Diastereo- and Enantioselective Conjugate Addition of 3-Substituted xindoles to itroolefins Catalyzed by a Chiral i(ac) 2 -Diamine Complex under Mild Conditions Yan-Yan Han,, Zhi-Jun Wu, Wen-Bing Chen,, Xi-Lin Du, Xiao-i Zhang, and Wei-Cheng Yuan*, yuanwc@cioc.ac.cn ational Engineering Research Center of Chiral Drugs, Chengdu Institute of rganic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China Department of General Surgery, TangDu Hospital, The Fourth Military dical University, Xi an 710038, China Graduate School of Chinese Academy of Sciences, Beijing, 100049, China Supporting Information Table of Contents 1. General remarks........s1 2. Synthesis of catalyst L4-8.......... S1 3. General procedure for the asymmetric conjugate addition reaction.....s4 4. The determination of the absolute and relative stereochemistry the products........s8 5. References......S10 6. MR and HPLC spectra of new compounds........s11
1. General remarks Reagents were purchased from commercial sources and were used as received unless mentioned otherwise. Reactions were monitored by thin layer chromatography using silica gel HSGF254 plates. 1 H MR and 13 C MR (300 and 75 MHz, respectively) spectra were recorded in CDCl 1 3 H MR chemical shifts are reported in ppm relative to tetramethylsilane (TMS) with the solvent resonance employed as the internal standard (CDCl 3 at 7.26 ppm). 13 C MR chemical shifts are reported in ppm from tetramethylsilane (TMS) with the solvent resonance as the internal standard (CDCl 3 at 77.20 ppm). lting points were recorded on a Buchi lting Point B-545. 2. Synthesis of catalyst L4-8 H +Tf 2 pyridine H CH 2 Cl 2 H Tf PhMgBr, icl 2 (dppe) THF H Ph A B Tf 2 pyridine CH 2 Cl 2 Tf Ph CH 3 MgBr, icl 2 (dppe) t Bu CH 3 Ph BS, AIB cyclohexane C D CH 2 Br Diamine R * H R * H Ph K 2 C 3,EtH reflux (R) Ph Ph E L4-8 L4: (ar, R, R, ar), R = Ph L5: (ar, S, S, ar), R = Ph L6: (ar, R, R, ar), R = -(CH 2 ) 4 - L7: (ar, S, S, ar), R = -(CH 2 ) 4 - L8: (ar, ar), R = H To a solution of (R)-(+)-1,1'-bi-2-naphthol (8.5 g, >99% ee, 30.0 mmol) in dry methylene chloride (120.0 ml) were added dry pyridine (6.0 ml, 75.0 mmol) and triflic anhydride (5.6 ml, 33.0 mmol) at 5-10 C (bath temperature) under nitrogen atmosphere. After the addition, the solution was allowed to stir at room temperature overnight. Then 4 M HCl aqueous solution was added until the mixture was acidic. The resultant mixture was extracted with DCM, and washed with saturated acl solution. The organic layer was dried over a 2 S 4, concentrated, and the residue was purified by column chromatography (hexanes/ethyl acetate = 20/1) to give A (9.5 g, 76% yield) as a yellow oil. (R)-1-(2-Hydroxynaphthalen-1-yl)naphthalen-2-yl trifluoromethanesulfonate H Tf (A) 1,21 H MR (300 MHz, CDCl 3 ) δ 8.12 (d, J = 9.0 Hz, 1H), 7.99 (dd, J = 15.0, 8.1 Hz, 2H), 7.88 (d, J = 7.8 Hz, 1H), 7.62-7.57 (m, 2H), 7.45-7.44 (m, 2H), 7.38-7.30 (m, 2H), 7.28-7.26 (m, 1H), 7.02 (d, J = 8.1 Hz, 1H). - 1 -
To a mixture of A (9.0 g, 22.0 mmol) and icl 2 (dppe) (116.0 mg, 0.22 mmol) in dry THF (30.0 ml) were added slowly tetrahydrofuran phenylmagnisum bromide solution (220.0 mmol) at room temperature under nitrogen atmosphere. Then the resulting mixture was heated under reflux for 8 h. After quenching with saturated H 4 Cl solution, the mixture was filtrated. The filtrate was extracted with ethyl acetate, and the combined organic layer was dried over a 2 S 4, concentrated, and the residue was purified by column chromatography (hexanes/ethyl acetate = 20/1) to give B (6.9 g, 90% yield) as a yellow