Useful Applications of Enantioselective (4+2)-Cycloaddition Reactions to the Synthesis of Chiral 1,2-Amino Alcohols, 1,2-Diamines and β- Amino Acids

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1 Supporting Information for Useful Applications of Enantioselective (4+2)-Cycloaddition Reactions to the Synthesis of Chiral 1,2-Amino Alcohols, 1,2-Diamines and β- Amino Acids Karla Mahender Reddy, Barla Thirupathi, and E. J. Corey* These authors contributed equally Department of Chemistry and Chemical Biology, Harvard University Cambridge, Massachusetts, Table of Contents 1. Materials and Methods page S2 2. Synthesis of Precatalysts page S2 3. Synthesis of Chiral 1,2-Amino Alcohols page S3 4. Synthesis of Chiral 1,2-Diamines page S6 5. Synthesis of β-amino Acids page S8 5.1 NMR Experiment for compound 29 page S8 6. Synthesis of Boronic Acid Derivatives page S10 7. References page S11 8. Copies of 1 H and 13 C NMR spectra page S12 9. Chiral HPLC traces page S25 S1

2 1. Materials and Methods Unless stated otherwise, reactions were performed in flame-dried glassware under a positive pressure of nitrogen using anhydrous solvents. CH 2 Cl 2, MeCN, toluene, benzene and THF were purified by passage through a PPT / Glass Contour Solvent Purification System under argon. Hexane and Et 2 O were freshly distilled from CaH 2 before use. Commercial grade reagents and solvents were used without further purification unless otherwise stated. Diisopropylethylamine, triethylamine and diisopropylamine were distilled from CaH 2 before use. Thin-layer chromatography (TLC) was performed using Merck silica gel 60 F254 pre-coated plates (0.25 mm) and visualization was done by UV, or alternatively by I 2, KMnO 4, CAM or p-anisaldehyde staining. Flash chromatography was performed using Silicycle SiliaFlash F60 (40 63 μm particle size). NMR spectra were recorded in the Laukien Purcell Instrumentation Center at Harvard University on Varian Spectrometer at the indicated frequency ( MHz). 1 H and 13 C NMR chemical shifts are reported as δ using residual solvent as an internal standard. High-resolution mass spectral analyses were performed using a Bruker microtofii ESI spectrometer. IR was measured on a Bruker ALPHA FT-IR. Optical rotations were measured with a Perkin- Elmer 241 Polarimeter at the indicated temperature with a sodium lamp (D line, 589 nm). Melting points (mp) are uncorrected and were recorded on a Fisher Johns melting point apparatus. HPLC measurements were performed on an Agilent 1100 Series HPLC using the indicated parameters. 2. Synthesis of Precatalysts General Procedure for the Preparation of Precatalysts 1 : According to the published procedure, 1 to a solution of prolinol (450 mg, 1.38 mmol) and diisopropylethylamine (0.5 ml, 2.76 mmol) in anhydrous toluene (6 ml) in a 25 ml flame-dried round bottom flask under nitrogen at 23 C was added a solution of dibromo(2,5-difluorophenyl)borane (387 mg; 1.38 mmol) in anhydrous toluene (3 ml) via syringe over 20 min at 23 C. After the addition was complete, the resulting pale yellow suspension was stirred at 23 C for 1 h. Stirring was stopped and the solids were allowed to settle at the bottom of the flask. The supernatant solution was concentrated under reduced pressure on a Schlenk line to afford a pale yellow oil which was pure by NMR. The product could be used directly for catalytic experiments or, alternatively, was taken up in anhydrous toluene to afford a 0.2 M solution of F2/F2 precatalyst. A similar procedure was used for the synthesis of F2/F0 or F10/F0 or F0/F0 precatalysts with dibromo(otolyl)borane 1, expect that benzene was used as solvent and the reaction was performed at 45 C for 1 h. S2

