Supporting Information for: Synthesis of Chiral Tryptamines via a Regioselective Indole Alkylation

Transcription

1 Supporting Information for: Synthesis of Chiral Tryptamines via a Regioselective Indole Alkylation Jens Wolfard, Jie Xu,* Haiming Zhang, and Cheol K. Chung* Department of Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States 1. General Information... page S-2 Analytical Information... page S-2 Reagent Information... page S-2 General Considerations... page S-2 2. General Procedure A: Boc Protection... page S-2 3. Compound Data 3l-t... page S-3 4. General Procedure B: Sulfamidate Formation... page S-4 5. Compound Data 5a-t... page S-5 6. General Procedure C: Indole Alkylation... page S-9 7. Compound Data 6a-t... page S-9 8. Synthesis of Cipargamin and TIK page S References... page S NMR Spectra... page S-22 S-1

2 1. General Information Analytical Information: 1 H, 13 C and 19 F Nuclear Magnetic Resonance spectra were recorded on a Bruker 400 MHz instrument at ambient temperature. All 1 H NMR spectra were measured in parts per million (ppm) relative to residual chloroform signal (δ 7.26) or DMSO (δ 2.50) in the deuterated solvent unless otherwise stated. Data for 1 H NMR are reported as follows: chemical shift, multiplicity (br = broad signal, s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet), coupling constants in Hertz and integration. All 13 C NMR spectra are reported in ppm relative to deuterochloroform (δ 77.06) or DMSO-d 6 (δ 39.53) and were obtained with complete 1 H decoupling unless otherwise stated. All 19 F NMR spectra were obtained with complete 1 H decoupling. HPLC analyses were performed on an Agilent 1260 Infinity HPLC system with a UV detector at 220 nm using an Ace Super C18 column. Melting points were obtained using a Buchi B-540 Melting Point Apparatus and are uncorrected. IR spectra were recorded on a Bruker Alpha Platinum-neat spectrometer and are reported in frequency of absorption (cm 1 ). High resolution mass spectrometry (HRMS) data was acquired on a Thermo Scientific Orbitrap Fusion mass spectrometer. Reagent Information: All reagents and solvents were purchased from commercial suppliers and used with no additional purification. All reagents and solvents were purchased from commercial suppliers and used with no additional purification. Anhydrous solvent (dichloromethane) was utilized, but no effort was undertaken to further increase the purity of other commercially available solvents. General Considerations: All reactions (<6 mmol) were carried out in screw-cap vials equipped with a Teflon septa under a nitrogen atmosphere. Flash column chromatography was performed using a Teledyne Isco CombiFlash Rf instrument with pre-packed RediSepRf Gold silica cartridges. Yields reported in the publication are of isolated material and are corrected for residual solvents. All new compounds are characterized by 1 H NMR, 13 C NMR, IR, melting point, and HRMS, and their purity was confirmed by HPLC analysis. Copies of 1 H, 13 C, and 19 F NMR spectra can be found at the end of the Supporting Information. 2. General Procedure A: Boc Protection Scheme S1: Boc Protection of Chiral Amino-alcohol To a slurry of (S)-2-amino-2-(4-methoxyphenyl)ethan-1-ol hydrochloride (1.04 g, 5.10 mmol, 100 mol %) in THF (4.4 ml) was added Boc 2 O (1.21 ml, 5.61 mmol, 110 mol %), NaHCO 3 (451 mg, 5.10 mmol, 100 mol %), and water (4.4 ml) at room temperature. The solution was stirred S-2

3 at room temperature for 18 h, extracted with iproac (20 ml x 2). The organic layer was washed with saturated NaHCO 3 solution (10 ml), brine (10 ml), dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure to provide the product without further purification. All the yields reported are corrected based on residual solvent from 1 H NMR. 3 Compound Data tert-butyl (S)-(2-hydroxy-1-(4-methoxyphenyl)ethyl)carbamate (3l): General Procedure A above was performed to yield compound 3l (1.36 g, 100% yield) as a white solid. mp: C; FTIR (neat, cm -1 ) 3370, 2984, 2837, 1681, 1613, 1512, 1461; 1 H NMR (400 MHz, CDCl 3 ): δ (m, 2H), (m, 2H), 5.10 (d, J = 7.2 Hz, 1H), 4.72 (br, 1H), 3.82 (t, J = 5.6 Hz, 2H), 3.80 (s, 3H), 2.35 (br, 1H), 1.43 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ): δ 159.1, 156.2, 131.6, 127.7, 114.2, 80.0, 66.8, 56.4, 55.3, HRMS: calcd for C 14 H 21 NO 4 Na [M+Na] + = , observed = ; consistent with data for the known compound. 1 F NHBoc OH tert-butyl (S)-(1-(3-fluorophenyl)-2-hydroxyethyl)carbamate (3m): General Procedure A above was performed with (S)-2-amino-2-(3-fluorophenyl)ethan-1-ol (1.36 g, 8.73 mmol, 100 mol %) to yield compound 3m (2.23 g, 100% yield) as a white solid. mp: C; FTIR (neat, cm -1 ) 3251, 3059, 2977, 2901, 1671, 1587, 1543; 1 H NMR (400 MHz, CDCl 3 ): δ 7.33 (ddd, J = 7.6, 7.6, 6.0 Hz, 1H), (m, 1H), (m, 2H), 5.24 (br, 1H), 4.77 (br, 1H), (m, 2H), 2.02 (br, 1H), 1.44 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ): δ (d, 1 J CF = 246 Hz), 156.0, 142.5, (d, 3 J CF = 9 Hz), (d, 4 J CF = 3 Hz), (d, 2 J CF = 21 Hz), (d, 2 J CF = 21 Hz), 80.2, 66.2, 56.3, 28.3; 19 F NMR (CDCl 3, 376 MHz): δ HRMS: calcd for C 13 H 18 FNO 3 Na [M+Na] + = , observed = F 3 C NHBoc OH tert-butyl (S)-(1-(3-fluorophenyl)-2-hydroxyethyl)carbamate (3n): General Procedure A above was performed with (S)-2-amino-2-(3-(trifluoromethyl)phenyl)ethan-1-ol hydrochloride (1.00 g, 4.12 mmol, 100 mol %) to yield compound 3n (1.26 g, 100% yield) as a white solid. mp: C; FTIR (neat, cm -1 ) 3368, 3254, 2979, 2939, 1691, 1510, 1453, S-3

4 1333; 1 H NMR (400 MHz, CDCl 3 ): δ (m, 2H), (m, 2H), 5.31 (d, J = 6.4 Hz, 1H), 4.83 (br, 1H), 3.92 (ddd, J = 11.2, 6.8, 4.0 Hz, 1H), (m, 1H), 1.94 (br, 1H), 1.43 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ): δ 156.1, 141.1, (q, 2 J CF = 32 Hz), 130.1, 129.0, (q, 3 J CF = 4 Hz), (q, 1 J CF = 270 Hz), (q, 3 J CF = 4 Hz), 80.3, 65.8, 56.3, 28.2; 19 F NMR (CDCl 3, 376 MHz): δ HRMS: calcd for C 14 H 18 F 3 NO 3 Na [M+Na] + = , observed = tert-butyl (R)-(1-cyclopropyl-2-hydroxyethyl)carbamate (3q): General Procedure A above was performed with (R)-2-amino-2-cyclopropylethan-1-ol (1.16 g, 11.5 mmol, 100 mol %) to yield compound 3q (2.31 g, 100% yield) as a white solid. mp: C; FTIR (neat, cm -1 ) 3358, 2974, 2937, 1682, 1521, 1366; 1 H NMR (400 MHz, CDCl 3 ): δ 4.80 (br, 1H), 3.80 (ddd, J = 10.8, 6.8, 3.2 Hz, 1H), 3.67 (ddd, J = 10.8, 6.0, 4.8 Hz, 1H), 2.94 (dtd, J = 9.6, 6.4, 3.2 Hz, 1H), 2.81 (br, 1H), 1.45 (s, 9H), 0.85 (dtt, J = 9.6, 8.0, 4.8 Hz, 1H), (m, 2H), (m, 2H); 13 C NMR (100 MHz, CDCl 3 ): δ 156.6, 79.7, 66.3, 57.9, 28.4, 13.0, 3.3, 2.9. HRMS: calcd for C 10 H 19 NO 3 Na [M+Na] + = , observed = tert-butyl ((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)carbamate (3t): General Procedure A above was performed with (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol (5.15 g, 34.5 mmol, 100 mol %) to yield compound 3t (8.61 g, 100% yield) as a white solid. mp: C; FTIR (neat, cm -1 ) 3428, 3350, 2983, 2933, 1688, 1509; 1 H NMR (400 MHz, CDCl 3 ): δ (m, 1H), (m, 3H), 5.17 (br, 1H), 5.05 (br, 1H), 4.57 (ddd, J = 7.2, 4.8, 2.0 Hz, 1H), 3.12 (dd, J = 16.8, 5.2 Hz, 1H), 2.91 (dd, J = 16.8, 2.4 Hz, 1H), 2.31 (d, J = 4.8 Hz, 1H), 1.50 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ): δ 156.3, 140.9, 139.9, 128.2, 127.1, 125.3, 124.5, 79.9, 73.6, 58.9, 39.4, HRMS: calcd for C 14 H 19 NO 3 Na [M+Na] + = , observed = ; consistent with data for the known compound General Procedure B: Sulfamidate Formation Scheme S2: Synthesis of Cyclic Sulfamidate To a cold (-40 C) solution of SOCl 2 (10.9 ml, 149 mmol, 250 mol %) in CH 2 Cl 2 (60.0 ml) was added a solution of tert-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate (15.0 g, 59.7 S-4

