Supporting Information:

Transcription

1 Supporting Information: An rganocatalytic Asymmetric Sequential Allylic Alkylation/Cyclization of Morita-Baylis-Hillman Carbonates and 3-Hydroxyoxindoles Qi-Lin Wang a,b, Lin Peng a, Fei-Ying Wang a, Ming-Liang Zhang a,b, Li-Na Jia a,b, Fang Tian a, Xiao-Ying Xu a, *, Li-Xin Wang a, * a Key Laboratory of Asymmetric Synthesis and Chirotechnology of Sichuan Province, Chengdu Institute of rganic Chemistry, Chinese Academy of Sciences, Chengdu , China b University of Chinese Academy of Sciences, Beijing 10049, China wlxioc@cioc.ac.cn; xuxy@cioc.ac.cn. Table of Contents 1. General methods S2 2. ptimization studies S2 3. General procedures for the synthesis of compounds 3 S7 4. Characterization of compounds 3 S7 5. Crystal data for 3a and 3g S13 6. Synthesis of 4 and 5 S17 7. Selected 1 H NMR and 13 C NMR spectra S18 8. HPLC chromatograms S28 S1

2 1. General methods Commercial grade solvent was dried and purified by standard procedures as specified in Purification of Laboratory Chemicals, 4th Ed (Armarego, W. L. F.; Perrin, D. D. Butterworth Heinemann: 1997). NMR spectra were recorded with tetramethylsilane as the internal standard. 1 H NMR spectra were recorded at 300 MHz, and 13 C NMR spectra were recorded at 75 MHz (Bruker Avance). 1 H NMR chemical shifts (δ) are reported in ppm relative to tetramethylsilane (TMS) with the solvent signal as the internal standard (CDCl 3 at 7.26 ppm, (CD 3 ) 2 S at 2.50 ppm). 13 C NMR chemical shifts are reported in ppm from tetramethylsilane (TMS) with the solvent resonance as the internal standard (CDCl 3 at ppm, (CD 3 ) 2 S at ppm). Data are given as: s (singlet), d (doublet), t (triplet), q (quartet), dd (double of doublet) or m (multiplets), coupling constants (Hz) and integration. Flash column chromatography was carried out using silica gel eluting with ethyl acetate and petroleum ether. Highresolution mass spectra were obtained with the Q-TF-Premier mass spectrometer. Reactions were monitored by TLC and visualized with ultraviolet light. Enantiomeric excess was determined by HPLC analysis on chiralpak AD-H, or IC columns. ptical rotations are reported as follows: [α] 20 D (C in g/100 ml, CHCl 3 ). 2. ptimization studies Table S1: Screening of catalysts a S2

3 entry cat. time(h) yield(%) b Ee (%) c 1 4a e 2 4b c d e 5 d 4f d 4g d 4h d 4i d 4j d 4k d 4l d 4m d 4n S3

4 (a) Unless otherwise specified, the reaction was conducted on a scale of 0.20 mmol 1a and 1.1 equiv. 2a in the presence of 20 mol% catalyst in 1.0 ml dichloromethane at 30 o C. All reactions afforded 3a as a single diastereomer. (b) Isolated yield. (c) Determined by HPLC with a Chiralpak-AD column. (d) The reaction did not work. (e) Contrary configuration. Table S2 Screening of solvents a entry solvent time(h) yield(%) b ee(%) c 1 DCM CHCl CCl ,2-DCE CH 3 Cl cyclohexane CH 3 CN ethyl acetate butyl acetate DMC DEC toluene mesitylene THF DME i-prh (a) Unless otherwise specified, the reaction was conducted on a scale of 0.20 mmol 1a and 1.1 equiv. 2a in the presence of 20 mol% catalyst in 1.0 ml solvent at 30 o C. All reactions afforded 3a as a single diastereomer. (b) Isolated yield. (c) Determined by HPLC with a Chiralpak-AD column. Table S3: Screening of substrate ratios a entry x y ratio time(h) yield(%) b ee(%) c : : : S4