3 3. Synthesis of Chiral 1,2-Amino Alcohols (E)-3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)acryloyl chloride (15): To a stirred solution of S1 1 (1.0 g, 4.71 mmol) in THF-H 2 O (3:1, 6 ml) was added LiOH (594 mg, 14.1 mmol) at 0 C. After being stirred for 8 h at 23 C, the reaction mixture was then acidified with 2 N HCl to ph ~2 and extracted with EtOAc (20 ml 4). The combined organic extract was washed with brine (10 ml) and dried over Na 2 SO 4, filtered and concentrated to give the crude acid which was directly used for the next reaction without further purification. To a stirred solution of above crude acid in CH 2 Cl 2 (8 ml) was added oxalyl chloride (0.6 ml, 7.06 mmol) followed by one drop of DMF at 0 C. After 2 h stirring at 23 C, CH 2 Cl 2 was removed in vacuo and the resulting reaction mixture was evapourately distilled at 0.1 mm to give acid chloride 15 (0.9 g, 90% yield) as a colorless oil. 1 H NMR (CDCl 3, 500 MHz): δ = (d, J = 15 Hz, 1H), (d, J = 15 Hz, 1H), (s, 12H); 13 C NMR (CDCl 3, 125 MHz): δ = 166.8, 141.4, 133.6, 84.6, 53.4, 24.7; Benzyl ((1R,2R,3S,4R)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[2.2.1]hept-5-en-2- yl)carbamate (S2): A 0.2 M solution of F2/F2-oxazaborolidine in toluene (1.80 ml, mmol) was placed in a 25 ml oven- and flame-dried round-bottom flask and the solvent was removed under reduced pressure on a Schlenk line. The residue was taken up in anhydrous CH 2 Cl 2 and the resulting clear solution was cooled to 78 C under positive pressure of nitrogen. A freshly prepared, pre-mixed 0.3 M solution of Tf 2 NH (0.244 mmol) and TiCl 4 (1 M in CH 2 Cl 2, mmol) in anhydrous CH 2 Cl 2 was added and the resulting pale red solution was stirred at 78 C for 30 min. To the resulting solution at 78 C was added acid chloride 15 (0.54 ml, 4.88 mmol), followed by slow addition of cyclopentadiene (4.3 ml, 48.4 mmol) over a period of 20 minutes. The reaction mixture was stirred at 78 C for 2 h and monitored by NMR (aliquot withdrawn by syringe cooled with CO 2 (s), quenched with MeOH). After completion of reaction, the reaction mixture was diluted with anhydrous CH 2 Cl 2 (4 ml) and the solution was cannulated into a stirred solution of NaN 3 (1.9 g, 28.6 mmol) in acetone (5 ml) at 20 C under nitrogen atmosphere. Additional CH 2 Cl 2 (2x2 ml) was used to assist the transfer and the resulting reaction mixture was allowed to warm to 23 C and vigorously stirred for 8 h. The reaction mixture was then concentrated and resulting residue was treated with saturated aqueous NH 4 Cl (5 ml) and extracted with Et 2 O (2x30 ml). The combined organic extract was washed with brine (10 ml) and dried over Na 2 SO 4, filtered and S3

