Construction of Cyclic Sulfamidates Bearing Two gem-diaryl Stereocenters through a Rhodium-Catalyzed Stepwise Asymmetric Arylation Protocol

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1 Supporting Information for: Construction of Cyclic Sulfamidates Bearing Two gem-diaryl Stereocenters through a Rhodium-Catalyzed Stepwise Asymmetric Arylation Protocol Yu-Fang Zhang, Diao Chen, Wen-Wen Chen and Ming-Hua Xu* State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai , China xumh@simm.ac.cn Table of Contents 1. General...S2 2. General procedure for Rh-catalyzed 1,4-addition of α,β-unsaturated cyclic ketimines 1...S2 3. General procedure for Rh-catalyzed 1,2-addition of ketimines 3a..S2 4. Procedure for Rh-catalyzed arylation of ketimine 6 S3 5. Characterization data and HPLC chromatogram of addition products S4 6. Synthetic transformations of arylation products...s33 7. Copies of 1 H NMR and 13 C NMR spectra...s37 S1

2 1. General All anaerobic and moisture-sensitive manipulations were carried out with standard Schlenk techniques under pre-dried nitrogen or argon. Solvents were dried and distilled by standard procedures. NMR spectra were recorded on a Mercury 300 spectrometer (300 MHz for 1 H), and Varian spectrometer (400 MHz for 1 H, 100 MHz or 125 MHz for 13 C). Chemical shifts are reported in δ ppm referenced to an internal SiMe 4 standard for 1 H NMR and chloroform-d (δ 77.36) for 13 C NMR. HRMS were recorded on a Q-TOF mass spectrometer with ESI resource or Magnetic Sector for EI. Optical rotations were measured on a Perkin-Elmer 241 MC polarimeter. HPLC was performed on a JASCO 2000 instrument by using Daicel columns with 2-propanol/hexane as the eluent. 2. General procedure for Rh-catalyzed 1,4-addition of α,β-unsaturated cyclic ketimines 1 Under Ar atmosphere, a solution of substrate α,β-unsaturated ketimine 1 (0.20 mmol), [Rh(COE) 2 Cl] 2 (2.5 mol %, 3.6 mg, 0.01 mmol of Rh), ligand L7 (5.0 mol %, 3.2 mg, 0.01 mmol), and arylboronic acid (0.40 mmol) in 1.0 ml of toluene was stirred at room temperature for 30 min. To this mixture was added aqueous K 2 HPO 4 (66 µl, 1.5 M, 0.10 mmol) and then the resulting mixture was stirred at room temperature (unless noted otherwise) for 12 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate as an eluent to afford the corresponding addition product 3 (Note: For HPLC reference, (±)-3 was obtained with [Rh(COD) 2 Cl] 2 as catalyst under the same conditions). 3. General procedure for Rh-catalyzed 1,2-addition of ketimine 3 Under Ar atmosphere, a solution of substrate ketimine 3 (0.10 mmol), [Rh(COE) 2 Cl] 2 (1.5 mol %, 1.1 mg, mmol of Rh), ligand L1 (1.0 mg, mmol), and arylboronic acid 2b (0.20 mmol) in 1.0 ml of toluene was stirred at room temperature for 30 min. To this mixture was added aqueous KF (0.2 ml, 1.5M, 0.30 mmol) and then the resulting mixture was stirred at 80 o C (unless noted otherwise) for 12 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate as an eluent to afford the corresponding addition product 4. S2

3 4. Procedure for Rh-catalyzed arylation of ketimine 6 Under Ar atmosphere, a solution of substrate α,β-unsaturated ketimine 6 (0.20 mmol), [Rh(COE) 2 Cl] 2 (2.5 mol %, 3.6 mg, 0.01 mmol of Rh), ligand L7 (5.0 mol %, 3.2 mg, 0.01 mmol), and p-tolylboronic acid 2a (0.40 mmol, 2 equiv) in 1.0 ml of toluene was stirred at room temperature for 30 min. To this mixture was added aqueous K 2 HPO 4 (66 µl, 1.5 M, 0.10 mmol) and then the resulting mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate as an eluent to afford 1,4-adduct 7 and double arylation product 8 respectively (Note: For HPLC reference, (±)-7 was obtained with [Rh(COD) 2 Cl] 2 as catalyst under the same conditions). Double arylation product 8 was obtained as the sole product in the presence of 3 equiv of p-tolylboronic acid 2a (0.60 mol) for 24 h. S3

4 5. Characterization data and HPLC of addition products (R)-4-(2-phenyl-2-(p-tolyl)ethyl)benzo[e][1,2,3]oxathiazine 2,2-dioxide (3a) White solid, 75 mg, 99% % yield, 93% ee. [α] 20 D = (c 1.0, CHCl 3 ). 1 H NMR (300 MHz, CDCl 3 ) δ 7.69 (dd, J = 8. 0, 1.5 Hz, 1H), (m, 1H), (m, 11H), 4.73 (t, J = 7.55 Hz, 1H), 3.70 (d, J = 7.5 Hz, H 2H), (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 178.9, 153.8, 143.2, 140.0, 137.2, 136.8, 129.7, 129.0, 128.3, 128.0, 127.9, 127.1, 126.0, 119.4, 116.7, 47.9, 41.8, HRMS (ESI): m/z [M-H] - calcd for C22H18NO3S: ; found: HPLC: Chiralpak IC column (250( mm); detected at 224 nm; hexane/ /i-propanol = ml/min; Retention time: 25.3 min (major), 28.8 min. 93% ee. 80/20; flow = 0.7 S4

