions: CHIRALCEL OD-H, hexane/2-propanol = 1/5, flow rate = 0.5 ml min -1, major enantiomer: t R = 9.83 min; minor enantiomer: t R = min. 24 [α] D (c 0.25, CHCl 3 ) [lit. [α] RT D = 36.8 (c 0.95, CHCl 3 ) for 92% ee of (R)-enantiomer] Synthesis and reaction of N-acetylated 2-aminochalcone Substrate 6a was synthesized by the following procedure. 1a (67.0 mg, mmol) was dissolved to CH 2 Cl 2 (1 ml) and NEt 3 (0.840 ml, 6.02 mmol), AcCl (0.430 ml, 6.02 mmol) was added slowly to the solution at room temperature. After being stirred for 15 h, volatile materials were removed under reduced pressure. The residue was purified by silica-gel flash column chromatography (AcOEt/hexanes = 1/5) to give 6a (74.5 mg, mmol, 94%). Reaction of 6a was carried out according to the following procedure. A magnetic stirrer bar was placed in a test-tube under nitrogen atmosphere, then dried with a heat gun under reduced pressure and the test-tube was refilled with nitrogen. 6a (26.5 mg, mmol), phosphoric acid (R)-3g (6.8 mg, 10 µmol) were added to the test-tube successively under nitrogen atmosphere at room temperature. Benzene (0.5 ml) and cyclohexane (0.5 ml) was added to the test-tube. After being stirred for 3 days at 70 o C, the volatile materials were removed under reduced pressure, and the S13

14 residue was purified by preparative thin layer chromatography on silica gel (AcOEt / hexane = 1/5) to give 1.0 mg ( mmol, 4%) of (S)-7a. (S)-7a (4%, 97% ee) 9 Pale yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ: 2.43 (s, 3H), 3.25 (dd, J = 18, 5.6 Hz, 1H), 3.38 (dd, J = 17.6, 2.0 Hz, 1H), 6.47 (brs, 1H), , (m, 7H), (m, 1H), (m, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 23.4, 29.7, 42.5, 125.1, 125.5, 126.1, 126.8, 127.3, 127.5, 128.6, 134.4, 137.9, 141.8, 170.1, HPLC conditions: CHIRALPAK IC, hexane/2-propanol = 1/1, flow rate = 0.7 ml min -1, major enantiomer: t R = min; minor enantiomer: t R = min [α] D (c 0.10, CHCl 3 ) [lit. [α] D (c 0.66, CHCl 3 ) for (S)-enantiomer of 99% ee] 9 References (1) Climent, M. J.; Corma, A.; Iborra, S.; Martí, L. J. ACS Catal. 2015, 5, (2) Zhao, F.; Zhao, Q.-J.; Zhao, J.-X.; Zhang, D.-Z.; Wu, Q.-Y.; Jin, Y.-S. Chem. Nat. Compd. 2013, 49, (3) Akila, S.; Selvi, S.; Balasubramanian, K. Tetrahedron 2001, 57, (4) Zhang, X.; Song, X.; Li, H.; Zhang, S.; Chen, X.; Yu, X.; Wang, W. Angew. Chem. Int. Ed. 2012, 51, (5) Cheng, S.; Zhao, L.; Yu, S. Adv. Synth. Catal. 2014, 356, (6) Lee, J.-I.; Jung, H.-J. J. Korean Chem. Soc. 2007, 51, (7) Li, J.; Jin, L.; Yu, C.; Su, W. J. Chem. Res. 2009, 3, (8) Kanagaraj, K.; Pichumani, K. J. Org. Chem. 2013, 78, S14

15 (9) Lei, B.-L.; Ding, C.-H.; Yang, X.-F.; Wao, X.-L.; Hou, X.-L. J. Am. Chem. Soc. 2009, 131, (10) Bhattacharya, R. N.; Kundu, P.; Maiti, G. Synth. Commun. 2010, 40, (11) Kawaii, S.; Endo, K.; Tokiwano, T.; Yoshizawa, Y. Anticancer Res. 2012, 32, (12) Mondal, B.; Pan, S. C. Org. Biomol. Chem. 2014, 12, (13) Tollari, S.; Cenini, S.; Ragaini, F.; Cassar, L. J. Chem. Soc., Chem. Commun. 1994, 15, (14) T. Wang, L.-G. Zhuo, Z. Li, F. Chen, Z. Ding, Y. He, Q.-H. Fan, J. Xiang, Z.-X. Yu, A. S. C. Chan, J. Am. Chem. Soc. 2011, 133, S15

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