Supporting Information Enantioselective Synthesis of 3-Alkynyl-3-Hydroxyindolin-2-ones by Copper-Catalyzed Asymmetric Addition of Terminal Alkynes to Isatins Ning Xu, Da-Wei Gu, Jing Zi, Xin-Yan Wu, and Xun-Xiang Guo* 1
Table of Contents 1. General Information... 3 2. Experimental Details and Analytical Data.3 3. Transformation of Product 3aa into 4......19 4. Transformation of Product 3aa into 5......20 5. X-ray Structure of Product 3qa....21 6. References and Notes... 22 7. 1 H and 13 C NMR Spectra.....23 8. HPLC Spectra... 59 2
1. General Information. Toluene was distilled over benzophenone ketyl under N 2. MTBE was distilled over CaSO 4 under N 2. Other solvents were purified by usual methods before used. All commercial reagents were used without further purification. NMR spectra were recorded on a 400 spectrometer (400 MHz for 1 H, 100 MHz for 13 C) with deuterated chloroform (CDCl 3 ) as a solvent at 298K. Chemical shifts are reported in δ ppm referenced to an internal SiMe 4 standard for 1 H NMR, chloroform-d (δ 77.16) for 13 C NMR: the following abbreviations are used; s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet. HRMS were obtained on an ESI-TOF mass spectrometer. Falsh column chromatography was performed on silica gel (300-400 mesh). 2. Experimental Details and Analytical Data 2.1 General Procedure for the Synthesis of Substituted Isatins. [1] O NaH, RBr O N DMF, o C H CF 3 CF 3 O N R O To a mixture of 7-CF 3 substituted isatin (1.08 g, 5.0 mmol) and DMF (5.0 ml), NaH (132 mg, 5.5 mmol) was added slowly under N 2 atmosphere and the mixture was stirred at room temperature for 0.5 h. Then the mixture was cooled to 0 o C, and 4-nitrile benzyl bromide (1.08 g, 5.5 mmol) was added dropwise. The mixture was stirred at 0 C until the reaction completed by TLC. The mixture was heated to room temperature and 0.2 M HCl (10 ml) was added, extracted with ethyl acetate, and dried over MgSO 4. After evaporation of the solvent, the residue was purified by recrystallization with EtOH to give the product 1g. 3
N O O Compound 1g (72% yield): White solid, mp: 166-167 o C; 1 H NMR (400 MHz, CDCl 3 ): δ 7.94-7.86 (m, 2H), 7.62 (d, J = 8.4 Hz, 2H), CF 3 1g CN 7.33-7.29 (m, 3H), 5.26 (s, 2H). 13 C NMR (100 MHz, CDCl 3 ): δ 46.2 (q, J = 5.1 Hz), 111.7, 114.9 (q, J = 32.3 Hz), 118.6, 120.3, 122.6 (q, J = 272.7 Hz), 124.3, 126.7, 129.4, 132.6, 136.0 (q, J = 6.0 Hz), 140.7, 148.19, 148.20, 159.3, 181.0. HRMS (ESI) calcd for C 17 H 10 N 2 O 2 F 3 (M + H) +, 331.0694, found 331.0688. O N CF 3 1h O Compound 1h (58% yield): White solid, mp: 164-165 o C; 1 H NMR (400 MHz, CDCl 3 ): δ 7.99-7.87 (m, 3H), 7.84 (d, J = 8.1 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.63-7.52 (m, 2H), 7.35-7.24 (m, 2H), 7.02 (d, J = 7.2 Hz, 1H), 5.69 (s, 2H). 13 C NMR (100 MHz, CDCl 3 ): δ 44.3 (q, J = 5.2 Hz), 115.1 (q, J = 32.3 Hz), 120.3, 120.9, 122.1, 122.5 (q, J = 272.7 Hz), 123.9, 125.3, 126.2, 126.6, 128.0, 129.1, 129.2, 129.9 (d, J = 0.9 Hz), 130.4, 133.9, 136.1 (q, J = 5.7 Hz), 149.0 (d, J = 1.4 Hz), 159.2, 181.6. HRMS (ESI) calcd for C 20 H 13 NO 2 F 3 (M + H) +, 356.0898, found 356.0902. O N CF Et 3 1j O Compound 1j (65% yield): White solid, mp: 125-126 o C; 1 H NMR (400 MHz, CDCl 3 ): δ 7.90 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 7.3 Hz, 1H), 7.25 (t, J = 7.7 Hz, 1H), 4.01 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 13.0 (d, J = 2.8 Hz), 38.1 (q, J = 5.0 Hz), 114.4 (q, J = 33.3 Hz), 120.2, 122.8 (q, J = 272.7 Hz), 123.4, 128.9, 135.7 (q, J = 6.1 Hz), 148.6 (d, J = 1.4 Hz), 159.0, 182.1. HRMS (ESI) calcd for C 11 H 9 NO 2 F 3 (M + H) +, 244.0585, found 244.0577. O N CF Bu 3 1k O Compound 1k (61% yield): White solid, mp: 130-132 o C; 1 H NMR (400 MHz, CDCl 3 ): δ 7.88 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 7.3 Hz, 1H), 7.22 (t, J = 7.7 Hz, 1H), 3.98-3.81 (m, 2H), 1.64 (dd, J = 15.7, 8.0 Hz, 2H), 1.40 (dd, J = 15.0, 7.5 4
Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 13.7, 20.1, 29.9, 43.0 (q, J = 4.6 Hz), 114.6 (q, J = 33.3 Hz), 120.3, 122.9 (q, J = 272.7 Hz), 123.4, 128.9, 135.8 (q, J = 6.2 Hz), 148.9 (d, J = 1.3 Hz), 159.2, 182.2. HRMS (ESI) calcd for C 13 H 13 NO 2 F 3 (M + H) +, 272.0898, found 272.0890. O Compound 1l (74% yield): White solid, mp: 149-150 o C; 1 H NMR (400 F 3 C N Bn O MHz, CDCl 3 ): δ 7.73 (d, J = 7.7 Hz, 1H), 7.42-7.30 (m, 6H), 7.01 (s, 1H), 1l 4.97 (s, 2H). 13 C NMR (100 MHz, CDCl 3 ): δ 44.5, 107.9 (q, J = 3.8 Hz), 110.9, 121.1 (q, J = 3.7 Hz), 122.9 (q, J = 272.7 Hz), 125.9, 127.7, 128.7, 129.4, 133.9, 139.1 (q, J = 32.3 Hz), 151.0, 157.6, 182.6. HRMS (ESI) calcd for C 16 H 11 NO 2 F 3 (M + H) +, 306.0742, found 306.0729. 2.2 General Procedure for Cu-Catalyzed Asymmetric Addition of Terminal Alkynes to Isatins. To a mixture of CuI (1.9 mg, 0.01 mmol) and L6 [2] (7.1 mg, 0.012 mmol), MTBE (0.5 ml) was added under N 2 atmosphere and the mixture was stirred at room temperature for 30 mins. Then isatin 1a (61.0 mg, 0.20 mmol), phenylacetylene (21.4 mg, 0.21 mmol), Et 3 N (40.5 mg, 0.4 mmol), and MTBE (0.5 ml) were added to the mixture. The mixture was stirred at 40 C for 72 h. After completion, the mixture was cooled to room temperature and was passed through a short column of Celite with ethyl acetate as an eluent. After evaporation of the solvent, the residue was subjected to a column chromatography on silica gel with DCM as an eluent to give the product 3aa. 5
