Supplementary information Construction of bispirooxindoles containing three quaternary stereocenters in a cascade using a single multifunctional organocatalyst Bin Tan 1, Nuno R. Candeias 1,2 & Carlos F. Barbas, III 1 * 1 The Skaggs Institute for Chemical Biology and Departments of Chemistry and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037. 2 Faculdade de Farmácia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa. Fax: 858-784-2583; E-mail: carlos@scripps.edu Table of Contents General information...2 General procedure for preparation of 3-substituted oxindole (1a-h and 4)...3 General procedure for preparation of arylidenoxindoles (2a-h)....8 Typical Procedure for the construction of bispirocyclic oxindoles......12 Typical Procedure for the construction of bispirocyclic oxindoles with different esters 22 Changing protecting group.......27 Synthesis of the other enantiomer............28 Experimental procedure for the deprotection of product 3b. 29 Experimental procedure for synthesis of catalyst VIII.........30 Experimental procedure for synthesis of catalyst XI.........31 Proposed activation mode of catalyst and substrates...........32 Control experiment for the mechanism studies..........32 X-ray structures of 3e and 3p............34 NMR Spectra.......37 HPLC Chromatograms.......8-78 1 nature chemistry www.nature.com/naturechemistry 1
General information Analytical thin layer chromatography (TLC) was performed using Merck 60 F254 precoated silica gel plate (0.2 mm thickness) with QF 254 indicator. Further visualization was possible by staining with basic solution of potassium permanganate or acidic solution of ceric molybdate. Column chromatography was performed using EM Science 230-400-mesh silica gel. Columns were typically packed as slurry in hexane prior to use. Proton nuclear magnetic resonance spectra ( 1 H NMR) were recorded on Bruker AMX 500 spectrophotometer (CDCl 3 as solvent). Chemical shifts for 1 H NMR spectra are reported as δ in units of parts per million (ppm) downfield from SiMe 4 (δ 0.0) and relative to the signal of chloroform (δ 7.26, singlet). Multiplicities were given as: s (singlet), d (doublet), t (triplet), q (quartet), dd (double of doublet) or m (multiplets). The number of protons (n) for a given resonance is indicated by nh. Coupling constants are reported as a J value in Hertz. Carbon nuclear magnetic resonance spectra ( 13 C NMR) are reported as δ in units of parts per million (ppm) downfield from SiMe 4 (δ 0.0) and relative to the signal of chloroform (δ 77.16, triplet). Enantioselectivities were determined by high performance liquid chromatography (HPLC) on Hatachi detectors ( = 254 nm) employing a Daicel Chiralpak AD-H. Absolute configuration of the products was determined by X-ray. High resolution mass spectrometry (HRMS) was performed by the Scripps Research Institute Mass Spectrometer Center. Racemic compounds were obtained by using 50 mol% DABCO as catalyst. 2 nature chemistry www.nature.com/naturechemistry 2
General procedure for preparation of arylideneoxindoles (1a-h and 4) 1. Jensen, T. & Madsen, R. J. Org. Chem. 2009, 74, 3990-3992. 2. Beccalli, E. M. & Marchesini, A. Tetrahedron, 1993, 49, 4741-4758. Method A: To a red suspension of benzyl protected intermediates (2.0 mmol) in MeOH (10 ml) was added 10% palladium on carbon catalyst (0.2 mmol). The insoluble mixture was stirred with a hydrogen balloon at room temperature for about 1 hour. After the red color disappeared, the mixture was diluted with DCM (20 ml), filtrated with celite and evaporated to give a residue, which was purified by column chromatography on silica gel to afford the desired product as a white solid. (Compound 1a, 1c, 1d, 1e, 1g) Method B: To a red suspension of benzyl protected intermediates (2.0 mmol) in CH 3 CN (10 ml) was added indium chloride (0.2 mmol) and sodium borohydride (4.0 mmol). After around 1 hour the color changed from red to pale yellow. The mixture was diluted with H 2 O (20 ml), extracted with ethyl acetate (1 x 20 ml) and DCM (1 x 20 ml), dried over Na 2 SO 4, filtered and evaporated to give a residue, which was purified by column chromatography on silica gel to afford the desired product as a white solid. (Compound 1b, 1f, 1h and 4) 1-Benzyl-3-(2-oxo-2-phenylethyl)indolin-2-one (1a) 1 H-NMR (500MHz, CDCl 3 ): 8.01-7.99 (m, 2H), 7.59-7.57 (m, 1H), 7.49-7.46 (m, 2H), 7.37-7.24 (m, 7H), 7.14 (t, J = 7.5 Hz, 1H), 6.74 (d, J = 8.0 Hz, 3 nature chemistry www.nature.com/naturechemistry 3
1H), 4.98 (s, 2H), 4.18 (dd, J = 9.0, 3.0 Hz, 1H), 3.90 (dd, J = 18.0, 3.0 Hz, 1H), 3.41 (dd, J = 18.5, 9.0 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): 196.80, 177.77, 143.40, 136.32, 135.88, 133.45, 129.04, 128.76, 128.71, 128.68, 128.15, 127.96, 127.57, 124.38, 122.50, 109.03, 43.94, 41.20, 40.05. HRMS (ESI) calcd for [M+H] C 23 H 20 NO 2, m/z: 342.1488, observed: 342.1491. 1-Benzyl-3-(2-(4-fluorophenyl)-2-oxoethyl)indolin-2-one (1b) 1 H-NMR (500MHz, CDCl 3 ): 8.04-8.01 (m, 2H), 7.37-7.23 (m, 6H), 7.17-7.13 (m, 3H), 6.96 (t, J = 7.5 Hz, 1H), 6.75 (d, J = 7.5 Hz, 1H), 4.97 (s, 2H), 4.16 (dd, J = 8.5, 3.0 Hz, 1H), 3.87 (dd, J = 18.0, 3.0 Hz, 1H), 3.45 (dd, J = 19.0, 9.0 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): 195.63, 178.10, 143.85, 136.27, 133.22, 133.20, 131.29, 131.22, 129.33, 129.20, 128.46, 128.03, 127.33, 124.75, 122.95, 116.34, 116.17, 109.51, 44.39, 41.62, 40.35. HRMS (ESI) calcd for [M+H] C 23 H 19 FNO 2, m/z: 360.1394, observed: 360.1402. 1-Benzyl-3-(2-(3-methoxyphenyl)-2-oxoethyl)indolin-2-one (1c) 1 H-NMR (500MHz, CDCl 3 ): 7.58 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.39-7.32 (m, 5H), 7.29-7.24 (m, 2H), 7.17-7.12 (m, 2H), 6.97-6.94 (m, 1H), 6.74 (d, J = 8.0 Hz, 1H), 5.00 (d, J = 16.0 Hz, 1H), 4.96 (d, J = 15.5 Hz, 1H), 4.16 (d, J = 16.0 Hz, 1H), 3.90-3.85 (m, 1H), 3.85 (s, 4 nature chemistry www.nature.com/naturechemistry 4