5 (R)-4-(2-(4-methoxyphenyl)-2-phenylethyl)benzo[e][1,2,3]oxathiazine 2,2-dioxidee (3b) White solid, 71 mg, 90% % yield, 93% ee. [α] 20 D = (c 0.8, CHCl 3 ). 1 H NMR (300 MHz, CDCl 3 ) δ 7.67 (dd, J = 19.0, 7.9 Hz, 2H), (m, 9H), 6.80 (d, J = 8.5 Hz, 2H), 4.73 (t, J = 7.6 Hz, 1H), 3.75 (s, 3H), 3.70 (d, J = 7.5 Hz, 2H) ). 13 C NMR (125 MHz, CDCl 3 ) δ 178.9, 158.7, 153.9, 143.4, 137.2, 135.1, , , 128.3, 128.0, 127.2, 126.0, 119.5, 116.8, 114.4, 55.6, 47.6, HRMS (ESI): m/z [M-H][ - calcd for C22H18NO4S: ; found: HPLC: Chiralpak AD-H column (250 mm); detected at 224 nm; hexane/i-propanol = 95/5; flow = 1.0 ml/min; Retention time: 36.4 min (major), 41.6 min. 93% ee. S5

6 (R)-4-(2-(4-chlorophenyl)-2-phenylethyl)benzo[e][1,2,3]oxathiazine 2,2-dioxide (3c) White solid, 71 mg, 89% yield, 91% ee. [α] 20 D = 3.40 (c 0.8, CHCl 3 ). 1 H NMR (300 MHz,, CDCl 3 ) δ (m, 2H), (m, 11H), 4.78 (t, J = 7.4 Hz, 1H), 3.71 (d,( J = 7.5 Hz, 2H). 13 C NMR (150 MHz, CDCl 3 ) δ 178.3, 153.9, 142.6, 141.5, 137.4, 133.0, 129.5, 129.2, 128.1, 128.0, 127.5, 126.1, 119.6, 116.7, 47.3, HRMS (ESI): m/z [M-H] - calcd for C21H15NO3SCl: ; found: HPLC: Chiralpak IC column (250( mm); detected at 224 nm; hexane/ /i-propanol = ml/min; Retention time: 34.3 min (major), 39.0 min. 91% ee. 85/15; flow = 0.8 S6

7 (R)-4-(2-phenyl-2-(o-tolyl)ethyl)benzo[e][1,2,3]oxathiazine 2,2-dioxide (3d) White solid, 72 mg, 96% yield, 99% ee. [α] 20 D = (c 1.0, CHCl3). 1 3 H NMR (300 MHz, CDCl 3 ) δ (m, 2H), (m, 11H), 4.96 ( t, J = 7.4 Hz, 1H), 3.73 (d, J = 7.5 Hz, 2H), 2.26 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 179.0, 153.9, 142.6, 140.8, , 136.9, 131.4, 129.0, 128.3, 128.2, 127.2, 127.1, 126.5, 126.4, 126.0, 119.5, 116.9, 44.3, 42.1, HRMS (ESI): m/z [M-H] - calcd for C22H18NO3S: ; found: HPLC: Chiralpak AY-H column (250 mm); detected at 224 nm; hexane/i-propanol = 85/15; flow = 0.7 ml/min; Retention time: 27.4 min, 32.1 min (major). 99% ee. S7

8 (R)-4-(2-(2-bromophenyl)-2-phenylethyl)benzo[e][1,2,3]oxathiazine 2,2-dioxide (3e) White solid, 84 mg, 95% yield, 99% ee. [α] 20 D = 2.00 (c 1.0,, CHCl 3 ). 1 H NMR (300 MHz, CDCl 3 ) δ 7.78 (d, J = 7.9 Hz, 1H), (m, 1H), 7.54 (d, J = 7.8 Hz, 1H), (m, 9H), 7.09 ( d, J = 3.7 Hz, 1H), 5.25 (t, J = 7.4 Hz, 1H), (m, 2H). 13 C NMR (125 MHz, CDCl3) 3 δ 177.0, 153.0, 141.0, 140.4, 136.2, 132.8, 128.1, 127.8, 127.4, 127.2, 127.1, 126.4, 125.1, 124.2, 118.6, 115.6, 45.9, HRMS (ESI): m/z [M-H] - calcd for C21H15NO3SBr: ; found: HPLC: Chiralpak AD-3 column (250 mm); detected at 224 nm; hexane/i-propanol = 95/5; flow = 0.7 ml/min; Retention time: 39.6 min (major), 44.5 min. 99% ee. S8

9 (R)-4-(2-(2-fluorophenyl)-2-phenylethyl)benzo[e][1,2,3]oxathiazine 2,2-dioxide 2 (3f) White solid, 68 mg, 89% yield, 85% ee. [α] 20 D = (c 1.0, CHCl3). 1 3 H NMR (300 MHz, CDCl 3 ) δ 7.80 (d, J = 7.9 Hz, 1H), (m, 1H), (m, 9H), (m, 2H), 5.00 (t, J = 7.5 Hz, 1H), 3.79 (d, J = 7.6 Hz, 2H). 13 C NMR (125 MHz, CDCl 3 ) δ 178.2, (d, J CF = 245 Hz), 153.9, 141.6, 137.2, (d, J CF = 13.8 Hz), (d,, J CF = 3.8 Hz), , , , 127.5, 126.1, (d, J CF = 3.8 Hz),, 119.6, (d, J CF = Hz), 42.4, HRMS (ESI):( m/z [M-H] - calcd for C21H15NO3SF: ; found: HPLC: Chiralpak IC column (250( mm); detected at 224 nm; hexane/ /i-propanol = ml/min; Retention time: 38.5 min (major), 45.1 min. 85% ee. 85/15; flow = 0.8 S9

