Palladium-Catalyzed Enantioselective Synthesis of Cyclic Sulfamidates and Application to a Synthesis of Verubecestat. Supporting Information

Transcription

1 Palladium-Catalyzed Enantioselective Synthesis of Cyclic Sulfamidates and Application to a Synthesis of Verubecestat Wenyong Chen*, Dongfang Meng, Blaise N Zemba and William J. Morris Process Research & Development, Merck & Co., Rahway, New Jersey 765 USA Supporting Information Table of Contents General Experimental Details S-1 General Procedure for Catalyst Screening for Arylation of Cyclic Iminosulfate S-1 General Procedure for Evaluating Pd-Catalyzed Arylation of Cyclic Iminosulfate S-2 General Procedure for Pd-Catalyzed Arylation with Substituted Arylboronic acids S-3 General Procedure for Pd-Catalyzed Arylation with Substituted Cyclic Iminosulfates S-14 Procedure for the Functionalization of Cyclic sulfamidates S-19 Procedure for the Formal Synthesis of Verubecestat S-2 1 H and 13 C NMR Spectra for All New Compounds S-22 General Experimental Details All air-sensitive manipulations were conducted under an inert atmosphere in a nitrogen-filled glovebox or by standard Schlenk techniques. The PHOX ligands were prepared according to the literature procedure. 1 The racemic samples were prepared by running reactions with a racemic catalyst. Chemical reagents were used as received from suppliers. NMR spectra were taken on Bruker 4 MHz or 5 MHz spectrometers. High resolution mass spectra (HRMS) were obtained on Accurate-Mass Time-of-Flight (TOF) mass spectrometer and reported as m/z (relative intensity). Enantiomeric excess was determined by SFC. Products were visualized on TLC plates by UV or by staining with KMnO 4. General Procedure for Catalyst Screening for Arylation of Cyclic Iminosulfate Table 1. Metal, Ligand, and Additive Screen for enantioselective arylation of cyclic iminosulfate 2a a S 1

2 entry metal ligand M/L additive yield/% b ee/% c 1 d [Rh(cod)OH] 2 L1 1:2.5 K 3 PO e Pd(CH 3 CN) 2 Cl 2 L2 1:1.5 none - 3 e Pd(CH 3 CN) 2 Cl 2 L2 1:1.5 AgBF f Pd(TFA) 2 L3 1:1.5 none - 5 e Ni(dme)Cl2 L2 1:1.5 AgBF 4-6 e CoI 2 L4 1:1.5 none - 7 e Pd L2 1:1.5 AgSbF a 3. equiv 1a and 1. equiv 2a were used in screening. Absolute configuration of the arylation product was determined by chemical correlation. b Determined by HPLC analysis with mesitylene as internal standard. c Determined by chiral HPLC analysis of the reaction mixture. d Dioxane as solvent. e 1,2-Dichloroethane as solvent. f 1,1,1-Trifluoroethanol as solvent. In a nitrogen-filled dry-box, the cyclic iminosulfate (.4 mmol, 1. equiv), [Rh(cod)OH] 2 (.2 µmol,.5 equiv),, additive (.4 mmol, 1. equiv) and two solvents (Toluene, dioxane) were added to vials in a 96-well plate (preplated with twenty-four chiral ligands (.11 µmol,.11 equiv)). The plate was sealed with a PTFE sheet and stirred at 7 C for 1 h. The crude reaction mixture was assayed with UPLC-MS after mesitylene was added as internal standard. General Procedure for Evaluating Pd-catalyzed Arylation of Cyclic Iminosulfate Table 2. Evaluation of ligands, additives and solvents in the Pd-catalyzed enantioselective arylation of cyclic iminosulfate 2a a entry R additive b solvent Yield/% c ee/% d 1 ipr none DCE Bn none DCE - 3 Ph none DCE - 4 t-bu none DCE Adamantyl none DCE Adamantyl none DCB Adamantyl K 2 CO 3 DCB Adamantyl MgO DCB Adamantyl CaO DCB e Adamantyl MgO DCB f Adamantyl MgO DCB a 4. equiv 1a and 1. equiv 2a were used in the reactions. b 1. equiv additive. c Determined by HPLC analysis with mesitylene as internal standard. d Determined by chiral HPLC analysis of the isolated product. e 1.2 equiv 1a, 3 mol % Pd-adamantyl-PHOX catalyst, 6 mol % AgSbF 6. f 2. equiv 1a, 3 mol % Pd-adamantyl-PHOX catalyst, 6 mol % AgSbF 6. S 2