3H), 3.48 (dd, J = 18.0, 9.0 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): 197.09, 178.20, 160.31, 143.85, 138.10, 136.31, 130.11, 129.44, 129.20, 128.41, 128.01, 127.73, 124.77, 122.94, 121.26, 120.55, 112.65, 109.47, 55.89, 44.39, 41.68, 40.55. HRMS (ESI) calcd for [M+H] C 24 H 22 NO 3, m/z: 372.1594, observed: 372.1598. 1-Benzyl-3-(2-(furan-2-yl)-2-oxoethyl)indolin-2-one (1d) 1 H-NMR (500MHz, CDCl 3 ): 7.58 (d, J = 0.5 Hz, 1H), 7.36-7.23 (m, 7H), 7.16-7.13 (m, 1H), 6.95 (t, J = 7.5 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.54 (dd, J = 3.5, 1.5 Hz, 1H), 4.96 (s, 2H), 4.14 (dd, J = 9.0, 3.0 Hz, 1H), 3.75 (dd, J = 18.0, 3.5 Hz, 1H), 3.34 (dd, J = 18.0, 9.0 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): 186.41, 177.89, 152.70, 147.06, 143.82, 136.30, 129.20, 129.15, 128.47, 128.00, 127.72, 124.81, 122.95, 117.92, 112.83, 109.49, 44.36, 41.29, 39.97. HRMS (ESI) calcd for [M+H] C 21 H 18 NO 3, m/z: 332.1281, observed: 332.1284. 1-Benzyl-3-(2-oxo-2-(thiophen-2-yl)ethyl)indolin-2-one (1e) 1 H-NMR (500MHz, CDCl 3 ): 7.76 (d, J = 8.5 Hz, 1H), 7.67 (d, J = 9.5 Hz, 1H), 7.35-7.26 (m, 7H), 7.17-7.13 (m, 1H), 6.96 (t, J = 7.5 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 5.00 (d, J = 15.5 Hz, 1H), 4.94 (d, J = 15.5 Hz, 1H), 4.16 (dd, J = 9.0, 2.5 Hz, 1H), 3.84 (dd, J = 17.5, 3.0 Hz, 1H), 3.40 (dd, J = 17.5, 9.0 Hz, 1H). 5 nature chemistry www.nature.com/naturechemistry 5
13 C-NMR (125 MHz, CDCl 3 ): 190.13, 177.89, 143.82, 143.79, 136.27, 134.42, 132.74, 129.20, 128.63, 128.48, 128.01, 127.73, 124.91, 122.98, 109.48, 100.00, 44.40, 41.67, 40.84. HRMS (ESI) calcd for [M+H] C 21 H 18 NO 2 S, m/z: 348.1053, observed: 348.1050. 1-Benzyl-5-bromo-3-(2-oxo-2-phenylethyl)indolin-2-one (1f) 1 H-NMR (500MHz, CDCl 3 ): 8.00 (dd, J = 8.5, 1.0 Hz, 2H), 7.60-7.57 (m, 1H), 7.49-7.46 (m, 2H), 7.35-7.26 (m, 5H), 6.90-6.89 (m, 1H), 6.68-6.61 (m, 2H), 4.96 (s, 2H), 4.16-4.14 (m, 1H), 3.91-3.87 (m, 1H), 3.69 (s, 3H), 3.49-3.44 (m, 1H). 13 C-NMR (125 MHz, CDCl 3 ): 197.27, 177.86, 156.33, 137.31, 136.76, 136.38, 133.90, 130.84, 129.19, 129.12, 128.60, 127.98, 127.72, 112.71, 112.04, 109.76, 56.15, 44.46, 42.03, 40.56. HRMS (ESI) calcd for [M+H] C 24 H 22 NO 3, m/z: 372.1594, observed: 372.1593. 1-Benzyl-3-(2-oxopropyl)indolin-2-one (1h) To a red suspension of benzyl protected intermediate (2.0 mmol) in CH 3 CN (10 ml) was added indium chloride (0.2 mmol) and sodium borohydride (4.0 mmol). After around 30 minutes the color changed from red to pale yellow. The mixture was diluted with H 2 O (20 ml), extracted with ethyl acetate (1 x 20 ml) and DCM (1 x 20 ml), dried over Na 2 SO 4, filtered and evaporated to give a residue, which was purified by column chromatography on silica gel to afford the desired product 1h as a white solid with 55% yield. 6 nature chemistry www.nature.com/naturechemistry 6
1 H NMR (500 MHz, CDCl 3 ) 7.37-7.10 (m, 7H), 6.97 (dd, J = 10.9, 4.1 Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H), 5.03-4.86 (m, 2H), 3.94 (dd, J = 8.5, 3.3 Hz, 1H), 3.31 (dd, J = 18.3, 3.5 Hz, 1H), 2.91 (dd, J = 18.3, 8.6 Hz, 1H), 2.22 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) 205.16, 177.42, 143.32, 135.79, 128.79, 128.70, 127.94, 127.52, 127.22, 124.06, 122.45, 109.01, 44.36, 43.83, 41.01, 29.89. HRMS (ESI) calcd for [M+H] C18H17NO2, m/z: 280.1332, observed: 280.1343. 1-(4-Bromobenzyl)-3-(2-oxo-2-phenylethyl)indolin-2-one (4) To a red suspension of 4-Br-benzyl protected intermediate (2.0 mmol) in CH 3 CN (10 ml) was added indium chloride (0.2 mmol) and sodium borohydride (4.0 mmol). After around 1 hour the color changed from red to pale yellow. The mixture was diluted with H 2 O (20 ml), extracted with ethyl acetate (1 x 20 ml) and DCM (1 x 20 ml), dried over Na 2 SO 4, filtered and evaporated to give a residue, which was purified by column chromatography on silica gel to afford the desired product 4 as a white solid with 65% yield. 1 H NMR (500 MHz, CDCl 3 ) 8.10-.88 (m, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.49-7.46 (m, 4H), 7.27-7.24 (t, J = 8.5 Hz, 3H), 7.16 (t, J = 7.7 Hz, 1H), 6.97 (t, J = 7.5 Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H), 4.93 (q, J = 15.8 Hz, 2H), 4.13 (dd, J = 8.3, 2.7 Hz, 1H), 3.89 (dd, J = 18.2, 3.1 Hz, 1H), 3.52 (dd, J = 18.2, 8.5 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ) 196.60, 177.73, 143.14, 136.27, 134.96, 133.47, 131.89, 129.07, 128.93, 128.68, 128.13, 127.98, 124.30, 122.64, 121.51, 108.83, 43.35, 41.20, 39.79. HRMS (ESI) calcd for [M+H] C23H19BrNO2, m/z: 420.0594, observed: 420.0610. 7 nature chemistry www.nature.com/naturechemistry 7
General procedure for preparation of arylidenoxindoles (2a-h) 3. Amit, N. & Rahul, J. Indian J. Chem. 2008, 47B, 117-128. Wittig reagent (2 mmol, 1 equiv) was added to a solution of the acetyl isatin or acetyl substituted isatin (2.4 mmol, 1.2 equiv) in CHCl 3 or DCM (5 ml) in a 25 ml round bottom flask. The solution was stirred at rt for 30 min. The mixture was purified by flash chromatography to afford the desired products around 60% yields. (E)-Methyl 2-(1-acetyl-2-oxoindolin-3-ylidene)acetate (2a) 1 H-NMR (500MHz, CDCl 3 ): 8.68 (d, J = 8.0 Hz, 1H), 8.29 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 7.5, 1H), 7.26-7.23 (m, 1H), 6.94 (s, 1H), 3.91 (s, 3H), 2.71 (s, 3H). 13 C-NMR (125 MHz, CDCl 3 ): 170.27, 167.85, 165.58, 142.15, 136.50, 132.98, 128.14, 125.36, 122.80, 120.33, 116.42, 52.33, 26.82. HRMS (ESI) calcd for [M+H] C 13 H 12 NO 4, m/z: 246.0761, observed: 246.0767. (E)-1-Acetyl-3-(2-oxo-2-phenylethylidene)indolin-2-one (2b) 8 nature chemistry www.nature.com/naturechemistry 8