4 concentrated to give the crude azide which was directly used for the next reaction without further purification. The enantiopurity of the boronyl acid chloride adduct was measured after conversion to the methyl ester by optical rotation as 96% ee. 1 The stirred solution of above crude azide in toluene (12 ml) was heated to 100 C for 2 h, then benzyl alcohol (0.6 ml, 11.8 mmol) was added and heating continued for 6 h. The resulting solution was concentrated and purified by column chromatography (SiO 2, 40% EtOAc/hexanes) to afford S2 (1.31 g, 69% yield over three steps, 96% ee) as a viscous liquid. FTIR (neat, cm -1 ): 3422, 2976, 1701, 1509, 1371, 1272, 1212, 1102, 732; 1 H NMR (CDCl 3, 500 MHz): δ = (m, 5H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (s, 12H), (m, 1H); 13 C NMR (CDCl 3, 125 MHz): δ = 155.6, 141.2, 130.8, 128.3, 128.0, 127.9, 83.3, 66.4, 53.8, 47.3, 46.6, 45.0, 24.6, 24.5; HRMS(ESI): calcd for C 21 H 28 BNO 4 Na [MNa] +, ; found, ; Optical rotation: [α] 23 D = (c = 1, CHCl 3 ) for an enantiomerically enriched sample of 96% ee. Benzyl ((1R,2S,3S,4S)-3-hydroxybicyclo[2.2.1]hept-5-en-2-yl)carbamate (16): To a stirred solution of S2 (100 mg; 0.27 mmol) in THF:EtOH (3:1, 3 ml) at 0 C were added a 2.0 M aqueous KHCO 3 solution (0.27 ml, 0.54 mmol), followed by slow addition of H 2 O 2 (0.1 ml, 30% aqueous, 1.08 mmol) over 5 min. The resulting reaction mixture was stirred at 0 C for 2 h and then treated with saturated aqueous Na 2 S 2 O 3 (5 ml) and extracted with EtOAc (3x10 ml). The combined organic extract was washed sequentially with water (10 ml), brine (10 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (SiO 2, hexanes/etoac 1:1) to afford 16 (63 mg, 90% yield) as a viscous liquid. FTIR (neat, cm -1 ): 3413, 1690, 1509, 1327, 1254, 1057, 725; 1 H NMR (CDCl 3, 500 MHz): δ = 7.35 (m, 5H), (m, 1H), (m, 1H), 5.08 (s, 2H), 4.58 (d, J = 7.2 Hz, 1H), 3.74 (d, J = 5.7 Hz, 1H), 3.45 (s, 1H), 2.91 (s, 1H), 2.84 (s, 1H) 2.80 (s, 1H); 13 C NMR (CDCl 3, 125 MHz): δ = 156.8, 137.4, 136.3, , 128.5, 128.1, 80.3, 66.9, 62.3, 49.7, 45.6, 44.4; HRMS(ESI): calcd for C 15 H 17 NO 3 [MH] +, ; found, ; Optical rotation: [α] 23 D = (c = 1, CHCl 3 ) for an enantiomerically enriched sample of 96% ee. Benzyl ((1R,2R,3S,4R)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[2.2.2]oct-5-en-2-yl) carbamate (S3): A 0.2 M solution of F2/F2-oxazaborolidine in toluene (0.90 ml, mmol) was placed in a 25 ml oven- and flame-dried round-bottom flask and the solvent was removed under reduced pressure on a Schlenk line. The S4

5 residue was taken up in anhydrous CH 2 Cl 2 and the resulting clear solution was cooled to 78 C under positive pressure of nitrogen. A freshly prepared, pre-mixed 0.3 M solution of Tf 2 NH (0.122 mmol) and TiCl 4 (1 M in CH 2 Cl 2, mmol) in anhydrous CH 2 Cl 2 was added and the resulting pale red solution was stirred at 78 C for 30 min. To the resulting solution at 78 C was added acid chloride 15 (0.27 ml, 2.44 mmol), followed by slow addition of 1,3-cyclohexadiene (0.7 ml, 7.32 mmol) over a period of 20 minutes and stirring continued for 1 h at 78 C. The reaction mixture was then brought to 40 C, stirred for 4 h, and monitored by NMR (aliquot withdrawn by syringe cooled with CO 2 (s), quenched with MeOH). After completion of reaction, the reaction mixture was diluted with anhydrous CH 2 Cl 2 (4 ml) and the solution was cannulated into a stirred solution of NaN 3 (0.95 g, 14.3 mmol) in acetone (5 ml) at 20 C under nitrogen atmosphere. Additional CH 2 Cl 2 (2x2 ml) was used to assist the transfer and the resulting reaction mixture was allowed to warm to 23 C and vigorously stirred for 8 h. The reaction mixture was then concentrated and resulting residue was treated with saturated aqueous NH 4 Cl (5 ml) and extracted with Et 2 O (2x30 ml). The combined organic extract was washed with brine (10 ml) and dried over Na 2 SO 4, filtered and concentrated to give the crude azide which was directly used for the next reaction without further purification. The stirred solution of above crude azide in toluene (6 ml) was heated to 100 C for 2 h, and then benzyl alcohol (0.3 ml, 5.5 mmol) was added and heating was continued for 6 h. The resulting solution was concentrated and purified by column chromatography (SiO 2, 40% EtOAc/hexanes 1:3) to afford S3 (630 mg, 70% yield over three steps, 90% ee) as a viscous liquid. FTIR (neat, cm -1 ): 3420, 2973, 1698, 1515, 1391, 1282, 1232, 1120, 742; 1 H NMR (CDCl 3, 500 MHz): δ = (m, 5H), (t, J = 7.4 Hz, 1H), (t, J = 7.4 Hz, 1H), (m, 2H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 3H), (s, 12H), (m, 1H), (m, 1H); 13 C NMR (CDCl 3, 125 MHz): δ = 155.4, 138.6, 129.7, , 128.5, 128.2, 128.0, 127.0, 83.5, 66.4, 52.3, 35.4, 31.6, 24.8, 22.7, 22.6, 0.5; HRMS(ESI): calcd for C 22 H 30 BNO 4 Na [MNa] +, ; found, ; HPLC (Chiralcel OD-H, 0.46cm 25cm, hexane/ i PrOH 98:2, 1.0 ml/min, 254 nm): major: 5.1 min; minor: 6.6 min; Optical rotation: [α] 23 D = (c = 1, CHCl 3 ) for an enantiomerically enriched sample of 92% ee. Benzyl ((1R,2S,3S,4S)-3-hydroxybicyclo[2.2.2]oct-5-en-2-yl)carbamate (17): To a stirred solution of S3 (150 mg; mmol) in THF:EtOH (3:1, 3 ml) at 0 C were added a 2.0 M aqueous KHCO 3 solution (0.4 ml, 0.84 mmol), followed by slow addition of H 2 O 2 (0.12 ml, 30% aqueous, 1.64 mmol) over 5 min. The resulting reaction mixture was stirred at 0 C for 2 h and then treated with saturated aqueous Na 2 S 2 O 3 (5 ml) and extracted with EtOAc (3x10 ml). The combined organic extract was washed sequentially with water (10 ml), brine (10 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (SiO 2, hexanes/etoac 1:1) to afford 17 (98 mg, 87% yield) as a white solid. M.P: C; FTIR (neat, cm -1 ): 3418, 1695, 1519, 1337, 1264, 1077, 742; 1 H NMR (CDCl 3, 500 MHz): δ = (m, 5H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), 3.46 S5