oil. H Ph (R)-1-(2-Phenylnaphthalen-1-yl)naphthalen-2-ol (B) 2 1 H MR (300 MHz, CDCl 3 ) δ 8.11-8.04 (m, 2H), 7.86-7.83 (m, 2H), 7.94 (d, J = 8.4 Hz, 1H), 7.61-7.57 (m, 1H), 7.50-7.23 (m, 8H), 7.14-7.13 (m, 3H), 5.24 (br s, 1H). To a solution of B (6.0 g, 17.0 mmol) in dry DCM (125.0 ml) were added dry pyridine (3.0 ml, 34.0 mmol), then Tf 2 (3.7 ml, 22.0 mmol) was added slowly to the mixture at 5-10 C (bath temperature) under nitrogen atmosphere. The mixture was allowed to stir at room temperature until B was consumed. Then 4 M HCl aqueous solution was added until the solution was acidic. The resultant mixture was extracted with DCM, and the combined organic layers were washed with saturated acl solution, dried over a 2 S 4, concentrated, and the residue was purified by column chromatography (hexanes/ethyl acetate = 50/1) to give C (7.5 g, 92% yield) as a white solid. (R)-1-(2-Phenylnaphthalen-1-yl)naphthalen-2-yl trifluoromethanesulfonate Tf (C) 1,2 Mp. 127.8-128.3 o C; 1 H MR (300 MHz, CDCl 3 ) δ 8.09 (d, J = 8.4 Hz, 1H), Ph 7.98-7.95 (m, 2H), 7.92-7.89 (m, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.58-7.53 (m, 1H), 7.52-7.40 (m, 3H), 7.33-7.26 (m, 2H), 7.17 (d, J = 8.4 Hz, 1H), 7.10-7.01 (m, 5H); 13 C MR (75 MHz, CDCl 3 ) δ 134.5, 132.8, 132.6, 131.9, 130.3, 129.6, 129.4, 128.7, 128.3, 128.1, 128.0, 127.9, 127.7, 127.6, 127.3, 126.8, 126.7, 126.5, 126.0, 119.4; HRMS (ESI): Calculated for C 27 H 17 F 3 a 3 S [M+a] + : 501.0748, found: 501.0743. To a mixture of C (7.0 g, 15.0 mmol) and icl 2 (dppe) (396.0 mg, 0.75 mol) in dry t Bu (20.0 ml) were added slowly methyl tert-butyl ether bromide methylmagnism solution (220.0 mmol) at room temperature under 2 atmosphere. The resulting mixture was heated under reflux for 12 h. After quenching with saturated H 4 Cl solution and filtrated, the filtrate was extracted with ethyl acetate, and the combined organic layers were dried over a 2 S 4, concentrated, and the residue was purified by column chromatography (hexanes) to give D (5.0 g, 98% yield) as a yellow oil. (R)-2-thyl-1-(2-phenylnaphthalen-1-yl)naphthalene (D) 3 CH 1 3 H MR (300 MHz, CDCl 3 ) δ 8.03 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), Ph 7.49-7.46 (m, 1H), 7.39-7.34 (m, 1H), 7.29-7.23 (m, 4H), 7.14-7.11 (m, 1H), 7.07-6.99 (m, 5H), 1.92 (s, 3H); 13 C MR (75 MHz, CDCl 3 ) δ 141.7, 139.3, 134.6, 134.5, 134.0, 132.8, 132.7, 131.6, 128.8, 128.5, 128.4, 128.0, 127.9, 127.4, 127.3, 126.7, 126.4, 126.0, 125.8, 124.6, 20.4; HRMS (ESI): Calculated for C 27 H 20 a [M+a] + : 367.1451, found: 367.1457. - 2 -
To a suspension of D (3.0 g, 8.7 mmol) in dry cyclohexane (350.0 ml) were added -bromosuccinimide (BS, 3.4 g, 19.2 mmol) followed by 2,2'-azobisiso butyronitrile (AIB, 140 mg, 0.87 mmol) at room temperature. The resulting mixture was heated under reflux for 24 h under 2 atmosphere. After cooling to room temperature, the mixture was filtrated, concentrated and the residue was purified by column chromatography (hexanes) to give E (2.3 g, 63% yield) as a yellow oil. (R)-2-(Bromomethyl)-1-(2-phenylnaphthalen-1-yl)naphthalene (E) 3 CH 1 2 Br H MR (300 MHz, CDCl 3 ) δ 8.09 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 1H), 7.58-7.44 (m, 3H), Ph 7.31-7.26 (m, 3H), 7.17 (d, J = 8.4 Hz, 1H), 7.15-7.10 (m, 5H), 4.23 (d, J = 10.2 Hz, 1H), 4.14 (d, J = 10.2 Hz, 1H); 13 C MR (75 MHz, CDCl 3 ) δ 141.2, 139.5, 135.6, 133.7, 133.4, 132.8, 132.7, 132.6, 132.4, 128.8, 128.7, 128.6, 128.2, 128.0, 127.9, 127.6, 127.2, 127.1, 126.7, 126.5, 126.4, 126.0, 32.4; HRMS (ESI): Calculated for C 27 H 19 Bra [M+a] + : 