5 mmol, 100 mol %) in CH 2 Cl 2 (60.0 ml) over 60 min at -40 C. Pyridine (25.3 ml, 313 mmol, 525 mol %) was then added to the reaction mixture over 30 min at -40 C. The reaction mixture was stirred at -40 C for 2 h, solvent swapped to CH 2 Cl 2 /iproac (1:1) mixture, filtered. The filtrate was washed with saturated brine solution (20 ml), dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure. The residue was dissolved in CH 3 CN (60.0 ml) at 0 C. NaIO 4 (14.0 g, 65.7 mmol, 110 mol %), RuCl 3 (61.9 mg, mmol, 0.5 mol %), and water (60.0 ml) were added into the reaction mixture at 0 C and stirred for 15 min. The reaction mixture was then warmed to room temperature and stirred at room temperature for 2 h, extracted with iproac (20 ml), washed with saturated NaHCO 3 solution (15 ml), saturated brine solution (15 ml), dried (Na 2 SO 4 ), filtered, purified by chromatography on SiO 2. Specific gradient used for each sample is included in the characterization data. All the yields reported are corrected based on residual solvent from 1 H NMR. 5 Compound Data tert-butyl (R)-4-benzyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (5a): General Procedure B above was performed with tert-butyl (R)-(1-hydroxy-3-phenylpropan-2- yl)carbamate (15.0 g, 59.7 mmol, 100 mol %) to yield compound 5a (18.7 g, 56% yield) as a white solid. Column Gradient: 0 to 5% CH 3 OH in CH 2 Cl 2. mp: C; FTIR (neat, cm -1 ) 3261, 2979, 2903, 1712, 1673, 1540; 1 H NMR (400 MHz, CDCl 3 ): δ (m, 5H), (m, 2H), (m, 1H), 3.37 (dd, J = 14.0, 4.0 Hz, 1H), (m, 1H), 1.56 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ): δ 148.5, 135.2, 129.5, 129.1, 127.5, 85.6, 68.8, 58.6, 37.9, HRMS: calcd for C 14 H 23 N 2 O 5 S [M+NH 4 ] + = , observed = tert-butyl (S)-4-phenyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (5k): General Procedure B above was performed with tert-butyl (S)-(2-hydroxy-1-phenylethyl)carbamate (10.0 g, 42.1 mmol, 100 mol %) to yield compound 5k (5.23 g, 42% yield) as a white solid. Column Gradient: 0 to 5% CH 3 OH in CH 2 Cl 2. mp: C; FTIR (neat, cm -1 ) 2976, 1722, 1458, 1377; 1 H NMR (400 MHz, CDCl 3 ): δ (m, 5H), 5.28 (dd, J = 6.4, 4.0 Hz, 1H), 4.87 (dd, J = 9.2, 6.4 Hz, 1H), 4.39 (dd, J = 9.2, 4.4 Hz, 1H), 1.42 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ): δ 148.3, 137.0, 129.2, 129.1, 126.2, 85.5, 71.8, 60.8, HRMS: calcd for C 13 H 21 N 2 O 5 S [M+NH 4 ] + = , observed = S-5

6 tert-butyl (S)-4-(4-methoxyphenyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (5l): General Procedure B above was performed with 3l (1.45 g, 5.42 mmol, 100 mol %) to yield compound 5l (1.05 g, 59% yield) as a white solid. Column Gradient: 0 to 5% CH 3 OH in CH 2 Cl 2. mp: C; FTIR (neat, cm -1 ) 2979, 2933, 2838, 1721, 1636, 1510, 1457; 1 H NMR (400 MHz, CDCl 3 ): δ (m, 2H), (m, 2H), 5.24 (dd, J = 6.8, 4.4 Hz, 1H), 4.84 (dd, J = 9.2, 6.8 Hz, 1H), 4.39 (dd, J = 9.2, 4.4 Hz, 1H), 3.82 (s, 3H), 1.44 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ): δ 160.2, 148.3, 128.9, 127.7, 114.6, 85.5, 72.0, 60.5, 55.4, HRMS: calcd for C 14 H 23 N 2 O 6 S [M+NH 4 ] + = , observed = tert-butyl (S)-4-(3-fluorophenyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (5m): General Procedure B above was performed with 3m (1.45 g, 5.68 mmol, 100 mol %) to yield compound 5m (0.702 g, 39% yield) as a white solid. Column Gradient: 0 to 50% iproac in Heptane. mp: C; FTIR (neat, cm -1 ) 2976, 1722, 1636, 1594, 1458; 1 H NMR (400 MHz, CDCl 3 ): δ (m, 1H), (m, 1H), (m, 1H), (m, 1H), 5.28 (dd, J = 6.8, 3.6 Hz, 1H), 4.88 (dd, J = 9.2, 6.8 Hz, 1H), 4.39 (dd, J = 9.2, 3.6 Hz, 1H), 1.47 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ): δ (d, 1 J CF = 246 Hz), 148.2, (d, 3 J CF = 7 Hz), (d, 3 J CF = 8 Hz), (d, 4 J CF = 3 Hz), (d, 2 J CF = 21 Hz), (d, 2 J CF = 22 Hz), 86.0, 71.6, 60.2 (d, 4 J CF = 3 Hz), 27.9; 19 F NMR (CDCl 3, 376 MHz): δ HRMS: calcd for C 13 H 20 FN 2 O 5 S [M+NH 4 ] + = , observed = tert-butyl (S)-4-(3-(trifluoromethyl)phenyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (5n): General Procedure B above was performed with 3n (1.00 g, 3.28 mmol, 100 mol %) to yield compound 5n (0.528 g, 44% yield) as a white solid. Column Gradient: 0 to 50% iproac in Heptane. mp: C; FTIR (neat, cm -1 ) 2989, 1720, 1463, 1373, 1325; 1 H NMR (400 MHz, CDCl 3 ): δ (m, 3H), (m, 1H), 5.35 (dd, J = 6.8, 4.0 Hz, 1H), 4.92 (dd, J = 9.2, 6.8 Hz, 1H), 4.41 (dd, J = 9.2, 3.6 Hz, 1H), 1.46 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ): δ 148.2, 138.2, (q, 2 J CF = 32 Hz), 130.1, 129.4, (q, 3 J CF = 4 Hz), (q, 1 J CF = 270 Hz), (q, 3 J CF = 4 Hz), 86.2, 71.4, 60.2, 27.8; 19 F NMR (CDCl 3, 376 MHz): δ HRMS: calcd for C 14 H 20 F 3 N 2 O 5 S [M+NH 4 ] + = , observed = S-6