1 H-NMR (500MHz, CDCl 3 ): 8.31 (t, J = 8.0 Hz, 2H), 8.29 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 2.0 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.56-7.53 (m, 2H), 7.45-7.42 (m, 1H), 7.20-7.17 (m, 1H), 2.76 (s, 3H). 13 C-NMR (125 MHz, CDCl 3 ): 190.92, 170.33, 168.26, 142.02, 137.20, 134.69, 134.10, 132.93, 128.99, 128.79, 127.72, 126.79, 125.28, 126.60, 116.54, 26.84. HRMS (ESI) calcd for [M+H] C 18 H 14 NO 3, m/z: 292.0968, observed:292.0977. (E)-1-Acetyl-3-(2-(4-chlorophenyl)-2-oxoethylidene)indolin-2-one (2c) 1 H-NMR (500MHz, CDCl 3 ): 8.34 (d, J = 8.0 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H), 8.03-8.02 (m, 2H), 7.81 (s, 1H), 7.51-7.50 (m, 2H), 7.47-7.43 (m, 1H), 7.21-7.18 (m, 1H), 2.75 (s, 3H). 13 C-NMR (125 MHz, CDCl 3 ): 189.97, 170.71, 168.64, 142.61, 141.13, 136.05, 135.68, 133.66, 130.58, 129.77, 127.39, 127.13, 125/76, 120.94, 117.02, 27.23. HRMS (ESI) calcd for [M+H] C 18 H 13 ClNO 3, m/z 326.0578, observed: 326.0573. (E)-1-Acetyl-5-bromo-3-(2-oxo-2-phenylethylidene)indolin-2-one (2d) 1 H-NMR (500MHz, CDCl 3 ): 8.56 (s, 1H), 8.20 (d, J = 8.5 Hz, 1H), 8.09 (d, J = 8.0 Hz, 2H), 7.93 (s, 1H), 7.68-7.65 (m, 1H), 7.57-7.54 (m, 3H), 2.75 (s, 3H). 13 C-NMR (125 MHz, CDCl 3 ): 190.76, 170.45, 168.02, 141.34, 137.57, 136.02, 134.71. 130.10, 129.48, 129.28, 129.26, 122.73, 178.90, 118.43, 27.19. 9 nature chemistry www.nature.com/naturechemistry 9
HRMS (ESI) calcd for [M+H] C 18 H 13 BrNO 3, m/z: 370.0073, observed: 370.0057. (E)-1-Acetyl-5-fluoro-3-(2-oxo-2-phenylethylidene)indolin-2-one (2e) 1 H-NMR (500MHz, CDCl 3 ): 8.33-8.30 (m, 1H), 8.15 (dd, J = 9.0, 3.0 Hz, 1H), 8.10-8.08 (m, 2H), 7.95 (s, 1H), 7.68-7.65(m, 1H), 7.57-7.54 (m, 2H), 7.18-7.13 (m, 1H), 2.76 (s, 3H). 13 C-NMR (125 MHz, CDCl 3 ): 190.46, 170.11, 167.95, 160.70, 158.76, 138.27, 137.10, 134.39, 134.31, 129.07, 128.83, 128.80, 121.93, 119.59, 119.41, 117.87, 117.81, 114.08, 113.87, 26.73. HRMS (ESI) calcd for [M+H] C 18 H 13 FNO 3, m/z: 310.0874, observed: 310.0864. (E)-Methyl 2-(1-acetyl-6-chloro-2-oxoindolin-3-ylidene)acetate (2f) 1 H-NMR (500MHz, CDCl 3 ): 8.64 (d, J = 8.5 Hz, 1H), 8.32 (s, 1H), 7.20-7.18 (m, 1H), 6.88 (s, 1H), 2.70 (s, 3H). 13 C-NMR (125 MHz, CDCl 3 ): 170.05, 167.45, 165.43, 142.72, 138.91, 135.56, 129.11, 125.51, 123.09, 118.71, 116.96, 52.41, 26.68. HRMS (ESI) calcd for [M+H] C 13 H 11 ClNO 4, m/z: 280.0371, observed: 280.0378. (E)-Ethyl 2-(1-acetyl-2-oxoindolin-3-ylidene)acetate (2g) 10 nature chemistry www.nature.com/naturechemistry 10
1 H-NMR (500MHz, CDCl 3 ): 8.68 (d, J = 8.0 Hz, 1H), 8.29 (dd, J = 8.0, 0.5 Hz, 1H), 7.46-7.43 (m, 1H), 7.26-7.22 (m, 1H), 6.91 (s, 1H), 4.34 (q, J = 7.0 Hz, 2H), 2.72 (s, 3H), 1.39 (t, J = 7.0, 3H). 13 C-NMR (125 MHz, CDCl 3 ): 170.28, 167.89, 165.14, 142.08, 136.20, 132.85, 128.12, 125.31, 123.43, 120.38, 116.38, 61.43, 26.81, 14.13. HRMS (ESI) calcd for [M+H] C 14 H 14 NO 4, m/z: 260.0917, observed: 260.0926. (E)-1-acetyl-3-(2-oxo-2-(o-tolyl)ethylidene)indolin-2-one (2h) 1 H NMR (500 MHz, CDCl 3 ) 8.30 (dd, J = 11.9, 7.9 Hz, 2H), 7.77 (d, J = 7.7 Hz, 1H), 7.68 (s, 1H), 7.54-7.42 (m, 2H), 7.32 (m, 2H), 7.19 (t, J = 7.7 Hz, 1H), 2.75 (s, 3H), 2.65 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) 194.05, 170.36, 168.35, 141.95, 139.32, 137.03, 133.79, 132.82, 132.63, 132.29, 130.57, 130.12, 126.60, 126.03, 125.28, 120.64, 116.56, 26.81, 21.37. HRMS (ESI) calcd for [M+H] C 19 H 16 NO 3, m/z: 306.1125, observed: 306.1135. 11 nature chemistry www.nature.com/naturechemistry 11
Typical Procedure for the construction of bispirocyclic oxindoles via organocatalytic domino Michael-aldol reactions (Table 2): The multifunctional catalyst VIII (0.0075 mmol, 0.15 equiv) was added to a solution of 3- substituted oxindole 1 (0.05 mmol, 1.0 equiv) and methyleneindolinone 2 (0.075 mmol, 1.5 equiv) in DCM (0.2-0.4 ml) at room temperature (23 C). After 24 hours, the product was afforded by silica gel flash column chromatography using gradient elution (EtOAc/Hexane = 1:10 to 1:8). Product 3b (Table 2, entry 1) 1 H-NMR (500 MHz, CDCl 3 ) 8.07 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 7.5 Hz, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.37-7.23 (m, 8H), 7.19-7.09 (m, 5H), 7.04-6.95 (m, 7H), 6.36 (d, J = 8.0 Hz, 1H), 5.32 (s, 1H), 5.22 (d, J = 15.5 Hz, 1H), 4.37 (d, J = 15.5 Hz, 1H), 4.32 (d, J = 14.0 Hz, 1H), 2.59 (d, J = 14.0 Hz, 1H), 2.48 (s, 3H). 13 C-NMR (125 MHz, CDCl 3 ) 196.55, 184.10, 178.53, 171.03, 142.13, 141.37, 137.59, 135.20, 132.98, 130.50, 129.49, 129.44, 128.99, 128.60, 128.56, 128.32, 128.22, 127.97, 127.48, 126.68, 126.32, 126.05, 125.68, 124.88, 124.62, 116.31, 109.18, 85.33, 67.71, 66.32, 54.62, 46.97, 45.06, 26.87. HPLC: Chiralpak AD-H (hexane/i-proh = 90/10, flow rate 2 ml/min, = 254 nm), t R (minor) = 9.6 min, t R (major) = 18.8 min; 97:3 er. 12 nature chemistry www.nature.com/naturechemistry 12