445.0563, found: 445.0562. Typical procedure for the synthesis of ligand L4-8 4 To a solution of E (1.0 g, 2.4 mmol) in ethanol (15.0 ml) were added anhydrous potassium carbonate (1.3 g, 9.6 mmol), followed by the chiral diamine or 1,2-ethylenediamine (1.1 mmol) at room temperature. Then it was heated under reflux for 24 h, after cooling to room temperature, the solvent was removed. CH 2 Cl 2 was then added, and the resulting mixture was washed with water. After dried over a 2 S 4, concentrated, the residue was purified by column chromatography (hexanes/ethyl acetate) to obtain L4-8 as a white solid (58-62% yield). (1R,2R)-1,2-Diphenyl-(R)- 1, 2 Ph Ph -bis((r)-(1-(2-phenylnaphtha len-1-yl) naphthalen-2-yl)methyl)ethane- 1,2-diamine (L4) H H White solid, yield 62%; mp. 207.5-208.2 o C; [α] 20 D = +36.1 (c 1.05, CH 2 Cl 2 ); 1 H MR (300 MHz, CDCl 3 ) δ 7.98-7.95 (m, 2H), Ph Ph 7.93-7.91 (m, 2H), 7.88-7.86 (m, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.42-7.36 (m, 4H), 7.34-7.30 (m, 2H), 7.26-7.15 (m, 4H), 7.05 (d, J = 8.4 Hz, 2H), 6.97-6.90 (m, 2H), 6.88-6.77 (m, 12H), 6.73-6.70 (m, 4H), 6.18 (d, J = 7.2 Hz, 4H), 3.09 (s, 2H), 3.03 (d, J = 12.9 Hz, 2H), 2.88 (d, J = 12.9 Hz, 2H), 1.47 (br, 2H); 13 C MR (75 MHz, CDCl 3 ) δ 141.5, 140.5, 139.2, 137.0, 134.5, 134.0, 133.6, 133.3, 132.7, 132.3, 128.6, 128.4, 128.1, 128.0, 127.9, 127.6, 127.4, 127.3, 126.8, 126.6, 126.4, 126.3, 126.2, 126.0, 125.8, 125.1, 68.6, 49.7. HRMS (ESI): Calculated for C 68 H 53 2 [M+H] + : 897.4231, found: 897.4203. H Ph H Ph (1S,2S)-(R)- 1, 2 -Bis((1-(2-phenylnaphthalen-1-yl)naphthale n-2-yl)methyl)cyclohexane-1,2-diamine (L7) Yellow solid, yield 60%, mp. 89.6-90.7 o C; [α] 20 D = +85.3 (c 0.48, CH 2 Cl 2 ); 1 H MR (300 MHz, CDCl 3 ) δ 8.03 (d, J = 8.4 Hz, 2H), 7.93-7.90 (m, 4H), 7.83 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.47-7.41 (m, 2H), 7.39-7.37 (m, 2H), 7.31-7.26 (m, 4H), 7.20-7.16 (m, 4H), 7.10-7.02 (m, 10H), 3.25 (d, J = 14.1 Hz, 2H), 3.18 (d, J = 14.1 Hz, 2H), 1.70 (br s, 2H), 1.60-1.58 (m, 2H), 1.32-1.31 (m, 2H), 1.16-1.14 (m, 4H), 0.91-0.90 (m, 2H); 13 C MR (75 MHz, CDCl 3 ) δ 141.4, 139.2, 133.8, 133.1, - 3 -
132.7, 132.2, 128.9, 128.8, 128.3, 128.1, 127.9, 127.8, 127.5, 126.8, 126.7, 126.6, 126.5, 126.4, 126.0, 125.8, 125.1, 61.0, 48.7, 30.5, 24.4. HRMS (ESI): Calculated for C 60 H 51 2 [M+H] + : 799.4075, found: 799.4047. H H Ph Ph (R)- 1, 2 -Bis((1-(2-phenylnapht halen-1-yl) naphthalen-2-yl) methyl) ethane-1,2-diamine (L8) White solid, yield 58%; mp. 98.8-100.0 o C; [α] 20 D = +86.0 (c 0.57, CH 2 Cl 2 ); 1 H MR (300 MHz, CDCl 3 ) δ 8.03 (d, J = 8.4 Hz, 2H), 7.95-7.89 (m, 4H), 7.86-7.83 (m, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.51-7.41 (m, 6H), 7.31-7.26 (m, 4H), 7.22-7.17 (m, 2H), 7.12-7.02 (m, 12H), 3.25 (d, J = 13.8 Hz, 2H), 3.17 (d, J = 13.8 Hz, 2H), 2.05 (s, 4H), 1.33 (br s, 2H); 13 C MR (75 MHz, CDCl 3 ) δ 141.4, 139.1, 136.4, 134.4, 134.2, 133.6, 133.1, 132.6, 132.2, 128.7, 128.3, 128.2, 128.0, 127.9, 127.7, 127.5, 126.8, 126.7, 126.6, 126.5, 126.4, 126.1, 125.8, 125.1, 51.2, 48.4. HRMS (ESI): Calculated for C 56 H 45 2 [M+H] + : 745.3602, found: 745.3577. 