HO Ph Compound 3aa (94% yield, 92% ee (S)): White solid, mp: 88-89 o C; The ee CF 3 N Bn O was measured by HPLC (Chiralcel AD-H column, λ = 254 nm, eluent: n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 14.12 min (R), t 2 = 3aa 22.13 min (S)); [α] D 20-64.6 (c 0.55, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): δ 7.85 (d, J = 6.6 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.45-7.35 (m, 2H), 7.35-7.08 (m, 9H), 5.22 (s, 2H), 4.40 (brs, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 45.8 (q, J = 5.2 Hz), 68.0, 85.0, 87.3, 113.8 (q, J = 33.3 Hz), 121.3, 123.2 (q, J = 272.7 Hz), 125.6, 127.1, 128.4, 128.5 (q, J = 6.1 Hz), 128.6, 128.9, 129.3, 131.9, 132.2, 135.6, 140.38, 140.39, 175.7. HRMS (ESI) calcd for C 24 H 17 NO 2 F 3 (M + H) +, 408.1211, found 408.1218. HO N CF 3 3ba O Ph Me Compound 3ba (90% yield, 91% ee (S)): White solid, mp: 147-148 o C; The ee was measured by HPLC (Chiralcel AD-H column, λ = 254 nm, eluent: n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 20 12.20 min (R), t 2 = 19.85 min (S)); [α] D -76.8 (c 0.59, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): δ 7.84 (d, J = 7.3 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.45-7.37 (m, 2H), 7.35-7.19 (m, 4H), 7.09-7.00 (m, 4H), 5.17 (s, 2H), 4.40 (brs, 1H), 2.27 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 21.1, 45.6 (q, J = 5.0 Hz), 67.9, 85.0, 87.2, 113.8 (q, J = 33.3 Hz), 121.4, 123.2 (q, J = 272.7 Hz), 123.5, 125.6, 128.4, 128.6 (q, J = 6.1 Hz), 128.9, 129.3, 129.4, 131.9, 132.2, 132.6, 136.7, 140.5, 175.7. HRMS (ESI) calcd for C 25 H 19 NO 2 F 3 (M + H) +, 422.1368, found 422.1357. HO N CF 3 O Ph t Bu Compound 3ca (92% yield, 92% ee (S)): White solid, mp: 155-157 o C; The ee was measured by HPLC (Chiralcel AD-H column, λ = 254 nm, eluent: n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 8.55 3ca min (R), t 2 = 10.91 min (S)); [α] D 20-67.7 (c 0.57, CH 2 Cl 2 ); 1 H NMR 6
(400 MHz, CDCl 3 ): δ 7.85 (d, J = 7.4 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.48-7.41 (m, 2H), 7.37-7.22 (m, 6H), 7.08 (d, J = 8.3 Hz, 2H), 5.19 (s, 2H), 3.98 (brs, 1H), 1.26 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ): δ 31.4, 34.5, 45.6 (q, J = 5.1 Hz), 67.9, 85.0, 87.2, 113.9 (q, J = 33.3 Hz), 121.4, 123.5, 123.6 (q, J = 272.7 Hz), 125.4, 125.5, 128.4, 128.6 (q, J = 6.1 Hz), 128.9, 129.4, 131.3, 131.8, 132.2, 132.59, 140.63, 140.7, 150.0, 175.6. HRMS (ESI) calcd for C 28 H 25 NO 2 F 3 (M + H) +, 464.1837, found 464.1836. HO N CF 3 3da O Ph F Compound 3da (97% yield, 92% ee (S)): White solid, mp: 131-132 o C; The ee was measured by HPLC (Chiralcel AD-H column, λ = 254 nm, eluent: n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 12.69 20 min (R), t 2 = 18.69 min (S)); [α] D -60.7 (c 0.61, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): δ 7.86 (d, J = 7.3 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.47-7.38 (m, 2H), 7.37-7.22 (m, 4H), 7.12 (dd, J = 8.5, 5.2 Hz, 2H), 6.97-6.89 (m, 2H), 5.17 (d, J = 2.2 Hz, 2H), 4.19 (brs, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 45.3 (q, J = 5.1 Hz), 67.9, 84.8, 87.4, 113.8 (q, J = 33.3 Hz), 115.6 (d, J = 22.2 Hz), 121.2, 123.2 (q, J = 272.7 Hz), 123.8, 127.4 (d, J = 8.0 Hz), 128.5, 128.6 (q, J = 6.1 Hz), 129.0, 129.5, 131.4, 131.8, 132.2, 140.2, 140.3, 162.1 (d, J = 246.4 Hz), 175.6. HRMS (ESI) calcd for C 24 H 16 NO 2 F 4 (M + H) +, 426.1117, found 426.1123. HO N CF 3 3ea O Ph Cl Compound 3ea (96% yield, 92% ee (S)): White solid, mp: 187-188 o C; The ee was measured by HPLC (Chiralcel AD-H column, λ = 254 nm, eluent: n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 14.10 20 min (R), t 2 = 20.82 min (S)); [α] D -28.8 (c 0.45, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): δ 7.87 (d, J = 7.3 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.40 (d, J = 7.1 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 7.26 (d, J = 6.9 Hz, 3H), 7.19 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.3 Hz, 2H), 7