10 (R)-4-(2-(naphthalen-1-yl)-2-phenylethyl)benzo[e][1,2,3]oxathiazinee 2,2-dioxide (3g) White solid, s 81 mg,, 98% yield, 99% ee. [α] 20 0 D = (c 1.0, CHCl3). 1 3 H NMR (300 MHz, CDCl 3 ) δ (m, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 4H), (m, 6H), 7.14 (d, J = 6.8 Hz, 1H) ), (t, J = 7.1 Hz, 1H), (m, 2H). 13 C NMR (125 MHz, CDCl 3 ) δ 179.0, , 142.8, 138.7, 137.2, 134.5, 131.7, 129.2, 129.1, , , 128.1, 127.3, 126.8, 126.1, 126.0, 125.5, 124.7, 123.9, 119.5, 116.9, , HRMS (ESI):( m/z [M-H] - calcd for C25H18NO3S: ; ; found: HPLC: Chiralpak AD-H column (250 mm); detected at 224 nm; hexane/i-propanol = 95/5; flow = 0.7 ml/min; Retention time: 23.6 min (major), 30.4 min. 99% ee. S10

11 (R)-4-(2-(naphthalen-2-yl)-2-phenylethyl)benzo[e][1,2,3]oxathiazinee 2,2-dioxide (3h) White solid, 74 mg, 90% yield, 91% ee. [α] 20 D = (c 1.0,, CHCl 3 ). 1 H NMR (300 MHz, CDCl 3 ) δ (m, 5H), (m, 1H), (m, 2H), (m, 8H), (t, J = 7.3 Hz, 1H), 3.81 (d, J = 7.4 Hz, 2H). 13 C NMR (125 MHz, CDCl 3 ) δ 177.8, 152.8, 141.8, 139.5, 136.2, 132.7, 131.6, 128.1, 127.9, 127.3, 127.2, 127.1, 126.9, 126.3, 125.7, 125.6, , , 125.0, 118.5, 115.8, 47.2, HRMS (ESI): m/z [M-H] - calcd for C25H18NO3S: ; found: HPLC: Chiralpak AD-H column (250 mm); detected at 224 nm; hexane/i-propanol = 85/15; flow = 0.7 ml/min; Retention time: 23.1 min (major), 27.4 min. 91% ee. S11

12 (R)-4-(2-phenyl-2-(m-tolyl)ethyl)benzo[e][1,2,3]oxathiazine 2,2-dioxide (3i) White solid, 72 mg, 96% yield, 83% ee. [α] 20 D = (c 1.0,, CHCl 3 ). 1 H NMR (300 MHz, CDCl 3 ) δ (m, 2H), (m, 8H), 7.00 (dd, J = 14.7, 7.1 Hz, 3H), 4.72 (t, J = 7.4 Hz, 1H), 3.70 (d, J = 7.5 Hz, 2H), 2.27 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 178.9, 153.9, 143.0, 142.9, 138.7, 137.1, 129.1, 129.0, 128.9, 128.2, 128.1, 128.0, 127.2, 126.0, 125.0, 119.5,, 116.8, 48.3, 41.8, HRMS (ESI): m/z [M-H] - calcd for C22H18NO3S: ; found: HPLC: Chiralpak AD-H column (250 mm); detected at 224 nm; hexane/i-propanol = 95/5; flow = 0.7 ml/min; Retention time: 24.5 min (major), 26.6 min. 83% ee. S12

13 (R)-3-ethyl-3-(3-methoxyphenyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (3j) White solid, 72 mg,, 92% yield, 84% ee. [α] 20 D = 5.03 (c 1.0, CHCl 3 ). 1 H NMR (300 MHz, CDCl 3 ) δ 7.68 (dd, J = 17.4, 7. 8 Hz, 2H), (m, 8H), (m, 3H), 4.77 (t, J = 7.4 Hz, 1H), 3.75 (s, 3H), 3.73 (d, J = 7. 6 Hz, 2H). 133 C NMR (1255 MHz, CDCl 3 ) δ 178.4, 159.8, 153.5, 144.3, 142.5, 136.8, 129.7, 128.7, 127.9, 127.7, , 125.7, 120.1, 119.2, 116.5, 113.9, 112.0, 55.2, 47.9, HRMS (ESI): m/z [M-H] - calcd for C 22 H18NO 1 4 S: ; found: HPLC: Chiralpak IC column (250( mm); detected at 224 nm; hexane/ /i-propanol = ml/min; Retention time: 50.3 min, 75.5 min (major). 84% ee. 85/15; flow = 0.7 S13