5 : : : : : : : (a) Unless otherwise specified, the reaction was conducted with the substrate ratio outlined in the table in the presence of 20 mol% catalyst in 1.0 ml DMC at 30 o C. All reactions afforded 3a as a single diastereomer. (b) Isolated yield. (c) Determined by HPLC with a Chiralpak-AD column. Table S4: Screening of concentrations a entry x time(h) yield(%) b ee(%) c (a) Unless otherwise specified, the reaction was conducted on a scale of 0.20 mmol 1a and 3.0 equiv. 2a in the presence of 20 mol% catalyst in x ml DMC at 30 o C. All reactions afforded 3a as a single diastereomer. (b) Isolated yield. (c) Determined by HPLC with a Chiralpak-AD column. Table S5: Screening of catalyst loadings a entry x time(h) yield(%) b ee(%) c (a) Unless otherwise specified, the reaction was conducted on a scale of 0.20 mmol 1a and 3.0 equiv. 2a in the presence of x mol% catalyst in 1.5 ml DMC at 30 o C. All reactions afforded 3a as a single diastereomer. (b) Isolated yield. (c) Determined by HPLC with a Chiralpak-AD column. Table S6: Screening of temperatures a S5

6 entry T time(h) yield(%) b ee(%) c (a) Unless otherwise specified, the reaction was conducted on a scale of 0.20 mmol 1a and 3.0 equiv. 2a in the presence of 15 mol% catalyst in 1.5 ml DMC at the specified temperature. All reactions afforded 3a as a single diastereomer. (b) Isolated yield. (c) Determined by HPLC with a Chiralpak-AD column. Table S7: Screening of molecular sieves a entry x time(h) yield(%) b ee(%) c (a) Unless otherwise specified, the reaction was conducted on a scale of 0.20 mmol 1a and 3.0 equiv. 2a with molecular sieve (100 mg) as an additive in the presence of 15 mol% catalyst in 1.5 ml DMC at 5 o C. All reactions afforded 3a as a single diastereomer. (b) Isolated yield. (c) Determined by HPLC with a Chiralpak-AD column. Table S8: Acid additive screening a H N CH 3 + Ph Boc Me S6 QD (15 mol%) 5 ÅMS(100mg) acid (15 mol%) DMC (1.5 ml) 5 o N C 1a 2a 3a entry acid time(h) yield(%) b ee(%) c 1 PhC 2 H 41 NR NR 2 d hydroquinone d (R)-BINL d (S)-BINL ,4-di-tert-butylphenol ,6-di-tert-butylphenol (a)unless otherwise specified, the reaction was conducted on a scale of 0.20 mmol 1a and 3.0 CH 3 Ph

7 equiv. 2a with 100 mg 5 Å MS and 15mol% acid as additives in the presence of 15 mol% catalyst in 1.5 ml DMC at 5 o C. All reactions afforded 3a as a single diastereomer. (b) Isolated yield. (c) Determined by HPLC with a Chiralpak-AD column. (d) 7.5 mol% acid was added. 3. Genaral procedures for the synthesis of compounds 3. quinidine (15 mol%) H Boc hydroquinone (7.5 mol%) 5 Å MS (100 mg) R 2 + C Ar 2 CH 3 N DMC (1.5 ml) R 2 Ar R 1 5 o N C R Quinidine (15 mol %), hydroquinone (7.5 mol %) and 5 Å MS (100 mg) were added to a solution of 1 (0.2 mmol) and 2 (0.6 mmol) in DMC (1.5 ml). Then, the mixture was cooled to 5 o C. After stirred for the indicated time, the reaction mixture was directly subjected to flash column chromatography on silica gel (petroleum ether/ethyl acetate) to afford the corresponding products Characterization of compounds 3. (2R,3R)-1'-methyl-4-methylene-3-phenyl-3H-spiro[furan-2,3'-indoline]-2',5(4 H)-dione (3a) Reaction time: 41 h; Light yellow solid, [a] D 20 = (c 0.88, N CH 3 CHCl 3 ), 64% yield, > 20:1 dr, 89% ee; HPLC: Chiralcel AD-H column, hexane/i-prh = 85/15, flow rate 1.0 ml/min, UV detection at 254 nm, t major = 14.6 min, t minor = 12.3 min; 1 H NMR (300 MHz, CDCl 3 ), δ 7.55 (d, J= 9 Hz, 1H), 7.37 (t, J= 3 Hz, 1H), (m, 4H), 6.99 (d, J= 6 Hz, 2H), 6.65 (d, J= 6 Hz, 1H), 6.58 (d, J= 3 Hz, 1H), 5.64 (d, J= 3 Hz, 1H), 4.51 (t, J= 3 Hz, 1H), 2.78 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 172.1, 169.2, 144.4, 136.0, 131.6, 131.3, 129.2, 128.4, 124.5, 124.2, 123.4, 123.2, 108.6, 85.3, 56.0, 25.8; HRMS (EI) Calcd. for C19H15N3 [M] + : , Found: (2R,3R)-1'-allyl-4-methylene-3-phenyl-3H-spiro[furan-2,3'-indoline]-2',5(4H)-dio ne (3b) Reaction time: 44 h; Yellow solid, [a] 20 D = (c 0.48, CHCl 3 ), 52% yield, > 20:1 dr, 87% ee; HPLC: Chiralcel AD-H column, hexane/i-prh = 85/15, flow rate 1.0 ml/min, UV detection at 254 nm, t major = 13.3 min, t minor = 11.0 min; 1 H NMR (300 MHz, CDCl 3 ), δ 7.56(d, J= 6 Hz, 1H), (m, 1H), (m, 4H), 7.01 (d, J= 6 Hz, 2H), 6.61 (t, J= 6 Hz, 2H), 5.67 (d, J= 3 Hz, 1H), (m, 1H), 4.80 S7

