Cu(I)-Catalyzed Asymmetric Multicomponent Cascade Inverse. Electron-Demand aza-diels-alder/nucleophilic Addition/Ring-Opening

Transcript

1 Cu(I)-Catalyzed Asymmetric Multicomponent Cascade Inverse Electron-Demand aza-diels-alder/nucleophilic Addition/Ring-Opening Reaction Involving 2-Methoxyfurans as Efficient Dienophiles Rong Huang, Xin Chang, Jun Li, and Chun-Jiang Wang* Supporting Information Table of Contents I. General Remarks...S2 II. General Procedure for Racemic Multicomponent Cascade IEDDA/Nucleophilic Addition/Ring-Opening Reaction of 2-Methoxyfurans with Azoalkenes...S2 III. General Procedure for Asymmetric Multicomponent Cascade IEDDA/Nucleophilic Addition/Ring-Opening Reaction of 2-Methoxyfurans with Azoalkenes...S2-14 IV. Synthetic Transformation of the adduct 3a...S14-16 V. Experiments to Confirm the Intermediate 4 with Other Trapping Agents as the Nucleophile...S16-18 VI. VII. The absolute Configuration Determination of (3R,4R)-3c...S18 Proposed Working Model for the Stereochemistry of this Multicomponent Cascade IEDDA/Nucleophilic Addition/Ring-Opening Reaction...S19 VIII. IX. References...S19 1 H NMR and 13 C NMR Spectra...S20-77 X. HPLC Chromatograms...S S1

2 I. General Remarks 1 H NMR spectra were recorded on a VARIAN Mercury 300 MHz spectrometer or Bruker 400 MHz spectrometer in CDCl3. Chemical shifts are reported in ppm with the internal TMS signal at 0.0 ppm as a standard. The data are reported as (s = single, d = double, t = triple, q = quarte, m = multiple or unresolved, brs = broad single, coupling constant(s) in Hz, integration). 13 C NMR spectra were recorded on a VARIAN Mercury 75 MHz spectrometer or Bruker 100 MHz spectrometer in CDCl3 or d6-dmso. Chemical shifts are reported in ppm with the internal chloroform signal at 77.0 ppm as a standard. The content of water in solvents were determined by a Kari-Fischer instrument. Enantiomeric ratios were determined by HPLC, using a chiralpak AD-H or ID column with hexane and i-proh as solvents. -Halo N-benzoyl hydrazine 1 and 2-methoxyfurans 2 were prepared according to the literature procedure. II. General Procedure for Racemic Multicomponent Cascade IEDDA/Nucleophilic Addition/Ring-Opening Reaction of 2-Methoxyfurans with Azoalkenes Under argon atmosphere, racemic i Pr-Box (7.3 mg, mmol) and Cu(MeCN)4BF4 (7.9 mg, mmol) were dissolved in 5 ml CH2Cl2 (solvent CH2Cl2 was distilled over calcium hydried followed by adding water to reach a water content of 0.27% (v/v) in the solvent), and stirred at room temperature for about 30 min. Then, -halo N-benzoyl hydrazone 2 (0.5 mmol), Na2CO3 (0.75 mmol) and 2-methoxyfuran 1 (0.75 mmol) were added sequentially. Once starting material 2 was consumed (monitored by TLC), then the organic solvent was removed and the residue was purified by column chromatography to give the product, which was used as the racemic sample for the chiral HPLC analysis. III. General Procedure for Asymmetric Multicomponent Cascade IEDDA/Nucleophilic Addition/Ring-Opening Reaction of 2-Methoxyfurans with Azoalkenes catalyzed by Cu(I)/ t BuBox Complex Under argon atmosphere, (S,S)- t Bu-Box (6.5 mg, mmol) and Cu(MeCN)4BF4 (6.3 mg, 0.02 mmol) were dissolved in 2.0 ml CH2Cl2 (solvent CH2Cl2 was distilled over calcium hydried followed by adding water to reach a water content of 0.27% (v/v) in the solvent), and S2