14 (R)-4-(2-(3,4-dimethoxyphenyl)-2-phenylethyl)benzo[e][1,2,3]oxathiazine 2,2-dioxide (3k) 20 Whitee solid, 77 mg, 91% yield, 94% ee. [α] D = (c 1.0, CHCl3). 1 3 H NMR (300 MHz, CDCl 3 ) δ 7.66 (dd, J = 15.7,, 7.8 Hz, 2H), (m, 7H), 6.75 ( d, J = 4.6 Hz, 3H), 4.74 (t, J = 7.4 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.70 ( dd, J = 7.4, 4.5 Hz, 2H). 13 C NMR (125 MHz, CDCl 3 ) δ 179.1, 153.8, 149.2,, 148.2, 143.2, 137.2, 135.6, 129.0, 128.3, 127.9, 127.2, 126.0, 119.7, , 112.0,, 111.5, 56.19, 56.17, 48.0, HRMS (ESI): m/z [M-H] - calcd for C 23 H 20 NO 5 S: ; found: HPLC: Chiralpak AD-H column (250 mm); detected at 224 nm; hexane/i-propanol = 80/20; flow = 0.7 ml/min; Retention time: 20.4 min (major), 30.0 min. 94% ee. S14

15 (R)-6-methyl-4-(2-(naphthalen-1-yl)-2-phenylethyl)benzo[e][1,2,3]oxathiazine 2,2-dioxide (3l)) White solid, s 84 mg,, 98% yield, 98% ee. [α] 2 0 D = (c 1.0, CHCl3). 1 H NMR (300 MHz, CDCl 3 ) δ (m, 1H), (m, 2H), (m, 5H), (m, 5H), 7.12 (dd, J = 18.9, 7.66 Hz, 2H), 5.56 (t, J = 6.0, 1H), (m, 2H), 2.28 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 179.2, 151.8, , 137.9, 136.0, , 131.7, 129.2, 129.1, 128.2, 128.1, 127.2, 126.8, 126.1, 125.5, 124.8, 124.0, 119.1, 116.7,, 44.3, 41.9, HRMS (ESI):( m/z [M-H] - calcd for C26H21NO3S: ; found: HPLC: Chiralpak AD-H column (250 mm); detected at 224 nm; hexane/i-propanol = 95/5; flow = 1.0 ml/min; Retention time: 18.6 min (major), 22.8 min. 98% ee. S15

16 (R)-6-methyl-4-(2-phenyl-2-(p-tolyl)ethyl)benzo[e][1,2,3]oxathiazinee 2,2-dioxide (3m) White solid, 55 mg, 70% % yield, 94% ee. [α] 20 D = (c 1.0,, CHCl 3 ). 1 H NMR (300 MHz, CDCl 3 ) δ (m, 2H), (m, 5H), (m, 5H), 4.73 (t, J = 7.4 Hz, 1H) ), 3.68 (d, J = 7.4 Hz, 2H), 2.35 (s, 3H) ), 2.28 (s, 3H) ). 13 C NMR (150 MHz, CDCl 3 3) δ 179.0, 151.8, 143.3, 140.1, 137.9, 136.8, 136.0, 129.7, 129.0, 128.2, 128.1, 128.0, 127.1, 119.1, 116.6, 47.9, 41.9, 21.3, HRMS (ESI): m/z [M-H] - calcdd for C23H20NO3S: ; found: HPLC: Chiralpak IC column (250( mm); detected at 224 nm; hexane/ /i-propanol = ml/min; Retention time: 29.7 min (major), 33.8 min. 94% ee. 85/15; flow = 1.0 S16

17 (R)-6-chloro-4-(2-phenyl-2-(p-tolyl)ethyl)benzo[e][1,2,3]oxathiazine 2,2-dioxide (3n) White solid, 72 mg, 92% % yield, 90% ee. [α] 20 D = 0.17 (c 1.0, CHCl 3 ). 1 H NMR (300 MHz, CDCl 3 ) δ (m, 2H), (m, 6H), (m, 4H), 4.71 (t, J = 7.5 Hz, 1H), 3.68 (d, J = 7.5 Hz, 2H), 2.28 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 178.1, 152.2, 143.0, 139.8, 137.0, 136.8, 131.5, 129.8, 129.1, 128.0, 127.9, 127.3, 120.9, 117.7, 48. 1, 42.0, HRMS (ESI): m/z [M-H] - calcd for C22H17N NO3SCl: ; found: HPLC: Chiralpak IC column (250( mm); detected at 224 nm; hexane/ /i-propanol = ml/min; Retention time: 27.2 min (major), 32.8 min. 90% ee. 85/15; flow = 0.7 S17

18 (S)-4-(2-(3-chlorophenyl)-2-phenylethyl)benzo[e][1,2,3]oxathiazine 2,2-dioxide 2 (3o) White solid, 69% mg, 87% yield, 82% ee. [α] 20 D = 4.17 (c 1.0, CHCl 3 ). 1 H NMR (300 MHz, CDCl 3 ) δ 7.70 (dd, J = 18.6, 8.5 Hz, 2H), (m, 11H), (t, J = 7.3 Hz, 1H), 3.73 (d, J = 7.3 Hz, 2H). 13 C NMR (125 MHz, CDCl 3 ) δ 178.1, 153.9, 145.1, 142.3, 137.3, 134.9, 130.1, 129.3, 128.2, 128.1, 127.6, 127.5, 126.5, 126.1, 119.6, 116.7, 47.6, HRMS ( ESI): m/z [M-H] - calcd for C 21 H 15 NO 3 SCl: ; found: HPLC: Chiralpak IC column (250( mm); detected at 224 nm; hexane/ /i-propanol = ml/min; Retention time: 33.2 min, 36.0 min (major). 82% ee. 85/15; flow = 0.8 S18