8 (d, J= 12 Hz, 1H), 4.55 (t, J= 3 Hz, 1H), (m, 2H), N (m, 1H); 13 C NMR (75 MHz, CDCl 3 ) δ 171.9, 169.2, 143.7, 135.9, 131.6, 131.2, 129.9, 129.4, 128.8, 126.1, 124.4, 124.2, 123.4, 123.3, 116.8, 109.5, 85.2, 55.9, 42.0; HRMS (EI) Calcd. for C21H17N3 [M] + : , Found: (2R,3R)-1'-benzyl-4-methylene-3-phenyl-3H-spiro[furan-2,3'-indoline]-2',5(4H)-d ione (3c) Reaction time: 44 h; Yellow solid, [a] D 20 = (c 0.36, CHCl 3 ), N Bn 45% yield, > 20:1 dr, 88% ee; HPLC: Chiralcel AD-H column, hexane/i-prh = 85/15, flow rate 1.0 ml/min, UV detection at 254 nm, t major = 20.2 min, t minor = 19.0 min; 1 H NMR (300 MHz, CDCl 3 ), δ 7.57 (d, J= 9 Hz, 1H), (m, 1H), (m, 9H), 6.64 (d, J= 3 Hz, 1H), 6.42 (d, J= 9 Hz, 1H), 6.38 (d, J= 6 Hz, 2H), 5.71 (d, J=3 Hz, 1H), 5.01 (d, J= 15 Hz, 1H), 4.63 (t, J= 3 Hz, 1H), 4.25 (d, J= 15 Hz, 1H); 13 C NMR (75 MHz, CDCl 3 ) δ 172.2, 169.2, 143.7, 136.1, 131.8, 131.3, 130.9, 129.7, 129.2, 128.9, 128.6, 128.6, 128.4, 127.3, 126.3, 124.4, 124.3, 123.5, 123.4, 109.9, 85.1, 55.6, 43.7; HRMS (EI) Calcd. for C25H19N3 [M] + : , Found: (2R,3R)-1'-butyl-4-methylene-3-phenyl-3H-spiro[furan-2,3'-indoline]-2',5(4H)-di one (3d) Reaction time: 44 h; Light yellow solid, [a] D 20 = (c 0.25, N Bu CHCl 3 ), 38% yield, >20:1 dr, 86% ee; HPLC: Chiralcel AD-H column, hexane/i-prh = 85/15, flow rate 1.0 ml/min, UV detection at 254 nm, t major = 9.8 min, t minor = 8.3 min; 1 H NMR (300 MHz, CDCl 3 ), δ 7.55 (d, J= 9 Hz, 1H), 7.36 (dd, J= 6 Hz, 1H), 7.22 (d, J= 6 Hz, 2H), 7.17 (d, J= 6 Hz, 2H), 7.00 (d, J= 6 Hz, 2H), 6.67 (d, J= 6 Hz, 1H), 6.61 (d, J= 3 Hz, 1H), 5.68 (d, J= 3 Hz, 1H), 4.53 (t, J= 3 Hz, 1H), (m, 1H), (m, 1H), (m, 4H), 0.72 (t, J= 6 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 172.0, 169.2, 144.2, 136.1, 131.8, 131.3, 129.4, 128.8, 124.7, 124.4, 123.3, 123.2, 123.1, 108.8, 85.0, 55.8, 39.7, 28.9, 19.6, 13.6; HRMS (EI) Calcd. for C22H21N3 [M] + : , Found: S8