6 3.39 (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H); 13 C NMR (CDCl 3, 125 MHz): δ = 156.9, 136.2, 134.3, 130.5, 128.5, 128.2, 128.1, 78.4, 66.8, 60.1, 36.4, 34.8, 24.5, 15.9; HRMS(ESI): calcd for C 16 H 20 NO 3 [MH] +, ; found, ; Optical rotation: [α] 23 D = (c = 1, CHCl 3 ) for an enantiomerically enriched sample of 92% ee. 4. Synthesis of Chiral 1,2-Diamines Dibenzyl ((1R,2S,3S,4S)-bicyclo[2.2.1]hept-5-ene-2,3-diyl)dicarbamate (21): A 0.2 M solution of F2/F2-oxazaborolidine in toluene (0.90 ml, mmol) was placed in a 25 ml oven- and flame-dried round-bottom flask and the solvent was removed under reduced pressure on a Schlenk line. The residue was taken up in anhydrous CH 2 Cl 2 and the resulting clear solution was cooled to 78 C under positive pressure of nitrogen. A freshly prepared, pre-mixed 0.3 M solution of Tf 2 NH (0.122 mmol) and TiCl 4 (1 M in CH 2 Cl 2, mmol) in anhydrous CH 2 Cl 2 was added and the resulting pale red solution was stirred at 78 C for 30 min. To the resulting solution at 78 C was added the fumaryl chloride (0.27 ml, 2.44 mmol), followed by slow addition of cyclopentadiene (1.05 ml, 12.2 mmol) over a period of 20 minutes. The reaction mixture was stirred at 78 C for 1 h and monitored by NMR (aliquot withdrawn by syringe cooled with CO 2 (s), quenched with MeOH). After completion of reaction, the reaction mixture was diluted with anhydrous CH 2 Cl 2 (3 ml) and the solution was cannulated into a stirred solution of NaN 3 (950 mg, 14.6 mmol) in acetone (5 ml) at 20 C under nitrogen atmosphere. Additional CH 2 Cl 2 (2x1 ml) was used to assist the transfer and the resulting reaction mixture was allowed to warm to 23 C and vigorously stirred for 8 h. The reaction mixture was then concentrated and resulting residue was treated with saturated aqueous NH 4 Cl (5 ml) and extracted with EtOAc (2x30 ml). The combined organic extract was washed with brine (10 ml) and dried over Na 2 SO 4, filtered and concentrated to give the crude diazide which was directly used for the next reaction without further purification. The enantiopurity of the intial fumarylchloride adduct was measured by rotation after conversion to the bis benzyl ester as 97% ee. 2 The stirred solution of above crude diazide in toluene (6 ml) was heated to 100 C for 3 h, and then benzyl alcohol (0.6 ml, 11.8 mmol) was added and heating continued for 8 h. The resulting solution was concentrated and purified by column chromatography (SiO 2, 40% EtOAc/hexanes) to afford 21 (554 mg, 58% over three steps, 97% ee) as a white solid. M.P: C; FTIR (neat, cm -1 ): 3320, 1681, 1536, 1454, 1331, 1281, 1241, 1023, 733; 1 H NMR (CDCl 3, 500 MHz): δ = (m, 10H), 6.35 (bs, 1H), 6.16 (d, J = 10 Hz, 1H), 5.38 (bs, 1H), (m, 4H), 4.74 (bs, 1H), 3.91 (d, J = 5.0 Hz, 1H), 3.20 (bs, 1H), 2.97(bs, 1H), 2.88 (bs, 1H), (m, 2H); 13 C NMR (CDCl 3, 125 MHz): δ = 156.0, 138.1, 136.3, 134.4, 128.5, , 66.9, 60.4, 59.4, 48.8, 45.5, 45.3; HRMS(ESI): calcd for C 23 H 25 N 2 O 4 [MH] +, ; found, ; Optical rotation: [α] 23 D = (c = 1, CHCl 3 ) for an enantiomerically enriched sample of 97% ee. S6