5.17 (q, J = 3.7 Hz, 2H), 4.55 (brs, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 45.3 (q, J = 5.2 Hz), 67.9, 84.7, 87.4, 113.8 (q, J = 33.3 Hz), 121.2, 123.1 (q, J = 272.7 Hz), 123.8, 127.1, 128.5, 128.6 (q, J = 6.1 Hz), 128.8, 129.0, 129.5, 131.9, 132.2, 133.0, 134.2, 140.1, 175.9. HRMS (ESI) calcd for C 24 H 16 NO 2 ClF 3 (M + H) +, 442.0822, found 442.0815. Ph Compound 3fa (88% yield, 90% ee (S)): White solid, mp: 189-190 o C; HO N CF 3 3fa O Br The ee was measured by HPLC (Chiralcel AD-H column, λ = 254 nm, eluent: n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 15.03 20 min (R), t 2 = 21.89 min (S)); [α] D -65.6 (c 0.38, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): δ 7.86 (d, J = 7.2 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.46-7.24 (m, 8H), 7.02 (d, J = 8.4 Hz, 2H), 5.15 (d, J = 6.2 Hz, 2H), 4.07 (brs, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 45.4 (q, J = 5.1 Hz), 67.9, 84.7, 87.5, 113.8 (q, J = 33.3 Hz), 121.1, 121.2, 123.1 (q, J = 272.7 Hz), 123.8, 127.5, 128.5, 128.6 (q, J = 6.1 Hz), 129.1, 129.5, 131.77, 131.84, 132.2, 134.8, 140.10, 140.11, 175.8. HRMS (ESI) calcd for C 24 H 16 NO 2 F 3 Br (M + H) +, 486.0317, found 486.0316. HO N CF 3 3ga O Ph CN Compound 3ga (92% yield, 90% ee (S)): White solid, mp: 150-151 o C; The ee was measured by HPLC (Chiralcel AD-H column, λ = 254 nm, eluent: n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 20 37.02 min (R), t 2 = 52.19 min (S)); [α] D -69.8 (c 0.58, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): δ 7.88 (d, J = 7.2 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.3 Hz, 2H), 7.43-7.21 (m, 8H), 5.24 (d, J = 2.3 Hz, 2H), 4.46 (brs, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 45.6 (q, J = 5.0 Hz), 67.8, 84.5, 87.6, 111.2, 113.7 (q, J = 33.3 Hz), 118.7, 121.1, 123.1 (q, J = 272.7 Hz), 124.0, 126.4, 128.5, 128.7 (q, J = 6.1 Hz), 129.1, 129.6, 131.8, 132.1, 132.5, 139.7, 141.4, 175.6. HRMS (ESI) calcd for C 25 H 16 N 2 O 2 F 3 (M + H) +, 433.1164, found 433.1176. 8
HO Ph Compound 3ha (91% yield, 90% ee (S)): White solid, mp: 175-176 o C; The N O ee was measured by HPLC (Chiralcel AD-H column, λ = 254 nm, eluent: CF 3 n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 22.54 min (R), t 2 = 3ha 31.19 min (S)); [α] D 20-56.4 (c 0.62, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): δ 7.97 (d, J = 8.3 Hz, 1H), 7.89 (t, J = 8.1 Hz, 2H), 7.71 (d, J = 8.2 Hz, 1H), 7.63-7.50 (m, 3H), 7.49-7.40 (m, 2H), 7.33-7.23 (m, 5H), 7.04 (d, J = 7.2 Hz, 1H), 5.68 (s, 2H), 4.22 (brs, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 43.8 (q, J = 5.0 Hz), 68.0, 85.0, 87.4, 113.9 (q, J = 33.3 Hz), 120.8, 121.3, 122.2, 123.1 (q, J = 272.7 Hz), 123.7, 125.5, 126.0, 126.4, 127.6, 128.5, 128.7 (q, J = 6.1 Hz), 128.99, 129.03, 129.4, 130.5, 130.6, 131.8, 132.2, 133.8, 140.6, 175.5. HRMS (ESI) calcd for C 28 H 19 NO 2 F 3 (M + H) +, 458.1368, found 458.1357. HO Ph Compound 3ia (96% yield, 92% ee (S)): White solid, mp: 143-145 o C; The CF 3 N Me O ee was measured by HPLC (Chiralcel OD-H column, λ = 254 nm, eluent: n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 7.64 min (S), t 2 = 3ia 18.73 min (R)); [α] D 20-47.6 (c 0.53, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): δ 7.80 (d, J = 7.2 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.45-7.39 (m, 2H), 7.34-7.21 (m, 4H), 4.12 (brs, 1H), 3.44 (q, J = 2.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 29.5 (q, J = 6.5 Hz), 67.9, 84.9, 87.0, 113.5 (q, J = 33.3 Hz), 121.4, 123.0 (q, J = 272.7 Hz), 123.4, 128.33 (q, J = 6.1 Hz), 128.35, 128.5, 129.3, 131.7, 140.0, 140.1, 175.0. HRMS (ESI) calcd for C 18 H 13 NO 2 F 3 (M + H) +, 332.0898, found 332.0905. HO N CF Et 3 3ja O Ph Compound 3ja (98% yield, 93% ee (S)): White solid, mp: 115-116 o C; The ee was measured by HPLC (Chiralcel OD-H column, λ = 254 nm, eluent: n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 6.68 min (S), t 2 = 9
15.96 min (R)); [α] D 20-50.1 (c 0.56, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): δ 7.81 (d, J = 6.8 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.44-7.37 (m, 2H), 7.33-7.18 (m, 4H), 4.61 (brs, 1H), 4.07-3.89 (m, 2H), 1.26 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 12.9 (q, J = 2.0 Hz), 38.1 (q, J = 5.0 Hz), 67.9, 85.0, 86.9, 113.3 (q, J = 33.3 Hz), 121.5, 123.2, 123.4 (q, J = 272.7 Hz), 128.3, 128.4 (q, J = 6.1 Hz), 128.8, 129.2, 132.2, 140.37, 140.39, 175.2. HRMS (ESI) calcd for C 19 H 15 NO 2 F 3 (M + H) +, 346.1055, found 346.1067. HO N CF Bu 3 3ka O Ph Compound 3ka (97% yield, 93% ee (S)): White solid, mp: 81-83 o C; The ee was measured by HPLC (Chiralcel OD-H column, λ = 254 nm, eluent: n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 6.04 min (S), t 2 = 20 16.76 min (R)); [α] D -60.6 (c 0.60, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): δ 7.80 (d, J = 7.2 