The Asymmetric Synthesis of CF3- Containing. Spiro[pyrrolidin-3,2 -oxindole] through the Organocatalytic. 1, 3-dipolar Cycloaddition Reaction

Transcript

1 Electronic Supplementary Material (ESI) for ChemComm. This journal is The Royal Society of Chemistry 2015 The Asymmetric Synthesis of CF3- Containing Spiro[pyrrolidin-3,2 -oxindole] through the Organocatalytic 1, 3-dipolar Cycloaddition Reaction Mingxia Ma, Yuanyuan Zhu, Quantao Sun, Xiaoyuan Li, Jinhuan Su, Long Zhao, Yanyan Zhao, Shuai Qiu, Wenjin Yan*, Kairong Wang * and Rui Wang * Table of Contents A. General Information S2 B. General Procedure for Syntheses of the N-(2, 2, 2-Trifluoroethyl) Isatin-derived Imines (GP1) and Their Analytical Data S2 C. Reaction Condition Optimization S8 D. Representative Procedure S9 E. Analytical Data and HPLC Chromatogram of the Addition Products S10 F. Crystal Structure of 1g S36 G. Crystal Structure of 3k S37 H. Copies of 1 H, 13 C and 19 F NMR spectra S38 S1

2 A. General Information Reactions were monitored by thin layer chromatography (TLC), and compounds were visualized with a UV light at 254 nm. Column chromatography purifications were carried out using silica gel. 1 H, 13 C and 19 F NMR spectra were recorded on a Bruker (300 MHz) spectrometer in CDCl 3, unless otherwise stated, using tetramethylsilane (TMS) as internal standard. Data are presented as follows: chemical shift, integration, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet) and coupling constant in He 20 z (Hz). Mass peaks are identified by the corresponding m/z values. The ee values determination was carried out using chiral high-performance liquid chromatography (HPLC) with Chiracel AD-H column, Chiracel OD-H column and Chiracel IA column. Optical rotations were measured on a digital polarimeter and are reported as follows: [α] D T (concentration (g/100 ml), solvent). All solvents were obtained from commercial sources and were purified according to standard procedures. The catalyst was prepared according to literature procedure. [1] Reference: [1] a) M. Marigo, T. C. Wabnitz, D. Fielenbach, K. A. Jørgensen, Angew. Chem. 2005, 117, 804; Angew. Chem. Int. Ed. 2005, 44, 794; b) Y. Hayashi, H. Gotoh, T. Hayashi, M. Shoji, Angew. Chem. 2005, 117, 4284; Angew. Chem. Int. Ed. 2005, 44, B. General Procedure for Syntheses of the N-(2,2,2-Trifluoroethyl) Isatin-derived Imines (GP1) and Their Analytical Data Isatin (10 mmol), 2,2,2-trifluoroethylamine hydrochloride (15 mmol) and p-toluenesulfonic acid (0.5 mmol) were suspended in toluene (10 ml) in a two-neck flask with a water separator and a condenser. The mixture was then heated to separate the water until complete disappearance of the starting materials, after which it was cooled to room temperature, washed with a small quantity of saturated NaHCO 3 solution and dried by Na 2SO 4. After an evaporation of the organic solvent, the crude residue was purified by flash chromatography (silica gel, hexane/ethyl acetate) and afforded the resulting ketimine as described below. 1-methyl-3-((2,2,2-trifluoroethyl)imino)indolin-2-one(1a) S2

3 Ketimine 1a was obtained according to GP1. Chromatography on a silica gel using hexane/acoet as an eluent afforded 1.89 g of 1a in 78.1% yield as a yellow solid, mp = H NMR (300 MHz, CDCl3) δ 7.69 (d, J = 7.5 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 4.83 (q, J = 9.6 Hz, 2H), 3.23(s, 3H). 13 C NMR (75 MHz, CDCl3) δ 158.6, 155.7, 146.2, 133.8, (q, J CF = Hz), 123.4, 122.9, 120.5, 108.8, 53.5 (q, J CF = 32.0 Hz), F NMR (282 MHz, CDCl3) δ 71.9, HRMS (ESI) m/z calcd for C11H9F3N2NaO [M+Na] + : , found ((2,2,2-trifluoroethyl)imino)indolin-2-one(1b) Ketimine 1b was obtained according to GP1. Chromatography on a silica gel using hexane/acoet as an eluent afforded 1.69 g of 1b in 74.1% yield as a yellow solid, mp = H NMR (300 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.72 (d, J = 7.5 Hz, 1H), 7.42 (t, J = 7.8, 1H), 7.12 (t, J = 7.5, 1H), 6.89 (d, J = 8.1 Hz, 1H), 4.82 (q, J = 9.7 Hz, 2H). 13 C NMR (75MHz, DMSO-d6) δ 159.7, 156.4, 145.3, 134.0, 122.4, 122.3, 120.6, (q, J CF = Hz), 110.9, 52.3 (q, J CF = 31.0 Hz). 19 F NMR (282 MHz, DMSO-d6) δ -70.0, HRMS (ESI) m/z calcd for C10H7F3N2NaO [M+Na] + : , found benzyl-3-((2,2,2-trifluoroethyl)imino)indolin-2-one(1c) Ketimine 1c was obtained according to GP1. Chromatography on a silica gel using hexane/acoet as an eluent afforded 2.39 g of 1c in 75.2% yield as a yellow solid, mp = H NMR (300 MHz, CDCl3) δ 7.73 (d, J = 7.5 Hz, 1H), (m, 6H), S3

4 7.09 (t, J = 7.5 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), (m, 4H). 13 C NMR (75 MHz, CDCl3) δ 158.6, 155.6, 145.5, 134.9, 133.7, 129.0, 128.0, 127.4, (q, J CF = Hz), 123.5, 123.1, 120.7, 109.8, 53.6 (q, J CF = 32.3 Hz), F NMR (282 MHz, CDCl3) δ -71.1, HRMS (ESI) m/z calcd for C17H13F3N2NaO [M+Na] + : , found chloro-1-methyl-3-((2,2,2-trifluoroethyl)imino)indolin-2-one(1d) Ketimine 1d was obtained according to GP1. Chromatography on a silica gel using hexane/acoet as an eluent afforded 1.88 g of 1d in 68.1% yield as a yellow solid, mp = H NMR (300 MHz, CDCl3) δ 7.36 (t, J = 8.1 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 4.87 (q, J = 9.6 Hz, 2H), 3.24 (s, 3H). 13 C NMR (75 MHz, C 3D 6O) δ 158.4, 155.2, 149.3, 135.1, 131.3, (q, J CF = Hz), 125.6, 117.5, 108.8, 54.3 (q, J CF = 32.0 Hz), F NMR (282 MHz, CDCl3) δ HRMS (ESI) m/z calcd for C11H9ClF3N2O [M+H] + : , found methoxy-1-methyl-3-((2,2,2-trifluoroethyl)imino)indolin-2-one(1e) Ketimine 1e was obtained according to GP1. Chromatography on a silica gel using hexane/acoet as an eluent afforded 1.99 g of 1e in 73.2% yield as a yellow solid, mp = H NMR (300 MHz, CDCl3) δ 7.27 (d, J = 1.8 Hz, 1H), 7.01 (dd, J = 8.4, 2.7 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 4.84 (q, J = 9.7 Hz, 2H), 3.83 (s, 3H), 3.20 (s, 3H). 13 C NMR (75 MHz, CDCl3) δ 158.6, 156.5, 156.0, 139.9, (q, J CF = Hz), 121.1, 120.0, 109.6, 107.8, 55.9, 53.4 (q, J CF = 32.0 Hz), F NMR (282 MHz, CDCl3) δ HRMS (ESI) m/z calcd for C12H11F3N2NaO2 [M+Na] + : , found ,5-dimethyl-3-((2,2,2-trifluoroethyl)imino)indolin-2-one(1f) S4