19 (S)-4-(2-phenyl-2-(m-tolyl)ethyl)benzo[e][1,2,3]oxathiazine 2,2-dioxide (3i ) White solid, 75 mg, 99% yield, 98% ee. [α] 20 D = (c 1.0,, CHCl 3 ). 1 H NMR (300 MHz, CDCl 3 ) δ (m, 2H), (m, 8H), 7.01 (dd, J = 13.1, 6.9 Hz, 3H), 4.73 (t, J = 7.4 Hz, 1H), 3.71 (d, J = 7.5 Hz, 2H) H), 2.28 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 178.9, 153.8, 143.0, 142.9, 138.7, 137.1, 128.3, 128.1, 128.0, 127.2, 126.0, 125.0, 119.5, 116.8, 48.3, 41.8, HRMS (ESI):( m/z [M-H] - calcd for C 22 H 18 NO 3 S: ; ; found: HPLC: Chiralpak AD-H column (250 mm); detected at 224 nm; hexane/i-propanol = 95/5; flow = 0.7 ml/min; Retention time: 24.4 min, 26.3 min (major). 88% ee. S19

20 (S)-4-(2-phenyl-2-(p-tolyl)ethyl)benzo[e][1,2,3]oxathiazine 2,2-dioxide (3a ) White solid, 67 mg, 89% % yield, 87% ee. [α] 20 D = 0.25 (c 1.0, CHCl 3 ). 1 H NMR (300 MHz,, CDCl 3 ) δ (m, 2H), (m, 11H), 4.73 (t, J = 7.4 Hz, 1H), 3.69 (d,( J = 7.5 Hz, 2H), 2.26 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 178.9, 153.8, , 140.0, 137.2, 136.8, 129.7, 129.0, 128.3, 128.0, 127.9, 127.1, 126.0, 119.4, 116.8, 47.9, 41.8, HRMS (ESI): m/z [M-H] - calcdd for C 22 H 18 NO 3 S: ; found: f HPLC: Chiralpak IC column (250( mm); detected at 224 nm; hexane/ /i-propanol = ml/min; Retention time: 25.6 min, 28.8 min (major). 87% ee. 80/20; flow = 0.7 S20

21 (R)-4-(2-(naphthalen-1-yl)-2-(p-tolyl)ethyl)benzo[e][1,2,3]oxathiazine 2,2-dioxidee (3p) White solid, 85 mg, 99% yield, 99% ee. [α] 20 D = (c 1.0, CHCl3). 1 3 H NMR (300 MHz, CDCl 3 ) δ (m, 1H), (m, 2H), 7.63 (dd, J = 13.6, 7.8 Hz,, 2H), 7.46 (d, J = 4.5 Hz, 4H), (m, 4H), 7.04 (d, J = 7.5 Hz, 2H),, 5.56 (t, J = 7.1 Hz, 1H), (m, 2H), 2.25 (s,, 3H). 13 C C NMR (125 MHz, CDCl 3 ) δ 179.1, 153.7, 139.8, 138.9, 137.1, 136.8, , 131.6, 129.7, 129.2, 128.2, 128.1, 128.0, 126.7, , , 125.5, 124.6, 123.9, 119.4, , 43.6, 42.0, HRMS (ESI): m/z [M-H] - calcd for C 26 H 21 NO 3 S: S ; found: HPLC: Chiralpak AD-H column (250 mm); detected at 224 nm; hexane/i-propanol = 95/5; flow = 1.0 ml/min; Retention time: 21.4 min (major), 26.2 min. 99% ee. S21

22 (S)-4-(2-(2-fluorophenyl)-2-phenylethyl)benzo[e][1,2,3] oxathiazine 2,2-dioxide 2 (3f ) White solid, 71 mg, 93% yield, 86% ee. [α] 20 D = 8.65 (c 1.0, CHCl 3 ). 1 H NMR (300 MHz, CDCl 3 ) δ 7.80 (d, J = 8.0 Hz, 1H), (m, 1H), (m, 9H), (m, 2H), 5.00 (t, J = 7.6 Hz, 1H) ), 3.78 (d, J = 7.6 Hz, 2H) ). 13 C NMR (125 MHz, CDCl 3 ) δ 178.3, (d, J CF = Hz), 153.9, 141.6, 137.2, (d, J CF = 13.8 Hz), (d, J CF = 5.0 Hz), 129.1, , , , , 126.1, (d, J CF = 3..8 Hz), 119.6,, 116.6, (d, J CF = Hz), 42.3, HRMS (ESI):( m/z [M-H] - calcd for C 21 H 16 NO 3 SF: ; found: HPLC: Chiralpak IC column (250 mm); detected at 224 nm; hexane/i-propanol = 85/ /15; flow = 0.8 ml/min; Retention time: 38.0 min, 43.2 min (major). 86% ee. S22