3 stirred at room temperature for about 30 min. The reaction temperature was dropped to -40 o C and then -halo N-benzoyl hydrazone 2 (0.2 mmol), Na2CO3 (0.3 mmol) and 2-methoxyfuran 1 (0.3 mmol) were added sequentially. Once starting material was consumed (monitored by TLC), the organic solvent was removed and the residue was purified by column chromatography to give the product, which was then directly analyzed by HPLC to determine the enantiomeric excess. 3a Methyl 2-((3R,4R)-2-benzoyl-4-hydroxy-6-phenyl-2,3,4,5-tetrahydropyridazin-3-yl)acetate: Yield (78%); white solid, mp o C; [ ] 25 D = (c 1.16, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.73 (d, J = 6.9 Hz, 2H), 7.60 (d, J = 5.1 Hz, 2H), (m, 6H), (m, 1H), (m, 1H), 4.11 (s, 1H), 3.68 (s, 3H), 3.08 (dd, J = 18.3, 6.0 Hz, 1H), 2.77 (dd, J = 14.4, 6.3 Hz, 1H), 2.58 (dd, J = 18.3, 10.8 Hz, 1H), 2.46 (dd, J = 14.4, 6.9 Hz, 1H); 13 C NMR (CDCl3, TMS, 75 MHz) δ 172.4, 170.6, 146.8, 136.0, 134.6, 130.5, 129.8, 129.5, 128.4, 127.3, 125.5, 62.7, 52.1, 50.2, 31.1, 28.3; HRMS Calcd. For C20H21O4N2 + : , found: The product was analyzed by HPLC to determine the enantiomeric excess: 98% ee (chiralpak ID, i-propanol/hexane = 30/70, flow rate 0.5 ml/min, λ = 254 nm); tr = and min. 3b Methyl 2-((3R,4R)-2-benzoyl-6-(4-bromophenyl)-4-hydroxy-2,3,4,5-tetrahydropyridazin-3-yl)acetate: Yield (77%); white solid, mp o C; [ ] 25 D = (c 1.05, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.70 (d, J = 7.5 Hz, 2H), (m, 7H), (m, 1H), 4.44 (m, 1H), 3.71 (s, 3H), 3.51 (s, 1H), 3.05 (dd, J = 18.0, 6.3 Hz, 1H), S3

4 2.74 (dd, J = 14.7, 7.2 Hz, 1H), (m, 2H); 13 C NMR (CDCl3, TMS, 75 MHz) δ 172.4, 170.6, 145.7, 134.9, 134.4, 131.5, 130.6, 129.7, 127.4, 127.0, 123.9, 62.5, 52.2, 50.2, 31.1, 28.1; HRMS Calcd. For C20H20O4N2Br + : , found: The product was analyzed by HPLC to determine the enantiomeric excess: 93% ee (chiralpak ID, i-propanol/hexane = 30/70, flow rate 0.5 ml/min, λ = 254 nm); tr = and min. 3c Methyl 2-((3R,4R)-2-benzoyl-6-(3-chlorophenyl)-4-hydroxy-2,3,4,5-tetrahydropyridazin-3-yl)acetate: Yield (65%); white solid, mp o C; [ ] 25 D = (c 0.71, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.72 (d, J = 6.6 Hz, 2H), (m, 5H), (m, 2H), (m, 1H), 4.44 (m, 1H), 3.71 (s, 3H), 3.42 (s, 1H), 3.05 (dd, J = 18.9, 5.1 Hz, 1H), 2.74 (dd, J = 14.4, 6.9 Hz, 1H), (m, 2H); 13 C NMR (DMSO, 100 MHz) δ 171.8, 169.8, 146.0, 139.1, 135.6, 132.2, 130.9, 130.6, 129.5, 128.5, 127.7, 124.9, 122.2, 61.7, 52.0, 50.6, 30.8, 28.9; HRMS Calcd. For C20H20O4N2Cl + : , found: The product was analyzed by HPLC to determine the enantiomeric excess: 94% ee (chiralpak ID, i-propanol/hexane = 30/70, flow rate 0.5 ml/min, λ = 254 nm); tr = and min. 3d Methyl 2-((3R,4R)-2-benzoyl-6-(2-chlorophenyl)-4-hydroxy-2,3,4,5-tetrahydropyridazin- 3-yl)acetate: Yield (55%); white solid, mp o C; [ ] 25 D = (c 0.48, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.69 (d, J = 6.9 Hz, 2H), (m, 7H), (m, 1H), 4.43 (m, 1H), 3.74 (s, 3H), 3.58 (s, 1H), (m, 3H), 2.62 (dd, J = 14.7, 6.0 Hz, 1H); 13 C NMR (CDCl3, TMS, 100 MHz) δ 172.8, 170.4, 148.8, 136.8, 134.3, 132.2, 130.5, S4