5 Ketimine 1f was obtained according to GP1. Chromatography on a silica gel using hexane/acoet as an eluent afforded 1.92 g of 1f in 75.0% yield as a yellow solid, mp = H NMR (300 MHz, CDCl3) δ 7.54 (s, 1H), 7.25 (d, J = 7.2 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 4.83 (q, J = 9.7 Hz, 2H), 3.21 (s, 3H), 2.35 (s, 3H). 13 C NMR (75 MHz, CDCl3) δ 158.7, 155.9, 144.0, 134.1, 133.2, (q, J CF = Hz), 123.4, 120.4, 108.5, 53.4 (q, J CF = 32.0 Hz), 25.8, F NMR (282 MHz, CDCl3) δ HRMS (ESI) m/z calcd for C12H11F3N2NaO [M+Na] + : , found bromo-1-methyl-3-((2,2,2-trifluoroethyl)imino)indolin-2-one(1g) Ketimine 1g was obtained according to GP1. Chromatography on a silica gel using hexane/acoet as an eluent afforded 2.30 g of 1g in 71.9% yield as a yellow solid, mp = H NMR (300 MHz, CDCl3) δ 7.84 (d, J = 1.8 Hz, 1H), 7.59 (dd, J = 8.4, 2.1 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 4.83 (q, J = 9.7 Hz, 2H), 3.23 (s, 3H). 13 C NMR (75 MHz, CDCl3) δ 158.0, 154.7, 145.0, 136.2, 125.9, (q, J CF = Hz), 121.9, 116.3, 110.3, 53.7 (q, J CF = 32.3 Hz), F NMR (282 MHz, CDCl3) δ HRMS (ESI) m/z calcd for C11H8BrF3N2NaO [M+Na] + : , found chloro-1-methyl-3-((2,2,2-trifluoroethyl)imino)indolin-2-one(1h) Ketimine 1h was obtained according to GP1. Chromatography on a silica gel using hexane/acoet as an eluent afforded 2.01 g of 1h in 72.8% yield as a yellow solid, mp = H NMR (300MHz, CDCl3) δ 7.68 (d, J = 1.8 Hz, 1H), 7.43 (dd, J =8.4, 1.8 S5

6 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 4.82 (q, J = 9.7 Hz, 2H), 3.23 (s, 3H). 13 C NMR (75 MHz, CDCl3) δ 158.1, 154.9, 144.6, 133.3, 129.2, (q, J CF = Hz), 123.1, 121.6, 109.9, 53.7 (q, J CF = 32.3 Hz), F NMR (282 MHz, CDCl3) δ HRMS (ESI) m/z calcd for C11H8ClF3N2NaO [M+Na] + : , found fluoro-1-methyl-3-((2,2,2-trifluoroethyl)imino)indolin-2-one(1i) Ketimine 1i was obtained according to GP1. Chromatography on a silica gel using hexane/acoet as an eluent afforded 1.82 g of 1i in 70.0% yield as a yellow solid, mp = H NMR (300 MHz, CDCl3) δ 7.44 (dd, J = 7.5, 2.7 Hz, 1H), 7.18 (td, J = 8.7, 2.7 Hz, 1H), 6.79 (dd, J = 8.4, 3.6 Hz, 1H), 4.83 (q, J = 9.6 Hz, 2H), 3.23 (s, 3H). 13 C NMR (75 MHz, CDCl3) δ 161.1, 158.4, 157.9, 155.3, 142.2, (q, J CF = Hz), (d, J CF = 7.5 Hz), 115.1(dd, J CF = 712.5, 24 Hz), (d, J CF = 7.5 Hz), 53.6 (q, J CF = 32.3 Hz), F NMR (282 MHz, CDCl3): δ 71.9, HRMS (ESI) m/z calcd for C11H5F4N2NaO [M+Na] + : , found methyl-5-nitro-3-((2,2,2-trifluoroethyl)imino)indolin-2-one(1j) Ketimine 1j was obtained according to GP1. Chromatography on a silica gel using hexane/acoet as an eluent afforded 1.72 g of 1j in 59.9% yield as a yellow solid, mp = H NMR (300 MHz, CDCl 3 ) δ 8.56 (d, J = 2.3 Hz, 1H), 8.43 (dd, J = 8.7, 2.3 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 4.85 (q, J = 9.6 Hz, 2H), 3.35 (s, 3H). 13 C NMR (75 MHz, C 3D 6O) δ 159.5, 155.3, 152.5, 144.6, 130.5, (q, J CF =273.5 Hz), 121.7, 118.0, 110.6, 54.2 (q, J CF = 32.0 Hz), F NMR (282 MHz, CDCl3) δ HRMS (ESI) m/z calcd for C11H8BrF3N3NaO3 [M+Na] + : , found chloro-1-methyl-3-((2,2,2-trifluoroethyl)imino)indolin-2-one(1k) S6

7 Ketimine 1k was obtained according to GP1. Chromatography on a silica gel using hexane/acoet as an eluent afforded 2.01 g of 1k in 72.8% yield as a yellow solid, mp = H NMR (300 MHz, CDCl3) δ 7.64 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 6.85 (s, 1H) 4.81 (q, J = 9.6 Hz, 2H), 3.22 (s, 3H). 13 C NMR (75 MHz, CDCl3) δ 158.4, 154.5, 147.2, 139.8, (q, J CF = Hz), 123.9, 123.5, 118.8, 109.6, 53.6 (q, J CF = 32.3 Hz), F NMR (282 MHz, CDCl3) δ HRMS (ESI) m/z calcd for C11H8ClF3N2NaO [M+Na] + : , found chloro-1-methyl-3-((2,2,2-trifluoroethyl)imino)indolin-2-one(1l) Ketimine 1l was obtained according to GP1. Chromatography on a silica gel using hexane/acoet as an eluent afforded 2.04 g of 1l in 73.9% yield as a yellow solid, mp = H NMR (300 MHz, CDCl3) δ 7.64 (dd, J = 7.5, 0.6 Hz, 1H), 7.38 (dd, J = 8.1, 0.9 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 4.81 (q, J = 9.7 Hz, 2H), 3.60 (s, 3H). 13 C NMR (75 MHz, CDCl3) δ 158.6, 154.6, 141.7, 135.8, 124.2, 123.1, (q, J CF = Hz), 121.5, 116.2, 53.8 (q, J CF = 32.3 Hz), F NMR (282 MHz, CDCl3) δ HRMS (ESI) m/z calcd for C11H8ClF3N2NaO [M+Na] + : , found omo-1,5-dimethyl-3-((2,2,2-trifluoroethyl)imino)indolin-2-one(1m) Ketimine 1m was obtained according to GP1. Chromatography on a silica gel using hexane/acoet as an eluent afforded 2.30 g of 1m in 68.9% yield as a yellow solid, mp = H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), 7.32 (s, 1H), 4.80 (q, J = 9.7 S7