23 (S)-4-(2-(2-fluorophenyl)-2-(o-tolyl)ethyl)benzo[e][1,2,3]oxathiazinee 2,2-dioxide (3q) White solid, s 78 mg,, 99% yield, 99% ee. [α] 20 0 D = (c 1.0, CHCl3). 1 3 H NMR ( 300 MHz, CDCl 3 ) δ 7.79 (d, J = 7.8 Hz, 1H), (m, 1H),, 7.34 (dd, J = 11.3, 7.6 Hz, 2H), (m, 8H), (t, J = 7.55 Hz, 1H), 3.74 (d, J = 7.1 Hz, 2H), (s, 3H). 13 C NMR (125 MHz, M CDCl 3 ) δ 178.4, (J CF = Hz), 153.8, 139.4, 137.2, 136.8, 131.3, (J CF = 4.1 Hz), (J CF = 8.3 Hz), 128.1, 127.4, 126.8, 126.5, , (J CF = 3.3 Hz), 119.5, 116.6, 116.0, 115.8, 41.0, 37.6, HRMS (ESI): m/z [M-H] - calcd for C 22 H 18 NO 3 SF: ; found: HPLC: Chiralpak IC column (250 mm); detected at 224 nm; hexane/i-propanol = 85/ /15; flow = 1.0 ml/min; Retention time: 19.7 min, 21.4 min (major). 99% ee. S23

24 (R)-4-(4-methoxyphenyl)-4-((R)-2-phenyl-2-(p-tolyl)ethyl)-3,4-dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide (4a) White solid, 40 mg, 83% yield, 99.5% de. [α] 20 D = (c 1.0, CHCl 3 ). 1 H NMR (300 MHz, CDCl 3 ) δ (m, 1H), (m, 2H), 7.31 (d, J = 4.6 Hz, 5H), (m, 3H), 7.04 (s, 4H), 6.83 (d, J = 8.9 Hz, 2H), 4.68 (s, 1H), 3.84 (d, J = 10.5 Hz, 1H), 3.78 (s, 3H), 3.17 (dd, J = 14.9, 10.7 Hz, 1H), 2.92 (d, J = 15.2 Hz, 1H), 2.26 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 158.4, 151.0, 142.2, 140.5, 135.7, 135.0, 129.4, 129.3, 128.8, 128.4, 127.4, 127.3, 127.1, 126.3, 124.3, 122.2, 119.3, 112.9, 67.9, 54.6, 47.9, 46.7, HRMS (ESI): m/z [M-H] - calcd for C29H26NO4S: ; found: HPLC: Chiralpak IC column (250 mm); detected at 224 nm; hexane/i-propanol = 70/30; flow = 1.0 ml/min; Retention time: 9.4 min, 12.3 min, 18.7 min, 28.6 min (major). 99.5% de for 4a. The reaction of (±)-3a with p-methoxyphenylboronic acid 2b was conducted under rhodium catalysis with L7 (<10% ee) as ligand to afford 4a. The expected 1,2-addition could take place with concomitant formation of four stereoisomers. The corresponding HPLC spectrum of 4a is shown in Figure 1a. The reaction of (R)-3a (93% ee) with p-methoxyphenylboronic acid 2b was conducted under rhodium catalysis with L7 (<10% ee) as ligand. The corresponding HPLC spectrum of 4a is shown in Figure 1b. The reaction of (R)-3a (93% ee) with p-methoxyphenylboronic acid 2b was conducted under rhodium catalysis by using optically pure L1 as a ligand. The corresponding HPLC spectrum of 4a is shown in Figure 1c. The reaction of (R)-3a (93% ee) with p-methoxyphenylboronic acid 2b was conducted under rhodium catalysis by using optically pure L7 as a ligand. The corresponding HPLC spectrum of 4a is shown in Figure 1d. S24

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26 (R)-4-(4-methoxyphenyl)-4-((R)-2-phenyl-2-(o-tolyl)ethyl)-3,4-dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide (4b) White solid, s 33 mg, 68% yield, 99% ee. [α] 20 0 D = (c 1.0, CHCl3). 1 3 H NMR ( 300 MHz, CDCl 3 ) δ (d, J = 8.00 Hz, 2H), (m, 2H), (m, 11H), 6.83 (d, J = 8.8 Hz, 2H), 4.66 (s, 1H), 4.08 (d, J = 7. 6 Hz, 1H), 3.78 (s, 3H), 3.23 (dd, J = 15.0, 10.3 Hz, 1H), 2.86 (dd, J = 15.0, 2.7 Hz, 1H), 1.94 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 158.4, 151.1, 141.7, 141.4, 135.1, 134.9, 130.1, 129.5, 129.2, 128.5, 127.6, 127.2, 127.0, 126.1, 125.9, , 124.2, 122.2, 119.3, 112.9, 68.1, 54..6, 48.9, 42.6, HRMSS (ESI): m/z [M - H] - calcd for C29H H26NO4S: ; found: HPLC: Chiralpak AD-H column (250 mm); detected at 224 nm; hexane/i-propanol = 90/10; flow = 0.7 ml/min; Retention time: 10.8 min, 13.9 min (major). 99% ee. The reaction of (± ±)-3d with p-methoxyphenylboronic acid 2b was conducted underr rhodium catalysis by using L7 (<10% ee) as ligand to afford 4b. The expected 1,2-addition could take place with concomitant formation of fourr stereoisomers. The corresponding HPLC spectrum of 4b is shown in Figure 2a. The reaction of (R)-3d (99% ee) with p-methoxyphenylboronic acid 2bb was conducted under rhodium catalysis by using L7 (<10% ee) e as a ligand. The corresponding HPLC spectrum iss shown in Figure 2b. The reaction of (R)-3d (99% ee) with p-methoxyphenylboronic acid 2bb was conducted under rhodium catalysis by using optically pure L1 as a ligand. The corresponding HPLC spectrum is shown in Figure 2c. S26