5 130.1, 130.0, 129.8, 129.8, 127.4, 126.9, 62.7, 52.3, 50.0, 32.2, 31.4; HRMS Calcd. For C20H20O4N2Cl + : , found: The product was analyzed by HPLC to determine the enantiomeric excess: 93% ee (chiralpak ID, i-propanol/hexane = 30/70, flow rate 0.5 ml/min, λ = 254 nm); tr = and min. 3e Methyl 2-((3R,4R)-2-benzoyl-6-(4-fluorophenyl)-4-hydroxy-2,3,4,5-tetrahydropyridazin-3-yl)acetate: Yield (75%); white solid, mp o C; [ ] 25 D = (c 0.55, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.71 (d, J = 6.9 Hz, 2H), (m, 5H), (m, 2H), (m, 1H), 4.47 (m, 1H), 4.07 (s, 1H), 3.69 (s, 3H), 3.05 (dd, J = 18.0, 6.0 Hz, 1H), 2.76 (dd, J = 14.4, 6.3 Hz, 1H), 2.56 (dd, J = 18.0, 10.8 Hz, 1H), 2.46 (dd, J = 14.4, 6.9 Hz, 1H); 13 C NMR (CDCl3, TMS, 75 MHz) δ 174.1, 172.2, (d, JC-F = Hz), 147.1, 135.6, 133.2, 131.5, 130.6, 128.3, (d, JC-F = 22.0 Hz), 62.3, 51.8, 49.7, 30.2, 27.4; HRMS Calcd. For C20H20O4N2F + : , found: The product was analyzed by HPLC to determine the enantiomeric excess: 91% ee (chiralpak ID, i-propanol/hexane = 30/70, flow rate 0.5 ml/min, λ = 254 nm); tr = and min. 3f Methyl 2-((3R,4R)-2-benzoyl-6-(2-fluorophenyl)-4-hydroxy-2,3,4,5-tetrahydropyridazin- 3-yl)acetate: Yield (63%); white solid, mp o C; [ ] 25 D = (c 0.64, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.69 (d, J = 6.9 Hz, 2H), (m, 5H), (m, 2H), (m, 1H), (m, 1H), 3.74 (s, 3H), 3.49 (m, 1H), 3.04 (dd, J = 18.6, 5.7 Hz, 1H), (m, 2H), 2.56 (dd, J = 15.0, 6.3 Hz, 1H); 13 C NMR (CDCl3, TMS, 75 MHz) δ 174.0, 170.7, (d, JC-F = Hz), 146.9, 133.9, (d, JC-F = 8.3 Hz), 130.9, 129.8, S5

6 129.0, 127.5, 124.3, (d, JC-F = 22.2 Hz), 74.1, 50.4, 36.2, 28.7, 28.6; HRMS Calcd. For C20H20O4N2F + : , found: The product was analyzed by HPLC to determine the enantiomeric excess: 97% ee (chiralpak ID, i-propanol/hexane = 30/70, flow rate 0.5 ml/min, λ = 254 nm)); tr = and min. 3g Methyl 2-((3R,4R)-2-benzoyl-4-hydroxy-6-(p-tolyl)-2,3,4,5-tetrahydropyridazin-3- yl)acetate: Yield (78%); white solid, mp o C; [ ] 25 D = (c 0.88, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.73 (d, J = 6.9 Hz, 2H), (m, 5H), 7.13 (d, J = 7.5 Hz, 2H), (m, 1H), 4.44 (m, 1H), 3.77 (s, 1H), 3.69 (s, 3H), 3.07 (dd, J = 17.7, 5.4 Hz, 1H), 2.75 (dd, J = 14.4, 6.3 Hz, 1H), (m, 2H), 2.34 (s, 3H); 13 C NMR (CDCl3, TMS, 75 MHz) δ 172.4, 170.3, 146.7, 139.4, 134.5, 133.1, 130.2, 129.6, 128.9, 127.1, 125.2, 62.5, 51.9, 50.0, 30.8, 28.1, 21.0; HRMS Calcd. For C21H23O4N2 + : , found: The product was analyzed by HPLC to determine the enantiomeric excess: 98% ee (chiralpak ID, i-propanol/hexane = 30/70, flow rate 0.5 ml/min, λ = 254 nm); tr = and min. 3h Methyl 2-((3R,4R)-2-benzoyl-4-hydroxy-6-(m-tolyl)-2,3,4,5-tetrahydropyridazin-3-yl) acetate: Yield (69%); white solid, mp o C; [ ] 25 D = (c 0.73, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.75 (d, J = 6.9 Hz, 2H), (m, 5H), (m, 2H), (m, 1H), 4.44 (m, 1H), 3.71 (s, 3H), 3.44 (s, 1H), 3.09 (dd, J = 18.3, 6.3 Hz, 1H), 2.74 (dd, J = 15.0, 7.2 Hz, 1H), (m, 2H), 2.32 (s, 3H); 13 C NMR (CDCl3, TMS, 100 MHz) δ 172.5, 170.4, 146.8, 138.0, 136.0, 134.6, 130.5, 130.3, 130.0, 128.4, 127.3, 126.2, 122.7, 62.9, 52.2, 50.1, 31.3, 28.4, 21.4; HRMS Calcd. For C21H23O4N2 + : , found: S6