3. General procedure for L4 catalyzed asymmetric conjugate addition reaction R R 4 2 R R 2 3 i(ac)2 (10 mol%) 2 R R 2 L4 (12 mol%) 3 + 4 toluene, rt R 1 time 1a-i 2a-l R 3 1 To a mixture of 1 (33.0 mg, 0.15 mmol), i(ac) 2 (3.73 mg, 0.015 mmol), L4 (16.0 mg, 0.018 mmol) in dry toluene (3.0 ml) were added 2 (44.0 mg, 0.225 mmol) under 2 atmosphere. The reaction was stirred at room temperature (25-30 C) until 1 was consumed. Then the mixture was purified by column chromatography (hexanes/ethyl acetate =10:1) to give product 3. Ph 2 CEt (S)-Ethyl 3-methyl-3-((R)-2-nitro-1-phenylethyl)-2-oxoindoline-1-carboxylate (3aa): Yellow solid, mp. 108.9-110.0 o C; 91% yield, dr 99:1, 95% ee; [α] 20 D = +17.3 (c 2.65, CH 2 Cl 2 ); 1 H MR (300 MHz, CDCl 3 ) δ 7.76 (d, J = 8.1 Hz, 1H), 7.34-732 (m, 1H), 7.26-7.11 (m, 4H), 7.04-7.01 (m, 1H), 6.86-6.84 (m, 2H), 5.00-4.90 (m, 2H), 4.34 (q, J = 7.2 Hz, 2H), 3.95 (dd, J = 10.8, 4.5 Hz, 1H), 1.53 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H); 13 C MR (75 MHz, CDCl 3 ) δ 176.6, 150.2, 139.1, 133.9, 129.4, 129.2, 128.8, 128.4, 128.2, 124.7, 123.4, 115.3, 75.6, 63.3, 50.9, 50.8, 21.0, 14.1; HRMS (ESI): Calculated for C 20 H 20 2 5 a [M+a] + : 391.1263, found: 391.1264; HPLC: Chiralpak AD-H, i-propanol/hexane = 10/90, flow rate 1.0 ml/min, λ = 254 nm, t minor = 11.4 min, t major = 12.4 min. Br 2 CEt (S)-Ethyl 3-((R)-1-(4-bromophenyl)-2-nitroethyl) -3-methyl-2-oxoindoline -1-carboxylate (3ab): Yellow oil; 94% yield, dr 99:1, 95% ee; [α] 20 D = +3.5 (c 1.10, CH 2 Cl 2 ); 1 H MR (300 MHz, CDCl 3 ) δ 7.78 (d, J = 8.1 Hz, 1H), 7.40-7.35 (m, 1H), 7.30-7.21 (m, 3H), 7.09 (d, J = 7.5 Hz, 1H), 6.75 (d, J = 8.4 Hz, 2H), 4.98-4.80 (m, 2H), 4.37 (q, J = 7.2 Hz, 2H), 3.93 (dd, J = 11.1, 4.5 Hz, 1H), 1.52 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H); 13 C MR (75 MHz, CDCl 3 ) δ 176.3, 150.1, 139.1, 133.0, 131.4, 130.4, 129.5, 129.0, 124.9, 123.3, 122.7, 115.6, 75.4, 63.5, 50.8, 50.4, 21.3, 14.2; HRMS (ESI): Calculated for C 20 H 19 Bra 2 5 [M+a] + : 469.0374, found: 469.0370; ee was determined with the corresponding product by removing of the ethoxycarbonyl - 4 -
group. HPLC: Chiralpak AD-H, i-propanol/hexane = 10/90, flow rate 1.0 ml/min, λ = 254 nm, t major = 14.7 min, t minor = 16.8 min. Cl (S)-Ethyl 3-((R)-1-(4-chlorophenyl)-2-nitroethyl)-3-methyl-2-xoindoline- 1-carboxylate (3ac): Yellow oil, 93% yield, dr 99:1, 93% ee; [α] 20 D = +3.6 (c 2.00, CH 2 Cl 2 ); 1 H MR (300 MHz, CDCl 3 ) δ 7.78 (d, J = 8.1 Hz, 1H), 2 7.40-7.34 (m, 1H), 7.26-7.21 (m, 1H), 7.14-7.05 (m, 3H), 6.81 (d, J = 8.4 Hz, CEt 2H), 4.99-4.81 (m, 2H), 4.37 (q, J = 7.2 Hz, 2H), 3.95 (dd, J = 11.1, 4.5 Hz, 1H), 1.52 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H); 13 C MR (75 MHz, CDCl 3 ) δ 176.4, 150.1, 139.1, 134.5, 132.5, 130.1, 129.6, 129.5, 129.1, 128.5, 124.9, 123.3, 115.5, 75.5, 63.5, 50.8, 50.3, 21.3, 14.2; HRMS (ESI): Calculated for C 20 H 19 Cla 2 5 [M+a] + : 425.0865, found: 425.0859; ee was determined with the corresponding product by removing of the ethoxycarbonyl group. HPLC: Chiralpak AD-H, i-propanol/hexane = 10/90, flow rate 1.0 ml/min, λ = 254 nm, t major = 14.1 min, t minor = 15.5 min. 2 (S)-Ethyl 3-methyl-3-((R)-2-nitro-1-(4-nitrophenyl)ethyl)-2-oxoindoline -1-carboxylate (3ad): Yellow oil, 95% yield, dr 90:10, 88% ee; [α] 20 D = +5.6, (c 1.85,CH 2 Cl 2 ); 1 H MR (300 MHz, CDCl 3 ) δ 8.03 (d, J = 8.7 Hz, 2H), 7.79 2 (d, J = 8.1 Hz, 1H), 7.43-7.38 (m, 1H), 7.31-7.26 (m, 1H), 7.18-7.16 (m, 1H), CEt 7.11 (d, J = 8.7 Hz, 2H), 4.98-4.87 (m, 2H), 4.37 (q, J = 7.2 Hz, 2H), 4.12 (dd, J = 10.5, 5.1 Hz, 1H), 1.55 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H); 13 C MR (75 MHz, CDCl 3 ) δ 175.9, 149.9, 147.8, 141.5, 139.0, 129.9, 129.8, 128.6, 125.1, 123.3, 123.1, 115.6, 75.1, 63.7, 50.7, 50.5, 21.7, 14.1; HRMS (ESI): Calculated for C 20 H 19 a 3 7 [M+a] + : 436.1118, found: 436.1115; ee was determined with the corresponding product by removing of the ethoxycarbonyl group. HPLC: Chiralpak D-H, i-propanol/hexane = 10/90, flow