8 Hz, 2H), 3.47 (s, 3H), 2.53 (s, 3H). 13 C NMR (75 MHz, CDCl3) δ 158.6, 154.7, 142.9, 139.4, 125.1(q, J CF = Hz), 123.7, 122.6, 116.0, 53.8 (q, J CF = 32.0 Hz), 29.1, F NMR (282 MHz, CDCl3) δ HRMS (ESI) m/z calcd for C12H10BrF3N2NaO [M+Na] + : , found C. Reaction Condition Optimization Table 1: Optimization reaction conditions. [a] entry solvent time [h] yield [%] [b] dr [c] ee [%] [d] 1 DCM 40 98% > 20:1 97% 2 THF 36 96% > 20:1 99% 3 MTBE 44 94% 8:1 94%/55% 4 Tol 51 98% > 20:1 93% 5 Et 2O 50 98% > 20:1 92% 6 CH3CN 28 98% > 20:1 99% 7 DCE 28 98% > 20:1 95% 8 MeOH 70 98% > 20:1 88% [a] Reactions were carried out with 1a (0.2 mmol), 2a (0.24 mmol), PhCOOH (0.02 mmol) and catalyst (0.02 mmol) in different solvents (0.1 M) at RT. [b] Yield of isolated 3a. [c] Determined by crude 1 H and 19 F NMR or chiral phase HPLC analysis. [d] Determined by chiral phase HPLC analysis. Table 2: Screening of different additives. [a]. entry additive time [h] yield[%] [b] dr [c] ee[%] [d] % > 20:1 98% 2 PhCOOH 28 98% > 20:1 99% 3 AcOH 30 98% > 20:1 93% 4 [e] ptsoh Et 3N [a] Reactions were carried out with 1a (0.2 mmol), 2a (0.24 mmol), corresponding additive (0.02 mmol) and catalyst (0.02 mmol) in CH 3CN (0.1 M) at RT. [b] Yield of isolated 3a. [c] Determined by crude 1 H and 19 F NMR or chiral phase HPLC analysis. [d] Determined by chiral phase HPLC analysis. [e] Did not react. S8

9 Table 3: Catalyst loading screening. [a] entry catalyst loading (eq.) time [h] yield[%] [b] dr [c] ee[%] [d] % > 20:1 99% % > 20:1 99% % > 20:1 99% 4 [e] [a] Reactions were carried out with 1a (0.2 mmol), 2a (0.24 mmol), corresponding additive and catalyst in CH 3CN (0.1 M) at RT. [b] Yield of isolated 3a. [c] Determined by crude 1 H and 19 F NMR or chiral phase HPLC analysis. [d] Determined by chiral phase HPLC analysis. [e] Did not react. Table 4: Screening for reaction concentration. [a] entry reaction concentration [b] time [h] yield[%] [c] dr [d] ee[%] [e] M 24 98% > 20:1 99% M 36 98% > 20:1 99% M 40 98% - 97% M 48 99% - 97% [a] Reactions were carried out with 1a (0.2 mmol), 2a (0.24 mmol), PhCOOH (3 mol%) and catalyst (3 mol%) in CH 3CN at RT. [b] Yield of isolated 3a. [c] Controled by addition of different quantity of solvent. [d] Determined by crude 1 H and 19 F NMR or chiral phase HPLC analysis. [e] Determined by chiral phase HPLC analysis. D. Representative Procedure A vial equipped with a magnetic stir bar was charged with appropriate ketimine (0.2 mmol), the catalyst (0.006 mmol), benzoic acid (3 mol%) and anhydrous acetonitrile (1 ml) at room temperature. Corresponding aldehyde (0.24 mmol) was added in one portion and the reaction was stirred for the designated time, after which it was concentrated and purified by column chromatography. Enantiomeric ratios of the pure products were determined using chiral HPLC. Racemates were prepared following the general procedure by combination of equivalent (R)- S9

10 and (S)-catalysts. E. Analytical Data and HPLC Chromatogram of the Addition Products (2'R,3'S,4'R,5'S)-1-methyl-2-oxo-4'-phenyl-5'-(trifluoromethyl)spiro[indoline-3,2'-pyrrol idine]-3'-carbaldehyde(3a) From 48.4 mg (0.2 mmol) ketimine 1a and cinnamaldehyde 30 μl (0.24 mmol, 1.2 equiv), 71.8 mg (96.0% yield) compound 3a was obtained as a colorless solid, mp = [α]d 20 = +35 (c = 1.0, CHCl3). Dr (>20:1) determined by 1 H and 19 F NMR analysis. 99% ee was determined by HPLC analysis (Daicel Chiralcel IA column, hexane/2-propanol 90:10, 1.0 ml/min). Retention time: tmajor = 15.5 and tminor = 14.3 min. 1 H NMR (300 MHz, CDCl3) δ 9.08 (d, J = 1.6 Hz, 1H), (m, 2H), (m, 5H), 7.13 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 7.7 Hz, 1H), (m, 1H), 4.23 (t, J = 10.2 Hz, 1H), 3.64 (dd, J = 10.6, 1.6 Hz, 1H), 3.26 (s, 3H), 2.76 (d, J = 5.4 Hz, 1H). 13 C NMR (75 MHz, CDCl3) δ 194.9, 176.8, 141.2, 135.7, 128.4, 127.3, 126.5, 126.3, 126.2, (q, J CF = Hz), 123.7, 122.0, 107.2, 66.0, 64.4, 63.6 (q, J CF = 29.3 Hz), 43.8, F NMR (282 MHz, CDCl3) δ HRMS (ESI) m/z calcd for C20H18F3N2O2 [M+H] + : , found AU min Name Retention Time Area % Area Height Int Type Peak Type BV Unknown VB Unknown S10

11 AU min Name Retention Time Area % Area Height Int Type Peak Type Bv Unknown vb Unknown (2'S,3'R,4'S,5'R)-1-methyl-2-oxo-4'-phenyl-5'-(trifluoromethyl)spiro[indoline-3,2'-pyrrol idine]-3'-carbaldehyde(3a ) From 48.4 mg (0.2 mmol) ketimine 1a and cinnamaldehyde 30 μl (0.24 mmol, 1.2 equiv) using (S)-diphenylprolinol silyl ether as catalyst, 73.3 mg ( 98.0 % yield) compound 3a was 20 obtained as a colorless solid, mp = C. [α] D = -48 (c = 1.0, CHCl 3). Dr (>20:1) determined by 1 H and 19 F NMR analysis. >99% ee was determined by HPLC analysis (Daicel Chiralcel IA column, hexane/2 propanol 95: 5, 1.0 ml/min). Retention time: t major = 24.6 and t minor = 27.7 min. 1H NMR (300 MHz, CDCl3) δ 9.08 (d, J = 1.6 Hz, 1H), (m, 2H), (m, 5H), 7.13 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 7.7 Hz, 1H), (m, 1H), 4.23 (t, J = 10.2 Hz, 1H), 3.63 (dd, J = 10.6, 1.5 Hz, 1H), 3.26 (s, 3H), 2.76 (d, J = 6.9 Hz, 13 1H). C NMR (75 MHz, CDCl 3) δ 194.9, 176.8, 141.2, 135.7, 128.4, 127.3, 126.5, 126.3, 126.2, (q, J CF = Hz), 123.7, 122.0, 107.2, 66.0, 64.4, 63.6 (q, J CF = 29.3 Hz), 43.8, F NMR (282 MHz, CDCl 3) δ HRMS (ESI) m/z calcd for C 20H 18F 3N 2O 2 [M+H] + : , found AU min S11

12 Name Retention Time Area % Area Height Int Type Peak Type BV Unknown VB Unknown AU min Name Retention Time Area % Area Height Int Type Peak Type bb Unknown bb Unknown (2'R,3'S,4'R,5'S)-2-oxo-4'-phenyl-5'-(trifluoromethyl)spiro[indoline-3,2'-pyrrolidine]-3'- carbaldehyde(3b) From 45.6 mg (0.2 mmol) ketimine 1b and cinnamaldehyde 30 μl (0.24 mmol, 1.2 equiv), mg ( 90.0% yield) compound 3b was obtained as a white solid, mp = C. [α] D = +46 (c = 1.0, CHCl 3). Dr (>20:1) determined by 1 H and 19 F NMR analysis. 88% ee was determined by HPLC analysis (Daicel Chiralcel IA column, hexane /2 propanol / dichloromethane 95:5:5, 1.0 ml/min ). Retention time: t major = 15.8 and t minor = 20.5 min. 1 H NMR (300 MHz, CDCl 3) δ 9.11 (d, J = 1.5 Hz, 1H), 8.55 (s, 1H), (m, 2H), (m, 5H), 7.12 (td, J = 7.7, 0.9 Hz, 1H), 6.92 (d, J = 7.7 Hz, 1H), (m, 1H), 4.23 (t, J = 10.3 Hz, 1H), 3.66 (dd, J = 10.8, 1.4 Hz, 1H), 2.59 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 194.9, 179.4, 138.2, 135.4, 128.4, 127.4, 126.9, 126.5, 126.3, 124.0, (q, J CF = Hz), 122.1, 109.1, 66.5, 64.4, 63.7 (q, J CF = 29.3 Hz), F NMR (282 MHz, CDCl 3) δ HRMS (ESI) m/z calcd for C 19H 16F 3N 2O 2 [M+H] + : , found S12