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.41-7.39 (m, 2H), 7.32-7.19 (m, 4H), 4.40 (brs, 1H), 3.97-3.82 (m, 2H), 1.69-1.59 (m, 2H), 1.43-1.33 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 13.8, 20.1, 29.7 (q, J = 2.1 Hz), 42.9 (q, J = 4.4 Hz), 67.9, 85.1, 86.9, 113.4 (q, J = 33.3 Hz), 121.5, 123.2, 123.5 (q, J = 272.7 Hz), 128.3, 128.5 (q, J = 6.1 Hz), 128.8, 129.2, 132.1, 132.2, 140.59, 140.60, 175.3. HRMS (ESI) calcd for C 21 H 19 NO 2 F 3 (M + H) +, 374.1368, found 374.1368. HO Ph Compound 3la (91% yield, 89% ee (S)): White solid, mp: 148-149 o C; F 3 C N Bn O The ee was measured by HPLC (Chiralcel AD-H column, λ = 254 nm, eluent: n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 20.68 3la min (R), t 2 = 22.78 min (S)); [α] D 20 +24.5 (c 0.53, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): δ 7.72 (d, J = 7.7 Hz, 1H), 7.46-7.23 (m, 11H), 6.93 (s, 1H), 4.94 (q, J = 15.8 Hz, 2H), 4.27 (brs, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 44.4, 69.4, 84.7, 87.4, 106.7 (q, J = 3.7 10
Hz), 121.1 (q, J = 4.0 Hz), 121.3, 123.6 (q, J = 272.7 Hz), 125.3, 127.3, 128.3, 128.4, 129.2, 129.4, 132.2, 132.75 (q, J = 33.3 Hz), 132.77, 134.4, 142.9, 174.1. HRMS (ESI) calcd for C 24 H 17 NO 2 F 3 (M + H) +, 408.1211, found 408.1216. F 3 C HO N Bn O Ph Compound 3ma (90% yield, 93% ee (S)): White solid, mp: 128-130 o C; The ee was measured by HPLC (Chiralcel OD-H column, λ = 254 nm, eluent: n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 3ma 11.67 min (R), t 2 = 16.40 min (S)); [α] D 20 +31.2 (c 0.56, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): δ 7.87 (s, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.44 (d, J = 6.9 Hz, 2H), 7.35-7.23 (m, 8H), 6.78 (d, J = 8.3 Hz, 1H), 4.94 (d, J = 4.0 Hz, 2H), 4.35 (brs, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 44.4, 69.4, 84.7, 87.5, 110.0, 121.3, 122.2 (q, J = 3.7 Hz), 124.1 (q, J = 272.7 Hz), 126.3 (q, J = 33.3 Hz), 127.3, 128.1 (q, J = 4.0 Hz), 128.2, 128.4, 129.2, 129.4, 129.7, 132.3, 134.5, 145.2, 174.4. HRMS (ESI) calcd for C 24 H 17 NO 2 F 3 (M + H) +, 408.1211, found 408.1222. MeO 2 C HO N Bn O Ph Compound 3na (78% yield, 80% ee (S)): White solid, mp: 148-150 o C; The ee was measured by HPLC (Chiralcel AD-H column, λ = 254 nm, eluent: n-hexane/i-proh = 80/20, flow rate: 3na 0.9 ml/min, t 1 = 38.61 min (R), t 2 = 41.30 min (S)); [α] D 20 +249.3 (c 0.48, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): δ 8.30 (d, J = 1.4 Hz, 1H), 7.98 (dd, J = 8.3, 1.7 Hz, 1H), 7.45 (d, J = 7.0 Hz, 2H), 7.34-7.25 (m, 8H), 6.76 (d, J = 8.3 Hz, 1H), 4.95 (s, 2H), 4.10 (s, 1H), 3.89 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 44.4, 52.3, 69.3, 84.9, 87.1, 109.7, 121.4, 125.8, 126.3, 127.2, 128.1, 128.3, 129.1, 129.3, 132.2, 132.9, 134.6, 146.2, 166.5, 174.5. HRMS (ESI) calcd for C 25 H 20 NO 4 (M + H) +, 398.1392, found 398.1383. 11
O 2 N HO N Bn O Ph Compound 3oa (93% yield, 84% ee (S)): White solid, mp: 144-146 o C; The ee was measured by HPLC (Chiralcel AD-H column, λ = 254 nm, eluent: n-hexane/i-proh = 70/30, flow rate: 0.9 ml/min, t 1 = 15.90 3oa min (S), t 2 = 28.94 min (R)); [α] D 20 +142.7 (c 0.99, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): δ 8.50 (d, J = 2.3 Hz, 1H), 8.20 (dd, J = 8.7, 2.3 Hz, 1H), 7.47-7.43 (m, 2H), 7.37-7.26 (m, 8H), 6.80 (d, J = 8.7 Hz, 1H), 4.98 (s, 2H), 4.41 (brs, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 44.7, 69.1, 84.0, 88.0, 109.9, 121.0, 127.3, 128.4, 128.5, 129.3, 129.6, 130.0, 132.3, 134.0, 134.4, 147.6, 174.5. HRMS (ESI) calcd for C 23 H 17 N 2 O 4 (M + H) +, 385.1188, found 385.1183. F HO N Bn O Ph Compound 3pa (87% yield, 82% ee (S)): White solid, mp: 45-46 o C; The ee was measured by HPLC (Chiralcel OD-H column, λ = 254 nm, eluent: n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 20.31 min (S), t 2 = 3pa 24.20 min (R)); [α] D 20 +28.5 (c 0.52, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): δ 7.46-7.41 (m, 2H), 7.37 (dd, J = 7.4, 2.6 Hz, 1H), 7.34-7.23 (m, 8H), 6.92 (td, J = 8.8, 2.6 Hz, 1H), 6.61 (dd, J = 8.6, 4.0 Hz, 1H), 4.90 (s, 2H), 4.64 (brs, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 44.4, 69.8 (d, J = 1.3 Hz), 85.1, 87.1, 110.8 (d, J = 7.9 Hz), 113.0, 113.2, 116.7, 116.9, 121.5, 127.3, 128.0, 128.4, 129.2 (d, J = 19.6 Hz), 130.6 (d, J = 8.2 Hz), 132.2, 134.8, 138.1 (d, J = 2.1 Hz), 159.9 (d, J = 243.4 Hz), 174.3. Br HO N Bn O Ph Compound 3qa (78% yield, 86% ee (S)): White solid, mp: 143-146 o C; The ee was measured by HPLC (Chiralcel OD-H column, λ = 254 nm, eluent: n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 15.46 min 3qa (R), t 2 = 22.06 min (S)); [α] D 20 +128.3 (c 0.54, CH 2 Cl 2 ); 1 H NMR (400 12