rate 1.0 ml/min, λ = 254 nm, t major = 20.9 min, t minor = 30.9 min. (S)-Ethyl3-((R)-1-(4-methoxyphenyl)-2-nitroethyl)-3-methyl-2-oxoindoline -1-carboxylate (3ae): Yellow oil, 74% yield, dr 99:1, 89% ee; [α] 20 D = +2.6 (c 1.45, CH 2 Cl 2 ); 1 H MR (300 MHz, CDCl 3 ) δ 7.78 (d, J = 8.1 Hz, 1H), 2 7.38-7.32 (m, 1H), 7.22-7.17 (m, 1H), 7.03 (d, J = 7.5 Hz, 1H), 6.77 (d, J = CEt 8.7 Hz, 2H), 6.66 (d, J = 8.7 Hz, 2H), 5.01-4.81 (m, 2H), 4.37 (q, J = 7.2 Hz, 2H), 3.90 (dd, J = 11.1, 4.5 Hz, 1H), 3.71 (s, 3H), 1.50 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H); 13 C MR (75 MHz, CDCl 3 ) δ 176.7, 159.5, 150.2, 139.1, 129.9, 129.6, 129.2, 125.8, 124.6, 123.4, 115.4, 113.6, 75.8, 63.3, 55.1, 51.0, 50.2, 21.0, 14.1; HRMS (ESI): Calculated for C 21 H 22 a 2 6 [M+a] + : 421.1374, found: 421.1370; HPLC: Chiralpak AD-H, i-propanol/hexane = 10/90, flow rate 1.0 ml/min, λ = 254 nm, t major = 16.9 min, t minor = 18.9 min. (S)-Ethyl 3-methyl-3-((R)-2-nitro-1-p-tolylethyl)-2-oxoindoline-1-carboxyl ate (3af): Yellow oil, 76% yield, dr 99:1, 85% ee; [α] 20 D = +11.4 (c 2.40, CH 2 Cl 2 ). 1 2 H MR (300 MHz, CDCl 3 ) δ 7.78 (d, J = 7.5 Hz, 1H), 7.37-7.32 (m, 1H), 7.26-7.17 (m, 1H), 7.01 (d, J = 7.5 Hz, 1H), 6.94 (d, J = 7.8 Hz, 2H), 6.74 (d, J = 8.1 Hz, 2H), 5.01-4.83 (m, 2H), 4.35 (q, J = 7.2 Hz, 2H), 3.90 (dd, CEt J = 11.1, 4.5 Hz, 1H), 2.24 (s, 3H), 1.51 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H); 13 C MR (75 MHz, CDCl 3 ) δ 176.7, 150.3, 139.1, 138.1, 130.8, 129.6, 129.1, 128.9, 128.7, 124.6, 123.5, 115.3, 75.7, 63.3, 50.9, 50.5, 21.1, 21.0, 14.1; HRMS (ESI): Calculated for C 21 H 22 a 2 5 [M+a] + : 405.1418, found: 405.1421; ee was determined with the corresponding product by removing of the ethoxycarbonyl group. HPLC: Chiralpak AD-H, i-propanol/hexane = 5/95, flow - 5 -
rate 1.0 ml/min, λ = 254 nm, t major = 25.6 min, t minor = 30.9 min. F (S)-Ethyl 3-((R)-1-(4-fluorophenyl)-2-nitroethyl)-3-methyl-2-oxoindoline -1-carboxylate (3ag): Yellow oil, 91% yield, dr 99:1, 96% ee; [α] 20 D = +7.4 (c 1.11, CH 2 Cl 2 ); 1 H MR (300 MHz, CDCl 3 ) δ 7.78 (d, J =8.1 Hz, 1H), 2 7.40-7.34 (m, 1H), 7.26-7.21 (m, 1H), 7.08 (d, J =6.9 Hz, 1H), 6.84 (d, J = 6.9 CEt Hz, 4H), 5.00-4.81 (m, 2H), 4.37 (q, J = 7.2 Hz, 2H), 3.97 (dd, J = 11.1, 4.5 Hz, 1H), 1.53 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H); 13 C MR (75 MHz, CDCl 3 ) δ 176.5, 163.0 (d, J = 246.5 Hz, 1C), 150.1, 139.1, 130.4 (d, J = 8.3 Hz, 1C), 129.7 (d, J = 3.3 Hz, 1C), 129.4, 129.2, 124.8, 123.3, 115.5, 115.2 (d, J = 21.4 Hz, 1C), 75.6, 63.5, 50.9, 50.2, 21.2, 14.1; HRMS (ESI): Calculated for C 20 H 19 Fa 2 5 [M+a] + : 409.1181, found: 409.1170; ee was determined with the corresponding product by removing of the ethoxycarbonyl group. HPLC: Chiralpak AD-H, i-propanol/hexane = 5/95, flow rate 1.0 ml/min, λ = 254 nm, t minor = 12.7 min, t major = 15.9 min. (S)-Ethyl 3-(R)-1-(2-bromophenyl)-2-nitroethyl)-3-methyl-2-oxoindoline Br 2-1-carboxylate (3ah): Yellow oil, 91% yield, dr 90:10, 95% ee; [α] 20 D = +40.2 (c 2.30, CH 2 Cl 2 ); 1 H MR (300 MHz, CDCl 3 ) δ 7.88 (d, J = 8.1 Hz, 1H), CEt 7.56-7.50 (m, 2H), 7.39-7.31 (m, 2H), 7.19-7.13 (m, 2H), 6.94 (d, J =7.5 Hz, 1H), 4.87-4.82 (m, 1H), 4.76-4.70 (m, 2H), 4.47 (q, J =6.9 Hz, 2H), 1.45 (t, J =7.2 Hz, 3H), 1.38 (s, 3H); 13 C MR (75 MHz, CDCl 3 ) δ 176.6, 150.5, 138.5, 134.2, 130.6, 129.8, 129.2, 128.9, 127.6, 125.2, 123.2, 115.1, 75.2, 63.7, 49.6, 47.1, 21.1, 14.2; HRMS (ESI): Calculated for C 20 H 19 Bra 2 5 [M+a] + : 469.0354, found: 469.0370; ee was determined with the corresponding product by removing of the