3 In a nitrogen-filled dry-box, 2-fluoro-5-bromo-phenylboronic acid 1a (.5 mmol, 4. equiv), the cyclic iminosulfate 2a (.125 mmol, 1. equiv), Pd complex (.125 mmol,.1 equiv), AgSbF 6 (.25 mmol,.2 equiv), DCE or 1,2-dichlorobenzene (DCB) were charged to a 1- dram vial. The vial was sealed with a cap containing a PTFE-lined silicone-septum, removed from the dry-box, and stirred at 7 o C for 1 h. The crude reaction mixture was concentrated under reduced pressure. The crude reaction mixture was purified by Prep TLC (eluting with hexanes:etoac, 3:1) to yield the product. (R)-4-(5-bromo-2-fluorophenyl)-4-methyl-1,2,3-oxathiazolidine-2,2-dioxide (3a) Representative procedure in 1 mmol scale: In a nitrogen-filled dry-box, Pd-AdamantylPHOX complex (32 mg,.1 mmol,.5 equiv) and AgSbF 6 (52 mg,.1 mmol,.1 equiv) was dissolved in.5 ml DCB in a 5-mL vial. After stirring for 15 min, the cyclic iminosulfate 2a (135 mg, 1. mmol, 1. equiv), MgO (4 mg,.125 mmol, 1. equiv), 2.5 ml 1,2- dichlorobenzene (DCB) and 2-fluoro-5-bromo-phenylboronic acid 1a (438 mg, 2. mmol, 2. equiv) were charged into the vial. The vial was sealed with a cap containing a PTFE-lined silicone-septum, removed from the dry-box, and stirred at 7 o C for 1 h. After filtration through a short plug of silica gel, the collected solution was concentrated in reduced pressure. The crude oil was purified by column chromatography (eluting with hexanes:etoac, 3:1) to yield the title compound as white solid in 9% yield (279 mg). The enantiomeric excess was determined by SFC analysis (22 nm, 25 C) t R 3.23 min (major); t R 3.11 min (minor) [(Chiralpak OD-H) 25% i-proh (25 mm IBA), 3. ml/min] to be 99%. 1 H NMR (5 MHz, Chloroform-d) δ 7.84 (dd, J = 7.1, 2.5 Hz, 1H), 7.48 (dq, J = 7.1, 2.3 Hz, 1H), 7.1 (dd, J = 11.1, 8.7 Hz, 1H), 4.85 (s, 1H), 4.74 (app. s, 2H), 1.83 (d, J = 1. Hz, 3H). 13 C NMR (126 MHz, Chloroform-d) δ (d, J = Hz), (d, J = 8.6 Hz), 13.9 (d, J = 13.7 Hz), 13.8 (d, J = 4. Hz), (d, J = 23.8 Hz), (d, J = 3.1 Hz), 78.8 (d, J = 8.4 Hz), 63.6 (d, J = 2.9 Hz), 26.9 (d, J = 3.4 Hz). 19 F NMR (471 MHz, CDCl 3 ) δ HRMS (ESI-) Calcd. for C 9 H 8 BrFNO 3 S ([M-H] - ): Found: General Procedure for Pd-Catalyzed Arylation with Substituted Arylboronic acids S 3

4 General Procedure A: In a nitrogen-filled dry-box, arylboronic acid 1 (.25 mmol, 2. equiv), the cyclic iminosulfate 2 (.125 mmol, 1. equiv), Pd-AdamantylPHOX complex (.625 mmol,.5 equiv), AgSbF 6 (.125 mmol,.1 equiv), MgO (.125 mmol, 1. equiv), and 1 ml 1,2-dichlorobenzene (DCB) were charged to a 1-dram vial. The vial was sealed with a cap containing a PTFE-lined silicone-septum, removed from the dry-box, and stirred at 7 o C for 1 h. The crude reaction mixture was concentrated under reduced pressure. The crude reaction mixture was purified by Prep TLC (eluting with hexanes:etoac, 3:1) to yield the product. General Procedure B: In a nitrogen-filled dry-box, arylboronic acid 1 (.25 mmol, 2. equiv), the cyclic iminosulfate 2 (.125 mmol, 1. equiv), Pd-AdamantylPHOX complex (.625 mmol,.5 equiv), AgSbF 6 (.125 mmol,.1 equiv), MgO (.125 mmol, 1. equiv), 2,6- Di-t-butyl-4-methylpyridine (DTBMP) (.625 mmol,.5 equiv) and 1 ml 1,2- dichlorobenzene (DCB) were charged to a 1-dram vial. The vial was sealed with a cap containing a PTFE-lined silicone-septum, removed from the dry-box, and stirred at 7 o C for 1 h. The crude reaction mixture was concentrated under reduced pressure. The crude reaction mixture was purified by Prep TLC (eluting with hexanes:etoac, 3:1) to yield the product. General Procedure C: In a nitrogen-filled dry-box, arylboronic acid 1 (.25 mmol, 2. equiv), the cyclic iminosulfate 2 (.125 mmol, 1. equiv), Pd- t Bu-PHOX complex (.625 mmol,.5 equiv), AgSbF 6 (.125 mmol,.1 equiv), MgO (.125 mmol, 1. equiv), and 1 ml 1,2-dichlorobenzene (DCB) were charged to a 1-dram vial. The vial was sealed with a cap containing a PTFE-lined silicone-septum, removed from the dry-box, and stirred at 7 o C for 1 h. The crude reaction mixture was concentrated under reduced pressure. The crude reaction mixture was purified by Prep TLC (eluting with hexanes:etoac, 3:1) to yield the product. (R)-4-methyl-4-(p-tolyl)-1,2,3-oxathiazolidine-2,2-dioxide(3b) Prepared according to the general procedure A (reaction time was 2h). The crude mixture was purified by Prep TLC to give the title compound as white solid in 95% yield (3. mg). The enantiomeric excess was determined by SFC analysis (22 nm, 25 C) t R 2.57 min (major); t R 2.9 min (minor) [(Chiralpak AD-H), 25% i-proh (25 mm IBA), 3. ml/min] to be 96%. 1 H NMR (5 MHz, Chloroform-d) δ 7.34 (d, J = 8.3 Hz, 2H), 7.25 (dd, J = 8.4,.8 Hz, 2H), 4.69 (s, 1H), 4.67 (d, J = 8.7 Hz, 1H), 4.6 (d, J = 8.7 Hz, 1H), 2.39 (s, 3H), 1.85 (s, 3H). 13 C NMR (126 MHz, CDCl 3 ) δ 138.5, 138.6, 129.8, 124.8, 8.4, 65.2, 27.4, 21.. HRMS (ESI-) Calcd. for C 1 H 12 NO 3 S ([M-H] - ): Found: S 4