MHz, CDCl 3 ): δ 7.73 (d, J = 1.9 Hz, 1H), 7.48-7.43 (m, 2H), 7.37-7.25 (m, 9H), 6.57 (d, J = 8.4 Hz, 1H), 4.90 (s, 2H), 4.24 (brs, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 44.3, 69.6, 84.9, 87.3, 111.6, 116.6, 121.4, 127.2, 128.1, 128.2, 128.4, 129.1, 129.3, 130.9, 132.3, 133.3, 134.6, 141.2, 173.8. HO Ph Compound 3ra [3] (16% yield, 85% ee (S)): White solid, mp: 134-136 o C; N Bn 3ra O The ee was measured by HPLC (Chiralcel AD-H column, λ = 254 nm, eluent: n-hexane/i-proh = 70/30, flow rate: 0.9 ml/min, t 1 = 12.13 min (R), t 2 = 16.43 min (S)); [α] D 25 +9.5 (c 0.49, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): δ 7.62 (d, J = 7.2 Hz, 1H), 7.43 (d, J = 7.2 Hz, 2H), 7.36-7.18 (m, 9H), 7.10 (d, J = 7.6 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 4.91 (d, J = 2.0 Hz, 2H), 4.17 (brs, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 44.2, 69.8, 85.6, 86.6, 110.0, 121.7, 123.9, 124.9, 127.3, 127.9, 128.3, 129.0, 129.1, 130.5, 132.2, 135.1, 142.2, 174.3. MeO HO N Bn O Ph Compound 3sa [3] (33% yield, 87% ee (S)): White solid, mp: 161-163 o C; The ee was measured by HPLC (Chiralcel AD-H column, λ = 254 nm, eluent: n-hexane/i-proh = 70/30, flow rate: 0.9 ml/min, t 1 = 3sa 14.12 min (R), t 2 = 22.13 min (S)); [α] D 25 +62.1 (c 1.02, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): δ 7.45 (dd, J = 8.0, 1.4 Hz, 2H), 7.36-7.22 (m, 9H), 6.76 (dd, J = 8.6, 2.6 Hz, 1H), 6.60 (d, J = 8.6 Hz, 1H), 4.90 (s, 2H), 4.14 (brs, 1H), 3.78 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 44.3, 56.0, 70.1, 85.7, 86.8, 110.7, 111.5, 115.5, 121.8, 127.3, 127.9, 128.4, 129.0, 129.1, 130.1, 132.2, 135.2, 135.5, 156.9, 174.2. Compound 3ab (99% yield, 93% ee (S)): White solid, mp: 115-117 o C; HO OMe The ee was measured by HPLC (Chiralcel AD-H column, λ = 254 nm, CF 3 N Bn 3ab O eluent: n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 28.30 13
min (R), t 2 = 32.61 min (S)); [α] D 20-48.8 (c 0.62, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): δ 7.88 (d, J = 7.1 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.37 (dd, J = 7.6, 1.6 Hz, 1H), 7.33-7.14 (m, 7H), 6.91-6.82 (m, 2H), 5.22 (s, 2H), 4.29 (brs, 1H), 3.84 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 45.7 (q, J = 5.2 Hz), 56.0, 68.0, 84.0, 88.9, 110.6, 110.9, 113.7 (q, J = 32.3 Hz), 120.6, 123.2 (q, J = 272.7 Hz) 123.5, 125.6, 127.1, 128.5 (q, J = 6.1 Hz), 128.6, 129.1, 131.0, 131.9, 134.0, 135.77, 135.78, 140.5, 160.7, 175.6. HRMS (ESI) calcd for C 25 H 19 NO 3 F 3 (M + H) +, 438.1317, found 438.1317. Compound 3ac (82% yield, 85% ee (S)): White solid, mp: 85-87 o C; HO Me The ee was measured by HPLC (Chiralcel AD-H column, λ = 254 nm, CF 3 N Bn O eluent: n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 17.76 min (R), t 2 = 24.67 min (S)); [α] D 20-44.3 (c 0.54, CH 2 Cl 2 ); 1 H NMR (400 3ac MHz, CDCl 3 ): δ 7.86 (d, J = 7.3 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.29-7.09 (m, 9H), 5.22 (s, 2H), 3.98 (brs, 1H), 2.37 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 20.7, 45.8 (q, J = 5.2 Hz), 68.0, 86.3, 88.8, 113.9 (q, J = 33.3 Hz), 121.1, 123.2 (q, J = 273.7 Hz), 123.6, 125.6, 125.7, 127.2, 128.5 (q, J = 6.1 Hz), 128.6, 128.8, 129.5, 129.7, 131.9, 132.5, 135.7, 140.5, 141.2, 175.6. HRMS (ESI) calcd for C 25 H 19 NO 2 F 3 (M + H) +, 422.1368, found 422.1371. HO Me Compound 3ad (95% yield, 94% ee (S)): White solid, mp: 87-88 o C; The ee was measured by HPLC (Chiralcel AD-H column, λ = CF 3 N Bn O 254 nm, eluent: n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 13.04 min (R), t 2 = 16.50 min (S)); [α] D 20-48.3 (c 0.61, 3ad CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): δ 7.85 (d, J = 7.3 Hz, 1H), 14
7.59 (d, J = 8.0 Hz, 1H), 7.29-7.09 (m, 10H), 5.21 (s, 2H), 4.56 (brs, 1H), 2.25 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 21.2, 45.7 (q, J = 5.2 Hz), 67.9, 84.6, 87.4, 113.8 (q, J = 33.3 Hz), 121.1, 123.1 (q, J = 273.7 Hz), 123.6, 125.6, 127.1, 128.3, 128.5 (q, J = 6.1 Hz), 128.6, 128.9, 129.2, 130.2, 132.0, 132.7, 135.7, 138.1, 140.32, 140.34, 175.8. HRMS (ESI) calcd for C 25 H 19 NO 2 F 3 (M + H) +, 422.1368, found 422.1380. Me Compound 3ae (93% yield, 93% ee (S)): White solid, mp: 147-148 HO o C; The ee was measured by HPLC (Chiralcel AD-H column, λ = CF 3 N Bn O 254 nm, eluent: n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 13.55 min (R), t 2 = 22.44 min (S)); [α] D 20-63.1 (c 0.65, CH 2 Cl 2 ); 3ae 1 H NMR (400 MHz, CDCl 3 ): δ 7.85 (d, J = 7.3 Hz, 1H), 7.59 (dd, J = 8.1 Hz, 1H), 7.30 (d, J = 7.9 Hz, 2H), 7.28-7.16 (m, 4H), 7.14 (d, J = 7.4 Hz, 2H), 7.05 (d, J = 7.9 Hz, 2H), 5.21 (s, 2H), 4.29 (brs, 1H), 2.31 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 21.6, 45.7 (q, J = 5.2 Hz), 68.0, 84.3, 87.5, 113.8 (q, J = 33.3 Hz), 118.2, 123.1 (q, J = 273.7 Hz), 123.6, 125.6, 128.4 (q, J = 6.1 Hz), 