7 Dibenzyl ((1R,2S,3S,4S)-bicyclo[2.2.2]oct-5-ene-2,3-diyl)dicarbamate (22): A 0.2 M solution of F2/F2-oxazaborolidine in toluene (0.90 ml, mmol) was placed in a 25 ml oven- and flame-dried round-bottom flask and the solvent was removed under reduced pressure on a Schlenk line. The residue was taken up in anhydrous CH 2 Cl 2 and the resulting clear solution was cooled to 78 C under positive pressure of nitrogen. A freshly prepared, pre-mixed 0.3 M solution of Tf 2 NH (0.122 mmol) and TiCl 4 (1 M in CH 2 Cl 2, mmol) in anhydrous CH 2 Cl 2 was added and the resulting pale red solution was stirred at 78 C for 30 min. To the resulting solution at 78 C was added the fumaryl chloride (0.27 ml, 2.44 mmol), followed by slow addition of 1,3-cyclohexadiene (0.7 ml, 7.32 mmol) over a period of 20 minutes. The reaction mixture was stirred at 78 C for 4 h and monitored by NMR (aliquot withdrawn by syringe cooled with CO 2 (s), quenched with MeOH). After completion of reaction, the reaction mixture was diluted with anhydrous CH 2 Cl 2 (3 ml) and the solution was cannulated into a stirred solution of NaN 3 (950 mg, 14.6 mmol) in acetone (5 ml) at 20 C under nitrogen atmosphere. Additional CH 2 Cl 2 (2x1 ml) was used to assist the transfer and the resulting reaction mixture was allowed to warm to 23 C and vigorously stirred for 8 h. The reaction mixture was then concentrated and resulting residue was treated with saturated aqueous NH 4 Cl (5 ml) and extracted with EtOAc (2x30 ml). The combined organic extract was washed with brine (10 ml) and dried over Na 2 SO 4, filtered and concentrated to give the crude diazide which was directly used for the next reaction without further purification. The enantiopurity of the intial fumarylchloride adduct was measured by rotation and HPLC after conversion to the bis benzyl ester as 92% ee. 2 The stirred solution of above crude diazide in toluene (6 ml) was heated to 100 C for 3 h, and then benzyl alcohol (0.6 ml, 11.8 mmol) was added and heating continued for 8 h. The resulting solution was concentrated and purified by column chromatography (SiO 2, 40% EtOAc/hexanes) to afford 22 (594 mg, 60% over three steps, 92% ee) as a white solid. M.P: C; FTIR (neat, cm -1 ): 3271, 2139, 1685, 1633, 1535, 1363, 1223, 700; 1 H NMR (CDCl 3, 500 MHz): δ = (m, 10H), 6.38 (t, J = 7.7 Hz, 1H), 6.18 (t, J = 7.7 Hz, 1H), 5.22 (s, 1H), (m, 4H), 4.78 (bs, 1H), 3.43 (d, J = 8.3 Hz, 1H), 3.28 (bs, 1H), 2.80 (bs, 1H), 2.66 (bs, 1H), 1.66 (dd, J = 26.7, 13.8 Hz, 2H), 1.34 (t, J = 13.0 Hz, 1H), 1.15 (t, J = 12.4 Hz, 1H); 13 C NMR (CDCl 3, 125 MHz): δ = 156.2, 155.8, 136.3, 136.2, 134.8, 131.3, 128.3, 128.1, 127.9, 66.7, 66.6, 58.5, 56.4, 36.1, 35.3, 23.9, 16.8; HRMS(ESI): calcd for C 24 H 26 N 2 O 4 [MH] +, ; found, ; Optical rotation: [α] 23 D = (c = 1, CHCl 3 ) for an enantiomerically enriched sample of 92% ee. Dibenzyl ((1S,2S)-4-methylcyclohex-4-ene-1,2-diyl)dicarbamate (23): A 0.2 M solution of F2/F2-oxazaborolidine in toluene (0.90 ml, mmol) was placed in a 25 ml oven- and flame-dried round-bottom flask and the solvent was removed under reduced pressure on a Schlenk line. The S7