5 (R)-4-(4-fluorophenyl)-4-methyl-1,2,3-oxathiazolidine 2,2-dioxide (3c) O O HN S O F Me Prepared according to the general procedure A. The crude mixture was purified by Prep TLC to give the title compound as white solid in 97% yield (28. mg). The enantiomeric excess was determined by SFC analysis (254 nm, 25 C) t R 2.36 min (major); t R 1.65 min (minor) [(Chiralpak AD-H), 25% i-proh (25 mm IBA), 3. ml/min] to be 99%. 1 H NMR (5 MHz, Chloroform-d) δ (m, 2H), 7.13 (t, J = 8.6 Hz, 2H), 4.69 (s, 1H), 4.65 (d, J = 8.7 Hz, 1H), 4.59 (d, J = 8.7 Hz, 1H), 1.85 (s, 3H). 13 C NMR (126 MHz, Chloroform-d) δ (d, J = Hz), (d, J = 3.3 Hz), (d, J = 8.2 Hz), (d, J = 21.7 Hz), 8.1, 64.9, F NMR (471 MHz, CDCl 3 ) δ HRMS (ESI-) Calcd. for C 9 H 9 NFO 3 S ([M-H] - ): Found: S 5

6 (R)-4-(4-chlorophenyl)-4-methyl-1,2,3-oxathiazolidine 2,2-dioxide (3d) Prepared according to the general procedure A. The crude mixture was purified by Prep TLC to give the title compound as white solid in 83% yield (28. mg). The enantiomeric excess was determined by SFC analysis (22 nm, 25 C) t R 3.39 min (major); t R 2.8 min (minor) [(ChiralPak AD-H), 25% i-proh (25 mm IBA), 3. ml/min] to be 99%. 1 H NMR (5 MHz, Chloroform-d) δ 7.42 (s,4h), 4.78 (s, 1H), 4.64 (d, J = 8.8 Hz, 1H), 4.59 (d, J = 8.7 Hz, 1H), 1.83 (s, 3H). 13 C NMR (126 MHz, CDCl 3 ) δ 139.7, 134.6, 129.3, , 8., 64.9, HRMS (ESI-) Calcd. for C 9 H 9 NClO 3 S ([M-H] - ): Found: (R)-4-(4-bromophenyl)-4-methyl-1,2,3-oxathiazolidine 2,2-dioxide (3e) Prepared according to the general procedure A. The crude mixture was purified by Prep TLC to give the title compound as white solid in 94% yield (34.2 mg). The enantiomeric excess was S 6

7 determined by SFC analysis (22 nm, 25 C) t R 2.79 min (major); t R 2.31 min (minor) [(ChiralPak AD-H), 25% i-proh (25 mm IBA), 3. ml/min] to be 99%. 1 H NMR (5 MHz, Chloroform-d) δ 7.57 (d, J = 8.7 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 4.79 (s, 1H), 4.64 (d, J = 8.7 Hz, 1H), 4.6 (d, J = 8.7 Hz, 1H), 1.83 (s, 3H). 13 C NMR (126 MHz, CDCl 3 ) δ 14.2, 132.3, 126.9, 122.7, 79.9, 65., HRMS (ESI-) Calcd. for C 9 H 9 NBrO 3 S ([M-H] - ): Found: (R)-4-(4-iodophenyl)-4-methyl-1,2,3-oxathiazolidine 2,2-dioxide (3f) O O HN S O I Prepared according to the general procedure A. The crude mixture was purified by Prep TLC to give the title compound as white solid in 78% yield (33. mg). The enantiomeric excess was determined by SFC analysis (22 nm, 25 C) t R 5.24 min (major); t R 2.92 min (minor) [(ChiralPak AD-H), 25% i-proh (25 mm IBA), 3. ml/min] to be >99%. 1 H NMR (5 MHz, Chloroform-d) δ 7.77 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), (m, 1H), 4.63 (d, J = 8.7 Hz, 1H), 4.59 (d, J = 8.7 Hz, 1H), 1.81 (s, 3H). 13 C NMR (126 MHz, CDCl 3 ) δ 141., 138.2, 127., 94.3, 79.9, 65.1, HRMS (ESI-) Calcd. for C 9 H 9 NIO 3 S ([M-H] - ): Found: Me S 7