9 2',5(4H)-dione (3e) Reaction time: 41 h; Colorless solid, [a] D 20 = (c 0.37, N CH 3 F CHCl 3 ), 85% yield, > 20:1 dr, 92% ee; HPLC: Chiralcel IC column, hexane/i-prh = 50/50, flow rate 0.7 ml/min, UV detection at 254 nm, t major = 24.7 min, t minor = 34.0 min; 1 H (2R,3R)-3-(4-fluorophenyl)-1'-methyl-4-methylene-3H-spiro[furan-2,3'-indoline]- NMR (300 MHz, CDCl 3 ), δ 7.54 (d, J = 9 Hz, 1H), 7.39 (t, J = 6 Hz, 1H), 7.20 (t, J= 6 Hz, 1H), (m, 2H), 6.88 (t, J= 9 Hz, 2H), 6.68 (d, J= 6 Hz, 1H), 6.59 (d, J= 6 Hz, 1H), 5.62 (d, J= 3 Hz, 1H), 4.50 (t, J= 3 Hz, 1H), 2.82 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 172.1, 168.9, (d, J= 246 Hz, 1C), 144.4, 136.2, 131.5, 131.1, 131.0, 127.5, 127.4, 124.2, (d, J= 23.9 Hz, 1C), (d, J= 21.4 Hz, 1C), 108.6, 85.0, 55.2, 25.9; HRMS (EI) Calcd. for C19H14FN3 [M] + : , Found: (2R,3R)-3-(4-chlorophenyl)-1'-methyl-4-methylene-3H-spiro[furan-2,3'-indoline]- 2',5(4H)-dione (3f) N CH 3 Cl Reaction time: 34 h; White solid, [a] D 20 = -2.2 (c 0.58, CHCl 3 ), 51% yield, >20:1 dr, 85% ee; HPLC: Chiralcel AD-H column, hexane/i-prh = 85/15, flow rate 1 ml/min, UV detection at 254 nm, t major = 11.4 min, t minor = 12.0 min; 1 H NMR (300 MHz, CDCl 3 ), δ 7.53 (d, J= 6 Hz, 1H), 7.39 (t, J= 6 Hz, 1H), (m, 3H), 6.95 (d, J= 6 Hz, 2H), 6.68 (d, J= 9 Hz, 1H), 6.58 (d, J= 3 Hz, 1H), 5.60 (d, J= 3 Hz, 1H), 4.49 (t, J= 3 Hz, 1H), 2.83 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 171.9, 168.8, 144.4, 135.9, 134.5, 131.5, 130.6, 130.3, 128.7, 126.3, 124.2, 123.5, 123.3, 108.8, 84.9, 55.2, 26.0; HRMS (EI) Calcd. for C19H14ClN3 [M] + : , Found: (2R,3R)-3-(4-bromophenyl)-1'-methyl-4-methylene-3H-spiro[furan-2,3'-indoline] -2',5(4H)-dione (3g) Reaction time: 34 h; White solid, [a] D 20 = (c 0.61, Br N CH 3 CHCl 3 ), 52% yield, >20:1 dr, 84% ee; HPLC: Chiralcel AD-H column, hexane/i-prh = 85/15, flow rate 1 ml/min, UV detection at 254 nm, t major = 11.8 min, t minor = 12.7 min; 1 H NMR (300 MHz, CDCl 3 ), S9