128.6, 128.9, 129.1, 132.0, 132.1, 135.7, 139.6, 140.36, 140.37, 175.7. HRMS (ESI) calcd for C 25 H 19 NO 2 F 3 (M + H) +, 422.1368, found 422.1369. OMe Compound 3af (78% yield, 89% ee (S)): White solid, mp: 128-130 HO o C; The ee was measured by HPLC (Chiralcel AD-H column, λ = CF 3 N Bn O 254 nm, eluent: n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 18.68 min (R), t 2 = 30.93 min (S)); [α] D 20-50.9 (c 0.55, 3af CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): δ 7.85 (d, J = 7.3 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.33 (d, J = 8.6 Hz, 2H), 7.27-7.12(m, 6H), 6.76 (d, J = 8.6 Hz, 2H), 5.21 (s, 2H), 4.54 (brs, 1H), 3.76 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 45.7 (q, J = 5.0 Hz), 55.4, 15
68.0, 83.8, 87.4, 113.3, 113.7 (q, J = 33.3 Hz), 114.0, 123.2 (q, J = 273.7 Hz), 123.6, 125.6, 127.1, 128.4 (q, J = 6.1 Hz), 128.6, 128.8, 132.1, 133.8, 135.7, 140.29, 140.30, 160.4, 175.9. HRMS (ESI) calcd for C 25 H 19 NO 3 F 3 (M + H) +, 438.1317, found 438.1302. Et Compound 3ag (96% yield, 92% ee (S)): White solid, mp: 124-125 o C; HO The ee was measured by HPLC (Chiralcel AD-H column, λ = 254 nm, CF 3 N Bn O eluent: n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 14.00 min (R), t 2 = 20.53 min (S)); [α] D 20-49.2 (c 0.59, CH 2 Cl 2 ); 1 H NMR 3ag (400 MHz, CDCl 3 ): δ 7.85 (d, J = 7.1 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.28-7.18 (m, 4H), 7.14 (d, J = 7.3 Hz, 2H), 7.11 (d, J = 8.2 Hz, 2H), 5.22 (s, 2H), 4.01 (brs, 1H), 2.62 (q, J = 7.6 Hz, 2H), 2.31 (t, J = 7.6 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 15.4, 29.0, 45.7 (q, J = 5.2 Hz), 67.9, 84.3, 87.6, 113.8 (q, J = 33.3 Hz), 118.5, 123.2 (q, J = 273.7 Hz), 123.6, 125.6, 127.2, 128.0, 128.5 (q, J = 6.1 Hz), 128.6, 128.9, 131.9, 132.2, 135.7, 140.45, 140.46, 146.0, 175.6. HRMS (ESI) calcd for C 26 H 21 NO 2 F 3 (M + H) +, 436.1524, found 436.1530. t Bu Compound 3ah (82% yield, 91% ee (S)): White solid, mp: 153-154 o C; The ee was measured by HPLC (Chiralcel AD-H column, λ = HO CF 3 N Bn O 254 nm, eluent: n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 6.96 min (R), t 2 = 17.39 min (S)); [α] D 20-54.4 (c 0.61, CH 2 Cl 2 ); 1 H 3ah NMR (400 MHz, CDCl 3 ): δ 7.85 (d, J = 7.1 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.30-7.12 (m, 8H), 5.22 (s, 2H), 4.59 (brs, 1H), 1.28 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ): δ 31.2, 35.0, 45.7 (q, J = 5.2 Hz), 68.0, 84.4, 87.5, 113.8 (q, J = 33.3 Hz), 118.3, 123.2 (q, J = 273.7 Hz), 123.6, 125.4, 125.6, 127.1, 128.4 (q, J = 6.1 Hz), 128.6, 128.9, 16
132.0, 132.1, 135.7, 140.4, 152.8, 175.9. HRMS (ESI) calcd for C 28 H 25 NO 2 F 3 (M + H) +, 464.1837, found 464.1843. F Compound 3ai (81% yield, 88% ee (S)): White solid, mp: 169-171 o C; HO The ee was measured by HPLC (Chiralcel AD-H column, λ = 254 nm, CF 3 N Bn O eluent: n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 13.97 min (R), t 2 = 25.87 min (S)); [α] D 20-51.7 (c 0.55, CH 2 Cl 2 ); 1 H NMR 3ai (400 MHz, CDCl 3 ): δ 7.84 (d, J = 6.6 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.43-7.35 (m, 2H), 7.30-7.17 (m, 4H), 7.14 (d, J = 7.1 Hz, 2H), 7.01-6.90 (m, 2H), 5.22 (s, 2H), 4.26 (brs, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 45.8 (q, J = 5.0 Hz), 67.9, 84.8, 86.2, 113.9 (q, J = 33.3 Hz), 115.8 (d, J = 22.2 Hz), 117.4 (d, J = 3.3 Hz), 123.1 (q, J = 272.7 Hz), 123.7, 125.6, 127.2, 128.64 (q, J = 6.1 Hz), 128.65, 128.9, 131.7, 134.2 (d, J = 8.6 Hz), 135.6, 140.43, 140.44, 163.2 (d, J = 252.5 Hz), 175.6. HRMS (ESI) calcd for C 24 H 16 NO 2 F 4 (M + H) +, 426.1117, found 426.1113. Compound 3aj (95% yield, 89% ee (S)): White solid, mp: 206-207 HO o C; The ee was measured by HPLC (Chiralcel AD-H column, λ = CF 3 N Bn 3aj O 254 nm, eluent: n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 16.98 min (R), t 2 = 24.60 min (S)); [α] D 20-40.5 (c 0.52, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): δ 8.23-8.13 (m, 1H), 7.95 (d, J = 7.3 Hz, 1H), 7.83 (dd, J = 9.0, 4.5 Hz, 2H), 7.65 (t, J = 8.1 Hz, 2H), 7.50 (dd, J = 9.2, 5.2 Hz, 2H), 7.37 (t, J = 7.7 Hz, 1H), 7.30-7.15 (m, 6H), 5.25 (d, J = 2.9 Hz, 2H), 4.17 (brs, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 45.8 (q, J = 5.1 Hz), 68.2, 85.7, 89.7, 114.0 (q, J = 32.3 Hz), 118.9, 123.2 (q, J = 272.7 Hz), 123.7, 125.1, 125.6, 125.9, 126.7, 127.2, 127.4, 128.5, 128.7, 128.8 (q, J = 6.1 Hz), 17