13 AU min 名称保留时间面积 % 面积高度积分类型峰类型 bb 未知 bb 未知 0.10 AU min 名称保留时间面积 % 面积高度积分类型峰类型 bb 未知 bb 未知 hexane /2 propanol / dichloromethane 95:5:5, 1.0 ml/min) (2'R,3'S,4'R,5'S)-1-benzyl-2-oxo-4'-phenyl-5'-(trifluoromethyl)spiro[indoline-3,2'-pyrrol idine]-3'-carbaldehyde(3c) From 63.6 mg (0.2 mmol) ketimine 1c and cinnamaldehyde 30 μl (0.24 mmol, 1.2 equiv), mg ( 89.0% yield) compound 3c was obtained as a white solid, mp = C. [α] D = +25 (c = 1.0, CHCl 3). Dr (>20:1) determined by 1 H and 19 F NMR analysis. 99% ee was determined by HPLC analysis (Daicel Chiralcel IA column, hexane/2 propanol 70:30, 1.0 S13

14 ml/min). Retention time: t major = 10.2 and t minor = 7.4 min. 1 H NMR (300 MHz, CDCl 3) δ 9.07 (d, J = 1.6, 1H), (m, 2H), (m, 8H), (m, 2H), 7.08 (td, J = 7.6, 0.8, 1H), 6.75 (d, J = 7.7, 1H), 4.93 (dd, J = 68.4, 15.6, 2H), (m, 1H), 4.26 (t, J = 10.4, 1H), 3.72 (dd, J = 10.9, 1.5, 1H), 2.86 (d, J = 7.0, 1H). 13C NMR (75 MHz, CDCl3) δ 196.4, 178.7, 142.0, 137.2, 135.1, 130.0, 129.1, 129.0, 128.3, 128.2, 128.0, 128.0, 127.2, (q, J CF = Hz), 125.4, 123.8, 109.9, 67.9, 66.6, 65.5 (q, J CF = 29.3 Hz), 45.7, F NMR (282 MHz, CDCl 3) δ HRMS (ESI) m/z calcd for C 26H 22F 3N 2O 2 [M+H] + : , found AU min Name Retention Time Area % Area Height Int Type Peak Type VV Unknown VV Unknown AU min Name Retention Time Area % Area Height Int Type Peak Type VV Unknown bb Unknown (2'R,3'S,4'R,5'S)-4-chloro-1-methyl-2-oxo-4'-phenyl-5'-(trifluoromethyl)spiro[indoline-3, 2'-pyrrolidine]-3'-carbaldehyde(3d) S14

15 From 55.2 mg (0.2 mmol) ketimine 1d and cinnamaldehyde 30 μl (0.24 mmol, 1.2 equiv), 75.9 mg ( 93.0% yield) compound 3d was obtained as a white solid, mp = C. 20 [α] D = -11 (c = 1.0, CHCl 3). Dr (>20:1) determined by 1 H and 19 F NMR analysis. >99% ee was determined by HPLC analysis (Daicel Chiralcel IA column, hexane/2 propanol 70:30, 1.0 ml/min). Retention time: t major = 6.3 min. 1 H NMR (300 MHz, CDCl 3) δ 9.48 (d, J = 1.0 Hz, 1H), (m, 2H), 7.38 (t, J = 7.5 Hz, 2H), (m, 2H), 7.05 (d, J = 8.2 Hz, 1H), 6.79 (d, J = 7.7 Hz, 1H), 4.59 (d, J = 3.8 Hz, 1H), 4.30 (t, J = 10.4 Hz, 1H), 3.60 (d, J = 10.6 Hz, 1H), 3.26 (s, 3H), 2.59 (s, 1H). 13 C NMR (75 MHz, CDCl3) δ 197.0, 179.2, 145.2, 137.6, 131.7, 131.5, 129.1, 128.3, 127.9, (q, J CF = Hz), 124.8, 123.9, 107.5, 67.8, 66.4, 65.6 (q, J CF = 19.7 Hz), 46.9, F NMR (282 MHz, CDCl 3) δ HRMS (ESI) m/z calcd for C 20H 17ClF 3N 2O 2 [M+H] + : , found AU min Name Retention Time Area % Area Height Int Type Peak Type VV Unknown VB Unknown AU min Name Retention Time Area % Area Height Int Type Peak Type bb Unknown (2'R,3'S,4'R,5'S)-5-methoxy-1-methyl-2-oxo-4'-phenyl-5'-(trifluoromethyl)spiro[indoline -3,2'-pyrrolidine]-3'-carbaldehyde(3e) S15

16 From 54.4 mg (0.2 mmol) ketimine 1e and cinnamaldehyde 30 μl (0.24 mmol, 1.2 equiv), mg ( 95.0% yield) compound 3e was obtained as a white solid, mp = C. [α] D = -21 (c = 1.0, CHCl 3). Dr (>20:1) determined by 1 H and 19 F NMR analysis. 98% ee was determined by HPLC analysis (Daicel Chiralcel IA column, hexane /2 propanol/ dichloromethane 95:5:0.5, 1.0 ml/min). Retention time: t major = 14.4 and t minor = 12.2 min. 1 H NMR (300 MHz, CDCl 3) δ 9.08 (d, J = 1.5 Hz, 1H), (m, 2H), 7.35 (t, J = 7.4 Hz, 2H), (m, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.85 (dd, J = 8.5, 2.5 Hz, 1H), 6.77 (d, J = 8.5 Hz, 1H), (m, 1H), 4.21 (t, J = 10.3 Hz, 1H), 3.79 (s, 3H), 3.64 (dd, J = 10.7, 1.4 Hz, 1H), 3.23 (s, 3H), 2.80 (d, J = 6.9 Hz, 1H). 13 C NMR (75 MHz, CDCl3) δ 194.8, 176.5, 155.0, 135.6, 134.4, 127.8, 127.3, 126.5, 126.2, (q, J CF = Hz), 112.6, 110.9, 107.6, 66.4, 64.5, 63.7 (q, J CF = 29.3 Hz), 54.1, 43.7, F NMR (282 MHz, CDCl 3) δ HRMS (ESI) m/z calcd for C 21H 20F 3N 2O 3 [M+H] + : , found AU min Name Retention Time Area % Area Height Int Type Peak Type VV Unknown VB Unknown AU min Name Retention Time Area % Area Height Int Type Peak Type BB Unknown S16