7 tert-butyl (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (5o): General Procedure B above was performed with tert-butyl (R)-(1-hydroxypropan-2-yl)carbamate (5.00 g, 28.5 mmol, 100 mol %) to yield compound 5o (3.85 g, 57% yield) as a white solid. Column Gradient: 0 to 5% CH 3 OH in CH 2 Cl 2. mp: C; FTIR (neat, cm -1 ) 3245, 2982, 1719, 1402, 1329; 1 H NMR (400 MHz, CDCl 3 ): δ 4.66 (dd, J = 9.2, 6.0 Hz, 1H), 4.41 (qdd, J = 6.4, 6.0, 2.8 Hz, 1H), 4.19 (dd, J = 9.2, 2.8 Hz, 1H), 1.54 (s, 9H), 1.50 (d, J = 6.4 Hz, 3 H); 13 C NMR (100 MHz, CDCl 3 ): δ 148.5, 85.4, 71.4, 53.8, 28.0, HRMS: calcd for C 8 H 19 N 2 O 5 S [M+NH 4 ] + = , observed = tert-butyl (R)-4-isopropyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (5p): General Procedure B above was performed with tert-butyl (R)-(1-hydroxy-3-methylbutan-2- yl)carbamate (5.00 g, 24.6 mmol, 100 mol %) to yield compound 5p (3.93 g, 60% yield) as a white solid. Column Gradient: 0 to 5% CH 3 OH in CH 2 Cl 2. mp: C; FTIR (neat, cm -1 ) 2977, 2946, 2910, 2882, 1734, 1459, 1373; 1 H NMR (400 MHz, CDCl 3 ): δ 4.55 (dd, J = 9.6, 6.4 Hz, 1H), 4.38 (dd, J = 9.6, 2.0 Hz, 1H), 4.17 (ddd, J = 6.4, 5.2, 1.6 Hz, 1H), 2.24 (qqd, J = 6.8, 6.8, 5.2 Hz, 1H), 1.53 (s, 9H), 1.00 (d, J = 6.8 Hz, 3 H), 0.95 (d, J = 6.8 Hz, 3 H); 13 C NMR (100 MHz, CDCl 3 ): δ 149.1, 85.3, 67.0, 62.0, 30.0, 27.9, 18.0, HRMS: calcd for C 10 H 23 N 2 O 5 S [M+NH 4 ] + = , observed = tert-butyl (R)-4-cyclopropyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (5q): General Procedure B above was performed with 3q (2.31 g, 11.5 mmol, 100 mol %) to yield compound 5q (1.36 g, 45% yield) as a white solid. Column Gradient: 0 to 5% CH 3 OH in CH 2 Cl 2. mp: C; FTIR (neat, cm -1 ) 2977, 1734, 1460, 1363; 1 H NMR (400 MHz, CDCl 3 ): δ 4.64 (dd, J = 9.2, 6.0 Hz, 1H), 4.40 (dd, J = 8.8, 2.0 Hz, 1H), 3.77 (ddd, J = 9.2, 6.0, 2.0 Hz, 1H), 1.54 (s, 9H), (m,1 H), (m, 2H), (m, 1H), (m, 1H); 13 C NMR (100 MHz, CDCl 3 ): δ 148.9, 85.3, 71.1, 61.6, 27.9, 14.3, 4.4, 1.7. HRMS: calcd for C 10 H 21 N 2 O 5 S [M+NH 4 ] + = , observed = S-7

8 tert-butyl (S)-4-phenyl-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide (5r): General Procedure B above was performed with tert-butyl (S)-(3-hydroxy-1-phenylpropyl)carbamate (2.00 g, 7.96 mmol, 100 mol %) to yield compound 5r (1.26 g, 51% yield) as a white solid. Column Gradient: 0 to 50% iproac. mp: C; FTIR (neat, cm -1 ) 2986, 1727, 1449, 1367; 1 H NMR (400 MHz, DMSO-d 6 ) (94:6 mixture of rotamers): δ (m, 4H), (m, 1H), 5.65 (dd, J = 4.4, 4.4 Hz, 0.94H), 5.53 (dd, J = 11.2, 4.4 Hz, 0.06H), 4.70 (ddd, J = 10.4, 7.2, 2.8 Hz, 0.94H), 4.51 (ddd, J = 8.8, 4.4, 4.4 Hz, 0.06H), 4.40 (ddd, J = 10.4, 10.4, 6.8 Hz, 1H), (m, 1H), (m, 1H), 1.41 (s, 8.46H), 1.12 (s, 0.54H); 13 C NMR (100 MHz, DMSO-d 6 ) (rotamers): δ 155.1, 143.0, 128.4(128.6), 127.0(127.3), 126.3(125.4), 78.1(84.3), 73.6(70.9), 50.5(60.0), 36.0, 28.2(27.4). HRMS: calcd for C 14 H 23 N 2 O 5 S [M+NH 4 ] + = , observed = tert-butyl (R)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (5s): General Procedure B above was performed with tert-butyl (R)-(2-hydroxypropyl)carbamate (6.25 g, 35.7 mmol, 100 mol %) to yield compound 5s (6.10 g, 72% yield) as a white solid. Column Gradient: 0 to 5% CH 3 OH in CH 2 Cl 2. mp: C; FTIR (neat, cm -1 ) 3370, 2956, 2938, 2837, 1681, 1512, 1461, 1366; 1 H NMR (400 MHz, CDCl 3 ): δ (m, 1H), 4.06 (dd, J = 9.6, 5.6 Hz, 1H), 3.63 (dd, J = 9.6, 9.2 Hz, 1H), 1.56 (d, J = 6.4 Hz, 3H), 1.53 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ): δ 148.6, 85.3, 76.2, 51.7, 27.9, HRMS: calcd for C 8 H 19 N 2 O 5 S [M+NH 4 ] + = , observed = tert-butyl (3aR,8aS)-8,8a-dihydroindeno[1,2-d][1,2,3]oxathiazole-3(3aH)-carboxylate 2,2- dioxide (5t): General Procedure B above was performed with 3t (9.12 g, 36.6 mmol, 100 mol %) to yield compound 5t (7.50 g, 66% yield) as a white solid. Column Gradient: 0 to 5% CH 3 OH in CH 2 Cl 2. mp: C; FTIR (neat, cm -1 ) 2988, 2937, 1732, 1462, 1375; 1 H NMR (400 MHz, CDCl 3 ): δ (m, 1H), (m, 3H), 5.71 (d, J = 5.6 Hz, 1H), 5.50 (dt, J = 6.0, 3.2 Hz, 1H), 3.38 (d, J = 3.2 Hz, 2H), 1.62 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ): δ 149.6, 138.4, 137.9, 129.9, 128.4, 126.2, 125.2, 85.7, 82.2, 65.0, 36.5, HRMS: calcd for C 14 H 21 N 2 O 5 S [M+NH 4 ] + = , observed = S-8

9 6 General Procedure C: Indole Alkylation To a cold (0 C) mixture of indole (264 mg, 2.25 mmol, 150 mol %), and CuCl (193 mg, 1.95 mmol, 130 mol %) in CH 2 Cl 2 (3.0 ml) was added MeMgCl (3.0 M in THF, 0.65 ml, 1.95 mmol, 130 mol %) over 10 min at 0 C. The reaction mixture was stirred at 0 C for 1 h and cooled to - 20 C. A solution of 5a (470 mg, 1.50 mmol, 100 mol %) in CH 2 Cl 2 (2.0 ml) was added into the reaction mixture over 30 min at -20 C. The reaction mixture was then stirred at -20 C for 18 h, quenched with 10% aqueous citric acid (5.0 ml) at 0 C, filtered, extracted with CH 2 Cl 2 (10.0 ml x 2), washed with saturated brine (20.0 ml x 2), dried (Na 2 SO 4 ), filtered, purified by chromatography on SiO 2. Specific gradient used for each sample is included in the characterization data. All the yields reported are corrected based on residual solvent from 1 H NMR. 7 Compound Data tert-butyl (R)-(1-(1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate (6a): General Procedure C above was performed between indole (280 mg, 2.39 mmol, 150 mol %) and 5a (500 mg, 1.60 mmol, 100 mol %) to yield compound 6a (424 mg, 76% yield) as a white solid. The C 3 (RT = 4.06 min) / N 1 (RT = 4.29 min) ratio was 97:3. Column Gradient: 0 to 50% iproac in Heptane. mp: C; FTIR (neat, cm -1 ) 3418, 3402, 3376, 2974, 2911, 1684, 1522; 1 H NMR (400 MHz, DMSO-d 6 ) (85:15 mixture of rotamers) : δ (br, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), (m, 2H), (m, 4H), 7.05 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 6.95 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 6.76 (d, J = 8.4 Hz, 0.85H), 6.34 (d, J = 9.2 Hz, 0.15H), (m, 1H), (m, 4H), 1.29 (s, 7.65H), 1.12 (s, 1.35H); 13 C NMR (100 MHz, DMSO-d 6 ) (rotamers): δ 155.1, 139.6, 136.1, 129.0, 128.0, 127.5, 125.8, 123.2, 120.8, 118.3, 118.1, 111.4, 111.3, 77.3, 52.6, 39.9, 30.4, 28.2(27.8). HRMS: calcd for C 22 H 26 N 2 O 2 Na [M+Na] + = , observed = S-9