7 The product was analyzed by HPLC to determine the enantiomeric excess: 97% ee (chiralpak ID, i-propanol/hexane = 30/70, flow rate 0.5 ml/min, λ = 254 nm); tr = and min. 3i Methyl 2-((3R,4R)-2-benzoyl-4-hydroxy-6-(o-tolyl)-2,3,4,5-tetrahydropyridazin-3-yl) acetate: Yield (60%); white solid, mp o C; [ ] 25 D = (c 0.65, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.58 (d, J = 7.2 Hz, 2H), (m, 4H), (m, 3H), (m, 1H), 4.42 (m, 1H), 3.74 (s, 3H), 3.47 (s, 1H), (m, 2H), (m, 2H), 2.09 (s, 3H); 13 C NMR (CDCl3, TMS, 75 MHz) 172.7, 171.1, 149.9, 136.6, 136.1, 135.0, 131.2, 130.0, 129.0, 128.6, 127.6, 127.4, 125.7, 62.7, 52.3, 49.7, 31.7, 31.2, 21.1; HRMS Calcd. For C20H18O3N2: , found: The product was analyzed by HPLC to determine the enantiomeric excess: 90% ee (chiralpak ID, i-propanol/hexane = 30/70, flow rate 0.5 ml/min, λ = 254 nm); tr = and min. 3j Methyl 2-((3R,4R)-2-benzoyl-4-hydroxy-6-(3-methoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-yl)acetate: Yield (75%); white solid, mp o C; [ ] 25 D = (c 0.56, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.72 (brs, 2H), 7.43 (brs, 3H), (m, 3H), 6.91 (brs, 1H), 5.56 (m, 1H), 4.46 (m, 1H), 3.92 (s, 1H), 3.69 (s, 6H), (m, 1H), (m, 1H), (m, 2H); 13 C NMR (CDCl3, TMS, 75 MHz) 172.4, 170.6, 159.4, 146.3, 137.4, 134.8, 130.3, 129.7, 129.4, 127.3, 118.0, 116.4, 109.5, 62.7, 55.0, 52.2, 50.2, 31.2, 28.2; HRMS Calcd. For C21H23O5N2 + : , found: The product was analyzed by HPLC to determine the enantiomeric excess: 98% ee (chiralpak ID, i-propanol/hexane = S7