17 BB Unknown (2'R,3'S,4'R,5'S)-1,5-dimethyl-2-oxo-4'-phenyl-5'-(trifluoromethyl)spiro[indoline-3,2'-py rrolidine]-3'-carbaldehyde(3f) From 51.2 mg (0.2 mmol) ketimine 1f and cinnamaldehyde 30 μl (0.24 mmol, 1.2 equiv), 71.4 mg ( 92.0% yield) compound 3f was obtained as a white solid, mp = C. 20 [α] D = +9 (c = 1.0, CHCl 3). Dr (>20:1) determined by 1 H and 19 F NMR analysis. >99% ee was determined by HPLC analysis (Daicel Chiralcel OD-H column, hexane/2 propanol 85:15, 1.0 ml/min). Retention time: t major = 9.0 min. 1 H NMR (300 MHz, CDCl 3) δ 9.08 (d, J = 1.3 Hz, 1H), 7.49 (d, J = 7.3 Hz, 2H), 7.36 (t, J = 7.4 Hz, 2H), (m, 1H), 7.13 (d, J = 7.9 Hz, 2H), 6.75 (d, J = 8.0 Hz, 1H), (m, 1H), 4.21 (t, J = 10.2 Hz, 1H), 3.63 (dd, J = 10.5, 1.1 Hz, 1H), 3.24 (s, 3H), 2.73 (d, J = 6.8 Hz, 1H), 2.35 (s, 3H). 13 C NMR (75 MHz, CDCl3) δ 195.6, 177.5, 139.5, 136.4, 132.5, 129.3, 127.9, 127.2, 126.9, 126.8, 125.0, (q, J CF = Hz), 107.6, 66.7, 65.0, 64.3 (q, J CF = 29.3 Hz), 44.3, 25.7, F NMR (282 MHz, CDCl 3) δ HRMS (ESI) m/z calcd for C 21H 20F 3N 2O 2 [M+H] + : , found AU min Name Retention Time Area % Area Height Int Type Peak Type BV Unknown Vb Unknown S17

18 0.60 AU min Name Retention Time Area % Area Height Int Type Peak Type bb Unknown (2'R,3'S,4'R,5'S)-5-bromo-1-methyl-2-oxo-4'-phenyl-5'-(trifluoromethyl)spiro[indoline-3,2'-pyrrolidine]-3'-carbaldehyde(3g) From 64.0 mg (0.2 mmol) ketimine 1g and cinnamaldehyde 30 μl (0.24 mmol, 1.2 equiv), mg ( 95.0% yield) compound 3g was obtained as a white solid, mp = C. [α] D = -55 (c = 1.0, CHCl 3). Dr (>20:1) determined by 1 H and 19 F NMR analysis. >99% ee was determined by HPLC analysis (Daicel Chiralcel AD-H column, hexane/2 propanol 90:10, 1.0 ml/min). Retention time: t major = 17.4 and t minor = 15.6 min. 1 H NMR (300 MHz, CDCl 3) δ 9.14 (d, J = 1.6 Hz, 1H), (m, 4H), (m, 2H), (m, 1H), (m, 1H), (m, 1H), 4.18 (t, J = 10.4 Hz, 1H), 3.63 (dd, J = 10.9, 1.6 Hz, 1H), 3.26 (s, 3H), 2.75 (d, J = 6.7 Hz, 1H). 13 C NMR (75 MHz, CDCl3) δ 195.3, 176.9, 140.9, 135.8, 131.9, 129.3, 128.1, 127.4, 127.1, 127.0, (q, J CF = Hz), 115.4, 109.3, 66.6, 65.1, 64.3 (q, J CF = 29.3 Hz), 44.5, F NMR (282 MHz, CDCl 3) δ HRMS (ESI) m/z calcd for C 20H 17BrF 3N 2O 2 [M+H] + : , found AU min S18

19 Name Retention Time Area % Area Height Int Type Peak Type BV Unknown VB Unknown AU min Name Retention Time Area % Area Height Int Type Peak Type bb Unknown BB Unknown (2'R,3'S,4'R,5'S)-5-chloro-1-methyl-2-oxo-4'-phenyl-5'-(trifluoromethyl)spiro[indoline-3, 2'-pyrrolidine]-3'-carbaldehyde(3h) From 55.2 mg (0.2 mmol) ketimine 1h and cinnamaldehyde 30 μl (0.24 mmol, 1.2 equiv), 76.7 mg ( 94.0% yield) compound 3h was obtained as a white solid, mp = C. 20 [α] D = -35 (c = 1.0, CHCl 3). Dr (>20:1) determined by 1 H and 19 F NMR analysis. >99% ee was determined by HPLC analysis (Daicel Chiralcel OD-H column, hexane/2 propanol 85:15, 1.0 ml/min). Retention time: t major = 13.1 min. 1 H NMR (300 MHz, CDCl 3) δ 9.13 (d, J = 1.6 Hz, 1H), (m, 2H), (m, 5H), 6.80 (dd, J = 7.6, 1.2 Hz, 1H), (m, 1H), 4.18 (t, J = 10.4 Hz, 1H), 3.64 (dd, J = 10.9, 1.6 Hz, 1H), 3.26 (s, 3H), 2.76 (d, J = 6.7 Hz, 1H). 13 C NMR (75 MHz, CDCl3) δ 196.2, 178.1, 141.4, 136.8, 130.0, 130.0, 129.3, 129.1, 128.2, 128.0, 125.7, (q, J CF = Hz), 109.8, 67.7, 66.2, 65.4 (q, J CF =29.5 Hz), 45.5, F NMR (282 MHz, CDCl 3) δ HRMS (ESI) m/z calcd for C 20H 17ClF 3N 2O 2 [M+H] + : , found S19

20 0.10 AU min Name Retention Time Area % Area Height Int Type Peak Type BV Unknown VB Unknown AU min Name Retention Time Area % Area Height Int Type Peak Type VB Unknown (2'R,3'S,4'R,5'S)-5-fluoro-1-methyl-2-oxo-4'-phenyl-5'-(trifluoromethyl)spiro[indoline-3, 2'-pyrrolidine]-3'-carbaldehyde(3i) From 52.0 mg (0.2 mmol) ketimine 1i and cinnamaldehyde 30 μl (0.24 mmol, 1.2 equiv), 72.1 mg ( 92.0% yield) compound 3i was obtained as a white solid, mp = C. 20 [α] D = +20 (c = 1.0, CHCl 3). Dr (>20:1) determined by 1 H and 19 F NMR analysis. 95% ee was determined by HPLC analysis (Daicel Chiralcel IA column, hexane /2 propanol / dichloromethane 95:5:5, 1.0 ml/min). Retention time: t major = and t minor = min. 1 H NMR (300 MHz, CDCl 3) δ 9.11 (d, J = 1.6 Hz, 1H), (m, 2H), (m, 2H), (m, 1H), 7.13 (dd, J = 7.6, 2.5 Hz, 1H), 7.05 (td, J = 8.7, 2.6 Hz, 1H), 6.81 (dd, J = 8.5, 4.0 Hz, 1H), (m, 1H), 4.18 (t, J = 10.4 Hz, 1H), 3.66 (dd, J = 11.0, 1.5 Hz, 1H), 3.26 (s, 3H), 2.80 (d, J = 6.9 Hz, 1H). 13 C NMR (75 MHz, CDCl3) δ 196.4, 178.1, (d, J CF =240 Hz), (d, J CF =2.25 Hz), 137.0, (d, J CF =7.5 Hz), 129.1, 128.2, 128.0, (q, J CF = Hz), (d, J CF =22.5 Hz), (d, J CF =22.5 Hz), (d, S20

21 J CF =7.5 Hz), 68.0 (d, J CF =1.5 Hz), 66.3, 65.4 (q, J CF = 29.3 Hz), 45.5, F NMR (282 MHz, CDCl 3) δ -75.0, HRMS (ESI) m/z calcd for C 20H 17F 4N 2O 2 [M+H] + : , found AU min Name Retention Time Area % Area Height Int Type Peak Type BV Unknown VB Unknown AU min Name Retention Time Area % Area Height Int Type Peak Type BV Unknown VB Unknown (2'R,3'S,4'R,5'S)-1-methyl-5-nitro-2-oxo-4'-phenyl-5'-(trifluoromethyl)spiro[indoline-3,2 '-pyrrolidine]-3'-carbaldehyde(3j) From 57.4 mg (0.2 mmol) ketimine 1j and cinnamaldehyde 30 μl (0.24 mmol, 1.2 equiv), 78.6 mg ( 58.0% yield) compound 3j was obtained as a yellow solid, mp = C. 20 [α] D = -73 (c = 1.0, CHCl 3). Dr (>20:1) determined by 1 H and 19 F NMR analysis. 94% ee was determined by HPLC analysis (Daicel Chiralcel AD-H column, hexane/2 propanol 70:30, 1.0 ml/min). Retention time: t major = 8.2 and t minor = 11.1 min. 1 H NMR (300 MHz, CDCl 3) δ 9.19 (d, J = 1.5 Hz, 1H), 8.32 (dd, J = 8.6, 2.2 Hz, 1H), 8.24 S21