10 tert-butyl (R)-(1-(5-methyl-1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate (6b): General Procedure C above was performed between 5-methyl-1H-indole (295 mg, 2.25 mmol, 150 mol %) and 5a (470 mg, 1.50 mmol, 100 mol %) to yield compound 6b (401 mg, 73% yield) as a white solid. The C 3 (RT = 4.24 min) / N 1 (RT = 4.52 min) ratio was 95:5. Column Gradient: 0 to 50% iproac in Heptane. mp: C; FTIR (neat, cm -1 ) 3413, 3368, 2974, 2927, 1685, 1524; 1 H NMR (400 MHz, DMSO-d 6 ) (85:15 mixture of rotamers): δ (br, 1H), (m, 7H), 7.07 (d, J = 2.0 Hz, 1H), 6.87 (dd, J = 8.4, 1.6 Hz, 1H), 6.74 (d, J = 8.8 Hz, 0.85H), 6.34 (d, J = 7.6 Hz, 0.15H), (m, 1H), (m, 4H), 2.36 (s, 3H), 1.30 (s, 7.65H), 1.16(s, 1.35H); 13 C NMR (100 MHz, DMSO-d 6 ) (rotamers): δ 155.1, 139.6, 134.5, 129.1, 128.0, 127.7, 126.4, 125.8, 123.2, 122.3, 117.9, 111.0, 110.9, 77.2, 52.7, 40.0, 30.2, 28.2(27.8), HRMS: calcd for C 23 H 29 N 2 O 2 [M+H] + = , observed = tert-butyl (R)-(1-phenyl-3-(5-phenyl-1H-indol-3-yl)propan-2-yl)carbamate (6c): General Procedure C above was performed between 5-phenyl-1H-indole (435 mg, 2.25 mmol, 150 mol %) and 5a (470 mg, 1.50 mmol, 100 mol %) to yield compound 6c (523 mg, 82% yield) as a white solid. The C 3 (RT = 4.53 min) / N 1 (RT = 4.81 min) ratio was 97:3. Column Gradient: 0 to 50% iproac in Heptane. mp: C; FTIR (neat, cm -1 ) 3427, 3411, 3392, 3310, 2977, 2929, 1715, 1696, 1506; 1 H NMR (400 MHz, DMSO-d 6 ) (85:15 mixture of rotamers): δ (br, 1H), 7.70 (s, 1H), (m, 2H), (m, 4H), (m, 3H), (m, 4H), 6.80 (d, J = 8.8 Hz, 0.85H), 6.39 (d, J = 9.2 Hz, 0.15H), (m, 1H), 2.87 (d, J =6.8 Hz, 2H), 2.77 (d, J = 6.8 Hz, 2H), 1.24 (s, 7.65H), 1.09 (s, 1.35H); 13 C NMR (100 MHz, DMSO-d 6 ) (rotamers): δ 155.1, 142.0, 139.6, 135.8, 130.7, 129.1, 128.6, 128.1, 128.0, 126.6, 126.0, 125.8, 124.0, 120.1, 116.6, 112.2, 111.6, 77.2, 53.1, 40.4, 30.1, 28.2(27.8). HRMS: calcd for C 28 H 31 N 2 O 2 [M+H] + = , observed = S-10

11 tert-butyl (R)-(1-(5-chloro-1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate (6d): General Procedure C above was performed between 5-chloro-1H-indole (341 mg, 2.25 mmol, 150 mol %) and 5a (470 mg, 1.50 mmol, 100 mol %) to yield compound 6d (345 mg, 60% yield) as a white solid. The C 3 (RT = 4.28 min) / N 1 (RT = 4.53 min) ratio was 96:4. Column Gradient: 0 to 50% iproac in Heptane. mp: C; FTIR (neat, cm -1 ) 3417, 3368, 2980, 2928, 1684, 1518; 1 H NMR (400 MHz, DMSO-d 6 ) (85:15 mixture of rotamers): δ (br, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), (m, 2H), (m, 4H), 7.04 (dd, J = 8.4, 2.0 Hz, 1H), 6.77 (d, J = 8.8 Hz, 0.85H), 6.34 (d, J = 8.8 Hz, 0.15H), (m, 1H), (m, 4H), 1.27 (s, 7.65H), 1.10 (s, 1.35H); 13 C NMR (100 MHz, DMSO-d 6 ) (rotamers): δ 155.1, 139.5, 134.6, 129.0, 128.8, 128.0, 125.8, 125.2, 122.9, 120.6, 117.7, 112.8, 111.5, 77.2, 52.9, 40.0, 30.1, 28.2(27.7). HRMS: calcd for C 22 H 25 ClN 2 O 2 Na [M+Na] + = , observed = tert-butyl (R)-(1-(5-methoxy-1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate (6e): General Procedure C above was performed between 5-methoxy-1H-indole (331 mg, 2.25 mmol, 150 mol %) and 5a (470 mg, 1.50 mmol, 100 mol %) to yield compound 6e (523 mg, 92% yield) as a white solid. The C 3 (RT = 3.94 min) / N 1 (RT = 4.16 min) ratio was 97:3. Column Gradient: 0 to 50% iproac in Heptane. mp: C; FTIR (neat, cm -1 ) 3368, 2975, 2933, 1692, 1680, 1516; 1 H NMR (400 MHz, DMSO-d 6 ) (85:15 mixture of rotamers): δ (s, 1H), (m, 2H), (m, 4H), 7.08 (d, J = 2.4 Hz, 1H), 6.91 (d, J = 2.4 Hz, 0.85H), 6.83 (br, 0.15H), 6.77 (d, J = 8.8 Hz, 0.85H), 6.70 (dd, J = 8.8, 2.4 Hz, 1H), 6.34 (d, J = 9.2 Hz, 0.15H), (m, 1H), 3.72 (s, 3H), (m, 4H), 1.29 (s, 7.65H), 1.13 (s, 1.35H); 13 C NMR (100 MHz, DMSO-d 6 ) (rotamers): δ 155.2, 152.9, 139.6, 131.3, 129.1, 128.0, 127.8, 125.8, 123.8, 111.9, 111.3, 110.8, 100.3, 77.3, 55.3, 52.8, 40.2, 30.2, 28.2(27.8). HRMS: calcd for C 23 H 29 N 2 O 3 [M+H] + = , observed = tert-butyl (R)-(1-phenyl-3-(5-(trifluoromethyl)-1H-indol-3-yl)propan-2-yl)carbamate (6f): General Procedure C above was performed between 5-(trifluoromethyl)-1H-indole (417 mg, 2.25 mmol, 150 mol %) and 5a (470 mg, 1.50 mmol, 100 mol %) to yield compound 6f (297 mg, 47% yield) as a white solid. The C 3 (RT = 4.32 min) / N 1 (RT = 4.56 min) ratio was 97:3. Column Gradient: 0 to 50% iproac in Heptane. mp: C; FTIR (neat, cm -1 ) 3417, 3368, 2980, 2929, 1684, 1519; 1 H NMR (400 MHz, DMSO-d 6 ) (85:15 mixture of rotamers): (br, 1H), 7.84 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), (m, 4H), (m, 3H), 6.80 (d, J = 8.8 S-11