10 δ 7.53 (d, J= 9 Hz, 1H), (m, 3H), 7.19 (t, J= 6 Hz, 1H), 6.89 (d, J= 9 Hz, 2H ), 6.69 (d, J= 6 Hz, 1H), 6.58 (d, J= 6 Hz, 1H), 5.60 (d, J= 3 Hz, 1H), 4.47 (d, J= 3 Hz, 1H), 2.84 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 171.9, 168.7, 144.3, 135.9, 131.7, 131.5, 131.0, 130.9, 128.3, 124.2, 123.5, 123.2, 122.7, 108.8, 84.8, 55.1, 26.0; HRMS (EI) Calcd. for C19H14BrN3 [M] + : , Found: (2R,3R)-1'-methyl-4-methylene-3-(p-tolyl)-3H-spiro[furan-2,3'-indoline]-2',5(4H) -dione (3h) Reaction time: 41 h; White solid, [a] D 20 = (c 0.42, CH 3 N CH 3 CHCl 3 ), 59% yield, >20:1 dr, 89% ee; HPLC: Chiralcel AD-H column, hexane/i-prh = 85/15, flow rate 1 ml/min, UV detection at 254 nm, t major = 10.0 min, t minor = 11.6 min; 1 H NMR (300 MHz, CDCl 3 ), δ 7.53 (d, J= 6 Hz, 1H), 7.37 (t, J= 7.5 Hz, 1H), 7.19 (t, J= 7.5 Hz, 1H), 6.99 (d, J= 6 Hz, 2H), 6.88 (d, J= 6 Hz, 2H), 6.66 (d, J= 6 Hz, 1H), 6.57 (d, J= 3 Hz, 1H), 5.62 (d, J= 3 Hz, 1H), 4.48 (t, J= 3 Hz, 1H), 2.81 (s, 3H), 2.26 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 172.2, 169.3, 144.5, 138.2, 136.3, 131.2, 129.2, 129.1, 128.5, 124.6, 124.2, 123.4, 123.0, 108.6, 85.3, 55.6, 25.9, 21.0; HRMS (EI) Calcd. for C20H17N3 [M] + : , Found: (2R,3R)-1'-methyl-4-methylene-3-(o-tolyl)-3H-spiro[furan-2,3'-indoline]-2',5(4H) -dione (3i) H 3 C Reaction time: 20 h; White solid, [a] D 20 = (c 0.13, CHCl 3 ), N CH 3 58% yield, >20:1 dr, 90% ee; HPLC: Chiralcel AD-H column, hexane/i-prh = 85/15, flow rate 1 ml/min, UV detection at 254 nm, t major = 11.5 min, t minor = 10.9min; 1 H NMR (300 MHz, CDCl 3 ), δ 7.55 (d, J= 9 Hz, 1H), (m, 2H), (m, 3H), 6.97 (d, J= 6 Hz, 1H), 6.67 (d, J= 6 Hz, 1H), 6.55 (d, J=3 Hz, 1H), 5.51 (d, J=3 Hz, 1H), 4.89 (t, J= 3 Hz, 1H), 2.83 (s, 3H), 1.74 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 172.5, 169.3, 144.3, 137.7, 137.6, 131.3, 130.6, 130.2, 129.7, 128.1, 125.0, 124.6, 124.0, 123.3, 123.2, 108.7, 85.4, 51.2, 26.0, 19.3; HRMS (EI) Calcd. for C20H17N3 [M] + : , Found: (2R,3S)-3-(2-chlorophenyl)-1'-methyl-4-methylene-3H-spiro[furan-2,3'-indoline]- S10