129.0, 130.0, 131.6, 131.8, 133.2, 133.5, 135.7, 140.5, 140.6, 175.7. HRMS (ESI) calcd for C 28 H 19 NO 2 F 3 (M + H) +, 458.1368, found 458.1364. HO S Compound 3ak (93% yield, 85% ee (S)): White solid, mp: 83-84 o C; The ee was measured by HPLC (Chiralcel AD-H column, λ = 254 nm, eluent: CF 3 N Bn 3ak O n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 16.98 min (R), t 2 = 25.66 min (S)); [α] D 20-53.3 (c 0.54, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): δ 7.84 (d, J = 6.9 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.37-7.08 (m, 8H), 6.93 (dd, J = 5.1, 3.7 Hz, 1H), 5.21 (s, 2H), 4.21 (brs, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 45.8 (q, J = 5.0 Hz), 68.1, 80.8, 88.7, 113.9 (q, J = 33.3 Hz), 121.1, 123.2 (q, J = 272.7 Hz), 123.7, 125.6, 127.2, 128.64 (q, J = 6.1 Hz), 128.65, 128.7, 129.0, 131.53, 133.9, 135.6, 140.41, 140.42, 175.4. HRMS (ESI) calcd for C 22 H 15 NO 2 F 3 S (M + H) +, 414.0776, found 414.0777. Compound 3al (96% yield, 91% ee (S)): White solid, mp: 67-69 o C; The HO ee was measured by HPLC (Chiralcel AD-H column, λ = 254 nm, eluent: CF 3 N Bn O n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 12.51 min (R), t 2 = 14.17 min (S)); [α] D 20-56.1 (c 0.58, CH 2 Cl 2 ); 1 H NMR (400 MHz, 3al CDCl 3 ): δ 7.78 (d, J = 6.7 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.30-7.18 (m, 4H), 7.12 (d, J = 7.2 Hz, 2H), 6.25-6.13 (m, 1H), 5.20 (s, 2H), 3.81 (brs, 1H), 2.12-2.03 (m, 4H), 1.63-1.52 (m, 4H). 13 C NMR (100 MHz, CDCl 3 ): δ 21.4, 22.2, 25.8, 28.7, 45.6 (q, J = 5.0 Hz), 67.8, 82.4, 89.2, 113.7 (q, J = 33.3 Hz), 119.4, 123.2 (q, J = 272.7 Hz), 123.5, 125.6, 127.1, 128.3 (q, J = 6.1 Hz), 128.6, 128.8, 132.1, 132.2, 135.7, 137.8, 137.9, 140.3, 175.8. HRMS (ESI) calcd for C 24 H 21 NO 2 F 3 (M + H) +, 412.1524, found 412.1522. 18
HO C 4 H 9 Compound 3am (28% yield, 84% ee (S)): White solid, mp: 81-83 o C; The CF 3 N Bn O ee was measured by HPLC (Chiralcel AD-H column, λ = 254 nm, eluent: n-hexane/i-proh = 70/30, flow rate: 0.9 ml/min, t 1 = 6.07 min (R), t 2 = 3am 6.96 min (S)); [α] D 25-18.3 (c 0.42, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): δ 7.76 (d, J = 7.2 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.31-7.16 (m, 4H), 7.11 (d, J = 7.2 Hz, 2H), 5.19 (s, 2H), 3.80 (brs, 1H), 2.23 (t, J = 7.1 Hz, 2H), 1.55-1.43 (m, 2H), 1.41-1.32 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H),. 13 C NMR (100 MHz, CDCl 3 ): δ 13.7, 18.7, 22.0, 30.3, 45.7 (q, J = 5.0 Hz), 67.5, 76.5, 89.1, 114.0 (q, J = 33.3 Hz), 123.2 (q, J = 272.7 Hz), 123.4, 125.6, 127.1, 128.3 (q, J = 6.1 Hz), 128.6, 128.7, 132.2, 135.8, 140.4, 175.8. HRMS (ESI) calcd for C 22 H 21 NO 2 F 3 (M + H) +, 388.1524, found 388.1526. 3. Transformation of product 3aa into 4 [4] To a solution of 10% Pd/C (5.3 mg) in EtOAc (1 ml) under H 2 atmosphere (balloon) at room temperature was added compound 3aa (40.7 mg, 0.1 mmol, 92% ee) and the mixture was stirred at room temperature for 1 h. Then the mixture was passed through a short column of Celite with ethyl acetate as an eluent. After evaporation of the solvent, the residue was subjected to a column chromatography on silica gel with PE/EtOAc (5/1) as an eluent to give the product 4. Compound 4 (97% yield, 90% ee (S)): White solid, mp: 107-109 o C; The ee was measured by HPLC (Chiralcel AD-H column, λ = 254 nm, eluent: n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 22.12 min (R), t 2 = 31.41 min (S)); [α] D 20-67.7 (c 1.12, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ 7.62 (d, J = 7.4 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.27-7.09 (m, 9H), 7.01 (d, J = 6.9 Hz, 2H), 5.11 (q, J = 17.0 Hz, 2H), 3.58 (brs, 1H), 2.56-2.44 (m, 2H), 2.41-2.24 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ): δ 29.6, 19
40.7, 45.7 (q, J = 4.8 Hz), 74.5, 113.5 (q, J = 33.3 Hz), 123.1, 123.7 (q, J = 272.7 Hz), 125.9, 126.3, 127.87, 127.91 (q, J = 6.1 Hz), 128.4, 128.6, 132.9, 136.0, 140.4, 141.0, 180.0. HRMS (ESI) calcd for C 24 H 21 NO 2 F 3 (M + H) +, 412.1524, found 412.1529. 4. Transformation of product 3aa into 5 [5] To a solution of 3aa (20.4 mg, 0.05 mmol, 92% ee) in EtOAc (1 ml) under H 2 atmosphere (balloon) at room temperature, quinoline (2.6 μl) and (Lindlar catalyst) Pd/CaCO 3 (2.0 mg) was added compound and the mixture was stirred at room temperature for 24 h. Then the mixture was passed through a short column of Celite with ethyl acetate as an eluent. After evaporation of the solvent, the residue was subjected to a column chromatography on silica gel with PE/EtOAc (5/1) as an eluent to give the product 5. Compound 5 (68% yield, 92% ee (S)): White solid, mp: 162-164 o C; The ee was measured by HPLC (Chiralcel AD-H column, λ = 254 nm, eluent: n-hexane/i-proh = 90/10, flow rate: 0.9 ml/min, t 1 = 15.59 min (R), t 2 = 25.48 min (S)); [α] D 20 +11.2 (c 0.55, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ 7.57 (d, J = 7.3 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.25-7.08 (m, 7H), 7.04 (d, J = 7.2 Hz, 2H), 7.01-6.93 (m, 2H), 6.82 (d, J = 12.1 Hz, 1H), 6.00 (d, J = 12.1 Hz, 1H), 4.94 (d, J = 17.2 Hz, 1H), 4.75 (d, J = 17.2 Hz, 1H), 3.32 (brs, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 45.4 (q, J = 4.8 Hz), 74.7, 113.5 (q, J = 33.3 Hz), 123.1, 123.2 (q, J = 272.7 Hz), 125.7, 127.0, 127.8, 127.9 (q, J = 6.1 Hz), 128.0, 128.5, 131.0, 133.8, 133.9, 135.9, 140.79, 140.81, 177.9. HRMS (ESI) calcd for C 24 H 19 NO 2 F 3 (M + H) +, 410.1368, found 410.1361. 20