12 Hz, 0.85H), 6.36 (d, J = 9.2 Hz, 0.15H), (m, 1H), 2.86 (d, J = 6.8 Hz, 2H), 2.76 (d, J = 6.8 Hz, 2H), 1.22 (s, 7.65H), 1.04 (s, 1.35H); 13 C NMR (100 MHz, DMSO-d 6 ) (rotamers): δ 155.1(154.6), 139.5, 137.6(137.7), 129.1, 128.0, 126.9, 125.8, (q, 1 J CF = 269 Hz), 125.6, (q, 2 J CF = 32 Hz), (q, 3 J CF = 4 Hz), (q, 3 J CF = 4 Hz), 112.9, 111.9, 77.2, 53.0(53.7), 40.3(41.0), 29.9(30.9), 28.1(27.6); 19 F NMR (DMSO-d 6, 376 MHz): δ HRMS: calcd for C 23 H 25 F 3 N 2 O 2 Na [M+Na] + = , observed = tert-butyl (R)-(1-(7-methyl-1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate (6g): General Procedure C above was performed between 7-methyl-1H-indole (295 mg, 2.25 mmol, 150 mol %) and 5a (470 mg, 1.50 mmol, 100 mol %) to yield compound 6g (371 mg, 68% yield) as a white solid. The C 3 (RT = 4.24 min) / N 1 (RT = 4.43 min) ratio was 96:4. Column Gradient: 0 to 50% iproac in Heptane. mp: C; FTIR (neat, cm -1 ) 3417, 3407, 3370, 2974, 2926, 1683, 1524; 1 H NMR (400 MHz, DMSO-d 6 ) (85:15 mixture of rotamers): δ (br d, J = 2.0 Hz, 1H), (m, 3H), (m, 4H), (m, 2H), 6.74 (d, J = 8.8 Hz, 0.85H), 6.34 (d, J = 7.6 Hz, 0.15H), (m, 1H), (m, 4H), 2.44 (s, 3H), 1.31 (s, 7.65H), 1.14 (s, 1.35H); 13 C NMR (100 MHz, DMSO-d 6 ) (rotamers): δ 155.2, 139.6, 135.7, 129.0, 128.0, 127.2, 125.8, 122.9, 121.3, 120.3, 118.4, 115.9, 111.9, 77.3, 52.6, 39.9, 30.5, 28.2(27.8), HRMS: calcd for C 23 H 29 N 2 O 2 [M+H] + = , observed = tert-butyl (R)-(1-(2-methyl-1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate (6h): General Procedure C above was performed between 2-methyl-1H-indole (295 mg, 2.25 mmol, 150 mol %) and 5a (470 mg, 1.50 mmol, 100 mol %) to yield compound 6h (386 mg, 71% yield) as a white solid. The C 3 (RT = 4.15 min) / N 1 (RT = 4.42 min) ratio was 99:1. Column Gradient: 0 to 50% iproac in Heptane. mp: C; FTIR (neat, cm -1 ) 3440, 3385, 2984, 2930, 1684, 1524; 1 H NMR (400 MHz, DMSO-d 6 ) (83:17 mixture of rotamers): δ (br, 1H), 7.39 (d, J = 7.6 Hz, 0.83H), 7.33 (d, J = 8.0 Hz, 0.17H), (m, 3H), (m, 3H), 6.96 (ddd, J = 8.0, 7.2, 1.2 Hz, 1H), 6.90 (ddd, J = 8.0, 8.0, 1.2 Hz, 1H), 6.73 (d, J = 8.8 Hz, 0.83H), 6.30 (d, J = 8.8 Hz, 0.17H), (m, 1H), 2.85 (dd, J = 14.0, 6.4 Hz, 1H), (m, 3H), 2.32 (s, 3H), 1.27 (s, 7.47H), 1.04 (s, 1.53H); 13 C NMR (100 MHz, DMSO-d 6 ) (rotamers): 155.1, 139.8, 135.2, 132.4, 128.9, 128.7, 128.0, 125.7, 119.8, 118.0, 117.5, 110.2, 107.4, 77.2, 53.4, 39.4, 29.9, 28.2(27.7), HRMS: calcd for C 23 H 28 N 2 O 2 [M] + = , observed = S-12

13 tert-butyl (R)-(1-phenyl-3-(2-phenyl-1H-indol-3-yl)propan-2-yl)carbamate (6i): General Procedure C above was performed between 2-phenyl-1H-indole (435 mg, 2.25 mmol, 150 mol %) and 5a (470 mg, 1.50 mmol, 100 mol %) to yield compound 6i (324 mg, 51% yield) as a white solid. The C 3 (RT = 4.51 min) / N 1 (RT = 4.88 min) ratio was 99:1. Column Gradient: 0 to 50% iproac in Heptane. mp: C; FTIR (neat, cm -1 ) 3380, 3354, 3376, 2981, 2932, 1683, 1508; 1 H NMR (400 MHz, DMSO-d 6 ) (82:18 mixture of rotamers) : δ (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.2 Hz, 2H), 7.44 (dd, J = 7.2, 7.2 Hz, 2H), 7.35 (dd, J = 7.2, 7.2 Hz, 2H), 7.21 (dd, J = 7.2, 7.2 Hz, 2H), (m, 5H), 6.79 (d, J = 9.2 Hz, 0.82H), 6.38 (d, J = 9.6 Hz, 0.18H), (m, 1H), 3.06 (dd, J =14.0, 6.8 Hz, 1H), 2.96 (dd, J = 14.4, 7.2 Hz, 1H), 2.64 (d, J = 6.8 Hz, 2H), 1.21 (s, 7.40H), 0.97 (s, 1.60H); 13 C NMR (100 MHz, DMSO-d 6 ) (rotamers): δ 155.0, 139.5, 136.0, 134.7, 133.0, 129.2, 128.9, 128.6, 128.0, 127.8, 127.1, 125.8, 121.3, 119.2, 118.5, 111.0, 109.2, 77.2, 53.4, 40.2, 28.1(27.6). HRMS: calcd for C 28 H 30 N 2 O 2 [M] + = , observed = tert-butyl (R)-(1-phenyl-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)propan-2-yl)carbamate (6j): General Procedure C above was performed between 1H-pyrrolo[2,3-c]pyridine (266 mg, 2.25 mmol, 150 mol %) and 5a (470 mg, 1.50 mmol, 100 mol %) to yield compound 6j (40 mg, 8% yield) as a white solid. The C 3 (RT = 2.78 min) / N 1 (RT = 3.02 min) ratio was 98:2. Column Gradient: 0 to 50% iproac in Heptane. mp: C; FTIR (neat, cm -1 ) 3360, 2978, 2931, 1685, 1625, 1524; 1 H NMR (400 MHz, CDCl 3 ) (90:10 mixture of rotamers): δ 8.56 (br, 1H), 8.28 (s, 1H), 7.57 (d, J = 6.4 Hz, 1H), (m, 2H), (m, 2H), (m, 2H), 6.70 (br, 1H), 5.44 (br, 0.10H), 5.24 (d, J = 5.6 Hz, 0.90H), 4.52 (dd, J = 13.2, 8.4 Hz, 1H), 4.36 (dd, J = 13.6, 4.8 Hz, 1H), (m, 1H), 3.00 (dd, J = 14.0, 7.6 Hz, 1H), 2.91 (dd, J = 14.0, 6.8 Hz, 1H), 1.27 (s, 8.10H), 1.11 (s, 0.90H); 13 C NMR (100 MHz, CDCl 3 ): δ 155.5, 152.4, 141.1, 136.8, 136.6, 131.4, 129.1, 128.9, 127.1, 125.7, 114.1, 102.6, 79.9, 60.8, 53.4, 38.3, HRMS: calcd for C 21 H 26 N 3 O 2 [M+H] + = , observed = S-13

14 tert-butyl (R)-(2-(1H-indol-3-yl)-1-phenylethyl)carbamate (6k): General Procedure C above was performed between indole (294 mg, 2.51 mmol, 150 mol %) and 5k (500 mg, 1.67 mmol, 100 mol %) to yield compound 6k (398 mg, 71% yield) as a white solid. The C 3 (RT = 3.92 min) / N 1 (RT = 4.16 min) ratio was 99:1. Column Gradient: 0 to 50% iproac in Heptane. mp: C; FTIR (neat, cm -1 ) 3416, 3401, 3371, 2980, 2909, 1683, 1524; 1 H NMR (400 MHz, DMSO-d 6 ) (85:15 mixture of rotamers): δ (br, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), (m, 5H), 7.20 (dd, J = 6.8, 7.2 Hz, 1H), 7.06 (dd, J = 7.6, 7.2 Hz, 1H), 7.02 (s, 1H), 6.98 (dd, J = 7.6, 7.2 Hz, 1H), (m, 1H), 3.08 (dd, J = 14.8, 8.8 Hz, 1H), 2.99 (dd, J = 14.4, 6.0 Hz, 1H), 1.31 (s, 7.65H), 1.08 (s, 1.35H); 13 C NMR (100 MHz, DMSO-d 6 ): δ 155.0, 144.5, 136.0, 128.0, 127.3, 126.5, 126.4, 123.2, 120.8, 118.3, 118.2, 111.3, 111.3, 77.6, 55.0, 32.8, HRMS: calcd for C 21 H 24 N 2 O 2 Na [M+Na] + = , observed = tert-butyl (R)-(2-(1H-indol-3-yl)-1-(4-methoxyphenyl)ethyl)carbamate (6l): General Procedure C above was performed between indole (264 mg, 2.25 mmol, 150 mol %) and 5l (495 mg, 1.50 mmol, 100 mol %) to yield compound 6l (378 mg, 69% yield) as a white solid. The C 3 (RT = 3.85 min) / N 1 (RT = 4.12 min) ratio was 99:1. Column Gradient: 0 to 50% iproac in Heptane. mp: C; FTIR (neat, cm -1 ) 3402, 3326, 2979, 2925, 2904, 1690, 1611, 1506; 1 H NMR (400 MHz, DMSO-d 6 ) (85:15 mixture of rotamers): δ (br, 1H), 7.54 (d, J = 8.0 Hz, 1H), (m, 2H), 7.24 (d, J = 8.8 Hz, 2H), 7.05 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), (m, 2H), 6.84 (d, J = 8.4 Hz, 2H), (m, 1H), 3.72 (s, 3H), 3.06 (dd, J = 14.8, 8.4 Hz, 1H), 2.96 (dd, J = 14.8, 6.4 Hz, 1H), 1.31 (s, 7.65H), 1.11 (s, 1.35H); 13 C NMR (100 MHz, DMSO-d 6 ): δ 157.9, 154.9, 136.4, 136.0, 127.5, 127.3, 123.2, 120.7, 118.3, 118.1, 113.4, 111.4, 111.2, 77.5, 55.0, 54.4, 32.8, HRMS: calcd for C 22 H 26 N 2 O 3 Na [M+Na] + = , observed = S-14