11 2',5(4H)-dione (3j) Cl Reaction time: 18 h; Red solid, [a] D 20 = (c 0.28, CHCl 3 ), N CH 3 29% yield, >20:1 dr, 92% ee; HPLC: Chiralcel IC column, hexane/i-prh = 50/50, flow rate 0.7 ml/min, UV detection at Br Reaction time: 18 h; Light yellow solid, [a] D 20 = (c 0.17, N CH 3 CHCl 3 ), 25% yield, >20:1 dr, 94% ee; HPLC: Chiralcel IC column, hexane/i-prh = 50/50, flow rate 0.7 ml/min, UV detection at 254 nm, t major = 29.6 min, t minor = 42.1 min; 1 H NMR 254 nm, t major = 28.0 min, t minor = 39.7 min; 1 H NMR (300 MHz, CDCl 3 ), δ 7.57 (d, J= 6 Hz, 1H), 7.52 (d, J= 6 Hz, 1H), (m, 1H), (m, 4H), 6.69 (d, J= 6 Hz, 1H), 6.57 (d, J= 3 Hz, 1H), 5.50 (d, J= 3 Hz, 1H), 5.29 (t, J= 3 Hz, 1H), 2.88 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 172.1, 168.8, 144.1, 137.0, 135.3, 131.3, 130.5, 129.6, 129.4, 128.8, 127.0, 125.5, 124.3, 123.3, 123.3, 108.6, 84.9, 50.4, 26.0; HRMS (EI) Calcd. for C19H14ClN3 [M] + : , Found: (2R,3S)-3-(2-bromophenyl)-1'-methyl-4-methylene-3H-spiro[furan-2,3'-indoline]- 2',5(4H)-dione (3k) (300 MHz, CDCl 3 ), δ 7.59 (d, J= 6 Hz, 1H), 7.51 (d, J= 6 Hz, 1H), (m, 3H), 7.13 (t, J= 9 Hz, 2H), 6.69 (d, J= 6 Hz, 1H), 6.56 (d, J= 3 Hz, 1H), 5.49 (d, J= 3 Hz, 1H), 5.30 (t, J= 3 Hz, 1H), 2.88 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 172.1, 168.7, 144.2, 137.3, 133.0, 132.9, 131.6, 131.3, 129.9, 128.8, 126.0, 125.9, 124.2, 123.4, 123.3, 108.6, 85.0, 53.0, 26.1; HRMS (EI) Calcd. for C19H14BrN3 [M] + : , Found: (2R,3R)-3-(3-chlorophenyl)-1'-methyl-4-methylene-3H-spiro[furan-2,3'-indoline]- 2',5(4H)-dione (3l) N CH 3 Cl Reaction time: 34 h; White solid, [a] D 20 = (c 0.29, CHCl 3 ), 67% yield, >20:1 dr, 83% ee; HPLC: Chiralcel AD-H column, hexane/i-prh = 85/15, flow rate 1 ml/min, UV detection at 254 nm, t major = 24.6 min, t minor = 13.9 min; 1 H NMR (300 MHz, CDCl 3 ), δ 7.53 (d, J= 6 Hz, 1H), 7.39 (t, J= 6 Hz, 1H), (m, 3H), 6.95 (t, J= 9 Hz, 2H), 6.69 (d, J= 6 Hz, 1H), 6.60 (d, J= 3 Hz, 1H), 5.64 (d, J= 3 Hz, 1H), 4.47 (d, J= 3 Hz, 1H), S11