8 (R)-4-methyl-4-(4-phenoxyphenyl)-1,2,3-oxathiazolidine 2,2-dioxide (3g) PhO O O HN S O Me Prepared according to the general procedure B. The crude mixture was purified by Prep TLC to give the title compound as white solid in 98% yield (37.4 mg). The enantiomeric excess was determined by SFC analysis (22 nm, 25 C) t R 4.13 min (major); t R 3.9 min (minor) [(ChiralPak AD-H), 25% i-proh (25 mm IBA), 3. ml/min] to be 98%. 1 H NMR (5 MHz, Chloroform-d) δ (m, 4H), (m, 1H), (m, 4H), 4.67 (d, J = 8.7 Hz, 1H), 4.6 (d, J = 8.7 Hz, 1H), 4.58 (s, 1H), 1.86 (d, J = 1.4 Hz, 3H). 13 C NMR (126 MHz, CDCl 3 ) δ 157.8, 156.4, 135.4, 129.9, 126.5, 123.9, 119.4, 118.8, 8.2, 64.9, HRMS (ESI) Calcd. for C 15 H 14 NO 4 S ([M-H] - ): Found: S 8

9 (R)-4-methyl-4-(4-(trifluoromethyl)phenyl)-1,2,3-oxathiazolidine 2,2-dioxide (3h) Prepared according to the general procedure A. The crude mixture was purified by Prep TLC to give the title compound as white solid in 97% yield (32.7 mg). The enantiomeric excess was determined by SFC analysis SFC analysis (22 nm, 25 C) t R 9.5 min (major); t R 4.41 min (minor) [(ChiralPak AD-H), 25% i-proh (25 mm IBA), 3. ml/min] to be 98%. 1 H NMR (5 MHz, Chloroform-d) δ 7.71 (dt, J = 8.2,.8 Hz, 1H), (m, 1H), 4.83 (s, 1H), 4.68 (d, J = 8.8 Hz, 1H), 4.65 (d, J = 8.8 Hz, 1H), 1.86 (s, 3H). 13 C NMR (126 MHz, CDCl 3 ) δ 145.2, 13.9 (q, J = 32.9 Hz), 127., (q, J = 3.7 Hz), (q, J = Hz), 79.8, 65.1, F NMR (471 MHz, CDCl 3 ) δ HRMS (ESI-) Calcd. for C 1 H 9 F 3 NO 3 S ([M-H] - ): Found: S 9

10 (R)-1-(3-(4-methyl-2,2-dioxido-1,2,3-oxathiazolidin-4-yl)phenyl)ethan-1-one (3i) O O O HN S O Me Prepared according to the general procedure A. The crude mixture was purified by Prep TLC to give the title compound as white solid in 95% yield (32.7 mg). The enantiomeric excess was determined by SFC analysis (22 nm, 25 C) t R 2.26 min (major); t R 1.89 min (minor) [(ChiralPak AD-H), 25% i-proh (25 mm IBA), 3. ml/min] to be 99%. 1 H NMR (5 MHz, Chloroform-d) δ 8.6 (t, J = 1.9 Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H), (m, 1H), 7.56 (t, J = 7.8 Hz, 1H), 5.3 (s, 1H), 4.7 (d, J = 8.8 Hz, 1H), 4.66 (d, J = 8.8 Hz, 1H), 2.65 (s, 3H), 1.87 (s, 3H). 13 C NMR (126 MHz, CDCl 3 ) δ 197.7, 142.1, 137.7, 129.8, 129.5, 128.6, 124.6, 8., 65.2, 27.6, HRMS (ESI-) Calcd. for C 11 H 12 NO 4 S ([M-H] - ): Found: S 1

11 (R)-4-(3-chlorophenyl)-4-methyl-1,2,3-oxathiazolidine 2,2-dioxide (3j) Cl O O HN S O Me Prepared according to the general procedure A. The crude mixture was purified by Prep TLC to give the title compound as white solid in 77% yield (28. mg). The enantiomeric excess was determined by SFC analysis (22 nm, 25 C) t R 2.17 min (major); t R 1.9 min (minor) [(ChiralPak AD-H), 25% i-proh (25 mm IBA), 3. ml/min] to be 97%. 1 H NMR (5 MHz, Chloroform-d) δ 7.47 (d, J = 2.2 Hz, 1H), (m, 3H), (m, 3H), 1.85 (s, 3H). 13 C NMR (126 MHz, CDCl 3 ) δ 143.2, 135.2, 13.5, 128.8, 125.4, 123.2, 79.7, 64.8, HRMS (ESI-) Calcd. for C 9 H 9 NClO 3 S ([M-H] - ): Found: S 11