15 tert-butyl (R)-(1-(3-fluorophenyl)-2-(1H-indol-3-yl)ethyl)carbamate (6m): General Procedure C above was performed between indole (263 mg, 2.25 mmol, 150 mol %) and 5m (475 mg, 1.50 mmol, 100 mol %) to yield compound 6m (382 mg, 72% yield) as a white solid. The C 3 (RT = 3.94 min) / N 1 (RT = 4.18 min) ratio was 99:1. Column Gradient: 0 to 50% iproac in Heptane. mp: C; FTIR (neat, cm -1 ) 3414, 3398, 3363, 3055, 2981, 1682, 1591, 1527; 1 H NMR (400 MHz, DMSO-d 6 ) (9:1 mixture of rotamers): δ (br, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), (m, 2H), (m, 2H), (m, 4H), (m, 1H), 3.06 (dd, J = 14.4, 8.4 Hz, 1H), 2.98 (dd, J = 14.4, 6.4 Hz, 1H), 1.30 (s, 8.1H), 1.08 (s, 0.9H); 13 C NMR (100 MHz, DMSO-d 6 ): δ (d, 1 J CF = 243 Hz), 155.0, (d, 3 J CF = 7 Hz), 136.0, (d, 3 J CF = 8 Hz), 127.2, 123.3, 122.6, 120.8, 118.3, 118.2, (d, 2 J CF = 21 Hz), (d, 2 J CF = 21 Hz), 111.3, 111.0, 77.8, 54.7, 32.5, 28.2; 19 F NMR (DMSO-d 6, 376 MHz): δ HRMS: calcd for C 21 H 23 FN 2 O 2 Na [M+Na] + = , observed = F 3 C NHBoc N H tert-butyl (R)-(2-(1H-indol-3-yl)-1-(3-(trifluoromethyl)phenyl)ethyl)carbamate (6n): General Procedure C above was performed between indole (176 mg, 1.50 mmol, 150 mol %) and 5n (368 mg, 1.00 mmol, 100 mol %) to yield compound 6n (320 mg, 79% yield) as a white solid. The C 3 (RT = 4.18 min) / N 1 (RT = 4.41 min) ratio was 98:2. Column Gradient: 0 to 50% iproac in Heptane. mp: C; FTIR (neat, cm -1 ) 3414, 3399, 3361, 2982, 2936, 1683, 1523; 1 H NMR (400 MHz, DMSO-d 6 ) (88:12 mixture of rotamers): δ (br, 1H), (m, 6H), 7.31 (d, J = 8.0 Hz, 1H), (m, 2H), 6.96 (ddd, J = 8.0, 7.2, 1.2 Hz, 1H), (m, 1H), 3.09 (dd, J = 14.4, 8.4 Hz, 1H), 3.00 (dd, J = 14.4, 6.4 Hz, 1H), 1.30 (s, 7.9H), 1.07 (s, 1.1H); 13 C NMR (100 MHz, DMSO-d 6 ): δ 155.1, 145.8, 136.1, 130.8, 129.0, (q, 2 J CF = 32 Hz), 127.3, (q, 1 J CF = 270 Hz), (q, 3 J CF = 4 Hz), 123.0, (q, 3 J CF = 4 Hz), 120.8, 118.3, 118.2, 111.3, 110.8, 77.9, 55.0, 32.5, 28.2; 19 F NMR (DMSO-d 6, 376 MHz): δ HRMS: calcd for C 22 H 23 F 3 N 2 O 2 Na [M+Na] + = , observed = S-15

16 tert-butyl (R)-(1-(1H-indol-3-yl)propan-2-yl)carbamate (6o): General Procedure C above was performed between indole (370 mg, 3.16 mmol, 150 mol %) and 5o (500mg, 2.11 mmol, 100 mol %) to yield compound 6o (406 mg, 70% yield) as a white solid. The C 3 (RT = 3.62 min) / N 1 (RT = 3.84 min) ratio was 99:1. Column Gradient: 0 to 50% iproac in Heptane. mp: C; FTIR (neat, cm -1 ) 3416, 3401, 3366, 2974, 2963, 1684, 1524; 1 H NMR (400 MHz, DMSO-d 6 ): δ (br, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.33 (ddd, J = 8.0, 1.2, 0.8 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 7.05 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 6.97 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), (m, 1H), 2.87 (dd, J = 14.0, 6.0 Hz, 1H), 2.65 (dd, J = 14.0, 7.6 Hz, 1H), 1.38 (s, 9H), 1.01 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, DMSO-d 6 ): δ 155.0, 136.1, 127.5, 123.1, 120.7, 118.4, 118.1, 111.6, 111.2, 77.3, 46.8, 32.2, 28.3, HRMS: calcd for C 16 H 22 N 2 O 2 Na [M+Na] + = , observed = tert-butyl (S)-(1-(1H-indol-3-yl)-3-methylbutan-2-yl)carbamate (6p): General Procedure C above was performed between indole (331 mg, 2.83 mmol, 150 mol %) and 5p (500 mg, 1.88 mmol, 100 mol %) to yield compound 6p (335 mg, 59% yield) as a white solid. The C 3 (RT = 3.97 min) / N 1 (RT = 4.14 min) ratio was 99:1. Column Gradient: 0 to 50% iproac in Heptane. mp: C; FTIR (neat, cm -1 ) 3417, 3402, 3362, 2978, 1686, 1526; 1 H NMR (400 MHz, DMSO-d 6 ) (85:15 mixture of rotamers): δ (br, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.31 (ddd, J = 8.0, 1.2, 0.8 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 7.04 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 6.96 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 6.59 (d, J = 9.2 Hz, 0.85H), 6.15 (d, J = 10.0 Hz, 0.15H), (m, 1H), 2.80 (dd, J = 14.8, 5.2 Hz, 1H), 2.68 (dd, J = 14.8, 8.8 Hz, 1H), (m, 1H), 1.32 (s, 7.65H), 1.12 (s, 1.35H), (m, 6H); 13 C NMR (100 MHz, DMSO-d 6 ): δ 155.6, 136.1, 127.5, 122.7, 120.7, 118.3, 118.0, 112.0, 111.2, 77.1, 55.6, 31.4, 28.3, 27.1, 19.4, HRMS: calcd for C 18 H 26 N 2 O 2 Na [M+Na] + = , observed = S-16