12 Reaction time: 24 h; Light yellow solid, [a] D 20 = -2.0 (c 0.13, Cl N CH 3 CHCl 3 ), 68% yield, >20:1 dr, 60% ee; HPLC: Chiralcel AD-H column, hexane/i-prh = 85/15, flow rate 1 ml/min, UV detection at 254 nm, t major = 13.3 min, t minor = 11.3 min; 1 H NMR (300 MHz, CDCl 3 ), δ 7.47 (d, J= 6 Hz, 1H), (m, 4H), 7.00 (d, J= 6 Hz, 2H), 6.66 (s, 1H), 6.61 (d, J= 3 Hz, 1H), 5.67 (d, J= 3 Hz, 1H), 4.48 (t, J= 3 Hz, 1H), 2.77 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 172.1, 168.9, 145.6, 137.3, 135.6, 131.3, 129.2, 128.8, 128.7, 128.6, 125.2, 123.7, 123.3, 109.5, 84.7, 55.9, 26.0; HRMS (EI) Calcd. for C19H14ClN3 [M] + : , Found: (2R,3R)-6'-bromo-1'-methyl-4-methylene-3-phenyl-3H-spiro[furan-2,3'-indoline] -2',5(4H)-dione (3n) Reaction time: 44 h; White solid, [a] D 20 = -2.0 (c 0.16, CHCl 3 ), Br N CH 3 62% yield, >20:1 dr, 86% ee; HPLC: Chiralcel AD-H column, hexane/i-prh = 85/15, flow rate 1 ml/min, UV detection at (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 171.9, 168.7, 144.4, 135.7, 134.3, 133.9, 131.6, 129.8, 129.4, 128.8, 127.5, 124.2, 123.6, 123.5, 108.8, 84.9, 55.4, 26.0; HRMS (EI) Calcd. for C19H14ClN3 [M] + : , Found: (2R,3R)-6'-chloro-1'-methyl-4-methylene-3-phenyl-3H-spiro[furan-2,3'-indoline]- 2',5(4H)-dione (3m) nm, t major = 13.3 min, t minor = 11.3 min; 1 H NMR (300 MHz, CDCl 3 ), δ 7.41 (d, J= 6 Hz, 1H), 7.34 (dd, J= 1.5 Hz, 1H), (m, 3H), 7.00 (dd, J= 1.5 Hz, 2H), 6.81 (d, J= 1.5 Hz, 1H), 6.60 (d, J= 3 Hz, 1H), 5.66 (d, J= 3 Hz, 1H), 4.48 (t, J= 3 Hz, 1H), 2.76 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 172.0, 168.9, 145.7, 135.6, 131.3, 129.2, 128.7, 128.6, 126.3, 125.5, 125.2, 123.6, 123.4, 112.2, 84.8, 55.9, 26.0; HRMS (EI) Calcd. for C19H14BrN3 [M] + : , Found: (2R,3R)-5'-fluoro-1'-methyl-4-methylene-3-phenyl-3H-spiro[furan-2,3'-indoline]- 2',5(4H)-dione (3o) Reaction time: 44 h; White solid, [a] 20 D = +1.2 (c 0.32, CHCl 3 ), 41% yield, >20:1 dr, 86% ee; HPLC: Chiralcel AD-H column, hexane/i-prh = 85/15, flow rate 1 ml/min, UV detection at 254 nm, t major = 15.7 min, t minor = 13.1 min; 1 H NMR (300 MHz, S12

13 CDCl 3 ), δ (m, 4H), (m, 3H), 6.60 (d, J= 3 F N CH 3 Hz, 1H), 6.57 (s, 1H), 5.66 (d, J= 3 Hz, 1H), 4.47 (s, 1H), 2.77 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 171.8, 168.7, (d, J= Hz, 1C), 140.3, 135.5, 131.2, 129.1, 128.6, 128.5, 123.6, 123.5, (d, J= 23.4 Hz, 1C), (d, J= 25.1 Hz, 1C), (d, J= 7.8 Hz, 1C), 85.0, 56.0, 25.9; HRMS (EI) Calcd. for C19H14FN3 [M] + : , Found: (R)-3-(4-fluorophenyl)-1',4-dimethyl-5H-spiro[furan-2,3'-indoline]-2',5-dione 4 White solid, 41% yield, 84% ee; HPLC: Chiralcel IC column, N CH 3 F hexane/i-prh = 50/50, flow rate 0.7 ml/min, UV detection at 254 nm, t major = 29.6 min, t minor = 42.1 min; 1 H NMR (300 MHz, CDCl 3 ), δ 7.39 (t, J= 6 Hz, 1H), 7.19 (d, J= 6 Hz, 1H), 7.10 (t, J= 6 Hz, 1H), 6.94 (d, J= 6 Hz, 4H), 6.85 (d, J= 6 Hz, 1H), 3.17 (s, 3H), 2.07 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 173.1, 170.3, (d, J= Hz, 1C), 154.7, 144.4, 131.7, 129.6, 129.5, 127.4, 126.0, (d, J= 69.5 Hz, 1C), 123.0, (d, J= 21.6 Hz, 1C), 109.2, 86.2, 26,8, 10.3; HRMS (ESI) Calcd. for C19H14FNNa3 [M+Na] + : , Found: (2R,3S,4S)-3-(4-fluorophenyl)-1',4-dimethyl-3H-spiro[furan-2,3'-indoline]-2',5(4 H)-dione 5 CH 3 White solid, 38% yield, >99:1 dr; 1 H NMR (300 MHz, CDCl 3 ), δ F N CH (d, J= 6 Hz, 1H), 7.37 (t, J= 6 Hz, 1H), 7.19 (t, J= 6 Hz, 1H), (m, 4H), 6.67 (d, J= 9 Hz, 1H), (m, 1H), 3.58 (d, J= 12 Hz, 1H), 2.84 (s, 3H), 1.26 (d, J= 6 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 177.3, 172.5, (d, J= Hz, 1C), 144.2, 131.3, (d, J= 8.1 Hz, 1C), 127.4, 127.4, 124.7, 124.0, 123.5, (d, J= 21.3 Hz, 1C), 108.6, 58.0, 37.3, 25.8, 13.4; HRMS (ESI) Calcd. for C19H16FNNa3 [M+Na] + : , Found: Crystal data for 3a and 3g S13