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28 (R)-4-((R)-2-(2-bromophenyl)-2-phenylethyl)-4-(4-methoxyphenyl)-3,4-dihydrobenzo[e][1,2,3]oxa thiazine 2,2-dioxide (4c) White solid, 34 mg, 62% yield. [α] 20 D = (c 1.0, CHCl 3 ). 1 H NMR (300 MHz, CDCl 3 ) δ (m, 13H), 7.22 (d, J = 8.2 Hz, 1H), (m, 1H), 6.86 (d, J = 8.6 Hz, 2H), 4.78 (s, 1H), 4.58 (d, J = 9.7 Hz, 1H), 3.79 (s, 3H), 3.29 (dd, J = 14.7, 10.2 Hz, 1H), 2.89 (d, J = 14.9 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ) δ 158.4, 150.8, 142.4, 140.7, 134.8, 132.5, 129.4, 129.1, 128.5, 127.6, 127.5, , , 127.0, 124.4, 123.7, 122.0, 119.2, 112.9, 67.9, 54.5, 48.0, HRMS (ESI): m/z [M-H] - calcd for C 28 H 23 NO 4 SBr: ; found: The racemic stereoisomers of 1,2-adduct 4c were inseparable in HPLC. Hence, the optical purity of 4c was determined by its cyclized product 5b (99% ee). S28

29 (R)-3-(2-phenyl-2-(p-tolyl)ethyl)benzo[d]isothiazole 1,1-dioxide (7) Whitee solid, 17 mg, 24% yield, 75% ee. [α]] 20 D = (c 1.0, CHCl3). 1 3 H NMR (300 MHz, CDCl 3 ) δ 7.86 (d, J = 6.9 Hz, H 1H), (m, 2H),, 7.54 (d, J = 7.7 Hz, 1H),, 7.27 (s, 4H), 7.17 (d, J = 6.66 Hz, 3H), 7.09 (d, J = 7. 7 Hz, 2H), 4.80 (t, J = 7.66 Hz, 1H), 3.67 (d, J = 7.5 Hz, 2H), (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 176.2, 144.4, 141.2, 141.1, 137.9, 135.0, 134.7, 132.6, 130.8, 130.1, 129.1, 128.9, 128.2, 125.2, 123.8, 48.7, 38.6, HRMS (ESI): m/z [M - H] - calcd for C22H18NO2S: ; found: HPLC: Chiralpak AS-H column (250 mm); detected at 224 nm; hexane/i-propanol = 70/30; flow = 0.6 ml/min; Retention time: 44.0 min, 52.9 min (major). 75% ee. S29

30 (R)-3-((R)-2-phenyl-2-(p-tolyl)ethyl)-3-(p-tolyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (8a) White solid, 85 mg, 94% yield, 95% de. [α] 20 D = (c 1.0, CHCl 3 ). 1 H NMR (300 MHz, CDCl 3 ) δ (m, 1H), (m, 4H), (m, 8H), (m, 4H), 4.52 (s, 1H), 4.08 (dd, J = 9.6, 3.5 Hz, 1H), (m, 2H), 2.36 (s, 3H), 2.29 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 144.3, 142.8, 139.3, 138.1, 137.2, 136.3, 133.1, 132.4, 129.3, 129.1, 128.5, 128.2, 127.3, 126.6, 125.9, 125.3, 123.8, 120.6, 68.0, 46.3, 45.5, 20.4, HRMS (ESI): m/z [M-H] - calcd for C29H26NO2S: ; found: HPLC: Chiralpak AD-H column (250 mm); detected at 224 nm; hexane/i-propanol = 70/30; flow = 0.7 ml/min; Retention time: 13.0 min, 16.1 min (major), 29.7 min, 32.2 min. 95% de for 8a. The reaction was carried out with ketimine 6 and 2.0 equiv of arylboronic acid 2a in the presence of 5.0 mol % of [Rh(COD)Cl], K 2 HPO 4 (1.5 M, 0.5 equiv) in 1.0 ml toluene at rt for 12 h to afford 8 with four stereoisomers. The corresponding HPLC spectrum of 8 is shown in Figure 3a. The reaction of (R)-7 (75% ee) with p-tolylboronic acid 2a was conducted under rhodium catalysis by using L7 (<10% ee) as a ligand to afford 8. The corresponding HPLC spectrum of 8 is shown in Figure 3b. The reaction of ketimine 6 and p-tolylboronic acid 2a (3 equiv) was performed under rhodium catalysis with optically pure L7 as a ligand for 24 h. The corresponding HPLC spectrum of 8 is shown in Figure 3c. The reaction of ketimine 6 and p-tolylboronic acid 2a (2 equiv) was performed under rhodium catalysis with optically pure L7 as a ligand for 12 h. The corresponding HPLC spectrum of 8 is shown in Figure 3d. The reaction of (R)-7 (75% ee) and p-tolylboronic acid 2a (2 equiv) was performed under rhodium catalysis with optically pure L7 as a ligand for 12 h. The corresponding HPLC spectrum of 8 is shown in Figure 3e. S30