8 residue was taken up in anhydrous CH 2 Cl 2 and the resulting clear solution was cooled to 78 C under positive pressure of nitrogen. A freshly prepared, pre-mixed 0.3 M solution of Tf 2 NH (0.122 mmol) and TiCl 4 (1 M in CH 2 Cl 2, mmol) in anhydrous CH 2 Cl 2 was added and the resulting pale red solution was stirred at 78 C for 30 min. To the resulting solution at 78 C was added the fumaryl chloride (0.27 ml, 2.44 mmol), followed by slow addition of isoprene (1.22 ml, 12.2 mmol) over a period of 20 minutes. The reaction mixture was stirred at 78 C for 6 h and monitored by NMR (aliquot withdrawn by syringe cooled with CO 2 (s), quenched with MeOH). After completion of reaction, the reaction mixture was diluted with anhydrous CH 2 Cl 2 (3 ml) and the solution was cannulated into a stirred solution of NaN 3 (950 mg, 14.6 mmol) in acetone (5 ml) at 20 C under nitrogen atmosphere. Additional CH 2 Cl 2 (2x1 ml) was used to assist the transfer and the resulting reaction mixture was allowed to warm to 23 C and vigorously stirred for 8 h. The reaction mixture was then concentrated and resulting residue was treated with saturated aqueous NH 4 Cl (5 ml) and extracted with EtOAc (2x30 ml). The combined organic extract was washed with brine (10 ml) and dried over Na 2 SO 4, filtered and concentrated to give the crude diazide which was directly used for the next reaction without further purification. The enantiopurity of the intial fumarylchloride adduct was measured by rotation and HPLC after conversion to the bis benzyl ester as 92% ee. 2 The stirred solution of above crude diazide in toluene (6 ml) was heated to 100 C for 3 h, and then benzyl alcohol (0.6 ml, 11.8 mmol) was added and heating continued for 8 h. The resulting solution was concentrated and purified by column chromatography (SiO 2, 40% EtOAc/hexanes) to afford 23 (596 mg, 62% over three steps, 92% ee) as a white solid. M.P: C; FTIR (neat, cm -1 ): 3315, 1686, 1545, 1464, 1341, 1291, 1241, 1033, 738; 1 H NMR (CDCl 3, 500 MHz): δ = (m, 10H), (m, 4H), (m, 2H), (m, 2H), (m, 2H), (m, 2H), (s, 3H); 13 C NMR (CDCl 3, 125 MHz): δ = 156.9, 136.5, 132.4, 128.5, , 128.0, 127.9, 127.6, 126.9, 118.8, 105.6, 66.7, 65.3, 51.9, 51.4, 37.1, 32.1, 22.8; HRMS(ESI): calcd for C 23 H 26 N 2 NaO 4 [MNa] +, ; found, ; Optical rotation: [α] 23 D = (c = 1, CHCl 3 ) for an enantiomerically enriched sample of 92% ee. 5. Synthesis of Chiral β-amino Acids 5.1 NMR Experiment: An oven-dried NMR tube under dry nitrogen was charged with a solution of S4 3 (5 mg, mmol, 1.0 equiv) in CDCl 3 (0.5 ml) at 23 C. TiCl 4 (1 M in CH 2 Cl 2, 25μl, mmol, 1.0 equiv) was added and the resulting solution was shaken for 5 min before an NMR was measured at the same temperature. S4: 1 H NMR (CDCl 3, 500 MHz): δ = (m, 2H), 4.62 (q, J = 8.2 Hz, 2H); 19 F NMR (CDCl 3, 376 MHz): δ = Trifluoroethyl trichlorotitanium fumarate (29): S8