22 (d, J = 2.2 Hz, 1H), (m, 2H), 7.40 (t, J = 7.3 Hz, 2H), (m, 1H), 6.98 (d, J = 8.6 Hz, 1H), (m, 1H), 4.23 (t, J = 10.5 Hz, 1H), 3.68 (dd, J = 11.4, 1.4 Hz, 1H), 3.35 (s, 3H), 2.83 (d, J = 6.5 Hz, 1H). 13 C NMR (75 MHz, CDCl3) δ196.2, 178.6, 148.3, 144.1, 136.1, 129.7, 129.3, 128.3, , 127.0, 120.9, (q, J CF = Hz), 108.6, 67.3, 66.4, 65.4 (q, J CF = 29.5 Hz), 45.9, F NMR (282 MHz, CDCl 3) δ HRMS (ESI) m/z calcd for C 20H 17F 3N 3O 4 [M+H] + : , found AU min Name Retention Time Area % Area Height Int Type Peak Type VB Unknown bb Unknown AU min Name Retention Time Area % Area Height Int Type Peak Type bv Unknown vb Unknown (2'R,3'S,4'R,5'S)-6-chloro-1-methyl-2-oxo-4'-phenyl-5'-(trifluoromethyl)spiro[indoline-3, 2'-pyrrolidine]-3'-carbaldehyde(3k) From 55.2 mg (0.2 mmol) ketimine 1k and cinnamaldehyde 30 μl (0.24 mmol, 1.2 equiv), 75.9 mg ( 93.0% yield) compound 3k was obtained as a colorless solid, mp = C. [α] D 20 = +26 (c = 1.0, CHCl 3). Dr (>20:1) determined by 1 H and 19 F NMR S22

23 analysis. >99% ee was determined by HPLC analysis (Daicel Chiralcel AD-H column, hexane/2 propanol 90:10, 1.0 ml/min). Retention time: t major = 14.3 and t minor = 12.0 min. 1 H NMR (300 MHz, CDCl 3) δ 9.10 (s, 1H), 7.46 (d, J = 7.4 Hz, 2H), 7.36 (t, J = 7.3 Hz, 2H), (m, 2H), 7.11 (d, J = 7.9 Hz, 1H), 6.87 (s, 1H), (m, 1H), 4.19 (t, J = 10.3 Hz, 1H), 3.63 (d, J = 10.7 Hz, 1H), 3.25 (s, 3H), 2.74 (d, J = 6.6 Hz, 1H). 13 C NMR (75 MHz, CDCl3) δ 196.2, 178.5, 144.0, 137.0, 136.0, 129.1, 128.2, 128.0, 126.5, 126.4, (q, J CF = Hz), 123.6, 109.7, 67.4, 66.1, 65.3 (q, J CF = 29.5 Hz), 45.5, F NMR (282 MHz, CDCl 3) δ HRMS (ESI) m/z calcd for C 20H 17ClF 3N 2O 2 [M+H] + : , found AU min Name Retention Time Area % Area Height Int Type Peak Type BV Unknown VB Unknown AU min Name Retention Time Area % Area Height Int Type Peak Type BB Unknown BB Unknown (2'R,3'S,4'R,5'S)-7-chloro-1-methyl-2-oxo-4'-phenyl-5'-(trifluoromethyl)spiro[indoline-3, 2'-pyrrolidine]-3'-carbaldehyde(3l) S23

24 From 55.2 mg (0.2 mmol) ketimine 1l and cinnamaldehyde 30 μl (0.24 mmol, 1.2 equiv), 76.7 mg ( 94.0% yield) compound 3l was obtained as a white solid, mp = C. 20 [α] D = +25 (c = 1.0, CHCl 3). Dr (>20:1) determined by 1 H and 19 F NMR analysis. >99% ee was determined by HPLC analysis (Daicel Chiralcel AD-H column, hexane/2 propanol 95:5, 1.0 ml/min). Retention time: t major = 32.8 min. 1 H NMR (300 MHz, CDCl 3) δ 9.08 (d, J = 1.4 Hz, 1H), (m, 2H), (m, 2H), (m, 3H), 7.05 (t, J = 7.5 Hz, 1H), (m, 1H), 4.19 (t, J = 10.3 Hz, 1H), (m, 4H), 2.73 (d, J = 6.6 Hz, 1H). 13 C NMR (75 MHz, CDCl3) δ 195.2, 178.1, 137.7, 136.0, 131.2, 130.1, 128.0, 127.1, 126.9, 123.5, 123.0, (q, J CF = Hz), 115.3, 66.1, 65.3, 64.2 (q, J CF = 29.3 Hz), 44.2, F NMR (282 MHz, CDCl 3) δ HRMS (ESI) m/z calcd for C 20H 17ClF 3N 2O 2 [M+H] + : , found AU min Name Retention Time Area % Area Height Int Type Peak Type bv Unknown vb Unknown AU min Name Retention Time Area % Area Height Int Type Peak Type bb Unknown (2'R,3'S,4'R,5'S)-5-bromo-1,7-dimethyl-2-oxo-4'-phenyl-5'-(trifluoromethyl)spiro[indoli ne-3,2'-pyrrolidine]-3'-carbaldehyde(3m) S24

25 From 66.8 mg (0.2 mmol) ketimine 1m and cinnamaldehyde 30 μl (0.24 mmol, 1.2 equiv), 85.8 mg ( 92.0% yield) compound 3m was obtained as a white solid, mp = C. 20 [α] D = -32 (c = 1.0, CHCl 3). Dr (>20:1) determined by 1 H and 19 F NMR analysis. 99% ee was determined by HPLC analysis (Daicel Chiralcel AD-H column, hexane/2 propanol 70:30, 1.0 ml/min). Retention time: t major = 9.2 and t minor = 7.5 min. 1 H NMR (300 MHz, CDCl 3) δ 9.10 (d, J = 1.5 Hz, 1H), 7.47 (d, J = 7.2 Hz, 2H), 7.36 (t, J = 7.3 Hz, 2H), (m, 2H), 7.22 (s, 1H), (m, 1H), 4.16 (t, J = 10.3 Hz, 1H), 3.58 (dd, J = 10.8, 1.4 Hz, 1H), 3.51 (s, 3H), 2.72 (d, J = 6.0 Hz, 1H), 2.53 (s, 3H). 13 C NMR (75 MHz, CDCl3) δ 196.4, 179.1, 139.7, 136.9, 136.2, 130.9, 129.1, 128.2, 128.0, 126.3, (q, J CF = Hz), 122.5, 116.2, 67.0, 66.3, 65.3 (q, J CF = 29.5 Hz), 45.4, 30.2, F NMR (282 MHz, CDCl 3) δ HRMS (ESI) m/z calcd for C 21H 19BrF 3N 2O 2 [M+H] + : , found AU min Name Retention Time Area % Area Height Int Type Peak Type VV Unknown VB Unknown AU min Name Retention Time Area % Area Height Int Type Peak Type VB Unknown S25