12 (R)-4-(2-fluorophenyl)-4-methyl-1,2,3-oxathiazolidine 2,2-dioxide (3k) F O O HN S O Me Prepared according to the general procedure A (reaction time: 2h). The crude mixture was purified by Prep TLC to give the title compound as white solid in 94% yield (27.1 mg). The enantiomeric excess was determined by SFC analysis (22 nm, 25 C) t R 3.1 min (major); t R 1.67 min (minor) [(ChiralPak AD-H), 25% i-proh (25 mm IBA), 3. ml/min] to be 98%. 1 H NMR (5 MHz, Chloroform-d) δ 7.67 (td, J = 8., 1.8 Hz, 1H), (m, 1H), 7.24 (td, J = 7.6, 1.3 Hz, 1H), 7.12 (ddd, J = 11.9, 8.2, 1.2 Hz, 1H), 4.86 (s, 1H), 4.78 (d, J = 2.4 Hz, 2H), (m, 3H). 13 C NMR (126 MHz, CDCl 3 ) δ (d, J = Hz), 13.4 (d, J = 8.6 Hz), (d, J = 12.2 Hz), (d, J = 3.7 Hz), (d, J = 3.2 Hz), (d, J = 22. Hz), 79.4 (d, J = 8.7 Hz), 64. (d, J = 2.7 Hz), 26.9 (d, J = 3.2 Hz). 19 F NMR (471 MHz, CDCl 3 ) δ HRMS (ESI-) Calcd. for C 9 H 9 NFO 3 S ([M-H] - ): Found: S 12

13 (R)-4-(2-methoxyphenyl)-4-methyl-1,2,3-oxathiazolidine 2,2-dioxide (3l) O O HN S O Me OMe Prepared according to the general procedure B. The crude mixture was purified by Prep TLC to give the title compound as white solid in 94% yield (27.1 mg). The enantiomeric excess was determined by SFC analysis (22 nm, 25 C) t R 4.2 min (major); t R 2.1 min (minor) [(ChiralPak AD-H), 25% i-proh (25 mm IBA), 3. ml/min] to be 99%. 1 H NMR (5 MHz, Chloroform-d) δ 7.51 (dd, J = 7.7, 1.7 Hz, 1H), 7.37 (ddd, J = 8.9, 7.5, 1.7 Hz, 1H), 7.5 (td, J = 7.6, 1.1 Hz, 1H), 6.97 (dd, J = 8.1, 1. Hz, 1H), 4.96 (s, 1H), 4.78 (d, J = 8.8 Hz, 1H), 4.73 (d, J = 8.8 Hz, 1H), 3.91 (s, 3H), 1.84 (s, 3H). 13 C NMR (126 MHz, CDCl 3 ) δ 155.7, 129.9, 128.7, 126.7, 121.3, 111.3, 79.7, 64.8, 55.4, HRMS (ESI-) Calcd. for C 1 H 12 NO 4 S ([M-H] - ): Found: S 13

14 General Procedure for Pd-Catalyzed Arylation with Substituted Cyclic Iminosulfates General Procedure C: In a nitrogen-filled dry-box, p-bromophenylboronic acid (.25 mmol, 2. equiv), the cyclic iminosulfate 2 (.125 mmol, 1. equiv), Pd-t-BuPHOX complex (.625 mmol,.5 equiv), AgSbF 6 (.125 mmol,.1 equiv), MgO (.125 mmol, 1. equiv), and 1 ml 1,2-dichlorobenzene (DCB) were charged to a 1-dram vial. The vial was sealed with a cap containing a PTFE-lined silicone-septum, removed from the dry-box, and stirred at 7 o C for 1 h. The crude reaction mixture was concentrated under reduced pressure. The crude reaction mixture was purified by Prep TLC (eluting with hexanes:etoac, 3:1) to yield the product. (R)-4-(4-bromophenyl)-4-ethyl-1,2,3-oxathiazolidine 2,2-dioxide (3m) O O HN S O Br Prepared according to the general procedure A. The crude mixture was purified by Prep TLC to give the title compound as white solid in 93% yield (35.5 mg). The enantiomeric excess was determined by SFC analysis (22 nm, 25 C) t R 4.99 min (major); t R 2.92 min (minor) [(ChiralPak AD-H), 25% i-proh (25 mm IBA), 3. ml/min] to be 95%. 1 H NMR (5 MHz, Chloroform-d) δ 7.55 (d, J = 8.7 Hz, 2H), (m, 2H), 4.63 (d, J = 8.7 Hz, 1H), 4.6 (d, J = 8.7 Hz, 1H), 4.59 (s, 1H), 2.15 (dd, J = 14.4, 7.3 Hz, 1H), (m, 1H), 1.54 (s, 3H),.84 (t, J = 7.4 Hz, 3H). 13 C NMR (126 MHz, CDCl 3 ) δ 138.6, 132.2, 127.2, 122.5, 79.2, 79.15, 68.5, 33.2, 8.1. HRMS (ESI-) Calcd. for C 1 H 12 BrNO 3 S ([M-H] + ): Found: S 14