17 tert-butyl (S)-(1-cyclopropyl-2-(1H-indol-3-yl)ethyl)carbamate (6q): General Procedure C above was performed between indole (264 mg, 2.25 mmol, 150 mol %) and 5q (395 mg, 1.50 mmol, 100 mol %) to yield compound 6q (292 mg, 65% yield) as a white solid. The C 3 (RT = 3.82 min) / N 1 (RT = 4.07 min) ratio was 99:1. Column Gradient: 0 to 50% iproac in Heptane. mp: C; FTIR (neat, cm -1 ) 3414, 3400, 3362, 2981, 2937, 1683, 1525; 1 H NMR (400 MHz, DMSO-d 6 ) (9:1 mixture of rotamers): δ (br, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.31 (ddd, J = 8.0, 1.2, 0.8 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 7.04 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 6.95 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 6.66 (d, J = 8.4 Hz, 0.9H), 6.26 (s, 0.1H), (m, 1H), 2.91 (dd, J = 14.4, 5.6 Hz, 1H), 2.85 (dd, J = 14.4, 8.0 Hz, 1H), 1.33 (s, 8.1H), 1.17(s, 0.9H), (m, 1H), (m, 1H), (m, 2H), (m, 1H); 13 C NMR (100 MHz, DMSO-d 6 ): δ 155.3, 136.0, 127.7, 122.9, 120.6, 118.4, 118.0, 111.6, 111.2, 77.2, 54.2, 30.4, 28.2, 16.0, 3.0, 1.9. HRMS: calcd for C 18 H 24 N 2 O 2 Na [M+Na] + = , observed = tert-butyl (S)-(3-(1H-indol-3-yl)-1-phenylpropyl)carbamate (6r): General Procedure C above was performed between indole (264 mg, 2.25 mmol, 150 mol %) and 5r (470 mg, 1.50 mmol, 100 mol %) to yield compound 6r (360 mg, 69% yield) as a white solid. The C 3 (RT = 4.03 min) / N 1 (RT = 4.28 min) ratio was 98:2. Column Gradient: 0 to 50% iproac in Heptane. mp: C; FTIR (neat, cm -1 ) 3390, 2979, 2929, 2859, 1681, 1507, 1457, 1364; 1 H NMR (400 MHz, CDCl 3 ) (80:20 mixture of rotamers): δ 8.04 (br, 0.2H), 7.96 (br, 0.8H), 7.66 (d, J = 8.0 Hz, 0.2H), 7.52 (d, J = 8.0 Hz, 0.8H), (m, 6H), (m, 1H), (m, 1H), 7.00 (br, 1H), 4.88 (br, 0.8H), 4.75 (br, 1H), 4.53 (br, 0.2H), (m, 0.4H), (m, 0.4H), (m, 1.6H), 2.16 (d, J = 8.8 Hz, 1.6 H), 1.42 (s, 9H); 13 C NMR (100 MHz, DMSO-d 6 ) (rotamers): δ 155.4(156.2), 143.0, 136.4(136.6), 128.6, 127.3, 127.2, 126.4, 121.8(122.0), 121.5(120.8), 119.0(119.2), 118.7, 115.3, 111.2(111.3), 79.5, 54.7(46.7), 37.2(31.6), 28.4(29.7), 21.9(18.7). HRMS: calcd for C 22 H 26 N 2 O 2 Na [M+Na] + = , observed = tert-butyl (R)-(2-(1H-indol-3-yl)propyl)carbamate (6s): General Procedure C above was performed between indole (264 mg, 2.25 mmol, 150 mol %) and 5s (356 mg, 1.50 mmol, 100 mol %) to yield compound 6s (319 mg, 78% yield) as a colorless liquid. The C 3 (RT = 3.64 min) / N 1 (RT = 3.82 min) ratio was 93:7. Column Gradient: 0 to 50% iproac in Heptane. FTIR (neat, cm -1 ) 3412, 3327, 2971, 2930, 1685, 1508, 1456; 1 H NMR (400 MHz, DMSO-d 6 ) (9:1 mixture of S-17

18 rotamers): δ (br, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.33 (ddd, J = 8.0, 1.2, 0.8 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 7.05 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 6.96 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 6.86 (dd, J = 6.0, 6.0 Hz, 0.9H), 6.51 (s, 0.1H), 3.29 (ddd, J = 13.2, 5.6, 5.6 Hz, 1H), (m, 1H), 2.97 (ddd, J = 13.2, 8.8, 6.0 Hz, 1H), 1.41 (s, 0.9H), 1.38 (s, 8.1H), 1.25 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, DMSO-d 6 ) (rotamers): δ 155.7, 136.4, 126.6, 121.0, 120.8, 118.6, 118.1, 117.9, 111.4, 77.4, 46.8, 30.9, 28.3(28.2), 18.4(18.2). HRMS: calcd for C 16 H 22 N 2 O 2 Na [M+Na] + = , observed = >99 %ee judged by chiral SFC analysis (Chiral Pak AD-3 column, 4.6 X 50 mm, MeOH with 0.1% NH 4 OH, 5-65%, 3 min) tert-butyl ((1S,2S)-2-(1H-indol-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate (6t): General Procedure C above was performed between indole (282 mg, 2.41 mmol, 150 mol %) and 5t (500 mg, 1.61 mmol, 100 mol %) to yield compound 6t (304 mg, 54% yield) as a white solid. The C 3 (RT = 4.07 min) / N 1 (RT = 4.29 min) ratio was 95:5. Column Gradient: 0 to 50% iproac in Heptane. mp: C; FTIR (neat, cm -1 ) 3387, 3351, 2980, 2938, 1691, 1500; 1 H NMR (400 MHz, DMSO-d 6 ) (87:13 mixture of rotamers): (br, 1H), 7.61 (d, J = 8.0 Hz, 1H), (m, 2H), (m, 4H), 7.17 (dd, J = 8.0, 4.0 Hz, 1H), 7.07 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 6.97 (ddd, J = 8.0, 6.8, 1.22 Hz, 1H), 5.18 (dd, J = 9.2, 9.2 Hz, 1H), 3.69 (dd, J = 18.4, 9.6 Hz, 0.87H), (m, 0.13H), 3.37 (dd, J = 15.2, 8.0 Hz, 0.87H), (m, 0.13H), (m, 0.13H), 2.99 (dd, J = 15.2, 10.4 Hz, 0.87H), 1.38 (s, 7.83H), 1.12 (s, 1.17H); 13 C NMR (100 MHz, DMSO-d 6 ) (rotamers): δ 155.9, 144.5, 141.3, 136.6, 127.2, 127.1, 126.4, 124.4, 123.3, 121.7, 120.9, 119.1, 118.2, 115.5, 111.4, 77.7, 60.8, 44.0, 37.2, 28.2 (27.7). HRMS: calcd for C 22 H 25 N 2 O 2 [M+H] + = , observed = S-18

19 8 Synthesis of Cipargamin and TIK-301 tert-butyl (S)-(1-(6-chloro-5-fluoro-1H-indol-3-yl)propan-2-yl)carbamate (9): To a cold (0 C) mixture of 6-chloro-5-fluoro-indole (7) (643 mg, 3.79 mmol, 150 mol %), and CuCl (325 mg, 3.29 mmol, 130 mol %) in CH 2 Cl 2 (3.0 ml) was added MeMgCl (3.0 M in THF, 1.10 ml, 3.29 mmol, 130 mol %) over 10 min at -10 C. The reaction mixture was stirred at 0 C for 1 h and cooled to -20 C. A solution of 8 (600 mg, 2.53 mmol, 100 mol %) in CH 2 Cl 2 (3.0 ml) was added into the reaction mixture over 30 min at -20 C. The reaction mixture was then stirred at -20 C for 18 h then at 0 C for 4 h, after which HPLC analysis showed complete conversion, quenched with 10% aqueous citric acid (5.0 ml) at 0 C, warmed to room temperature, filtered, extracted with CH 2 Cl 2 (6.0 ml x 2), washed with saturated brine (20.0 ml x 2), dried (Na 2 SO 4 ), filtered, purified by chromatography on SiO 2 (10-80% iproac in heptane) to give 9 as a viscous oil (539 mg, 65% yield). The C 3 (RT = 4.34 min) / N 1 (RT = 4.49 min) ratio was 99:1. FTIR (neat, cm -1 ) 3411, 3362, 2979, 2934, 1679, 1510, 1159; 1 H NMR (400 MHz, DMSO-d 6 ) δ (s, 1H), 7.50 (d, J = 10.4 Hz, 1H), 7.48 (d, J = 6.4 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), (m, 1H), 2.76 (dd, J = 14.2, 6.4 Hz, 1H), 2.66 (dd, J = 14.1, 6.7 Hz, 1H), 1.32 (s, 9H), 1.02 (d, J = 6.6 Hz, 3H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 155.5, (d, 1 J CF = Hz), 132.9, (d, 3 J CF = 8.5 Hz), 126.7, (d, 2 J CF = 21.4 Hz), (d, 3 J CF = 4.7 Hz), 112.6, (d, 2 J CF = 22.8 Hz), 77.9, 47.4, 32.3, 28.7, F NMR (DMSO-d 6, 376 MHz): δ HRMS: calcd for C 16 H 20 ClFN 2 O 2 Na [M+Na] + = , observed = Me F NH Cl Cl N H O N H Cipargamin: To a stirred solution of 9 (500 mg, 1.53 mmol, 100 mol %) in 2-propanol (5.00 ml) was added (1S)-(+)-10-camporsulfonic acid (1.07 g, 4.59 mmol, 300 mol %) as solid. The resulting mixture was warmed to 50 C for 4 h then cooled to room temperature. The reaction mixture was diluted with iproac (20 ml), washed with 1N NaOH (5 ml) and brine (5 ml), dried (Na 2 SO 4 ), filtered, and concentrated to thick brown oil, which was used in the next reaction without purification. The crude product was dissolved in ethanol (7.0 ml) and added 5- chloroindoline-2,3-dione (0.278 g, 1.53 mmol, 100 mol %), followed by ptsoh ( g, mmol, 8 mol %). The resulting mixture was heated to 90 C for 40 h, after which, HPLC analysis showed > 99% conversion. The reaction mixture was then cooled to room temperature, S-19