14 Crystal data and structure refinement for 3a: (CDCC number: CCDC ) Identification code Empirical formula 3a C19 H15 N 3 Formula weight Temperature Wavelength 100(2) K A Crystal system, space group Monoclinic, P 21 Unit cell dimensions a = (5) A alpha = 90 deg. b = (6) A beta = (10) deg. c = (7) A gamma = 90 deg. Volume (14) A^3 Z, Calculated density 4, Mg/m^3 Absorption coefficient mm^-1 F(000) 640 Crystal size Theta range for data collection Limiting indices 1.50 x 0.27 x 0.18 mm 3.11 to deg. -12<=h<=12, -12<=k<=10, -17<=l<=17 Reflections collected / unique / 4420 [R(int) = ] Completeness to theta = % Absorption correction Semi-empirical from equivalents S14

15 Max. and min. transmission and Refinement method Full-matrix least-squares on F^2 Data / restraints / parameters 4420 / 1 / 418 Goodness-of-fit on F^ Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Absolute structure parameter 0.02(12) Extinction coefficient (5) Largest diff. peak and hole and e.a^-3 Crystal data and structure refinement for 3g: (CDCC number: CCDC ) Identification code Empirical formula 3g C19 H14 Br N 3 Formula weight Temperature Wavelength 100(2) K A Crystal system, space group rthorhombic, P Unit cell dimensions a = (12) A alpha = 90 deg. b = (2) A beta = 90 deg. S15

16 c = (3) A gamma = 90 deg. Volume (5) A^3 Z, Calculated density 4, Mg/m^3 Absorption coefficient mm^-1 F(000) 776 Crystal size Theta range for data collection Limiting indices 0.60 x 0.50 x 0.04 mm 1.88 to deg. -9<=h<=9, -19<=k<=18, -24<=l<=24 Reflections collected / unique / 4490 [R(int) = ] Completeness to theta = % Absorption correction Semi-empirical from equivalents Max. and min. transmission and Refinement method Full-matrix least-squares on F^2 Data / restraints / parameters 4490 / 0 / 218 Goodness-of-fit on F^ Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Absolute structure parameter 0.030(9) Largest diff. peak and hole and e.a^-3 S16

17 6. Synthesis of 4 and 5 Typical Procedure for synthesis of 4: To a solution of compound 3e (0.1 g) in THF (9 ml) was added Pd/C (10 mg, 10% by weight on activated carbon). Hydrogenation was carried out under hydrogen atmosphere at room temperature and atmospheric pressure 12 h. Then, the reaction mixture was filtered and the filtrate was concentrated in vacuo. Purification of the residue by flash column chromatography afford the desired product 4 (41% yield, 84% ee). Typical Procedure for synthesis of 5: To a solution of compound 3e (56.4 mg) and CuCl (11.8 mg) in MeH (1 ml) was added NaBH 4 (20.6 mg). The reaction was stirred at room temperature for 0.5 h. Then, water (1 ml) was added and the reaction mixture was acidized to ph 4-5 by HCl and extracted with CH 2 Cl 2. rganic layer was dried over anhydrous Na 2 S 4, concentrated under vacuum and purified by flash column chromatography on silica gel to give the product 5 (38 % yield, >99:1 dr). S17

18 7. Selected 1 H NMR and 13 C NMR spectra S18

19 S19

20 S20

21 S21

22 S22

23 S23

24 S24

25 S25

26 S26

27 S27

28 8. HPLC chromatograms Total Total S28

29 Total Total S29

30 Total Total S30

31 Total Total S31

32 Total Total S32

33 Total Total S33

34 Total Total S34

35 Total Total S35

36 Total Total S36

37 Total Total S37

38 Total Total S38

39 Total Total S39

40 Total Total S40

41 Total Total S41

42 Total Total S42