ethoxycarbonyl group. HPLC: Chiralpak AD-H, i-propanol/hexane = 10/90, flow rate 1.0 ml/min, λ = 254 nm, t minor = 12.2 min, t major = 17.4 min. (S)-Ethyl3-((R)-1-(2-methoxyphenyl)-2-nitroethyl)-3-methyl-2-oxoindoline 2-1-carboxylate (3ai): Yellow oil, 74% yield, dr 75:25, 71% ee; [α] 20 D = +26.8 (c 1.11, CH 2 Cl 2 ); 1 H MR (300 MHz, CDCl 3 ) δ 7.85 (d, J = 8.1 Hz, 1H), CEt 7.31-7.25 (m, 2H), 7.16-7.05 (m, 3H), 6.78-6.73 (m, 2H), 4.96-4.94 (m, 2H), 4.50-4.41 (m, 2H), 3.54 (s, 3H), 1.55 (s, 3H), 1.44 (t, J = 7.8 Hz, 3H); 13 C MR (75 MHz, CDCl 3 ) δ 177.0, 158.0, 150.6, 138.6, 131.0, 129.4, 128.7, 124.4, 123.9, 123.8, 123.5, 120.3, 114.9, 110.0, 74.9, 63.4, 55.3, 50.1, 26.9, 14.3; HRMS (ESI): Calculated for C 21 H 22 2 a 6 [M+a] + : 421.1355, found: 421.1370; ee was determined with the corresponding product by removing of the ethoxycarbonyl group. HPLC: Chiralpak D-H, i-propanol/hexane = 10/90, flow rate 1.0 ml/min, λ = 254 nm, t minor = 13.6 min, t major = 14.5 min. (S)-Ethyl 3-((R)-1-(furan-2-yl)-2-nitroethyl)-3-methyl-2-oxoindoline-1- carboxylate (3aj): Yellow oil, 90 % yield, dr 90:10, 83 % ee; [α] 20 D 2 = +61.2 (c 1.10, CH 2 Cl 2 ); 1 H MR (300 MHz, CDCl 3 ) δ 7.87 (d, J = 8.1 Hz, 1H), CEt 7.36-7.31 (m, 2H), 7.14-7.09 (m, 1H), 6.70-6.68 (m, 1H), 6.28-6.26 (m, 1H), 6.09 (d, J = 3.0 Hz, 1H), 5.08-4.87 (m, 2H), 4.51-4.44 (m, 2H), 3.99 (dd, J = 11.1, 3.9 Hz, 1H), 1.53 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H); 13 C MR (75 MHz, CDCl 3 ) δ 176.6, 150.5, 148.7, 142.6, 138.4, 130.1, 129.1, 124.7, 123.6, 115.1, 110.5, 110.4, 73.4, 63.6, 50.0, 43.9, 20.4, 14.2; HRMS (ESI): Calculated for C 18 H 18 2 a 6 [M+a] + : 381.1059, found: 381.1057; ee was determined with the corresponding product by removing of the ethoxycarbonyl group. HPLC: Chiralpak AD-H, i-propanol/hexane = 10/90, flow rate 1.0 ml/min, λ = 254 nm, t minor = 12.3 min, t major = 16.0 min. - 6 -
S 2 CEt (S)-Ethyl 3-methyl-3-((R)-2-nitro-1-(thiophen-2-yl)ethyl)-2-oxoindoline1- carboxylate (3ak): White solid, mp. 160.1-161.6 o C; 91% yield, dr 99:1, 97% ee; [α] 20 D = +16.2 (c 1.59, CH 2 Cl 2 ); 1 H MR (300 MHz, CDCl 3 ) δ 7.84 (d, J = 8.1 Hz, 1H), 7.41-7.35 (m, 1H), 7.24-7.18 (m, 1H), 7.14-7.12 (m, 1H), 7.03-7.01 (m, 1H), 6.85-6.82 (m, 1H), 6.72-6.71 (m, 1H), 5.03 (dd, J = 12.6, 4.2 Hz, 1H), 4.79 (dd, J = 12.6, 11.1 Hz, 1H), 4.41 (q, J = 7.2 Hz, 2H), 4.30 (dd, J = 11.1, 4.2 Hz, 1H), 1.57 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H); 13 C MR (75 MHz, CDCl 3 ) δ 176.5, 150.4, 139.3, 136.1, 129.5, 129.4, 129.0, 128.4, 126.5, 125.9, 124.9, 123.5, 115.4, 77.0, 63.6, 51.0, 46.4, 21.3, 14.2; HRMS (ESI): Calculated for C 18 H 18 2 a 5 [M+a] + : 397.0837, found: 397.0829; ee was determined with the corresponding product by removing of the ethoxycarbonyl group. HPLC: Chiralpak D-H, i-propanol/hexane = 10/90, flow rate 1.0 ml/min, λ = 254 nm, t major = 15.8 min, t minor = 20.0 min. Ph Et 2 CEt (S)-ethyl 3-ethyl-3-((R)-2-nitro-1-phenylethyl)-2-oxoindoline-1- carboxylate (3ba): Yellow oil, 81% yield, dr 90:10, 85% ee; [α] 20 D = -0.1 (c 1.60, CH 2 Cl 2 ); 1 H MR (300 MHz, CDCl 3 ) δ 7.76 (d, J = 8.1 Hz, 1H), 7.39-7.33 (m, 1H), 7.24-7.20 (m, 1H), 7.19-7.04 (m, 4H), 6.86-6.83 (m, 2H), 4.956-4.89 (m, 2H), 4.35-4.32 (m, 2H), 4.00-3.97 (m, 1H), 2.10-1.98 (m, 2H), 1.35 (t, J = 7.2 Hz, 3H), 0.62-0.57 (m, 3H); 13 C MR (75 MHz, CDCl 3 ) δ 175.8, 150.1, 140.2, 134.0, 129.2, 128.9, 128.3, 128.1, 127.5, 124.7, 123.3, 115.3, 75.8, 63.5, 56.6, 51.0, 28.0, 14.2, 8.8; HRMS (ESI): Calculated for C 21 H 22 2 a 5 [M+a] + : 405.1430, found: 405.1421; HPLC: Chiralpak