Electronic Supplementary Material (ESI) for Chemical Communications. This journal is © The Royal Society of Chemistry 2018 Electronic Supplementary Information Catalytic stereoselective total synthesis of (+)-3'-(4-oxoquinazolin-3yl)spiro[1H-indole-3,5'- oxolane]-2,2'-dione, and pentacyclic core of tryptoquivalines Tao Wei and Darren J. Dixon* Department of Chemistry, Chemistry Research Laboratory University of Oxford, Mansfield Road, Oxford OX1 3TA, UK E-mail: [email protected] S 1 Contents 1. General information .................................................................................................................................. 4 2. Synthetic procedures ................................................................................................................................. 5 Compound 2 ............................................................................................................................................ 5 Compound 3 ............................................................................................................................................ 6 Compound 4 ............................................................................................................................................ 7 Compound 5 ............................................................................................................................................ 9 Compound 9 .......................................................................................................................................... 11 Compound 10 ........................................................................................................................................ 12 Compound 11 ........................................................................................................................................ 13 Compound 12 ........................................................................................................................................ 15 Compound 13 ........................................................................................................................................ 16 Compound 14 ........................................................................................................................................ 18 Compound 15 ........................................................................................................................................ 19 Compound 16 ........................................................................................................................................ 20 Compound 17 ........................................................................................................................................ 21 Compound 18 ........................................................................................................................................ 23 Compound 1 .......................................................................................................................................... 24 Compound S1 ........................................................................................................................................ 27 Compound S2 ........................................................................................................................................ 27 Compound 6 .......................................................................................................................................... 29 Compound 7 .......................................................................................................................................... 30 Compound 8 .......................................................................................................................................... 32 Compound S3 ........................................................................................................................................ 33 3. References ............................................................................................................................................... 36 4. NMR spectra ........................................................................................................................................... 37 Compound 2 .......................................................................................................................................... 