[ ] D 25 = +96.9 (c = 0.9, CH 2 Cl 2 ). IR (CH 2 Cl 2 ) 3329.6, 3027.0, 2969.3, 2361.3, 1744.3, 1716.1, 181.8, 1610.8, 1466.5, 1371.5, 1279.1, 1207.6, 1016.5, 760.0, 695.6 cm -1. HRMS (ESI) calcd for [M+H] C 41 H 33 N 2 O 5, m/z: 633.2384, observed: 633.2378. Product 3c (Table 2, entry 2) 1 H-NMR (500 MHz, CDCl 3 ) 8.06 (dd, J = 9.0, 5.0 Hz, 1H), 7.99 (d, J = 7.5 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.37-7.31 (m, 5H), 7.26-7.23 (m, 1H), 7.20-7.17 (m, 1H), 7.14-7.11 (m, 4H), 7.07-7.00 (m, 5H), 6.99-6.94 (m, 3H), 6.37 (d, J = 7.5 Hz, 1H), 5.24 (s, 1H), 5.20 (d, J = 15.0 Hz, 1H), 4.38 (d, J = 15.5 Hz, 1H), 4.30 (d, J = 14.0 Hz, 1H), 2.58 (d, J = 14.5 Hz, 1H), 2.47 (s, 3H). 13 C-NMR (125 MHz, CDCl 3 ) 196.47, 183.98, 178.14, 170.78, 161.11, 159.18, 142.14, 137.34, 137.26, 136.77, 135.14, 133.11, 130.30, 129.46, 129.08, 128.72, 128.60, 128.45, 128.36, 128.28, 128.04, 127.47, 126.63, 126.03, 124.64, 117.61, 117.54, 116.02, 115.85, 113.39, 113.19, 109.24, 85.39, 67.86, 66.55, 54.63, 46.90, 45.11, 26.77. HPLC: Chiralpak AD-H (hexane/i-proh = 90/10, flow rate 2 ml/min, = 254 nm), t R (minor) = 3.8 min, t R (major) = 11.3 min; 98:2 er. [ ] D 25 = +166.6 (c = 0.8, CH 2 Cl 2 ). IR (CH 2 Cl 2 ) 3270.9, 2968.8, 2231.0, 1741.5, 1717.2, 1685.5, 1466.0, 1371.4, 1215.0, 760.2, 698.9 cm -1. HRMS (ESI) calcd for [M+H] C 41 H 32 FN 2 O 5, m/z: 651.2294, observed: 651.2280. 13 nature chemistry www.nature.com/naturechemistry 13
Product 3d (Table 2, entry 3) 1 H-NMR (500 MHz, CDCl 3 ) 8.08 (d, J = 2.0 Hz, 1H), 7.97-7.95 (m, 2H), 7.46-7.44 (dd, J = 9.0, 2.0 Hz, 1H), 7.38-7.32 (m, 5H), 7.24-7.17 (m, 2H), 7.15-7.11 (m, 4H), 7.07-6.93 (m, 7H), 6.87 (d, J = 7.5 Hz, 1H), 5.24 (s, 1H), 5.20 (d, J = 15.0 Hz, 1H), 4.40 (d, J = 15.0 Hz, 1H), 4.29 (d, J = 14.5 Hz, 1H), 2.58 (d, J = 14.0 Hz, 1H), 2.47 (s, 3H). 13 C-NMR (125 MHz, CDCl 3 ) 196.48, 183.96, 177.81, 170.84, 142.14, 140.26, 137.30, 136.71, 135.13, 133.14, 132.43, 130.30, 129.48, 129.10, 128.75, 128.68, 128.63, 128.36, 128.32, 128.07, 127.51, 126.57, 126.03, 124.64, 117.91, 117.87 109.26, 85.35, 67.77, 66.56, 54.2, 46.87, 45.14, 26.81. HPLC: Chiralpak AD-H (hexane/i-proh = 90/10, flow rate: 2 ml/min, = 254 nm), t R (minor) = 7.1 min, t R (major) = 25.0 min; 98:2 er. [ ] 25 D = +204.2 (c = 1.0, CH 2 Cl 2 ). IR (CH 2 Cl 2 ) 3290.9, 2925.2, 2361.0, 1749.9, 1713.4, 1682.5, 1611.1, 1468.4, 1371.6, 1297.4, 753.5, 696.9 cm -1. HRMS (ESI) calcd for [M+H] C 41 H 32 BrN 2 O 5, m/z: 711.1489, observed: 711.1475. Product 3e (Table 2, entry 4) 1 H-NMR (500 MHz, CDCl 3 ) 8.06 (d, J = 8.0 Hz, 1H), 7.99-7.97 (m,1h), 7.94 (d, J = 7.5 Hz, 1H), 7.42-7.32 (m, 14 nature chemistry www.nature.com/naturechemistry 14
6H), 7.29-7.25 (m, 1H), 7.19-7.15 (m, 1H), 7.12-7.09 (m, 1H), 7.05-6.99 (m, 6H), 6.92 (s, 1H), 6.80-6.78 (m, 2H), 6.52-6.50 (m, 2H), 5.33 (s, 1H), 5.07 (d, J = 15.0 Hz, 1H), 4.59 (d, J = 15.0 Hz, 1H), 4.30 (d, J = 14.0 Hz, 1H), 2.58 (d, J = 14.0 Hz, 1H), 2.46 (s, 3H). 13 C-NMR (125 MHz, CDCl 3 ) 195.39, 183.95, 178.43, 170.98, 142.12, 139.39, 137.48, 130.41, 135.21, 135.11, 130.41, 129.58, 129.20, 128.74, 128.63, 128.60, 127.98, 126.73, 126.15, 126.02, 125.66, 124.90, 116.32, 109.23, 85.28, 67.76, 66.08, 54.56, 47.13, 45.27, 26.85. HPLC: Chiralpak AD-H (hexane/i-proh = 90/10, flow rate: 2 ml/min, = 254 nm), t R (minor) = 5.2 min, t R (major) = 11.4 min; 97:3 er. [ ] D 25 = +168.0 (c = 0.5, CH 2 Cl 2 ). IR (CH 2 Cl 2 ) 3322.7, 2919.8, 2235.1, 1747.8, 1680.0, 1610.7, 1481.1, 1296.1, 750.5 cm -1. HRMS (ESI) calcd for [M+H] C 41 H 32 ClN 2 O 5, m/z: 667.1994, observed: 667.1976. Product 3f (Table 2, entry 5) 1 H-NMR (500 MHz, CDCl 3 ) 8.10 (d, J = 7.5 Hz, 1H), 7.98-7.94 (m, 2H), 7.37-7.23 (m, 8H), 7.13-7.11 (m, 2H), 7.04-6.94 (m, 7H), 6.81-6.78 (m, 2H), 6.36 (d, J = 7.5 Hz, 1H), 5.30 (s, 1H), 5.21 (d, J = 15.0 Hz, 1H), 4.36 (d, J = 15.5 Hz, 1H), 4.28 (d, J = 14.0 Hz, 1H), 2.58 (d, J = 14.0 Hz, 1H), 2.53 (s, 3H). 13 C-NMR (125 MHz, CDCl 3 ) 196.44, 184.02, 178.53, 170.99, 163.83, 161.86, 142.12, 141.21, 136.87, 135.78, 133.04, 130.34, 129.63, 129.45, 129.05, 128.59, 128.34, 128.21, 128.09, 128.02, 15 nature chemistry www.nature.com/naturechemistry 15
127.48, 126.64, 126.06, 125.73, 124.95, 124.65, 116.38, 114.87, 114.71, 109.32, 100.00, 84.88, 67.64, 66.45, 54.57, 47.13, 45.07, 26.99. HPLC: Chiralpak AD-H (hexane/i-proh = 90/10, flow rate: 2 ml/min, = 254 nm), t R (minor) = 6.1 min, t R (major) = 12.8 min; 95:5 er. [ ] D 25 = +144.0 (c = 0.4, CH 2 Cl 2 ). IR (CH 2 Cl 2 ) 3244.3, 2923.0, 2234.6, 1734.9, 1680.6, 1608.4, 1465.8, 1277.2, 1165.4, 760.5 cm - 1. HRMS (ESI) calcd for [M+H] C 41 H 32 FN 2 O 5, m/z: 651.2294, observed: 651.2310. Product 3g (Table 2, entry 6) 1 H-NMR (500 MHz, CDCl 3 ) 8.09 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.36-7.23 (m, 9H), 7.13-7.12 (m, 2H), 7.06-7.01 (m, 2H), 6.98-6.95 (m, 4H), 6.73-6.68 (m, 2H), 6.43 (s, 1H), 6.36 (d, J = 8.0 Hz, 1H), 5.31 (s, 1H), 5.22 (d, J = 15.5 Hz, 1H), 4.36 (d, J = 15.5 Hz, 1H), 4.28 (d, J = 14.5 Hz, 1H), 3.43 (S, 3H), 2.59 (d, J = 14.0 Hz, 1H), 2.49 (s, 3H). 13 C-NMR (125 MHz, CDCl 3 ) 196.53, 184.11, 178.37, 171.01, 159.38, 142.12, 141.45, 139.12, 136.97, 135.19, 132.98, 130.46, 129.44, 128.99, 128.71, 128.56, 128.32, 128.21, 127.90, 127.47, 126.71, 126.52, 125.66, 124.82, 124.62, 118.00, 116.33, 115.43, 111.05, 109.19, 85.24, 67.61, 66.21, 55.29, 54.60, 46.92, 45.06, 26.86. 16 nature chemistry www.nature.com/naturechemistry 16
HPLC: Chiralpak AD-H (hexane/i-proh = 90/10, flow rate 2 ml/min, = 254 nm), t R (minor) = 7.3 min, t R (major) = 13.6 min; 98:2 er. [ ] D 25 = +205.5 (c = 0.6, CH 2 Cl 2 ). IR (CH 2 Cl 2 ) 3298.9, 2934.8, 1746.8, 1682.9, 1605.4, 1465.8, 1179.9, 753.9 cm -1. HRMS (ESI) calcd for [M+H] C 42 H 35 N 2 O 6, m/z: 663.249, observed: 663.2505. Product 3h (Table 2, entry 7) 1 H-NMR (500 MHz, CDCl 3 ) 8.21 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 7.0 Hz, 1H), 7.88 (d, J = 7.0 Hz, 1H), 7.37-7.28 (m, 6H), 7.26-7.23 (m, 2H), 7.19-7.18 (m, 1H), 7.11-7.09 (m, 2H), 7.02-6.94 (m, 6H), 6.86 (s, 1H), 6.19-6.18 (m, 1H), 5.93 (d, J = 3.0 Hz, 1H), 5.23 (s, 1H), 5.19 (d, J = 15.5 Hz, 1H), 4.34 (d, J = 15.5 Hz, 1H), 4.08 (d, J = 14.5 Hz, 1H), 2.68 (s, 3H), 2.59 (d, J = 14.5 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ) 196.30, 183.97, 178.20, 171.35, 152.28, 142.38, 142.16, 141.27, 136.86, 135.12, 133.04, 129.97, 129.52, 129.45, 129.02, 128.57, 128.32, 128.19, 127.48, 126.78, 126.30, 125.78, 125.07, 124.63, 116.41, 110.79, 109.17, 107.52, 82.40, 66.46, 66.31, 54.86, 47.29, 45.06, 27.10. HPLC: Chiralpak AD-H (hexane/i-proh = 90/10, flow rate 2 ml/min, = 254 nm), t R (minor) = 19.3 min, t R (major) = 27.8 min; 97:3 er. [ ] D 25 = +156.7 (c = 0.6, CH 2 Cl 2 ). IR (CH 2 Cl 2 ) 3271.5, 2933.7, 2360.8, 1751.3, 1681.2, 1611.3, 1485.4, 1278.9, 1173.0, 1016.9, 754.9 cm -1. 17 nature chemistry www.nature.com/naturechemistry 17