15 (R)-4-(4-bromophenyl)-4-phenethyl-1,2,3-oxathiazolidine 2,2-dioxide (3n) O O HN S O Br Ph Prepared according to the general procedure A. The crude mixture was purified by Prep TLC to give the title compound as white solid in 96% yield (45.7 mg). The enantiomeric excess was determined by SFC analysis (22 nm, 25 C) t R 7.88 min (major); t R 4.99 min (minor) [(ChiralPak AD-H), 25% i-proh (25 mm IBA), 3. ml/min] to be 99%. 1 H NMR (5 MHz, Chloroform-d) δ 7.62 (d, J = 8.6 Hz, 2H), (m, 4H), (m, 1H), (m, 2H), 4.69 (s, 1H), 4.65 (d, J = 8.7 Hz, 1H), 4.61 (d, J = 8.7 Hz, 1H), (m, 3H), (m, 1H). 13 C NMR (126 MHz, CDCl 3 ) δ 139.4, 138.5, 132.4, , 128.2, 127.2, 126.8, 122.8, 79.5, 68.1, 41.6, 3.1. HRMS (ESI-) Calcd. for C 16 H 15 BrNO 3 S ([M-H] - ): Found: S 15

16 ((R)-4-(4-bromophenyl)-4-isopropyl-1,2,3-oxathiazolidine 2,2-dioxide (3o) O O HN S O Br Prepared according to the general procedure C. The crude mixture was purified by Prep TLC to give the title compound as white solid in 89% yield (35.5 mg). The enantiomeric excess was determined by SFC analysis (22 nm, 25 C) t R 6.2 min (major); t R 3.15 min (minor) [(ChiralPak AD-H), 25% i-proh (25 mm IBA), 3. ml/min] to be 98%. 1 H NMR (5 MHz, Chloroform-d) δ 7.54 (d, J = 8.7 Hz, 2H), (m, 2H), 4.74 (d, J = 8.9 Hz, 1H), 4.65 (d, J = 8.9 Hz, 1H), 4.57 (s, 1H), (m, 1H), 1.55 (s, 3H), 1.1 (d, J = 6.8 Hz, 3H),.8 (d, J = 6.9 Hz, 3H). 13 C NMR (126 MHz, CDCl 3 ) δ 137.7, 131.8, 127.9, 127.9, 122.5, 77.8, 71.1, 36.6, 17.3, HRMS (ESI-) Calcd. for C 11 H 13 BrNO 3 S ([M-H] - ): Found: S 16

17 (R)-4-(4-bromophenyl)-4-cyclohexyl-1,2,3-oxathiazolidine 2,2-dioxide (3p) O O HN S O Br Prepared according to the general procedure C. The crude mixture was purified by Prep TLC to give the title compound as white solid in 9% yield (4.4 mg). The enantiomeric excess was determined by SFC analysis (22 nm, 25 C) t R 7.45 min (major); t R 4.3 min (minor) [(ChiralPak AD-H), 25% i-proh (25 mm IBA), 3. ml/min] to be 96%. 1 H NMR (5 MHz, Chloroform-d) δ (m, 2H), 7.23 (d, J = 8.7 Hz, 2H), 4.76 (d, J = 8.9 Hz, 1H), 4.64 (d, J = 8.9 Hz, 1H), 4.57 (s, 1H), (m, 3H), 1.74 (d, J = 13.4 Hz, 1H), 1.67 (d, J = 13.3 Hz, 1H), (m, 1H), (m, 2H), 1.5 (tt, J = 13.1, 3.7 Hz, 1H),.93 (qd, J = 13.2, 3.6 Hz, 1H),.8 (qd, J = 12.5, 3.7 Hz, 1H). 13 C NMR (126 MHz, CDCl 3 ) δ 138.1, 131.8, 127.8, 122.4, 77.5, 7.9, 46.9, 27.6, 27.2, 26., 25.8, HRMS (ESI-) Calcd. for C 14 H 17 BrNO 3 S ([M-H] - ): Found: (R)-4-(4-bromophenyl)-4-cyclopentyl-1,2,3-oxathiazolidine 2,2-dioxide (3q) O O HN S O Br S 17

18 Prepared according to the general procedure C. The crude mixture was purified by Prep TLC to give the title compound as white solid in 9% yield (38.8 mg). The enantiomeric excess was determined by SFC analysis (22 nm, 25 C) t R 9.21 min (major); t R 4.25 min (minor) [(ChiralPak AD-H), 25% i-proh (25 mm IBA), 3. ml/min] to be 95%. 1 H NMR (5 MHz, Chloroform-d) δ (m, 2H), (m, 2H), 4.71 (d, J = 8.8 Hz, 1H), 4.62 (d, J = 8.8 Hz, 1H), 4.52 (s, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 4H), (m, 1H). 13 C NMR (126 MHz, CDCl 3 ) δ 139.7, 131.9, 127.6, 122.3, 78.1, 69.9, 48.8, 27.8, 26.8, 25.2, HRMS (ESI-) Calcd. for C 13 H 15 BrNO 3 S ([M-H] - ): Found: (R)-4-(4-bromophenyl)-4-isobutyl-1,2,3-oxathiazolidine 2,2-dioxide (3r) O O HN S O Br Prepared according to the general procedure C. The crude mixture was purified by Prep TLC to give the title compound as white solid in 83% yield (34.5 mg). The enantiomeric excess was determined by SFC analysis (22 nm, 25 C) t R 3.8 min (major); t R 2.41 min (minor) [(ChiralPak AD-H), 25% i-proh (25 mm IBA), 3. ml/min] to be 95%. 1 H NMR (5 MHz, Chloroform-d) δ (m, 2H), (m, 2H), 4.61 (d, J = 8.7 Hz, 1H), 4.58 (s, 1H), 4.54 (d, J = 8.6 Hz, 1H), 2.3 (dd, J = 14.6, 5.2 Hz, 1H), 1.89 (dd, J = 14.7, 7.8 Hz, 1H), 1.4 (dqd, J = 7.8, 6.6, 5.3 Hz, 1H),.89 (d, J = 6.6 Hz, 3H),.75 (d, J = 6.7 Hz, 3H). 13 C NMR (126 MHz, CDCl 3 ) δ 138.8, 132.1, , 127.4, 122.4, 8.89, 8.86, 68.5, 48.76, 48.74, 24.5, 23.8, 23.6, HRMS (ESI-) Calcd. for C 12 H 15 BrNO 3 S ([M-H] - ): Found: S 18