37 Compound 3 .......................................................................................................................................... 38 S 2 Compound 4 .......................................................................................................................................... 39 Compound 5 .......................................................................................................................................... 40 Compound 9 .......................................................................................................................................... 41 Compound 10 ........................................................................................................................................ 42 Compound 11 ........................................................................................................................................ 43 Compound 12 ........................................................................................................................................ 44 Compound 13 ........................................................................................................................................ 45 Compound 14 ........................................................................................................................................ 46 Compound 15 ........................................................................................................................................ 47 Compound 16 ........................................................................................................................................ 48 Compound 17 ........................................................................................................................................ 49 Compound 18 ........................................................................................................................................ 50 Compound 1 .......................................................................................................................................... 51 Compound S1 ........................................................................................................................................ 52 Compound S2 ........................................................................................................................................ 53 Compound 6 .......................................................................................................................................... 54 Compound 7 .......................................................................................................................................... 55 Compound 8 .......................................................................................................................................... 56 Compound S3 ........................................................................................................................................ 57 Compound S3 nOe ................................................................................................................................ 58 S 3 1. General information All reagents bought from commercial sources were used as received. Organic solvents were evaporated under reduced pressure using a Büchi rotary evaporator. All solvents were commercially supplied or dried by filtration through activated alumina (powder ~150 mesh, pore size 58 Å, basic, Sigma-Aldrich) columns. Petrol ether (PE) refers to distilled light petroleum of fraction 30 - 40 °C. Toluene was distilled twice over calcium hydride. All reactions were followed by thin-layer chromatography (TLC) when practical, using Merck Kieselgel 60 F 254 fluorescent treated silica. Visualisation was accomplished under UV light (λmax= 254 nm) and by staining with KMnO staining dip. Chromatographic purification was performed on VWR 60 4 silica gel 40-63 μm using HPLC grade solvents that were used as supplied. High resolution mass spectra (HRMS) were recorded on a Bruker Daltonics MicroTOF mass spectrometer equipped with an ESI source or on a Micromass GCT equipped with an EI source unless otherwise specified. Infrared absorption spectra (IR) were recorded on a Bruker Tensor 27 FT-IR spectrometer from a thin film on a diamond ATR module. Only selected bands (ν ) are max reported in wavenumbers (cm-1). NMR spectra were recorded on Bruker spectrometers operating at 400 or 500 MHz (1H resonance). Proton chemical shifts (δ) are given in parts per million (ppm) relative to tetramethylsilane (TMS) with the solvent resonance (CDCl , δ = 7.26 ppm) as internal 3 standard. The following abbreviations are used to describe spin multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, dt = doublet of triplets, m = multiplet, br = broad signal. Coupling constants (J) are given in Hertz (Hz). 