9 1 H NMR (CDCl 3, 500 MHz): δ = (m, 2H), 4.67 (m, 2H); 19 F NMR (CDCl 3, 376 MHz): δ = ,2,2-Trifluoroethyl (1R,2S,3S,4S)-3-(((benzyloxy)carbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylate (31): A 0.2 M solution of F2/F0 oxazaborolidine in benzene (0.90 ml, mmol) was placed in a 25 ml oven- and flame-dried round-bottom flask and the solvent was removed under reduced pressure on a Schlenk line. The residue was taken up in anhydrous CH 2 Cl 2 (3 ml) and the resulting clear solution was cooled to 50 C under positive pressure of nitrogen. A solution of AlBr 3 (0.122 ml of 1.0 M in CH 2 Br 2, mmol) was added and the resulting reaction mixture was stirred at 50 C for 30 min. The reaction mixture was then cooled to 78 C and a solution of trifluoroethyl trichlorotitanium fumarate 29, prepared in situ from equimolar mixture of monotrifluoroethyl fumarate S4 3 (420 mg, 2.44 mmol) and TiCl 4 (1 M in CH 2 Cl 2, 2.4 ml, 2.44 mmol) in CH 2 Cl 2 (3 ml) was added. Cyclopentadiene (2.0 ml, 12.4 mmol) was then added down the wall of the flask over a period of 20 min and stirred at 78 C. The reaction was monitored by TLC and judged to be complete after 6 h. The reaction mixture was then treated with Et 3 N (0.1 ml) and diluted with Et 2 O (5 ml), brought to ambient temperature and filtered through a Celite pad. The filtrate was concentrated in vacuo to give the crude monotrifluoroethyl fumarate adduct 30 which was directly used for the next reaction without further purification. The enantiopurity of the intial monotrifluoroethyl fumarate adduct 30 was measured by rotation after conversion to the bis trifluoroethyl ester as 92% ee. 1 To a stirred solution of above crude monotrifluoroethyl fumarate adduct 30 in CH 2 Cl 2 (3 ml) was added oxalyl chloride (0.23 ml, 2.68 mmol) followed by one drop of DMF at 0 C. After 2 h stirring at 23 C, the reaction mixture was diluted with anhydrous CH 2 Cl 2 (2 ml) and the solution was cannulated into a stirred solution of NaN 3 (0.95 g, 14.3 mmol) in acetone (4 ml) at 20 C under nitrogen atmosphere. Additional CH 2 Cl 2 (2x1 ml) was used to assist the transfer and the resulting reaction mixture was allowed to warm to 23 C and vigorously stirred for 8 h. The reaction mixture was then concentrated and resulting residue was treated with saturated aqueous NH 4 Cl (5 ml) and extracted with EtOAc (2x30 ml). The combined organic extract was washed with brine (10 ml) and dried over Na 2 SO 4, filtered and concentrated to give the crude azide which was directly used for the next reaction without further purification. The stirred solution of above crude azide in toluene (6 ml) was heated to 100 C for 4 h, and then benzyl alcohol (0.3 ml, 5.5 mmol) was added and heating continued for 8 h. The resulting solution was concentrated and purified by column chromatography (SiO 2, 40% EtOAc/hexanes 1:3) to afford 31 (490 mg, 55% yield over three steps, 92% ee) as a colorless oil. FTIR (neat, cm -1 ): 3327, 2960, 1730, 1702, 1508, 1224, 1023, 726, 697; 1 H NMR (CDCl 3, 500 MHz): δ = (m, 5H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 2H); 13 C NMR (CDCl 3, 125 MHz): δ = 171.1, 153.4, 136.3, 136.2, 135.1, 128.5, 128.2, 128.1, 69.8, 66.9, 60.4, 60.0, 59.6, 55.2, 52.4, 48.8, 47.0, 45.3; HRMS (ESI): calcd for C 18 H 18 F 3 NNaO 4 S9