19 Procedure for the Funtionalization of Cyclic sulfamidates Benzyl (R)-4-(5-bromo-2-fluorophenyl)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2- dioxide (4) 3a (.5 mmol, 154 mg, 1. equiv) was dissolved in 2 ml THF in a 1-dram vial. To the vial was charged KOtBu (.55 mmol, 61.6 mg, 1.1 equiv). The mixture was stirred for 1 min. To the mixture was added CbzCl (.55 mmol, 93.8 mg, 1.1 equiv) through a syringe in 5 min. The resulted reaction mixture was stirred for 1 h at 25 C. After removing the solvent under vacuum, the reaction mixture was loaded on a column to yield the title compound 4 as a colorless oil in 9% yield (2 mg). 1 H NMR (5 MHz, Chloroform-d) (8:1 rotamer, major rotamer was reported) δ (m, 1H), (m, 6H), 7. (dd, J = 11.5, 8.7 Hz, 1H), 5.33 (d, J = 2.7 Hz, 2H), 4.76 (d, J = 9.4 Hz, 1H), 4.72 (s, 1H), 4.49 (d, J = 9.4 Hz, 1H), 2.4 (d, J = 1.9 Hz, 3H). 13 C NMR (126 MHz, Chloroform-d) δ 159.6, 157.7, 149.2, 134.3, (d, J = 9. Hz), (d, J = 3.1 Hz), 128.8, , 127.8, (d, J = 24.5 Hz), (d, J = 3.3 Hz), 78.7 (d, J = 8.3 Hz), 75.7 (d, J = 3.6 Hz), 69.4, 65.6 (d, J = 3.1 Hz), 23.2 (d, J = 4.9 Hz). HRMS (ESI) Calcd. for C 17 H 19 BrFN 2 O 5 S ([M+NH 4 ] + ): Found: (R)-4-(5-bromo-2-fluorophenyl)-4-methyloxazolidin-2-one (5) S 19

20 4 (.45 mmol, 2 mg, 1. equiv) was dissolved in 2 ml DMF in a 1-dram vial. The resulted reaction mixture was stirred for 12 h at 6 C. After removing the solvent under vacuum, the reaction mixture was loaded on a column to yield the title compound 5 as a colorless oil in 82% yield (11 mg). 1 H NMR (5 MHz, Chloroform-d) δ 7.47 (ddd, J = 14.2, 6.2, 3.4 Hz, 2H), 7.2 (dd, J = 1.8, 8.6 Hz, 1H), 6.48 (s, 1H), 4.57 (dd, J = 8.9, 2. Hz, 1H), 4.52 (d, J = 8.7 Hz, 1H), 1.74 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ 158.3, 157.5, 133., (d, J = 8.6 Hz), (d, J = 4.4 Hz), (d, J = 23.9 Hz), (d, J = 3.2 Hz), 76.2 (d, J = 5.2 Hz), 59.1, 27.9 (d, J = 3.3 Hz). HRMS (ESI) Calcd. for C 1 H 1 BrFNO 2 ([M+H] + ): Found: Procedure for the Formal Synthesis of Verubecestat (R)-4-(5-bromo-2-fluorophenyl)-4-methyl-2-phenoxy-4,5-dihydrothiazole (6) 3a (.5 mmol, 154 mg, 1. equiv) was dissolved in 2 ml DMF in a 1-dram vial. To the vial was charged KOtBu (.55 mmol, 61.6 mg, 1.1 equiv). The mixture was stirred for 1 min. To the mixture was added PhOCSCl (.55 mmol, 95. mg, 1.1 equiv) through a syringe in 5 min. The resulted reaction mixture was stirred for 5 h at 25 C. Then, the reaction mixture was heated to 6 C and stirred for 1 h at 6 C. After removing the solvent under vacuum, the reaction mixture was loaded on a column to yield the title compound 6 as a colorless oil in 86% yield (157 mg). 1 H NMR (599 MHz, Chloroform-d) δ 7.75 (dd, J = 7., 2.6 Hz, 1H), 7.4 (dd, J = 8.6, 7.3 Hz, 2H), 7.34 (ddd, J = 8.5, 4.3, 2.6 Hz, 1H), (m, 3H), 6.92 (dd, J = 11.1, 8.6 Hz, 1H), 3.78 (dd, J = 11.3, 3.8 Hz, 1H), 3.66 (d, J = 11.3 Hz, 1H), 1.64 (d, J =.9 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 165.1, (d, J = Hz), 154.5, (d, J = 13.8 Hz), (d, J = 8.6 Hz), (d, J = 4.6 Hz), 129.5, 125.9, 12.8, (d, J = 24.5 Hz), (d, J = 3.2 Hz), 75.7, 46.4 (d, J = 5.8 Hz), 26.6 (d, J = 2.9 Hz).HRMS (ESI) Calcd. for C 16 H 13 BrFNOS ([M+H] + ): Found: S 2