26 Bb Unknown (2'R,3'S,4'R,5'S)-4'-(2-chlorophenyl)-1-methyl-2-oxo-5'-(trifluoromethyl)spiro[indoline- 3,2'-pyrrolidine]-3'-carbaldehyde(3n) From 48.4 mg (0.2 mmol) ketimine 1a and 2-chlorocinnamaldehyde 40.0 mg (0.24 mmol, 1.2 equiv), 72.6 mg (89.0% yield) compound 3n was obtained as a white solid, mp = C. [α] D = +44 (c = 1.0, CHCl 3). Dr (>20:1) determined by 1 H and 19 F NMR analysis. >99% ee was determined by HPLC analysis (Daicel Chiralcel IA column, hexane/2 propanol 80:20, 1.0 ml/min). Retention time: t major = 11.7 min. 1 H NMR (300 MHz, CDCl 3) δ 9.16 (d, J = 2.1Hz, 1H), 7.64 (dd, J = 7.8, 1.5 Hz, 1H), (m, 4H), (m, 2H), 6.87 (d, J = 7.8 Hz, 1H), 4.93 (t, J = 10.3 Hz, 1H), (m, 1H), 3.65 (d, J = 10.3 Hz, 1H), 3.26 (s, 3H), 2.82 (d, J = 7.1 Hz, 1H). 13 C NMR (75 MHz, CDCl3) δ 196.6, 178.2, 142.9, 134.7, 134.4, 130.1, 129.0, 128.0, 127.7, 125.3, (q, J CF = Hz), 123.8, 108.9, 68.0, 66.1, 65.0 (q, J CF = 29.0 Hz), 41.6, F NMR (282 MHz, CDCl 3) δ HRMS (ESI) m/z calcd for C 20H 17ClF 3N 2O 2 [M+H] + : , found AU min Name Retention Time Area % Area Height Int Type Peak Type bb Unknown Bb Unknown S26

27 AU min Name Retention Time Area % Area Height Int Type Peak Type bb Unknown (2'R,3'S,4'R,5'S)-4'-(3-chlorophenyl)-1-methyl-2-oxo-5'-(trifluoromethyl)spiro[indoline- 3,2'-pyrrolidine]-3'-carbaldehyde(3o) From 48.4 mg (0.2 mmol) ketimine 1a and 3-chlorocinnamaldehyde 40.0 mg (0.24 mmol, 1.2 equiv), 75.1 mg (92.0% yield) compound 3o was obtained as a white solid, mp = C. [α] D = +15 (c = 1.0, CHCl 3). Dr (>20:1) determined by 1 H and 19 F NMR analysis. >99% ee was determined by HPLC analysis (Daicel Chiralcel OB-H column, hexane/2 propanol 80: 20, 1.0 ml/min). Retention time: t major = 18.5 min. 1 H NMR (300 MHz, CDCl 3) δ 9.07 (d, J = 1.2 Hz, 1H), 7.50 (d, J = 1.8 Hz, 1H), (m, 5H), 7.14 (td, J = 7.7, 0.5 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), (m, 1H), 4.19 (t, J = 10.1 Hz, 1H), 3.60 (dd, J = 10.3, 1.1 Hz, 1H), 3.28 (s, 3H), 2.72 (d, J = 6.6 Hz, 1H). 13 C NMR (75 MHz, CDCl3) δ 196.1, 178.6, 142.9, 139.8, 134.7, 130.3, 130.2, 128.4, 128.1, 127.6, 126.6, 125.4, (q, J CF = Hz), 123.8, 108.9, 67.6, 65.8, 65.0 (q, J CF = 29.5 Hz), 44.8, F NMR (282 MHz, CDCl 3) δ HRMS (ESI) m/z calcd for C 20H 17ClF 3N 2O 2 [M+H] + : , found S27

28 AU min 名称保留时间面积 % 面积高度积分类型峰类型 bv 未知 vb 未知 AU min 名称保留时间面积 % 面积高度积分类型峰类型 bb 未知 (2'R,3'S,4'R,5'S)-1-methyl-2-oxo-5'-(trifluoromethyl)-4'-(3-(trifluoromethyl)phenyl)spiro [indoline-3,2'-pyrrolidine]-3'-carbaldehyde(3p) From 48.4 mg (0.2 mmol) ketimine 1a and 3-trifluorocinnamaldehyde 48.0 mg (0.24 mmol, 1.2 equiv), 80.5 mg (91.0% yield) compound 3p was obtained as a white solid, mp 20 = C. [α] D = +21 (c = 1.0, CHCl 3). Dr (>20:1) determined by 1 H and 19 F NMR analysis. >99% ee was determined by HPLC analysis (Daicel Chiralcel IA column, hexane/2 propanol 95:5, 1.0 ml/min). Retention time: t major = 17.7 min. 1 H NMR (300 MHz, CDCl 3) δ 9.08 (d, J = 1.1 Hz, 1H), 7.73 (d, J = 9.2 Hz, 2H), (m, 2H), 7.39 S28

29 7.26 (m, 2H), 7.14 (td, J = 7.6, 0.8 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), (m, 1H), 4.29 (t, J = 10.0 Hz, 1H), 3.63 (dd, J = 10.2, 0.9 Hz, 1H), 3.28 (s, 3H), 2.74 (d, J = 6.5 Hz, 1H). 13 C NMR (75 MHz, CDCl3) δ 196.0, 178.6, 142.9, 138.9, 131.8, (q, J CF = 32.3Hz), 130.3, 129.6, 127.4, 125.5, (q, J CF = Hz), 125.1(q, J CF = 3.8 Hz), (q, J CF = 3.5 Hz), (q, J CF = Hz), 123.8, 108.9, 67.5, 65.7, 65.1 (q, J CF = 30.2 Hz), 44.8, F NMR (282 MHz, CDCl 3) δ -62.5, HRMS (ESI) m/z calcd for C 21H 17F 6N 2O 2 [M+H] + : , found AU min Name Retention Time Area % Area Height Int Type Peak Type BV Unknown VB Unknown AU min Name Retention Time Area % Area Height Int Type Peak Type BB Unknown (2'R,3'S,4'R,5'S)-4'-(4-methoxyphenyl)-1-methyl-2-oxo-5'-(trifluoromethyl)spiro[indolin e-3,2'-pyrrolidine]-3'-carbaldehyde(3q) S29

30 From 48.4 mg (0.2 mmol) ketimine 1a and 4-methoxy cinnamaldehyde 38.8 mg (0.24 mmol, 1.2 equiv), 66.3 mg (82.0% yield) compound 3q was obtained as a white solid, mp 20 = C. [α] D = -5 (c = 1.0, CHCl 3). Dr (10:1) determined by 1 H and 19 F and 19 F NMR analysis. >99% ee was determined by HPLC analysis (Daicel Chiralcel IA column, hexane/2 propanol 80:20, 1.0 ml/min). Retention time: t major = 17.8 min. 1 H NMR (300 MHz, CDCl 3) δ 9.19 (d, J = 2.2 Hz, 0.09H), 9.09 (d, J = 1.6 Hz, 0.90H), (m, 4H), (m, 1H), (m, 3H), (m, 1H), 4.19 (t, J = 10.3 Hz, 1H), 3.80 (s, 0.27H), 3.79 (s, 2.61H), 3.59 (dd, J = 10.7, 1.5 Hz, 1H), 3.27 (s, 2.72H), 3.25 (s, 0.27H), 2.73 (d, J = 6.8 Hz, 1H). 13 C NMR (75 MHz, CDCl3) δ 196.8, 178.6, 159.1, 142.8, 130.0, 129.2, 129.1, 128.1, (q, J CF = Hz), 125.3, 123.7, 114.4, 108.8, 67.7, 66.1, 65.3 (q, J CF = 29.0 Hz), 55.2, 44.8, F NMR (282 MHz, CDCl 3) δ -74.7, HRMS (ESI) m/z calcd for C 21H 20F 3N 2O 3 [M+H] + : , found AU min Name Retention Time Area % Area Height Int Type Peak Type BV Unknown VB Unknown AU min Name Retention Time Area % Area Height Int Type Peak Type VB Unknown (2'R,3'S,4'R,5'S)-1-methyl-2-oxo-4'-(p-tolyl)-5'-(trifluoromethyl)spiro[indoline-3,2'-pyrr olidine]-3'-carbaldehyde(3r) S30