HRMS (ESI) calcd for [M+H] C 39 H 31 N 2 O 6, m/z: 623.2177, observed: 623.2189. Product 3i (Table 2, entry 8) 1 H-NMR (500 MHz, CDCl 3 ) 8.13 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.92 (d, J = 7.5 Hz, 1H), 7.37-7.23 (m, 8H), 7.12-7.09 (m, 4H), 7.04-7.01 (m, 1H), 6.98-6.95 (m, 3H), 6.78-6.77 (m, 1H), 6.77 (s, 1H), 6.35 (d, J = 7.5 Hz, 1H), 5.27 (s, 1H), 5.20 (d, J = 15.0 Hz, 1H), 4.34 (d, J = 15.5 Hz, 1H), 4.18 (d, J = 14.0 Hz, 1H), 2.68 (d, J = 14.0 Hz, 1H), 2.62 (s, 3H). 13 C-NMR (125 MHz, CDCl 3 ) 196.36, 183.97, 178.44, 171.19, 142.15, 141.97, 141.61, 136.87, 135.12, 133.04, 130.05, 129.65, 129.44, 129.05, 128.58, 128.33, 128.19, 127.50, 126.73, 126.43, 126.19, 126.04, 125.84, 124.93, 124.64, 124.25, 116.31, 109.22, 84.39, 67.72, 66.39, 54.77, 48.72, 45.06, 27.07. HPLC: Chiralpak AD-H (hexane/i-proh = 90/10, flow rate 2 ml/min, = 254 nm), t R (minor) = 8.1 min, t R (major) = 16.6 min; 98:2 er. [ ] D 25 = +179.3 (c = 0.4, CH 2 Cl 2 ). IR (CH 2 Cl 2 ) 3305.1, 2922.9, 1746.0, 1714.1, 1680.7, 1610.9, 1466.5, 1371.4, 1230.3, 755.2 cm - 1. HRMS (ESI) calcd for [M+H] C 39 H 31 N 2 O 5 S, m/z: 639.1948, observed: 639.1941. Product 3j (Table 2, entry 9) 18 nature chemistry www.nature.com/naturechemistry 18
1 H-NMR (500 MHz, CDCl 3 ) 8.13 (d, J = 8.0 Hz, 1H), 7.96-7.95 (m, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.41-7.34 (m, 6H), 7.28-7.25 (m, 1H), 7.10-7.09 (m, 1H), 7.04-7.00 (m, 6H), 6.82-6.76 (m, 4H), 6.51-6.49 (m, 1H), 5.18 (s, 1H), 5.06 (d, J = 15.0 Hz, 1H), 4.57 (d, J = 15.0 Hz, 1H), 4.17 (d, J = 14.5 Hz, 1H), 2.68 (d, J = 14.5 Hz, 1H), 2.60 (s, 3H). 13 C-NMR (125 MHz, CDCl 3 ) 195.21, 183.82, 178.35, 171.15, 141.84, 141.57, 139.47, 135.10, 135.03, 129.96, 129.73, 129.59, 129.28, 128.76, 128.62, 128.60, 126.77, 126.49, 126.20, 126.04, 125.68, 124.96, 124.72, 124.26, 116.32, 109.27, 84.34, 67.77, 66.15, 54.70, 48.86, 45.26, 27.06. HPLC: Chiralpak AD-H (hexane/i-proh = 90/10, flow rate 2 ml/min, = 254 nm), t R (minor) = 6.5 min, t R (major) = 14.6 min; 98:2 er. [ ] D 25 = +187.2 (c = 1.1, CH 2 Cl 2 ). IR (CH 2 Cl 2 ) 3286.9, 2920.6, 1710.8, 1680.2, 1611.6, 1482.9, 1166.8, 752.3 cm -1. HRMS (ESI) calcd for [M+H] C 39 H 30 ClN 2 O 5 S, m/z: 673.1558, observed: 673.1563. Product 3k (Table 2, entry 10) 1 H-NMR (500 MHz, CDCl 3 ) 8.12 (d, J = 9.0 Hz, 1H), 7.96 (J = 7.5 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.37-7.30 (m, 5H), 7.26-7.23 (m, 1H), 7.15 (s, 1H), 7.12-7.10 (m, 3H), 7.06-7.01 (m, 2H), 6.98-6.94 (m, 3H), 6.83-7.79 (m, 2H), 6.36 (d, J = 8.5 Hz, 1H), 5.19 (d, J = 19 nature chemistry www.nature.com/naturechemistry 19
15.5 Hz, 1H), 5.19 (s, 1H), 4.36 (d, J = 15.0 Hz, 1H), 4.17 (d, J = 14.5 Hz, 1H), 2.68 (d, J = 14.0 Hz, 1H), 2.61 (s, 3H). 13 C-NMR (125 MHz, CDCl 3 ) 196.30, 183.85, 178.07, 170.96, 161.10, 159.17, 142.16, 141.74, 137.56, 136.66, 135.06, 133.18, 129.85, 129.46, 129.14, 128.62, 128.38, 128.25, 127.96, 127.89, 127.49, 126.67, 126.55, 126.30, 124.66, 124.34, 117.59, 117.53, 116.17, 115.99, 113.80, 113.60, 109.27, 84.45, 67.86, 66.61, 54.76, 48.67, 45.11, 26.98. HPLC: Chiralpak AD-H (hexane/i-proh = 90/10, flow rate 2 ml/min, = 254 nm), t R (minor) = 4.6 min, t R (major) = 16.9 min; 98:2 er. [ ] D 25 = +183.2 (c = 1.0, CH 2 Cl 2 ). IR (CH 2 Cl 2 ) 3284.9, 2923.6, 1732.9, 1681.2, 1611.3, 1482.2, 1296.5, 1166.1, 751.9 cm -1. HRMS (ESI) calcd for [M+H] C 39 H 30 FN 2 O 5 S, m/z: 657.1854, observed: 657.1850. Product 3l (Table 2, entry 11) 1 H NMR (500 MHz, CDCl 3 ) 8.17 (dd, J = 7.5, 0.8 Hz, 1H), 8.07 (dd, J = 8.0, 0.7 Hz, 1H), 7.94 (dd, J = 7.5, 1.1 Hz, 1H), 7.40-7.21 (m, 7H), 7.21-6.96 (m, 9H), 6.90 (s, 1H), 6.87 (t, J = 7.3 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.32 (d, J = 7.4 Hz, 1H), 5.36 (s, 1H), 5.21 (d, J = 15.4 Hz, 1H), 4.25 (dd, J = 14.7, 10.4 Hz, 2H), 2.54 (d, J = 14.2 Hz, 1H), 2.45 (s, 3H), 1.92 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) 197.51, 183.75, 178.42, 170.46, 141.58, 140.87, 139.05, 137.18, 135.49, 134.77, 131.61, 131.39, 130.51, 128.97, 128.50, 128.16, 128.04, 127.59, 127.54, 127.51, 20 nature chemistry www.nature.com/naturechemistry 20
126.14, 125.87, 125.56, 125.12, 124.47, 124.38, 124.09, 115.89, 108.79, 84.65, 67.57, 66.94, 54.07, 46.62, 44.62, 26.38, 20.66. HPLC: Chiralpak AD-H (hexane/i-proh = 90/10, flow rate: 2 ml/min, = 254 nm), t R (minor) = 5.0 min, t R (major) = 6.7 min; 91:9 er. [ ] D 25 = +172.9 (c = 1.0, CH 2 Cl 2 ). IR (CH 2 Cl 2 ) 3313.9, 3057.5, 2927.5, 1744.6, 1708.9, 1678.8, 1609.9, 1465.1, 1371.0, 1277.3, 1171.6, 1016.0, 755.5, 697.2 cm -1. HRMS (ESI) calcd for [M+H] C 42 H 35 N 2 O 5, m/z: 647.2540, observed: 647.2558. Product 3m (Table 2, entry 12) 1 H NMR (500 MHz, CDCl 3 ) 8.30 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 7.5 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.43-7.15 (m, 9H), 7.07 (d, J = 8.2 Hz, 2H), 7.04-6.86 (m, 4H), 6.36-6.24 (m, 2H), 5.16 (m, 2H), 4.31 (d, J = 15.3 Hz, 1H), 3.48 (d, J = 14.2 Hz, 1H), 2.89 (s, 3H), 2.38 (d, J = 14.2 Hz, 1H), 1.12 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) 196.31, 183.72, 179.50, 171.25, 141.71, 140.84, 136.44, 134.81, 132.55, 129.87, 129.00, 128.93, 128.38, 128.09, 127.87, 127.72, 127.08, 126.17, 125.57, 124.70, 124.06, 115.98, 108.62, 83.07, 67.07, 65.39, 54.91, 49.69, 44.57, 27.12, 19.90. HPLC: Chiralpak AD-H (hexane/i-proh = 90/10, flow rate: 2 ml/min, = 254 nm), t R (major) = 17.2 min, t R (minor) = 26.7 min; 97:3 er. [ ] D 25 = +121.3 (c = 0.8, CH 2 Cl 2 ). IR (CH 2 Cl 2 ) 3326.9, 3028.4, 2969.2, 1745.3, 1711.5, 1684.2, 1611.1, 1348.2, 755.7 cm -1. HRMS (ESI) calcd for [M+H] C 36 H 31 N 2 O 5, m/z: 571.2227, observed: 571.2224. 21 nature chemistry www.nature.com/naturechemistry 21