5. X-ray Structure of Product 3qa Table S-1 Crystal data and structure refinement for product 3qa Chemical formula C 23 H 16 BrNO 2 Formula Mass 418.28 Crystal system monoclinic Space group C 2/c Temperature/K 180(2) Wavelength/Å 1.54178 a/å 17.9232(8) b/å 12.4144(5) c/å 19.2095(8) α/ᵒ 90 β/ᵒ 116.7950(10) γ/ᵒ 90 Volume/Å 3 3815.3(3) Z 8 Calculated density Mg/m 3 1.456 Radiation type CuK\a Absorption coefficient/mm -1 3.074 F(000) 1696 Crystal size/mm 0.1 x 0.08 x 0.06 Theta range for data collection/ᵒ 4.51 to 68.29 Reflections collected/unique 18484/3380 Completeness to theta = 68.29 96.8 % Absorption correction None Refinement method Full-matrix least-squares on F 2 Data/restraints/parameters 3380/0/244 Goodness-of-fit on F 2 1.256 R int 0.0266 Final R I values (I > 2σ(I)) 0.0360 Final wr(f 2 ) values (I > 2σ(I)) 0.1109 Final R I values (all data) 0.0394 Final wr(f 2 ) values (all data) 0.1215 Largest diff. peak and hole/e.å 3 0.507 and -0.554 21
6. References and Notes 1. Li, C.; Guo, F.; Xu, K.; Zhang, S.; Hu, Y.; Zha, Z.; Wang, Z. Org. Lett. 2014, 16, 3192. 2. Wang, G.; Rexiti, R.; Sha, F.; Wu, X.-Y. Tetrahedron 2015, 71, 4255. 3. Chen, Q.; Tang, Y.; Huang, T.; Liu, X.; Lin, L.; Feng, X. Angew. Chem. Int. Ed. 2016, 55, 5286. 4. Sanz-Marco, A.; Garcίa-Ortiz, A.; Blay, G.; Fernández, I.; Pedro, J. R. Chem. Eur. J. 2014, 20, 668. 5. Bisai, V.; Suneja, A.; Singh, V. K. Angew. Chem. Int. Ed. 2014, 53, 10737. 22
7. 1 H and 13 C NMR Spectra Figure 1. 1 H and 13 C NMR spectra of compound 1g in CDCl 3 23
Figure 2. 1 H and 13 C NMR spectra of compound 1h in CDCl 3 24
Figure 3. 1 H and 13 C NMR spectra of compound 1j in CDCl 3 25
Figure 4. 1 H and 13 C NMR spectra of compound 1k in CDCl 3 26
Figure 5. 1 H and 13 C NMR spectra of compound 1l in CDCl 3 27
Figure 6. 1 H and 13 C NMR spectra of compound 3aa in CDCl 3 28
Figure 7. 1 H and 13 C NMR spectra of compound 3ba in CDCl 3 29
Figure 8. 1 H and 13 C NMR spectra of compound 3ca in CDCl 3 30
Figure 9. 1 H and 13 C NMR spectra of compound 3da in CDCl 3 31
Figure 10. 1 H and 13 C NMR spectra of compound 3ea in CDCl 3 32
Figure 11. 1 H and 13 C NMR spectra of compound 3fa in CDCl 3 33
Figure 12. 1 H and 13 C NMR spectra of compound 3ga in CDCl 3 34
Figure 13. 1 H and 13 C NMR spectra of compound 3ha in CDCl 3 35
Figure 14. 1 H and 13 C NMR spectra of compound 3ia in CDCl 3 36
Figure 15. 1 H and 13 C NMR spectra of compound 3ja in CDCl 3 37
Figure 16. 1 H and 13 C NMR spectra of compound 3ka in CDCl 3 38
Figure 17. 1 H and 13 C NMR spectra of compound 3la in CDCl 3 39
Figure 18. 1 H and 13 C NMR spectra of compound 3ma in CDCl 3 40
Figure 19. 1 H and 13 C NMR spectra of compound 3na in CDCl 3 41
Figure 20. 1 H and 13 C NMR spectra of compound 3oa in CDCl 3 42
Figure 21. 1 H and 13 C NMR spectra of compound 3pa in CDCl 3 43
Figure 22. 1 H and 13 C NMR spectra of compound 3qa in CDCl 3 44
Figure 23. 1 H and 13 C NMR spectra of compound 3ab in CDCl 3 45
Figure 24. 1 H and 13 C NMR spectra of compound 3ac in CDCl 3 46
Figure 25. 1 H and 13 C NMR spectra of compound 3ad in CDCl 3 47
Figure 26. 1 H and 13 C NMR spectra of compound 3ae in CDCl 3 48
Figure 27. 1 H and 13 C NMR spectra of compound 3af in CDCl 3 49
Figure 28. 1 H and 13 C NMR spectra of compound 3ag in CDCl 3 50
Figure 29. 1 H and 13 C NMR spectra of compound 3ah in CDCl 3 51
Figure 30. 1 H and 13 C NMR spectra of compound 3ai in CDCl 3 52
Figure 31. 1 H and 13 C NMR spectra of compound 3aj in CDCl 3 53
Figure 32. 1 H and 13 C NMR spectra of compound 3ak in CDCl 3 54
Figure 33. 1 H and 13 C NMR spectra of compound 3al in CDCl 3 55
Figure 34. 1 H and 13 C NMR spectra of compound 3am in CDCl 3 56
Figure 35. 1 H and 13 C NMR spectra of compound 4 in CDCl 3 57
Figure 36. 1 H and 13 C NMR spectra of compound 5 in CDCl 3 58
8. HPLC Spectra 1. HPLC of 3aa 59
2. HPLC of 3ba 60
3. HPLC of 3ca 61
4. HPLC of 3da 62
5. HPLC of 3ea 63
6. HPLC of 3fa 64
7. HPLC of 3ga 65
8. HPLC of 3ha 66
9. HPLC of 3ia 67
10. HPLC of 3ja 68
11. HPLC of 3ka 69
12. HPLC of 3la 70
13. HPLC of 3ma 71
14. HPLC of 3na 72
15. HPLC of 3oa 73
16. HPLC of 3pa 74
17. HPLC of 3qa 75
18. HPLC of 3ra 76
19. HPLC of 3sa 77
20. HPLC of 3ab 78
21. HPLC of 3ac 79
22. HPLC of 3ad 80
23. HPLC of 3ae 81
24. HPLC of 3af 82
25. HPLC of 3ag 83
26. HPLC of 3ah 84
27. HPLC of 3ai 85
28. HPLC of 3aj 86
29. HPLC of 3ak 87
30. HPLC of 3al 88
31. HPLC of 3am 89
32. HPLC of 4 90
33. HPLC of 5 91