13C-NMR spectra were recorded with complete proton decoupling. Carbon chemical shifts are reported in ppm (δ) relative to TMS with the solvent resonance (CDCl , δ = 77.16 ppm) as internal standard. 3 S 4 2. Synthetic procedures Compound 2 ᴅ-Tryptophan methyl ester hydrochloride (10 g, 39 mmol, 1.0 eq) and sodium hydrogen carbonate (13 g, 156 mmol, 4.0 eq) was dissolved in 130 mL of water and 130 mL of CH Cl ; 2 2 while stirring 2-nitrobenzoyl chloride (7.2 g, 39 mmol, 1.0 eq) was added into the reaction mixture dropwise. After stirring for 15 min, the bi-phase reaction mixture was separated, and the aqueous phase was extract with CH Cl , combined organic parts, washed with 1 N HCl, brine 2 2 and dried with MgSO , filtered and concentrated under vacuum. The residue was purified with 4 FCC CH Cl /Et O (from 100/1 to 8/1) to give a light yellow foam 14.28 g (99%). 2 2 2 m.p. 50 – 55 oC; [α] 25 –58.4 (c 0.48, CHCl ); D 3 IR (film) ν /cm-1: 3405, 3346, 1738, 1652, 1528, 1458, 1439, 1349, 1311, 1253, 1217, 1101, max 1011, 910, 850, 789, 735, 699, 648; 1H NMR (CDCl , 400 MHz) δ (ppm): 8.19 (s, 1H, Indole), 7.98 (dd, J = 7.9, 1.4 Hz, 1H, C H), 3 [ar] 7.68 – 7.44 (m, 3H, C H), 7.36 – 7.27 (m, 2H, C H), 7.15 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H, [ar] [ar] C[ar]H), 7.09 – 7.03 (m, 2H, C H), 6.43 (d, J = 8.0 Hz, 1H, CONH), 5.15 (dt, J = 8.0, 5.2 Hz, [ar] 1H, C H), 3.70 (s, 3H, C H), 3.45 (d, J = 5.3 Hz, 2H, C H); [2] [5] [3] S 5 13C NMR (CDCl , 100 MHz) δ (ppm): 172.2 (C ), 166.0 (C ), 146.8 (C ), 136.3 (C ), 133.8 3 [1] [4] [ar] [ar] (C ), 132.5 (C ), 130.8 (C ), 128.9 (C ), 127.8 (C ), 124.7 (C ), 123.4 (C ), 122.4 [ar] [ar] [ar] [ar] [ar] [ar] [ar] (C ), 119.9 (C ), 118.7 (C ), 111.5 (C ), 109.8 (C ), 53.5 (C ), 52.8 (C ), 27.6 (C ); [ar] [ar] [ar] [ar] [ar] [2] [5] [3] HRMS (ESI) [C H N O +H]+ requires m/z 368.1241, found m/z 368.1238. 19 17 3 5 Compound 3 Compound 2 (3.67 g, 10.0 mmol, 1.0 eq) was dissolved in a mixture of 250 mL methanol and 100 mL of water. Sodium periodate (8.6 g, 40.0 mmol, 4.0 eq) was added in one portion at room temperature. The reaction was stirred at r.t. for 3 days before 300 mL of water was added, then extracted with chloroform three times, washed with sat. NaHCO , brine, and dried with MgSO . 3 4 The organic layers were concentrated and the residue was dissolved in 150 mL methanol and 100 mL of water, sodium periodate (6.45 g, 30 mmol) was added. The reaction was stirred at room temperature for another 3 days, before 300 mL water was added, then extracted with chloroform three times, washed with sat. NaHCO , brine, and dried with MgSO . The organic layers were 3 4 concentrated and the residue which was dissolved in 240 mL methanol and 80 mL of dioxane, and 20 mL of 4 M HCl was added. Then the reaction was stirred for 1 h at room temperature, before basified with saturated NaHCO , and extracted with CH Cl for three times, washed with 3 2 2 brine and dried over MgSO , concentrated, the residue was purified with FCC (methanol / 4 CH Cl from 1/200 to 1/50) to give the yellow thick oil 3.12 g (84 %). 2 2 [α] 25 – 62.6 (c 1.01, CHCl ); D 3 S 6 IR (film) ν /cm-1: 3470, 3350, 1742, 1648, 1616, 1584, 1529, 1485, 1451, 1349, 1313, 1216, max 1162, 1114, 1042, 980, 905, 856, 790, 735, 700; 1H NMR (CDCl , 400 MHz) δ (ppm): 7.99 (dd, J = 8.1, 1.2 Hz, 1H, C H), 7.70 (dd, J = 8.2, 3 [ar] 1.5 Hz, 1H, C H), 7.63 (td, J = 7.5, 1.2 Hz, 1H, C H), 7.59 – 7.47 (m, 2H, C H), 7.25 (ddd, [ar] [ar] [ar] J = 8.4, 7.0, 1.5 Hz, 1H, C H), 7.04 (d, J = 8.5 Hz, 1H, CONH), 6.65 (ddd, J = 8.2, 7.1, 1.2 Hz, [ar] 1H, C H), 6.60 (dd, J = 8.4, 1.1 Hz, 1H, C H), 6.19 (s, 2H, NH ), 5.13 (dt, J = 8.1, 3.9 Hz, 1H, [ar] [ar] 2 C H), 3.87 – 3.68 (m, 5H, C H+C H); [2] [11] [3] 13C NMR (CDCl , 100 MHz) δ (ppm): 199.6 (C ), 171.8 (C ), 166.2 (C ), 150.7 (C ), 3 [4] [1] [12] [ar] 146.7 (C ), 135.3 (C ), 133.9 (C ), 132.6 (C ), 131.3 (C ), 130.8 (C ), 128.9 (C ), [ar] [ar] [ar] [ar] [ar] [ar] [ar] 124.7 (C ), 117.6 (C ), 117.2 (C ), 116.3 (C ), 53.0 (C ), 48.9 (C ), 40.7 (C ); [ar] [ar] [ar] [ar] [11] [2] [3] HRMS (ESI) [C H N O +H]+ requires m/z 372.1190, found m/z 372.1184. 