Typical Procedure for the construction of bispirocyclic oxindoles with different esters (Figure 4): The multifunctional catalyst VIII (0.01 mmol, 0.2 equiv) was added to a solution of 3-substituted oxindole 1 (0.05 mmol, 1.0 equiv) and methyleneindolinone ester 2 (0.075 mmol, 1.5 equiv) in DCM (0.2-0.4 ml) at room temperature (23 C). After 24 hours, the product was afforded by silica gel flash column chromatography using gradient elution (EtOAc/Hexane = 1:10 to 1:8). Product 3a (Figure 4) 22 nature chemistry www.nature.com/naturechemistry 22
1 H-NMR (500 MHz, CDCl 3 ) 8.18 (d, J = 7.0 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 7.0 Hz, 1H), 7.38-7.29 (m, 7H), 7.25-7.22 (m, 1H), 7.19-7.16 (m, 2H), 7.11 (t, J = 8.0 Hz, 2H), 7.02 (d, J = 7.5 Hz, 2H), 6.92 (s, 1H), 6.79 (d, J = 7.5 Hz, 1H), 5.32 (d, J = 16.0 Hz, 1H), 4.84 (d, J = 15.5 Hz, 1H), 4.55 (s, 1H), 4.29 (d, J = 14.5 Hz, 1H), 2.92 (s, 3H), 2.58 (d, J = 14.0 Hz, 1H), 2.42 (s, 3H). 13 C-NMR (100 MHz, CDCl 3 ) 183.91, 177.90, 170.82, 169.01, 142.89, 141.18, 137.57, 135.34, 131.85, 129.61, 129.28, 129.12, 128.65, 128.36, 128.00, 127.43, 126.08, 125.92, 124.95, 124.57, 116.20, 109.84, 85.85, 67.87, 62.29, 54.70, 51.98, 26.06, 44.81, 26.75. HPLC: Chiralpak AD-H (hexane/i-proh = 90/10, flow rate 2 ml/min, = 254 nm), t R (minor) = 8.4 min, t R (major) = 18.0 min; 95:5 er. [ ] D 25 = +91.5 (c = 0.4, CH 2 Cl 2 ). IR (CH 2 Cl 2 ) 3285.1, 2913.9, 2359.1, 1707.6, 1684.8, 1611.0, 1466.7, 1276.8, 1171.5, 756.5 cm - 1. HRMS (ESI) calcd for [M+H] C 36 H 30 N 2 O 6, m/z: 587.2177, observed: 587.2159. Product 3n (Figure 4) 1 H-NMR (500 MHz, CDCl 3 ) 8.17 (d, J = 8.5 Hz, 1H), 8.06 (J = 8.0 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.37-7.28 (m, 6H), 7.26-7.23 (m, 1H), 7.22-7.20 (m, 1H), 7.17-7.14 (m, 1H), 7.06-7.03 (m, 1H), 6.93 (s, 1H), 6.77 (d, J = 7.5 Hz, 1H), 6.72-6.70 (m, 2H), 6.69 (s, 1H), 23 nature chemistry www.nature.com/naturechemistry 23
5.31 (d, J = 15.5 Hz, 1H), 4.82 (d, J = 15.0 Hz, 1H), 4.54 (s, 1H),4.24 (d, J = 14.0 Hz, 1H), 3.42 (s, 3H), 2.91 (s, 3H), 2.58 (d, J = 14.0 Hz, 1H), 2.42 (s, 3H). 13 C-NMR (125 MHz, CDCl 3 ) 183.91, 177.75, 170.89, 168.99, 159.39, 142.88, 141.36, 139.10, 135.34, 131.82, 129.55, 129.28, 128.13, 128.75, 128.36, 127.89, 127.42, 126.10, 125.95, 124.89, 124.58, 117.84, 116.22, 115.39, 111.00, 109.85, 85.76, 67.78, 62.16, 55.28, 54.67, 51.97, 45.99, 44.81, 26.73. HPLC: Chiralpak AD-H (hexane/i-proh = 90/10, flow rate 2 ml/min, = 254 nm), t R (minor) = 14.3min, t R (major) = 18.1 min; 95:5 er. [ ] D 25 = +73.3 (c = 0.7, CH 2 Cl 2 ). IR (CH 2 Cl 2 ) 3309.3, 3057.6, 2942.7, 2362.4, 1744.8, 1709.8, 1682.7, 1610.5, 1466.9, 1277.4, 1170.3, 755.5 cm -1. HRMS (ESI) calcd for [M+H] C 37 H 33 N 2 O 7, m/z: 617.2282, observed: 617.2289. Product 3o (Figure 4) 1 H-NMR (500 MHz, CDCl 3 ) 8.17 (d, J = 8.0 Hz, 1H), 8.10 (J = 7.5 Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.38-7.25 (m, 7H), 7.22-7.17 (m, 2H), 7.15-7.12 (m, 1H), 6.82 (s, 1H), 6.76 (d, J = 7.5 Hz, 1H), 6.18-6.17 (m, 1H), 5.92 (dd, J = 3.5, 1.0 Hz, 1H), 5.30 (d, J = 15.5 Hz, 1H), 4.81 (d, J = 16.0 Hz, 1H), 4.46 (s, 1H),4.06 (d, J = 14.0 Hz, 1H), 2.91 (s, 3H), 2.65 (d, J = 14.5 Hz, 1H), 2.62 (s, 3H). 13 C-NMR (125 MHz, CDCl 3 ) 183.81, 177.52, 171.13, 168.76, 152.26, 142.94, 142.35, 141.16, 135.29, 131.33, 129.62, 129.28, 129.15, 128.37, 127.41, 126.16, 126.05, 24 nature chemistry www.nature.com/naturechemistry 24
125.88, 125.10, 124.58, 116.29, 110.85, 109.81, 107.60, 82.93, 66.43, 62.40, 54.95, 51.98, 46.45, 44.82, 26.96. HPLC: Chiralpak AD-H (hexane/i-proh = 90/10, flow rate 2 ml/min, = 254 nm), t R (minor) = 18.9 min, t R (major) = 32.9 min; 96:4 er. [ ] D 25 = +91.2 (c = 1.0, CH 2 Cl 2 ). IR (CH 2 Cl 2 ) 3300.1, 3057.6, 2919.8, 1706.5, 1678.3, 1569.5, 1466.7, 1359.0, 752.0 cm -1. HRMS (ESI) calcd for [M+H] C 34 H 29 N 2 O 7, m/z: 577.1969, observed: 577.1952. Product 3p (Figure 4) 1 H-NMR (500 MHz, CDCl 3 ) 8.13 (d, J = 7.5 Hz, 1H), 8.10 (J = 2.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.35-7.12 (m, 11H), 7.05-7.03 (m, 2H), 6.94 (s, 1H), 6.78 (d, J = 7.5 Hz, 1H), 5.30 (d, J = 15.5 Hz, 1H), 4.83 (d, J = 16.0 Hz, 1H), 4.49 (s, 1H), 4.25 (d, J = 14.0 Hz, 1H), 2.94 (s, 3H), 2.65 (d, J = 14.5 Hz, 1H), 2.41 (s, 3H). 13 C-NMR (125 MHz, CDCl 3 ) 183.44, 177.92, 170.83, 168.65, 141.96, 141.23, 137.31, 134.87, 134.00, 132.08, 129.71, 129.38, 129.17, 128.75, 128.55, 128.04, 127.40, 125.99, 125.87, 15.65, 124.95, 117.34, 116.26, 111.29, 85.77, 67.91, 62.05, 54.70, 52.21, 46.05, 44.91, 26.78. HPLC: Chiralpak AD-H (hexane/i-proh = 90/10, flow rate 2 ml/min, = 254 nm), t R (minor) = 11.4 min, t R (major) = 14.3 min; 94:6 er. [ ] D 25 = +93.2 (c = 0.5, CH 2 Cl 2 ). IR (CH 2 Cl 2 ) 3392.8, 2942.5, 1750.2, 1715.1, 1682,9, 1610.3,1470.6, 1390.0, 1287.6, 1168.1, 749.6.cm -1. 25 nature chemistry www.nature.com/naturechemistry 25