21 (R)-2-amino-2-(5-bromo-2-fluorophenyl)-N-(4-methoxybenzyl)-N-methylpropane-1- sulfonamide (7) To a 1-dram vial was charged NCS (.56 mmol, 73 mg, 4. equiv),.3 ml HCl (2M) and.25 ml MeCN. The solution was cooled to 1 C before charging 8 (.14 mmol, 5 mg, 1. equiv) in.25 ml MeCN. After stirring for 2 min at <2 C. PMBNHMe (.28 mmol,.41 ml, 2. equiv)was added to the solution. The resulting solution was stirred for 2 h at 25 C. To the solution, 1 M TBAF(.42 mmol,.42 ml, 3 equiv) was added to fully deprotect. After removing the solvent under vacuum, the reaction mixture was purified with Prep TLC to yield the title compound 7 as a colorless oil in 64% yield (4 mg). 1 H NMR (5 MHz, Chloroform-d) δ 7.86 (dd, J = 7.3, 2.6 Hz, 1H), 7.41 (ddd, J = 8.7, 4.3, 2.5 Hz, 1H), 7.21 (d, J = 8.3 Hz, 2H), 6.97 (dd, J = 11.8, 8.6 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 4.13 (d, J = 14.4 Hz, 1H), 3.96 (d, J = 14.4 Hz, 1H), 3.8 (s, 3H), 3.73 (d, J = 14. Hz, 1H), 3.35 (d, J = 14. Hz, 1H), 2.6 (s, 3H), 2.26 (s, 2H), 1.65 (s, 3H). 13 C NMR (126 MHz, Chloroform-d) δ 16.5, 159.4, 158.5, (d, J = 13.6 Hz), (d, J = 8.9 Hz), 13.9 (d, J = 4.5 Hz), 129.7, 127.5, (d, J = 25.9 Hz), (d, J = 2.9 Hz), 114.1, 59.6 (d, J = 5.5 Hz), 55.3, 53.4 (d, J = 3.4 Hz), 52.8, 33.5, 29.8 (d, J = 3.4 Hz). HRMS (ESI) Calcd. for C 18 H 23 BrFN 2 O 3 S ([M+H] + ): Found: Marinescu, S. C.; Nishimata,T. N.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 28, 1, 139. S 21

22 a S22

23 a E (d) C (d) A (d) B (d) F (d) G (d) H (d) I (d) D (d) S

24 a S24

25 b S25

26 b S

27 c S27

28 A (d) B (d) C (d) D (d) E (s) 8.15 F (s) 64.9 G (s) c S28

29 c S

30 d S

31 d S31

32 e S32

33 e S33

34 f S34

35 f S

36 g S36

37 g S

38 h S38

39 h S39

40 h S

41 i S41

42 i S42

43 j S43

44 j S

45 k S45

46 k S46

47 k S

48 l S48

49 l S49

50 m S5

51 m S51

52 n S52

53 n S53

54 o S54

55 o S55

56 p S56

57 p S57

58 q S58

59 q S59

60 r S6

61 r S61

62 S62

63 I (s) B (s) G (s) E (d) K (d) M (d) A (s) C (s) D (s) F (d) J (d) L (d) O (d) N (s) P (d) H (s) S

64 S64

65 B (s) D (d) F (d) A (s) C (d) E (d) H (d) G (s) 59.8 I (d) J (s) S

66 PROTON1 W. Chen SWMS CH 3 9 F 1 Br 11 S N 14 O S66

67 gHSQCAD W. Chen 2 SWMS Br N CH 3 9 F 1 8 O S f2 (ppm) S

68 gHMBCAD W. Chen 2 SWMS Br N CH 3 9 F 1 8 O S f2 (ppm) S

69 CARBON1 W. Chen SWMS Br N CH 3 9 F 1 8 O S S

70 gCOSY1 W. Chen SWMS f2 (ppm) S

71 NOE_DIF1 W. Chen SWMS S

72 FLUORINE1 W. Chen SWMS CH 3 9 F 1 Br 11 S N 14 O S72

73 zTOCSY1D1 W. Chen SWMS Selective band center: 7.46 (ppm); width: 16.3 (Hz) Br N CH 3 9 F 1 8 O S S

74 S74

75 G (s) O (s) B (s) E (d) J (d) M (s) Q (d) A (s) D (d) I (s) L (d) P (s) C (s) F (d) K (d) N (d) H (s) S