AD-H, i-propanol/hexane = 10/90, flow rate 1.0 ml/min, λ = 254 nm, t minor = 10.2 min, t major = 13.5 min. Ph Bn 2 CEt (S)-Ethyl 3-benzyl-3-((R)-2-nitro-1-phenylethyl)-2-oxoindoline-1- carboxylate (3ca): Yellow oil, 79% yield, dr 90:10, 76% ee; [α] 20 D = -1.1 (c 1.15, CH 2 Cl 2 ); 1 H MR (300 MHz, CDCl 3 ) δ 7.54-7.52 (m, 1H), 7.32-7.19 (m, 6H), 7.05-6.98 (m, 5H), 6.77-6.74 (m, 2H), 5.05-4.96 (m, 2H), 4.29-4.22 (m, 2H), 4.20-4.15 (m, 1H), 3.30 (d, J = 12.9 Hz, 1H), 3.06 (d, J = 12.9 Hz, 1H), 1.29 (t, J = 7.2 Hz, 3H); 13 C MR (75 MHz, CDCl 3 ) δ 175.1, 149.8, 139.9, 134.0, 129.8, 129.3, 128.8, 128.7, 128.4, 128.3, 127.8, 127.2, 126.9, 124.5, 123.8, 115.2, 75.9, 63.2, 57.2, 51.0, 44.7, 14.1; HRMS (ESI): Calculated for C 26 H 24 2 a 5 [M+a] + : 467.1589, found: 467.1577; ee was determined with the corresponding product by removing of the ethoxycarbonyl group. HPLC: Chiralpak AD-H, i-propanol/hexane = 20/80, flow rate 1.0 ml/min, λ = 254 nm, t minor = 8.29 min, t major = 11.5 min. Ph 2 CEt (S)-Ethyl 3,5-dimethyl-3-((R)-2-nitro-1-phenylethyl)-2-oxoindoline-1 -carboxylate (3da): White solid, mp. 141.5-143.7 o C; 95% yield, dr 99:1, 90% ee; [α] 20 D = -24.1 (c 2.04, CH 2 Cl 2 ); 1 H MR (300 MHz, CDCl 3 ) δ 7.64 (d, J = 8.4 Hz, 1H), 7.26-7.13 (m, 4H), 6.86 (d, J = 6.9 Hz, 2H), 6.80 (s, 1H), 5.02-4.86 (m, 2H), 4.34 (q, J = 7.2 Hz, 2H), 3.93 (dd, J = 10.8, 4.8 Hz, 1H), 2.31 (s, 3H), 1.50 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H); 13 C MR (75 MHz, CDCl 3 ) δ 176.7, 150.2, 136.6, 134.4, 133.9, 129.7, 129.4, 128.8, 128.4, 128.1, 124.0, 115.1, 75.6, 63.2, 50.9, 50.8, 29.3, 21.1, 14.2; HRMS (ESI): Calculated for C 21 H 22 2 a 5 [M+a] + : 405.1416, found: 405.1421; HPLC: Chiralpak D-H, i-propanol/hexane = 20/80, flow rate 1.0 ml/min, λ = 254 nm, t major = 6.4 min, t minor = 8.9 min. Ph (S)-Ethyl 5-fluoro-3-methyl-3-((R)-2-nitro-1-phenylethyl)-2-oxoindoline 2 F -1-carboxylate (3ea): White solid, mp. 132.6-133.7 o C; 94% yield, dr 90:10, CEt - 7 -
80% ee; [α] 20 D = +20.0 (c 1.20, CH 2 Cl 2 ); 1 H MR (300 MHz, CDCl 3 ) δ 7.80-7.76 (m, 1H), 7.26-7.15 (m, 3H), 7.05-7.04 (m, 1H), 6.90 (d, J = 7.5 Hz, 2H), 6.66-6.63 (m, 1H), 5.06-4.91 (m, 2H), 4.36 (q, J = 7.2 Hz, 2H), 3.93 (dd, J = 11.1, 4.5 Hz, 1H), 1.51 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H); 13 C MR (75 MHz, CDCl 3 ) δ 176.2, 159.8 (d, J = 243.6 Hz, 1C), 150.2, 134.9 (d, J = 2.4 Hz, 1C), 133.6, 131.4 (d, J = 7.9 Hz, 1C), 128.8, 128.7, 128.4, 116.8 (d, J = 7.8 Hz, 1C), 115.8 (d, J = 22.6 Hz, 1C), 111.2 (d, J = 24.5 Hz, 1C), 75.3, 63.7, 51.2, 50.5, 20.7, 14.1; HRMS (ESI): Calculated for C 20 H 19 Fa 2 5 [M+a] + : 409.1162, found: 409.1170; HPLC: Chiralpak AD-H, i-propanol/hexane = 10/90, flow rate 1.0 ml/min, λ = 254 nm, t R (minor) = 11.7 min, t R (major) = 15.5 min. Ph Bn 2 Boc (+)-tert-butyl 3-benzyl-3-(2-nitro-1-phenylethyl)-2-oxoindoline-1- carboxylate (3fa): 5 Yellow oil, yield 74%, dr 60:40; [α] 20 D = +3.0 (c 0.27, CH 2 Cl 2 ); 1 H MR (300 MHz, CDCl 3 ) δ 7.43-7.42 (m, 1H), 7.25-7.09 (m, 6H), 7.07-6.98 (m, 5H), 6.77-6.74 (m, 2H), 5.15-5.10 (m, 1H), 5.00-4.97 (m, 1H), 4.18-4.16 (m, 1H), 3.29 (d, J = 12.9 Hz, 1H), 3.14 (d, J = 12.9 Hz, 1H), 1.46 (s, 9H), 1.41 (t, J = 7.2 Hz, 3H). Ph 2 Cbz (+)-Benzyl 3-methyl-3-(2-nitro-1-phenylethyl)-2-oxoindoline-1-carboxylate (3ga): Yellow oil, yield 83%, dr 99:1; [α] 20 D = +26.2 (c 0.37, CH 2 Cl 2 ); 1 H MR (300 MHz, CDCl 3 ) δ 7.76 (d, J = 8.1 Hz, 1H), 7.41-7.31 (m, 6H), 7.23-7.21 (m, 1H), 7.18-7.03 (m, 4H), 6.81 (d, J = 7.2 Hz, 2H), 5.32 (s, 2H), 5.03 (dd, J = 11.1, 4.5 Hz, 1H), 4.90 (dd, J = 12.6, 11.1 Hz, 1H), 3.96 (dd, J = 11.1, 4.5 Hz, 1H), 1.55 (s, 3H); 13 C MR (75 MHz, CDCl 3 ) δ 176.5, 150.1, 139.1, 134.8, 133.8, 129.4, 129.3, 128.7, 128.6, 128.5, 128.4, 128.2, 128.0, 124.8, 123.4, 115.4, 75.6, 68.5, 51.1, 50.9, 21.0; HRMS (ESI): Calculated for C 25 H 22 a 2 5 [M+a] + : 453.1440, found: 453.1421. 