HRMS (ESI) calcd for [M+H] C 36 H 30 ClN 2 O 6, m/z: 621.1787, observed: 621.1793. Product 3q (Figure 4) 1 H-NMR (500 MHz, CDCl 3 ) 8.03 (d, J = 8.0 Hz, 1H), 7.89-7.88 (m, 2H), 7.37-7.28 (m, 7H), 7.17-7.15 (m, 1H), 7.11-7.08 (m, 2H), 7.02-7.00 (m, 2H), 6.94 (s, 1H), 6.75-6.72 (m, 1H), 6.66 (d, J = 8.5 Hz, 1H), 5.28 (d, J = 15.5 Hz, 1H), 4.80 (d, J = 16.0 Hz, 1H), 4.55 (s, 1H), 4.25 (d, J = 14.0 Hz, 1H), 3.80 (s, 3H), 2.96 (s, 3H), 2.57 (d, J = 14.0 Hz, 1H), 2.41 (s, 3H). 13 C-NMR (125 MHz, CDCl 3 ) 183.47, 177.94, 170.85, 168.96, 157.44, 141.17, 137.59, 136.22, 135.42, 133.17, 129.59, 129.30, 129.26, 128.62, 128.33, 127.44, 126.08, 125.93, 124.94, 116.18, 113.77, 112.94, 110.27, 85.81, 67.83, 62.28, 56.23, 55.04, 52.04, 46.27, 44.88, 26.77. HPLC: Chiralpak AD-H (hexane/i-proh = 90/10, flow rate 2 ml/min, = 254 nm), t R (minor) = 15.1 min, t R (major) = 22.7 min; 96:2 er. [ ] D 25 = +79.5 (c = 0.8, CH 2 Cl 2 ). IR (CH 2 Cl 2 ) 3301.5, 3056.7, 2926.6, 1742.4, 1710.8, 1677.9, 1602.9, 1491.4, 1372.2, 1276.1, 1168.5, 1033.9, 756.9, 697.5 cm -1. HRMS (ESI) calcd for [M+H] C 37 H 33 N 2 O 7, m/z: 617.2282, observed: 617.2253. Product 3r (Figure 4) 26 nature chemistry www.nature.com/naturechemistry 26
1 H-NMR (500 MHz, CDCl 3 ) 8.18 (d, J = 7.5 Hz, 1H), 8.03 (J = 7.5 Hz, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.39-7.28 (m, 7H), 7.26-7.23 (m, 1H), 7.18-7.15 (m, 2H), 7.11-7.08 (m, 2H), 7.01-6.99 (m, 2H), 6.92 (s, 1H), 6.80 (d, J = 7.5 Hz, 1H), 5.30 (d, J = 15.5 Hz, 1H), 4.82 (d, J = 15.5 Hz, 1H), 4.54 (s, 1H), 4.27 (d, J = 14.0 Hz, 1H), 3.46 (q, J = 7.5 Hz, 2H), 2.57 (d, J = 14.0 Hz, 1H), 2.40 (s, 3H), 0.35 (t, J = 7.0 Hz, 3H). 13 C-NMR (125 MHz, CDCl 3 ) 184.00, 177.53, 170.79, 168.56, 143.06, 141.20, 137.60, 135.38, 132.07, 129.55, 129.29, 129.08, 128.62, 128.40, 127.98, 127.63, 126.12, 126.06, 126.03, 125.90, 124.90, 124.65, 114.18, 109.75, 85.65, 68.04, 61.98, 61.47, 54.63, 46.39, 44.89, 26.74, 13.42. HPLC: Chiralpak AD-H (hexane/i-proh = 90/10, flow rate 2 ml/min, = 254 nm), t R (minor) = 6.3 min, t R (major) = 16.2 min; 95:5 er. [ ] D 25 = +103.7 (c = 0.9, CH 2 Cl 2 ). IR (CH 2 Cl 2 ) 3316.3, 3054.5, 2358.5, 1709.6, 1682.9, 1610.9, 1466.7, 1390.4, 1278.1, 1170.9, 1015.1, 758.3 cm -1. HRMS (ESI) calcd for [M+H] C 37 H 33 N 2 O 6, m/z: 601.2333, observed: 601.2324. Changing different protecting group 27 nature chemistry www.nature.com/naturechemistry 27
The multifunctional catalyst VIII (0.15 equiv) was added to a solution of 3-substituted oxindole 4 (0.05 mmol, 1.0 equiv) and methyleneindolinone ketone 2b (0.075 mmol, 1.5 equiv) in DCM (0.4 ml) at room temperature (23 C). After 24 hours, the reaction was complete, the product 5 was afforded with 83% yield by silica gel flash column chromatography using gradient elution (EtOAc/Hexane = 1:10 to 1:8). 1 H NMR (500 MHz, CDCl 3 ) 8.07 (d, J = 8.0 Hz, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.95 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.34 (t, J = 7.8 Hz, 1H), 7.30-7.24 (m, 2H), 7.17-7.09 (m, 7H), 7.07-6.95 (m, 6H), 6.86 (s, 1H), 6.30 (d, J = 7.8 Hz, 1H), 5.31 (s, 1H), 5.16 (d, J = 15.5 Hz, 1H), 4.43-4.22 (m, 2H), 2.56 (d, J = 14.2 Hz, 1H), 2.47 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) 196.04, 183.70, 178.04, 170.58, 137.07, 136.62, 132.16, 129.41, 127.90, 127.56, 127.04, 126.44, 125.79, 125.60, 125.21, 124.47, 124.38, 122.15, 115.91, 108.57, 84.92, 67.22, 65.85, 54.17, 46.55, 44.01, 26.45. HPLC: Chiralpak AD-H (hexane/i-proh = 90/10, flow rate: 2 ml/min, = 254 nm), t R (minor) = 9.3 min, t R (major) = 21.2 min; 95:5 er. [ ] 25 D = +143.6 (c = 1.0, CH 2 Cl 2 ). IR (CH 2 Cl 2 ) 33290.7, 2918.7, 2339.4, 1707.7, 1682.6, 1611.01, 1466.5, 1387.8, 1278.1, 1272.9, 756.0 cm -1. HRMS (ESI) calcd for [M+H] C 41 H 32 BrN 2 O 5, m/z: 711.1489, observed: 711.1456. Synthesis of the other enantiomer 28 nature chemistry www.nature.com/naturechemistry 28
The multifunctional catalyst XI (0.01 mmol, 0.2 equiv) was added to a solution of 3-substituted oxindole 1a (0.05 mmol, 1.0 equiv) and methyleneindolinone ketone 2b (0.075 mmol, 1.5 equiv) in DCM (0.1 ml) at room temperature (23 C). After 48 hours (the reaction wasn t complete), the product was afforded with 76% yield by silica gel flash column chromatography using gradient elution (EtOAc/Hexane = 1:10 to 1:8). HPLC: Chiralpak AD-H (hexane/i-proh = 90/10, flow rate 2 ml/min, = 254 nm), t R (major) = 8.0 min, t R (minor) = 17.7 min; Er = 5:95 (90% ee) [ ] D 25 = -156.0 (c = 0.6, CH 2 Cl 2 ). Experimental procedure for the deprotection of product 6 To a stirred solution of 3b (15 mg, 0.023 mmol) in ethanol (3 ml) was added concentrated HCl (1 ml), after stirred at 80 o C for 2 hours, the reaction was complete. Diluted with water (10 ml), extrated with DCM (10 ml x 2), dried over Na 2 SO 4, evaporated to obtain the deprotected product 4b with quatitative yield. 1 H NMR (500 MHz, CDCl 3 ) 8.15 (dd, J = 7.5, 1.0 Hz, 1H), 7.90 (d, J = 7.3 Hz, 1H), 7.29-6.94 (m, 23H), 6.66 (d, J = 7.7 Hz, 1H), 6.30 (d, J = 7.6 Hz, 1H), 5.32 (s, 1H), 5.23 (d, J = 15.3 Hz, 1H), 4.38 (d, J = 13.9 Hz, 1H), 4.28 (d, J = 15.4 Hz, 1H), 2.53 (d, J = 14.0 Hz, 1H). 29 nature chemistry www.nature.com/naturechemistry 29
13 C NMR (125 MHz, CDCl 3 ) 196.46, 183.84, 178.07, 141.63, 141.36, 137.99, 137.01, 134.87, 132.29, 130.34, 128.96, 128.65, 128.32, 128.03, 127.81, 127.67, 127.63, 127.43, 127.23, 127.06, 126.13, 125.90, 124.17, 121.81, 108.86, 108.51, 84.42, 66.98, 64.96, 54.21, 46.32, 44.54. HPLC: Chiralpak AD-H (hexane/i-proh = 90/10, flow rate 2 ml/min, = 254 nm), t R (minor) = 21.2 min, t R (major) = 43.7 min; 98:2 er. HRMS (ESI) calcd for [M+H] C39H30N2O4, m/z: 591.2278, observed: 591.2297. Experimental procedure for synthesis of catalyst VIII 4. Vakulya, B., Varga, S., Csámpai, A. & Soós, T. Org. Lett. 2005, 7, 1967-1969 5. Bassas, O., Huuskonen, J., Rissanen, K. & Koskinen, A. M. P. Eur. J. Org. Chem. 2009, 1340-1351. A solution of isothiocyanate HQ-NCS (367 mg, 1 mmol) in THF (3 ml) was added to a stirred solution of the (S)-binaphthyl diamine (284 mg, 1 mmol) in THF (3 ml) at 50 o C. After 8 hours, the solvent was removed under reduced pressure and the residue was purified by flash column 30 nature chemistry www.nature.com/naturechemistry 30