20 concentrated under vacuum to a thick oil, diluted with iproac (10 ml), washed with saturated NaHCO 3 solution (5 ml) and brine (5 ml), dried (Na 2 SO 4 ), filtered, concentrated and purified by chromatography on SiO 2 (10-100% iproac in heptane) to give the title compound as beige colored powder (544 mg, 91% yield). FTIR (neat, cm -1 ) 3285, 2964, 1710, 1618, 1454, 1177, 815, 555; 1 H NMR (400 MHz, DMSO-d 6 ) δ (s, 1H), (s, 1H), 7.44 (d, J = 10.0 Hz, 1H), 7.34 (dd, J = 8.3, 2.2 Hz, 1H), 7.28 (d, J = 6.4 Hz, 1H), 7.07 (d, J = 2.1 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 3.92 (d, J = 9.9 Hz, 1H), 3.13 (d, J = 5.9 Hz, 1H), 2.78 (dd, J = 15.1, 3.8 Hz, 1H), 2.40 (dd, J = 15.1, 10.5 Hz, 1H), 1.18 (d, J = 6.4 Hz, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 178.6, (d, 1 J CF = Hz), 142.1, 134.4, 134.4, 133.2, 129.6, 126.2, (d, 3 J CF = 8.8 Hz), 125.4, (d, 2 J CF = 21.2 Hz), 112.5, (d, 3 J CF = 4.7 Hz), 111.7, (d, 2 J CF = 22.8 Hz), 62.4, 44.6, 29.8, F NMR (DMSO-d 6, 376 MHz): δ HRMS: calcd for C 19 H 15 Cl 2 FN 3 O [M+H] + = , observed = >99 %ee judged by chiral SFC analysis (Chiralcel OD-3 column, 4.6 X 50 mm, MeOH with 0.1% NH 4 OH, 5-65%, 3 min, Retention time 1.87 min for cipargamin and 2.00 min for ent-cipargamin). tert-butyl (R)-(2-(6-chloro-5-methoxy-1H-indol-3-yl)propyl)carbamate (11): To a cold (0 C) mixture of 6-chloro-5-methoxy-1H-indole (10) (540 mg, 2.97 mmol, 150 mol %), and CuCl (255 mg, 2.58 mmol, 130 mol %) in CH 2 Cl 2 (3.0 ml) was added MeMgCl (3.0 M in THF, 0.86 ml, 2.58 mmol, 130 mol %) over 10 min at -0 C. The reaction mixture was stirred at 0 C for 1 h and cooled to -20 C. A solution of 5s (470 mg, 1.98 mmol, 100 mol %) in CH 2 Cl 2 (3.0 ml) was added into the reaction mixture over 30 min at -20 C. The reaction mixture was then stirred at -20 C for 18 h, quenched with 10% aqueous citric acid (5.0 ml) at 0 C, warmed to room temperature, filtered, extracted with CH 2 Cl 2 (10.0 ml x 2), washed with saturated brine (20.0 ml x 2), dried (Na 2 SO 4 ), filtered, purified by chromatography on SiO 2 (0-60% iproac in heptane) to give 11 as a pale yellow solid (504 mg, 67% yield). The C 3 (RT = S-20

21 3.71 min) / N 1 (RT = 3.87 min) ratio was 93:7. mp: C; FTIR (neat, cm -1 ) 3408, 3322, 2970, 2931, 1687, 1509, 1475, 1455; 1 H NMR (400 MHz, CDCl 3 ): δ 7.97 (br, 1H), 7.39 (s, 1H), 7.15 (s, 1H), 6.99 (d, J = 2.4 Hz, 1H), 4.56 (br, 1H), 3.95 (s, 3H), (m, 2H), (m, 1H), 1.42 (s, 9H), 1.35 (d, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ 156.1, 149.3, 131.2, 125.8, 121.7, 119.0, 118.8, 112.7, 101.7, 79.2, 56.9, 46.8, 31.6, 28.4, HRMS: calcd for C 17 H 23 ClN 2 O 3 [M] + = , observed = >99 %ee judged by chiral SFC analysis (Chiral Pak AD-3 column, 4.6 X 50 mm, MeOH with 0.1% NH 4 OH, 5-65%, 3 min). (R)-2-(6-chloro-5-methoxy-1H-indol-3-yl)propan-1-amine (12). To a stirred solution of 11 (490 mg, 1.45 mmol, 100 mol %) in 2-propanol (4.9 ml) was added L-camphorsulfonic acid (1.01 g, 4.34 mmol, 300 mol %). The reaction mixture was heated at 50 C for 16 h, after which HPLC analysis showed complete conversion, cooled to room temperature, diluted with iproac (10.0 ml), quenched with a solution of NaOH (289 mg, 7.23 mmol, 500 mol %) in H 2 O (5.0 ml), extracted with iproac (10.0 ml), washed with saturated brine (5.0 ml x 2), dried (Na 2 SO 4 ), filtered, and concentrated to dryness to provide 12 (289 mg, 84% yield) as a pale yellow liquid: FTIR (neat, cm -1 ) 3186, 2957, 2927, 2869, 1577, 1474, 1454, 1310; 1 H NMR (400 MHz, CDCl 3 ): δ 8.43 (br, 1H), 7.33 (s, 1H), 7.09 (s, 1H), 6.94 (s, 1H), 3.90 (s, 3H), (m, 1H), (m, 2H), 1.54 (br, 2H), 1.33 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ 149.2, 131.3, 125.9, 121.9, 119.2, 118.6, 112.7, 101.7, 56.9, 48.5, 34.3, HRMS: calcd for C 12 H 16 ClN 2 O [M+H] + = , observed = S-21

22 TIK-301. To a stirred solution of 12 (280 mg, 1.17 mmol, 100 mol %) in THF (2.5 ml) was added a solution of NaOH (93.8 mg, 2.35 mmol, 200 mol %) in H 2 O (2.5 ml) and acetic anhydride (222 µl, 2.35 mmol, 200 mol %). The reaction mixture was then stirred at room temperature for 2 h, after which HPLC analysis showed complete conversion, quenched with aqueous saturated NaHCO 3 solution (5.0 ml) and iproac (10.0 ml), extracted with iproac (10.0 ml), washed with saturated brine (10.0 ml x 2), dried (Na 2 SO 4 ), filtered, purified by chromatography on SiO 2 (0-60% iproac in heptane) to give TIK-301 as a pale yellow liquid (232 mg, 71% yield): FTIR (neat, cm -1 ) 3405, 3276, 2962, 2930, 1644, 1538, 1474, 1441, 1308; 1 H NMR (400 MHz, CDCl 3 ): δ 8.22 (br, 1H), 7.39 (s, 1H), 7.15 (s, 1H), 6.99 (dd, J = 2.8, 0.8 Hz, 1H), 5.51 (br, 1H), 3.93 (s, 3H), (m, 2H), (m, 1H), 1.91 (s, 2H), 1.35 (d, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ): 170.5, 149.0, 131.3, 125.7, 121.8, 118.4, 118.3, 112.8, 101.4, 56.8, 45.8, 30.9, HRMS: calcd for C 14 H 18 ClN 2 O 2 [M+H] + = , observed = References [1] O Brien, P.; Osborne, S. A.; Parker, D. D. J. Chem. Soc., Perkin Trans , [2] O Toole, S.E.; Connon, S. J. Org. Biomol. Chem. 2009, 7, H, 13 C and 19 F NMR Spectra S-22

23 S-23

24 S-24

25 S-25

26 S-26

27 S-27

28 S-28

29 S-29

30 S-30

31 S-31

32 S-32

33 S-33

34 S-34

35 S-35

36 S-36

37 S-37

38 S-38

39 S-39

40 S-40

41 Bn NHBoc N H 6a Bn NHBoc N H 6a S-41

42 S-42

43 S-43

44 S-44

45 S-45

46 Bn F 3 C NHBoc N H 6f Bn F 3 C NHBoc N H 6f S-46

47 Bn F 3 C NHBoc N H 6f S-47

48 S-48

49 S-49

50 S-50

51 Ph NHBoc N H 6k S-51

52 Ph NHBoc N H 6k OMe NHBoc N H 6l S-52

53 OMe NHBoc N H 6l S-53

54 S-54

55 F 3 C NHBoc N H 6n F 3 C NHBoc N H 6n S-55

56 F 3 C NHBoc N H 6n S-56

57 S-57

58 S-58

59 S-59

60 S-60

61 S-61

62 Me F NHBoc Cl 9 N H S-62

63 Me F NHBoc Cl 9 N H Me F NHBoc Cl 9 N H S-63

64 S-64

65 S-65

66 S-66

67 S-67

68 S-68