4. The determination of the absolute and relative stereochemistry the products (1) Literature 6 H 3 C Ph 2 Boc (3R,1S)-5 Literature 6 : HPLC (Chiralpak J-H, hexane/i-prh = 95:5, flow rate 1.00 ml/min, λ = 254 nm): t R (syn major enantiomer, (3R, 1S)-5) = 32.0 min, t R (syn minor enantiomer, (3S, 1R)-5) = 49.6 min. - 8 -
HPLC analysis Ph 2 Boc Ph 2 Boc (2) This work CH 3 + CEt 1a 2a 2 10 mol% i(ac) 2, 12 mol% L4 Toluene, 2, r.t. 91% yield H 3 C Ph CEt 3aa 95% ee 2 1mol/LaH H, r.t. 98% yield Ph H 3 C H 4 2 DMAP, (Boc) 2 DCM, r.t. 80% yield H 3 C Ph Boc (3S,1R)-5 87% ee The synthesis of 4 from 3aa and 5 from 4 are according to the literature. 7,8 2-9 -
H 3 C Ph 2 Boc (3S,1R)-5 enantiomer, (3S, 1R)-5) = 48.19 min. 1 H MR (300 MHz, CDCl 3 ) δ 7.67 (d, J = 8.1 Hz, 1H), 7.35-7.29 (m, 1H), 7.20-7.11 (m, 4H), 7.00 (d, J = 7.2 Hz, 1H), 6.82 (d, J = 7.2 Hz,, 2H), 5.03 (dd, J = 12.9, 4.5 Hz, 1H), 4.94-4.86 (m, 1H), 3.94 (dd, J = 11.1, 4.5 Hz, 1H), 1.52 (s, 12H); HPLC: Chiralpak J-H, hexane/i-prh = 95:5, flow rate 1.0 ml/min, λ = 254 nm, t R (syn minor enantiomer, (3R, 1S)-5) = 30.29 min, t R (syn major Ph 2 Boc 5. Reference [1] Hughes, L.; Verhoeven, T. R.; Reider, P. J.; rganic Syntheses, Coll. 2004, 10, 112. [2] Katsuki, T.; Suzuki, K.; Sasaki, H. Tetrahedron. 1994, 50, 11827. [3] Ikunaka, M.; Maruoka. K.; kuda, Y.; oi, T. rganic Process Research & Development, 2003, 7, 644. [4] Costa, A. M.; Jimeno, C.; Gavenonis, J.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 6929. [5] Kato, Y.; Furutachi, M.; Chen, Z.; Mitsunuma, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 9168. [6] Bui, T. Syed, S. Carlos F. Barbas III, C. F. J. Am. Chem. Soc. 2009, 131, 8758. [7] Gelmi, M. L.; Beccalli, E. M.; Clerici, F. Tetrahedron. 2003, 59, 4615. [8] Rajeswaran, W. G.; Cohen, L. A. Tetrahedron, 1998, 54, 11375. - 10 -
6. 1 H MR and 13 C MR Spectra of Compounds 1 H MR of A 1 H MR of B - 11 -
1 H MR and 13 C MR of C - 12 -
1 H MR and 13 C MR of D - 13 -
1 H MR and 13 C MR of E - 14 -
1 H MR and 13 C MR of L4-15 -
1 H MR and 13 C MR of L7-16 -
1 H MR and 13 C MR of L8-17 -
1 H MR and 13 C MR of 3aa - 18 -
1 H MR and 13 C MR of 3ab Br 2 CEt Br 2 CEt - 19 -
1 H MR and 13 C MR of 3ac Cl 2 CEt Cl 2 CEt - 20 -
1 H MR and 13 C MR of 3ad 2 2 CEt 2 2 CEt - 21 -
1 H MR and 13 C MR of 3ae 2 CEt 2 CEt - 22 -
1 H MR and 13 C MR of 3af - 23 -
1 H MR and 13 C MR of 3ag F 2 CEt F 2 CEt - 24 -
1 H MR and 13 C MR of 3ah CEt Br 2 CEt Br 2-25 -
1 H MR and 13 C MR of 3ai CEt 2 CEt 2-26 -
1 H MR and 13 C MR of 3aj 2 CEt 2 CEt - 27 -
1 H MR and 13 C MR of 3ak S 2 CEt S 2 CEt - 28 -
1 H MR and 13 C MR of 3ba Ph Et 2 CEt Et Ph 2 CEt - 29 -
1 H MR and 13 C MR of 3ca - 30 -
1 H MR and 13 C MR of 3da Ph 2 CEt Ph 2 CEt - 31 -
1 H MR and 13 C MR of 3ea F Ph 2 CEt F Ph 2 CEt - 32 -
1 H MR of 3fa 1 H MR and 13 C MR of 3ga - 33 -
- 34 -
HPLC of 3aa Ph 2 CEt - 35 -
HPLC of 3ab Br 2 H Br 2 H - 36 -
HPLC of 3ac Cl 2 H Cl 2 H - 37 -
HPLC of 3ad 2 2 H 2 2 H - 38 -
HPLC of 3ae 2 CEt 2 CEt - 39 -
HPLC of 3af 2 H 2 H - 40 -
HPLC of 3ag F 2 H - 41 -
HPLC of 3ah Br 2 H Br 2 H - 42 -
HPLC of 3ai 2 H - 43 -
HPLC of 3aj 2 H 2 H - 44 -
HPLC of 3ak - 45 -
HPLC of 3ba Et Ph CEt 2 Ph Et 2 CEt - 46 -
HPLC of 3ca Bn 2 H Bn 2 H - 47 -
HPLC of 3da Ph 2 CEt - 48 -
HPLC of 3ea F Ph 2 CEt F Ph 2 CEt - 49 -