chromatography to afford product with 78% yield. 1 H NMR (500 MHz, MeOD) 8.41 (s, 1H), 7.89-7.78 (m, 5H), 7.60 (dd, J = 20.2, 8.4 Hz, 2H), 7.34-7.28 (m, 2H), 7.08-6.93 (m, 5H), 6.81 (d, J = 8.8 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 5.98 (brs, 1H), 3.84 (s, 3H), 3.29 (brs, 1H), 3.02-2.99 (m, 2H), 2.57-2.52 (m, 1H), 2.21 (d, J = 10.6 Hz, 1H), 1.51-1.31 (m, 4H), 1.13-1.08 (m, 3H), 0.69-0.66 (m, 4H). 13 C NMR (125 MHz, MeOD) 183.61, 159.57, 148.36, 145.17, 145.13, 137.25, 135.60, 134.43, 134.01, 131.37, 130.66, 130.15, 129.63, 129.53, 129.33, 129.26, 129.09, 128.07, 127.73, 127.52, 127.21, 127.03, 124.82, 123.63, 123.12, 121.24, 119.67, 112.98, 104.49, 61.49, 58.34, 56.61, 42.62, 38.44, 29.38, 28.41, 26.77, 26.65, 12.40. [ ] 25 D = -68.8 (c = 0.9, CH 2 Cl 2 ). IR (CH 2 Cl 2 ) 3305.1, 2928.3, 2361.3, 1620.7, 1506.4, 1263.4, 819.0, 750.1 cm -1. HRMS (ESI) calcd for [M+H] C 41 H 42 N 5 OS, m/z: 652.3104, observed: 652.3120. Experimental procedure for synthesis of catalyst XI A solution of isothiocyanate QD-NCS (110 mg, 0.3 mmol) in THF (3 ml) was added to a stirred 31 nature chemistry www.nature.com/naturechemistry 31
solution of the (S)-binaphthyl diamine (100 mg, 0.35 mmol) in THF (3 ml) at 60 o C. After 4 hours, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography to afford product with 46% yield. 1 H NMR (500 MHz, MeOD) 8.43 (d, J = 4.7 Hz, 1H), 7.92 (d, J = 8.9 Hz, 1H), 7.89-7.79 (m, 4H), 7.68 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.36-7.33 (m, 2H), 7.17-7.05 (m, 4H), 6.93 (t, J = 7.4 Hz, 1H), 6.76-6.69 (m, 2H), 6.01 (s, 1H), 5.85 (ddd, J = 17.0, 10.4, 6.2 Hz, 1H), 5.11 (d, J = 17.3 Hz, 1H), 5.04 (d, J = 10.5 Hz, 1H), 3.91 (s, 3H), 3.11 (s, 1H), 3.04-2.94 (m, 1H), 2.86-2.78 (m, 3H), 2.24 (s, 1H), 1.49-1.43 (m, 3H), 1.22 (s, 1H), 1.11-1.06 (m, 1H), 0.83-0.79 (m, 1H). 13 C NMR (125 MHz, MeOD) 182.71, 158.42, 147.15, 144.10, 143.93, 140.81, 136.42, 134.18, 133.02, 132.74, 130.02, 129.63, 129.11, 128.40, 128.17, 127.88, 127.60, 126.93, 126.43, 126.37, 125.90, 125.73, 123.78, 122.73, 122.06, 119.76, 118.69, 114.19, 111.99, 103.01, 60.63, 55.48, 54.95, 49.08, 39.34, 31.73, 27.80, 26.40, 25.41. [ ] 25 D = +141.4 (c = 0.7, CH 2 Cl 2 ). IR (CH 2 Cl 2 ) 3323.5, 2918.5, 2868.4, 2359.2, 1602.9, 1507.2, 1263.6, 1029.7, 818.7, 750.2 cm -1. HRMS (ESI) calcd for [M+H] C41H40N5OS, m/z: 650.2948, observed: 650.2951. Proposed activation mode of catalyst and substrates (Figure 7) 32 nature chemistry www.nature.com/naturechemistry 32
Control experiment for mechanistic studies (Figure 8): No reaction at all (no hydrogen bond acceptor part like ester or ketone) X-ray stuctures of 3e and 3p (Figure 9) 33 nature chemistry www.nature.com/naturechemistry 33
Crystal data and structure refinement for 3e Identification code barbas 09 (TB341) 34 nature chemistry www.nature.com/naturechemistry 34
Empirical formula C45 H39 Cl N2 O7 Formula weight 755.23 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Monoclinic Space group P2(1) Unit cell dimensions a = 9.7093(6) Å α= 90. b = 11.9854(8) Å β= 93.883(5). c = 15.6951(11) Å γ = 90. Volume 1822.2(2) Å 3 Z 2 Density (calculated) 1.376 Mg/m 3 Absorption coefficient 1.403 mm -1 F(000) 792 Crystal size 0.40 x 0.40 x 0.06 mm 3 Crystal color, habit Colorless Plate Theta range for data collection 2.82 to 67.24. Index ranges -11<=h<=11, -14<=k<=14, -18<=l<=18 Reflections collected 5241 Independent reflections 5241 [R(int) = 0.0536] Completeness to theta = 65.00 98.8 % Absorption correction Multi-scan Max. and min. transmission 0.9205 and 0.6037 Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 5241 / 1 / 497 Goodness-of-fit on F 2 1.029 Final R indices [I>2sigma(I)] R1 = 0.0560, wr2 = 0.1318 R indices (all data) R1 = 0.0635, wr2 = 0.1398 Absolute structure parameter 0.02(3) Largest diff. peak and hole 0.306 and -0.380 e.å -3 Crystal data and structure refinement for 3p Identification code barbas07 (TB303 (6-Cl)) 35 nature chemistry www.nature.com/naturechemistry 35
Empirical formula C36 H29 Cl N2 O6 Formula weight 621.06 Temperature 123(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2(1) Unit cell dimensions a = 9.4062(6) Å α= 90 b = 27.3462(17) Å β= 97.5890(10) c = 12.0053(8) Å γ = 90 Volume 3061.0(3) Å 3 Z, Z 4, 2 Density (calculated) 1.348 g/cm 3 Absorption coefficient 0.176 mm -1 F(000) 1296 Crystal size 0.44 x 0.34 x 0.10 mm 3 Crystal color, habit Colorless plate Theta range for data collection 1.49 to 25.36 Index ranges -11<=h<=11, -32<=k<=26, -14<=l<=14 Reflections collected 22482 Independent reflections 9782 [R(int) = 0.0644] Completeness to theta = 25.36 99.5 % Max. and min. transmission 0.9826 and 0.9267 Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 9782 / 1 / 815 Goodness-of-fit on F 2 1.041 Final R indices [I>2sigma(I)] R1 = 0.0471, wr2 = 0.1178 R indices (all data) R1 = 0.0528, wr2 = 0.1232 Absolute structure parameter -0.03(5) Largest diff. peak and hole 0.364 and -0.320 e Å -3 36 nature chemistry www.nature.com/naturechemistry 36
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99 nature chemistry www.nature.com/naturechemistry 96
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