31 From 48.4 mg (0.2 mmol) ketimine 1a and 4-methylcinnamaldehyde 35.0 mg (0.24 mmol, 1.2 equiv), 69.9 mg (90.0% yield) compound 3r was obtained as a yellow solid, mp = C. [α] D = +20 (c = 1.0, CHCl 3). Dr (>20:1) determined by 1 H and 19 F NMR analysis. 99% ee was determined by HPLC analysis (Daicel Chiralcel IA column, hexane/2 propanol 80:20, 1.0 ml/min). Retention time: t major = 12.7 and t minor = 11.5 min. 1 H NMR (300 MHz, CDCl 3) δ9.08 (s, 1H), (m, 4H), (m, 3H), 6.87 (d, J = 7.8 Hz, 1H), (m, 1H), 4.20 (t, J = 10.3 Hz, 1H), 3.62 (d, J = 10.8 Hz, 1H), 3.27 (s, 3H), 2.75 (d, J = 6.9 Hz, 1H), 2.33 (s, 3H). 13 C NMR (75 MHz, CDCl 3) δ196.8, 178.5, 142.9, 137.6, 134.2, 130.1, 129.8, 128.3, 128.1, (q, J CF = Hz), 125.4, 123.7, 108.9, 67.8, 66.2, 65.4 (q, J CF = 65.4 Hz), 45.3, 26.7, F NMR (282 MHz, CDCl 3) δ HRMS (ESI) m/z calcd for C 21H 19F 3N 2NaO 2 [M+Na] + : , found AU min Name Retention Time Area % Area Height Int Type Peak Type BV Unknown VB Unknown AU min Name Retention Time Area % Area Height Int Type Peak Type bb Unknown S31

32 bb Unknown (2'R,3'S,4'R,5'S)-1-methyl-4'-(4-nitrophenyl)-2-oxo-5'-(trifluoromethyl)spiro[indoline-3, 2'-pyrrolidine]-3'-carbaldehyde(3s) From 48.4 mg (0.2 mmol) ketimine 1a and 4-nitro cinnamaldehyde 41.2 mg (0.24 mmol, 1.2 equiv), 80.5 mg (96.0% yield) compound 3s was obtained as a pale brown solid, mp = C. [α] D = +14 (c = 1.0, CHCl 3). Dr (>20:1) determined by 1 H and 19 F NMR analysis. >99% ee was determined by HPLC analysis (Daicel Chiralcel OD-H column, hexane/2 propanol 80:20, 1.0 ml/min). Retention time: t major = 37.6 min. 1 H NMR (300 MHz, CDCl 3) δ 9.09 (s, 1H), 8.21 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 8.7 Hz, 2H), 7.38 (t, J = 7.7 Hz, 1H), 7.28 (d, J = 7.0 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), (m, 1H), 4.33 (t, J = 9.7 Hz, 1H), 3.59 (d, J = 9.7 Hz, 1H), 3.29 (s, 3H), 2.73 (d, J = 6.1 Hz, 1H). 13 C NMR (75 MHz, CDCl3) δ195.8, 178.8, 147.4, 145.6, 143.0, 130.5, 129.5, (q, J CF = 257.3Hz), 126.8, 125.6, 124.2, 124.0, 109.1, 67.4, 65.4, 64.8 (q, J CF = 29.8Hz), 44.4, F NMR (282 MHz, CDCl 3) δ HRMS (ESI) m/z calcd for C 20H 17F 3N 3O 4 [M+H] + : , found AU min Name Retention Time Area % Area Height Int Type Peak Type bv Unknown vb Unknown S32

33 AU min Name Retention Time Area % Area Height Int Type Peak Type bb Unknown (2'R,3'S,4'S,5'S)-1,4'-dimethyl-2-oxo-5'-(trifluoromethyl)spiro[indoline-3,2'-pyrrolidine] -3'-carbaldehyde(3t) From 48.4 mg (0.2 mmol) ketimine 1a and crotonaldehyde 19.8 μl (0.24 mmol, equiv), 48.7 mg (78% yield) compound 3t was obtained as colorless oil. [α] D = +49 (c = 1.0, CHCl 3). Dr (>20:1) determined by 1 H and 19 F NMR analysis. 97% ee was determined by HPLC analysis (Daicel Chiralcel IA column, hexane/2 propanol 95:5, 1.0 ml/min). Retention time: t major = 18.0 and t minor = 16.3 min. 1 H NMR (300 MHz, CDCl 3) δ 9.09 (s, 1H), (m, 2H), 7.10 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 7.7 Hz, 1H), (m, 1H), 3.24 (s, 3H), (m, 2H), 2.67 (d, J = 6.5 Hz, 1H), 1.33 (d, J = 5.8 Hz, 3H). 13 C NMR (75 MHz, CDCl3) δ197.3, 178.2, 142.6, 129.8, 129.0, 125.0, 123.7, (q, J CF = Hz), 108.7, 68.0, 65.7, 65.1(q, J CF = 28.7 Hz), 35.0, 35.0, 26.7, F NMR (282 MHz, CDCl 3) δ -72.2, HRMS (ESI) m/z calcd for C 15H 16F 3N 2O 2 [M+H] + : , found AU min S33

34 Name Retention Time Area % Area Height Int Type Peak Type bv Unknown vb Unknown 0.20 AU min Name Retention Time Area % Area Height Int Type Peak Type bb Unknown bb Unknown (2'R,3'S,4'S,5'S)-1-methyl-2-oxo-4'-propyl-5'-(trifluoromethyl)spiro[indoline-3,2'-pyrrol idine]-3'-carbaldehyde(3u) From 48.4 mg (0.2 mmol) ketimine 1a and trans-2-hexenal 27.8 μl (0.24 mmol, 1.2 equiv), mg (88.0% yield) compound 3u was obtained as a amorphous solid. [α] D = +68 (c = 1.0, CHCl 3). Dr (>20:1) determined by 1 H and 19 F NMR analysis. >99% ee was determined by HPLC analysis (Daicel Chiralcel IA column, hexane/2 propanol 80:20, 1.0 ml/min). Retention time: t major = 6.4 and t minor = 7.6 min. 1 H NMR (300 MHz, CDCl 3) δ 9.28 (d, J = 2.8 Hz, 1H), (m, 2H), 7.09 (t, J = 7.6 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 4.13 (q, J = 6.8 Hz, 1H), 3.20 (s, 3H), (m, 2H), 2.55 (d, J = 6.4 Hz, 1H), (m, 1H), (m, 1H), (m, 2H), 0.92 (t, J = 7.2 Hz, 3H). 13 C NMR (75 MHz, CDCl 3) δ198.3, 178.7, 143.0, 130.0, 127.5, (q, J CF = Hz), 125.6, 123.4, 108.7, 68.7, 63.9 (q, J CF = 29.3 Hz), 63.0, 39.5, 34.8, 26.5, 20.6, F NMR (282 MHz, CDCl 3) δ -75.1, HRMS (ESI) m/z calcd for C 17H 20F 3N 2O 2 [M+H] + : , found S34

35 1.00 AU min Name Retention Time Area % Area Height Int Type Peak Type Vv Unknown vb Unknown AU min Name Retention Time Area % Area Height Int Type Peak Type VV Unknown BB Unknown S35

36 F. Crystal Structure of 1g S36

37 G. Crystal Structure of 3k S37

38 ppm S38

39 S ppm

40 ppm S

41 ppm ppm S41

42 ppm S42

43 ppm S43

44 ppm S44

45 S ppm

46 ppm S46

47 ppm ppm S47

48 72.12 S ppm

49 ppm S

50 ppm S50