18 17 3 6 Compound 4 S 7 The aniline compound 3 (1.6 g, 4.3 mmol, 1.0 eq) was dissolved in EtOH 15 mL and 48% HBF 4 (1.13 mL, 8.6 mmol, 2.0 eq), which was stirred for 30 min before at 0 oC 2-methyl-2- nitropropane (1.0 mL, 9.5 mmol, 2.2 eq) was added dropwise. Then at the same temperature, 50 mL of acetone was added to dissolve the participation, which solution was kept stirring for another 1 hour. At 0 oC, the above solution was added into a potassium iodide (9.7 g, 58.6 mmol, 14 eq) in 50 mL of acetone, and the reaction was kept stirring at the same temperature for another 1 hours. Then the reaction was exacted with ethyl acetate for three times, washed with sat. Na S O and brine, dried with MgSO , filtered and concentrated under vacuum, and the 2 2 3 4 residue was purified with FCC ethyl acetate / petrol ether (from 1/2 to 1/1) to give light yellow foam 1.30 g (63%). m.p. 46 – 47 oC; [α] 25 –9.9 (c 0.95, CHCl ); D 3 IR (film) ν /cm-1: 1745, 1690, 1653, 1615, 1578, 1530, 1437, 1349, 1312, 1220, 1219, 1041, max 990, 963, 911, 854, 760, 733, 698; 1H NMR (CDCl , 500 MHz) δ (ppm): 8.07 (dd, J = 8.6, 1.2 Hz, 1H, C H), 7.93 (dd, J = 7.9, 3 [ar] 1.1 Hz, 1H, C H), 7.74 – 7.65 (m, 1H, C H), 7.63 – 7.53 (m, 3H, C H), 7.44 (td, J = 7.6, 1.1 [ar] [ar] [ar] Hz, 1H, C H), 7.20 – 7.10 (m, 1H, C H), 7.01 (d, J = 8.1 Hz, 1H, CONH), 5.09 (dt, J = 7.9, [ar] [ar] 3.9 Hz, 1H, C H), 3.82 (s, 3H, C H), 3.76 (dd, J = 3.9, 2.8 Hz, 2H, C H); [1] [11] [2] S 8 13C NMR (CDCl , 125 MHz) δ (ppm): 202.2 (C ), 171.0 (C ), 166.3 (C ), 146.6 (C ), 3 [3] [10] [12] [ar] 142.2 (C ), 141.3 (C ), 134.1 (C ), 132.7 (C ), 132.5 (C ), 131.0 (C ), 128.9 (C ), [ar] [ar] [ar] [ar] [ar] [ar] [ar] 128.9 (C ), 128.5 (C ), 124.9 (C ), 91.3 (C ), 53.3 (C ), 49.2 (C ), 43.0 (C ); [ar] [ar] [ar] [5] [11] [1] [2] HRMS (ESI) [C H N O I+Na]+ requires m/z 504.9867, found m/z 504.9866. 18 15 2 6 Compound 5 Fe powder (2.3 g, 41 mmol, 10.0 eq) and NH Cl (4.4 g, 82 mmol, 20.0 eq) was suspended in 40 4 mL of ethanol and 40 mL of water, which was heated at 70 oC for 15 min; then at the same temperature the iodide compound 4 (2.0 g, 4.1 mmol, 1.0 eq) in 40 mL of ethanol was added. After 60 min, the reaction is finished. The mixture was filtered through Celite, washed with methanol, and the solid residue was reflux in ethyl acetate / methanol for 60 min and filtered through Celite again. The combined solution was extracted with ethyl acetate and washed with brine, dried with MgSO , filtered and concentrated to give a light yellow foam 1.85 g, which was 4 used directly without further purification. The aniline from above, yellow foam, (1.85 g) and p-toluenesulfonic acid monohydrate (450 mg) was dissolved in 30 mL of methanol and 30 mL trimethyl orthoformate. The mixture was stirred at 70 oC for 2.5 hours. The volatiles were removed and the residue was dissolved in CH Cl , washed with sat. NaHCO , brine, dried with MgSO , filtered and concentrated under 2 2 3 4 S 9 vacuum. The residue was purified with FCC ethyl acetate / petrol ether (from 1/2 to 1/1) to give colorless solid 1.56 g (82%). m.p. 137 – 140 oC; [α] 25 +115.8 (c 0.67, CHCl ); D 3 IR (film) ν /cm-1: 1747, 1674, 1608, 1581, 1564, 1473, 1434, 1382, 1354, 1287, 1232, 1213, max 1196, 1163, 1108, 1084, 1015, 998, 978, 913, 776, 760, 731, 701, 675, 644; 1H NMR (CDCl , 500 MHz) δ (ppm): 8.29 (s, 1H, C H), 8.24 (dd, J = 8.0, 1.4 Hz, 1H, C H), 3 [18] [ar] 7.88 (dd, J = 8.0, 1.1 Hz, 1H, C H), 7.80 – 7.69 (m, 2H, C H), 7.54 – 7.44 (m, 2H, C H), [ar] [ar] [ar] 7.38 (td, J = 7.6, 1.1 Hz, 1H, C H), 7.11 (td, J = 7.7, 1.7 Hz, 1H, C H), 5.35 (dd, J = 8.0, 4.3 [ar] [ar] Hz, 1H, C H), 4.06 (dd, J = 19.1, 4.3 Hz, 1H, C H’), 3.86 (dd, J = 19.1, 8.0 Hz, 1H, C H’’), [2] [3] [3] 3.76 (s, 3H, C H); [19] 13C NMR (CDCl , 125 MHz) δ (ppm): 200.7 (C ), 168.8 (C ), 161.2 (C ), 148.2 (C ), 3 [4] [1] [11] [ar] 147.2 (C ), 142.5 (C ), 141.2 (C ), 134.9 (C ), 132.6 (C ), 128.6 (C ), 128.4 (C ), [18] [ar] [ar] [ar] [ar] [ar] [ar] 127.9 (C ), 127.7 (C ), 126.8 (C ), 122.2 (C ), 91.3 (C ), 57.4 (C ), 53.5 (C ), 41.8 [ar] [ar] [ar] [ar] [6] [2] [19] (C ); [3] HRMS (ESI) [C H N O I+H]+ requires m/z 463.0149, found m/z 463.0149. 19 15 2 4 S 10