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33 6. Synthetic Transformations of Arylation Products Procedure: under argon atmosphere, a round bottom flask was charged with compound 4b (0.2 mmol, 1.0 equiv), NBS (0.2 mmol, 1.0 equiv), AIBN (0.02 mmol, 0.1 equiv) and 5 ml of CCl 4. The resulting mixture was stirred at refluxing temperature overnight. After cooling to room termperature, saturated aq Na 2 CO 3 solution was added to quench the reaction and the mixture was then extracted with ethyl acetate (15 ml 3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and evaporated to dryness to afford the crude bromination product, which was used without further purification in the next cyclization step. The above obtained crude product in DMF (1 ml) solution was added to a glass reaction vessel charged with NaH (0.22 mmol, 1.1 equiv) and fresh distilled DMF (1 ml) at 0 o C under argon atmosphere. The resulting solution was then stirred at ambient temperature for 3 h. After being quenched with water, the mixture was extracted with ethyl acetate (15 ml 3). The combined organic phase was then washed subsequently with 1N HCl, brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel flash chromatography using petroleum ether/ethyl acetate as an eluent to afford compound 5a in 84% yield for 2 steps. (13R,14aR)-14a-(4-methoxyphenyl)-13-phenyl-8,13,14,14a-tetrahydrobenzo[e]benzo[5,6][1,2,3]ox athiazino[3,4-a]azepine 6,6-dioxide (5a) White solid, 81 mg, 84% yield, 99% ee. [α] 20 D = (c 1.0, CHCl 3 ). 1 H NMR (300 MHz, CDCl 3 ) δ (m, 8H), (m, 7H), 6.86 (d, J = 8.1 Hz, 1H), 6.50 (d, J = 7.6 Hz, 1H), 4.67 (dd, J = 13.2, 7.7 Hz, 2H), 4.46 (d, J = 15.8 Hz, 1H), 3.82 (s, 3H), 3.41 (dd, J = 14.7, 10.9 Hz, 1H), 3.12 (d, J = 14.7 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ) δ 158.6, 146.6, 143.3, 142.7, 134.4, 133.0, 129.2, 128.4, , , 127.8, 126.7, 126.5, 125.9, 125.1, 118.4, 114.1, 72.2, 54.7, 48.7, 44.3, HRMS (EI): m/z [M] + calcd for C29H25NO4S: ; found: HPLC: Chiralpak IC column (250 mm); detected at 224 nm; hexane/i-propanol = 95/5; flow = 0.7 ml/min; Retention time: 47.0 min, 51.4 min (major). 99% ee. The reaction of (±)-3d with p-methoxyphenylboronic acid 2b was conducted under rhodium catalysis by using L7 (<10% ee) as a ligand. The expected 1,2-addition could take place with concomitant formation of four stereoisomers of 4b, which was then converted to 5a with four stereoisomers through the steps mentioned above. The corresponding HPLC spectrum of 5a is shown in Figure 4a. The reaction of (R)-3d (99% ee) with p-methoxyphenylboronic acid 2b was conducted under rhodium catalysis by using optically pure L1 as a ligand to afford 4b. From 1,2-adduct 4b with expected high diastereomeric excess, 5a could be obtained as a sole stereoisomer through the steps mentioned above. The corresponding HPLC spectrum of 5a is shown in Figure 4b. S33

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35 Procedure: under argon atmosphere, a solution of 4c (0.2 mmol, 1.0 equiv), CuI (5 mol %), N,N'-dimethylethanediamine (0.5 equiv) and K 2 CO 3 (3 equiv) in 1.0 ml of MeCN was stirred at 70 o C overnight. After EtOAc (10 ml) was added, the mixture was then passed through a pad of silica gel. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate as an eluent to afford the product 5b in 85% yield. (11bR,13R)-11b-(4-methoxyphenyl)-13-phenyl-11b,12-dihydro-13H-benzo[5,6][1,2,3]oxathiazino[ 3,4-a]quinoline 6,6-dioxide (5b) White solid, 80 mg, 85% yield, 99% ee. [α] 20 D = (c 1.0, CHCl 3 ). 1 H NMR (300 MHz, CDCl 3 ) δ (m, 3H), 7.31 (d, J = 4.2 Hz, 4H), (m, 6H), (m, 1H), 6.80 (dd, J = 13.2, 8.3 Hz, 3H), 4.26 (dd, J = 11.3, 7.8 Hz, 1H), 3.72 (s, 3H), 3.37 (dd, J = 14.6, 11.7 Hz, 1H), 3.10 (dd, J = 14.8, 7.7 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ) δ 159.4, 147.4, 144.9, 134.0, 133.9, 133.2, 130.6, 130.1, 129.5, , , 128.5, 128.3, 128.1, 127.3, 127.1, 126.9, 126.6, 119.3, 114.6, 70.2, 55.5, 42.0, HRMS (EI): m/z [M] + calcd for C28H23NO4S: ; found: HPLC: Chiralpak AD-H column (250 mm); detected at 224 nm; hexane/i-propanol = 80/20; flow = 0.7 ml/min; Retention time: 9.3 min, 18.9 min (major). 99% ee. The reaction of (±)-3e with p-methoxyphenylboronic acid 2b was conducted under rhodium catalysis by using L7 (<10% ee) as a ligand. The expected 1,2-addition could take place with concomitant formation of four stereoisomers of 4c, which was then converted to 5b with four stereoisomers through the steps mentioned above. The corresponding HPLC spectrum of 5b is shown in Figure 5a. The reaction of (R)-3e (99% ee) with p-methoxyphenylboronic acid 2b was conducted under rhodium catalysis by using optically pure L1 as a ligand to afford 4c. From 1,2-adduct 4c with expected high diastereomeric excess, 5b could be obtained as a sole stereoisomer through the steps mentioned above. The corresponding HPLC spectrum of 5b is shown in Figure 5b. S35

36 O O S O N Ph OMe S36

37 7. Copies of 1 H NMR and 13 C NMR spectra S37

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