10 [MNa] +, ; found, ; Optical rotation: [α] D 23 = (c = 1, CHCl 3 ) for an enantiomerically enriched sample of 92% ee. Dimethyl (1R,2S,3S,4S)-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate (S5) 4 : The physical and spectral data were identical to those previously reported for this compound. 4 FTIR (neat, cm -1 ): 1727, 1434, 1310, 1265, 1244, 1175, 1017, 908; 1 H NMR (CDCl 3, 500 MHz): δ = 6.25 (d, J = 5.5 Hz, 1H), 6.05 (d, J = 5.5 Hz, 1H), 3.70 (s, 3H), 3.62 (s, 3H), 3.35 (d, J = 4.3 Hz, 1H), 3.24 (s, 1H), 3.10 (s, 1H), 2.66 (d, J = 4.6 Hz, 1H), 1.60 (d, J = 8.8 Hz, 1H), 1.44 (d, J = 8.8 Hz, 1H); 13 C NMR (CDCl 3, 125 MHz): δ = 174.8, 173.6, 137.5, 135.1, 52.1, 51.7, 47.8, 47.5, 47.3, 47.1, 45.6; HRMS(ESI): calcd for C 11 H 14 O 4 [MH] +, ; found, ; Optical rotation: [α] 23 D = (c = 1, CHCl 3 ) for an enantiomerically enriched sample of 90% ee. 6. Synthesis of Boronic Acid Derivatives ((1R,2S,3R,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-en-2-yl)boronic acid (19): To a stirred solution of S6 (275 mg; mmol) in acetone:h 2 O (1:1, 4 ml) were added NH 4 OAc (0.63 g, 2.96 mmol) followed by NaIO 4 (250 mg, 2.96 mmol at 0 C. The resulting reaction mixture was stirred at 0 C for 6 h then filtered through a Celite pad. The filtrate was concentrated in vacuo to give the crude residue which was purified by column chromatography (SiO 2, hexanes/etoac 1:9) to afford 19 (155 mg, 80% yield) as a viscous liquid. 1 H NMR (CDCl 3, 500 MHz): δ = (m, 1H), 6.10 (dd, J = 5.7, 3.3 Hz, 1H), 4.13 (m, 1H), 3.67 (d, J = 0.8 Hz, 4H), 3.11 (m, 1H), 2.80 (m, 1H), 2.67 (dd, J = 3.5, 2.5 Hz, 1H), 1.91 (m,, 3H), 1.68 (dq, J = 8.8, 1.8 Hz, 1H); 11 B NMR (CDCl 3, 129 MHz): δ = Methyl (1R,2R,3S,4R)-3-(4-methyltetrahydro-2H-4l4,8l4-[1,3,2]oxazaborolo[2,3-b][1,3,2]oxazaborol-8- yl)bicyclo[2.2.1]hept-5-ene-2-carboxylate (20): A 25-ml, two-necked, round-bottomed flask equipped with a stir bar, a glass stopper and a 25-ml pressureequalizing addition funnel (containing a cotton plug and ca. 3 g of 4Å molecular sieves, and functioning as a Soxhlet extractor) fitted on top with a reflux condenser and a nitrogen inlet adaptor was charged with boronic acid 19 (81 mg, mmol), N-methyl diethanolamine (50 mg, mmol) and 6 ml of benzene. The S10

11 resulting solution was heated to reflux (bath temperature ~ 100 C). After 4 h, the reaction mixture was cooled to ambient temperature and concentrated in vacuo to afford 20 (125 mg, quantitaive) as a viscous liquid. 1 H NMR (CDCl 3, 500 MHz): δ = (m, 1H), (m, 1H), (m, 4H), (m, 2H), (s, 3H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 3H), (m, 1H), (m, 1H), (m, 1H), (m, 1H); 11 B NMR (CDCl 3, 129 MHz): δ = References 1). Reddy, K. M.; Bhimireddy, E.; Thirupathi, B.; Breitler, S.; Yu, S.; Corey, E. J. J. Am. Chem. Soc. 2016, 138, ). Thirupathi, B.; Breitler, S.; Reddy, K. M.; Corey, E. J. J. Am. Chem. Soc. 2016, 138, ). Mukherjee, S.; Corey, E. J. Org. Lett. 2010, 12, ) Kumar, S. N.; Yu, I. F.; Chein, R-J. Org. Lett. 2017, 19, S11

12 8. Copies of 1 H and 13 C NMR spectra S12

13 S13

14 S14

15 S15

16 S16

17 S17

18 S18

19 S19

20 S20

21 S21

22 S22

23 S23

24 S24

25 8. Chiral HPLC traces S25

26 S26

27 S27