8 30/70, flow rate 0.5 ml/min, λ = 254 nm); tr = and min. 3k Ethyl 2-((3R,4R)-2-benzoyl-4-hydroxy-6-(naphthalen-2-yl)-2,3,4,5-tetrahydropyridazin- 3-yl)acetate: Yield (70%); white solid, mp o C; [ ] 25 D = (c 0.28, CHCl3); 1 H NMR (CDCl3, TMS, 400 MHz) 8.02 (s, 1H), (m, 6H), (m, 5H), (m, 1H), (m, 1H), 3.98 (s, 1H), 3.70 (s, 3H), 3.24 (dd, J = 18.0, 6.0 Hz, 1H), 2.81 (dd, J = 14.4, 6.4 Hz, 1H), 2.72 (dd, J = 18.0, 11.2 Hz, 1H), 2.53 (dd, J = 14.4, 6.8 Hz, 1H); 13 C NMR (CDCl3, TMS, 75 MHz) 172.5, 170.6, 146.6, 134.7, 133.6, 132.8, 130.6, 129.9, 128.5, 128.1, 127.4, 126.9, 126.4, 125.6, 122.7, 62.9, 52.2, 50.3, 31.2, 28.2; HRMS Calcd. For C24H23O4N2 + : , found: The product was analyzed by HPLC to determine the enantiomeric excess: 96% ee (chiralpak ID, i-propanol/hexane = 30/70, flow rate 0.5 ml/min, λ = 254 nm); tr = and min. 3l Methyl 2-((3R,4R)-2-benzoyl-4-hydroxy-6-((E)-styryl)-2,3,4,5-tetrahydropyridazin-3-yl) acetate: Yield (68%); yellow solid, mp o C; [ ] 25 D = (c 0.47, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.70 (d, J = 6.6 Hz, 2H), (m, 8H), 6.91 (d, J = 16.8 Hz, 1H), 6.73 (d, J = 16.8 Hz, 1H), 5.46 (m, 1H), 4.37 (m, 1H), 3.73 (s, 3H), 3.29 (s, 1H), 2.98 (dd, J = 18.0, 6.0 Hz, 1H), 2.74 (dd, J = 14.7, 6.6 Hz, 1H), (m, 2H); 13 C NMR (CDCl3, TMS, 75 MHz) 172.7, 170.2, 148.4, 135.8, 134.3, 133.5, 130.6, 129.9, 128.7, 128.6, 127.5, 127.3, 126.9, 62.8, 52.3, 50.4, 31.2, 27.3; HRMS Calcd. For C22H23O4N2 + : , found: The product was analyzed by HPLC to determine the enantiomeric excess: 92% ee (chiralpak ID, i-propanol/hexane = 30/70, flow rate 0.5 S8

9 ml/min, λ = 254 nm); tr = and min. O Ph N N CO 2 Et OH 6a Ethyl 2-((3R,4R)-2-benzoyl-4-hydroxy-6-phenyl-2,3,4,5-tetrahydropyridazin-3-yl) acetate: Yield (70%); white solid, mp o C; [ ] 25 D = (c 1.03, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.72 (d, J = 6.9 Hz, 2H), 7.59 (d, J = 4.5 Hz, 2H), (m, 6H), (m, 1H), 4.42 (m, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.60 (s, 1H), 3.09 (dd, J = 18.0, 5.7 Hz, 1H), 2.76 (dd, J = 15.0, 6.9 Hz, 1H), (m, 2H), 1.26 (t, J = 7.2 Hz, 3H); 13 C NMR (CDCl3, TMS, 75 MHz) 172.3, 170.4, 146.5, 136.1, 134.7, 130.4, 129.8, 129.5, 128.4, 127.3, 125.4, 62.8, 61.2, 50.1, 31.5, 28.4, 14.0; HRMS Calcd. For C21H23O4N2 + : , found: The product was analyzed by HPLC to determine the enantiomeric excess: 98% ee (chiralpak AD-H, i-propanol/hexane = 30/70, flow rate 0.5 ml/min, λ = 254 nm); tr = and min. O Ph N N CO 2 Et OH Me 6b Ethyl 2-((3R,4R)-2-benzoyl-4-hydroxy-6-(p-tolyl)-2,3,4,5-tetrahydropyridazin-3-yl)acetate: Yield (75%); white solid, mp o C; [ ] 25 D = (c 0.76, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.71 (d, J = 6.9 Hz, 2H), (m, 5H), 7.12 (d, J = 7.8 Hz, 2H), (m, 1H), 4.40 (m, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.72 (s, 1H), 3.07 (dd, J = 18.0, 6.0 Hz, 1H), 2.76 (dd, J = 15.0, 6.9 Hz, 1H), (m, 2H), 2.34 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H); 13 C NMR (CDCl3, TMS, 75 MHz) 172.4, 170.3, 146.5, 139.7, 134.8, 133.4, 130.4, 129.9, 129.1, 127.3, 125.4, 63.0, 61.3, 49.9, 31.6, 28.4, 21.2, 14.0; HRMS Calcd. For C22H25O4N2 + : , found: The product was analyzed by HPLC to determine the enantiomeric excess: 97% ee (chiralpak AD-H, i-propanol/hexane = 30/70, flow rate 0.5 S9

10 ml/min, λ = 254 nm); tr = and min. 6c Ethyl 2-((3R,4R)-2-benzoyl-4-hydroxy-6-(3-methoxyphenyl)-2,3,4,5-tetrahydro-pyridazin-3-yl)acetate: Yield (75%); white solid, mp o C; [ ] 25 D = (c 1.20, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.72 (d, J = 6.9 Hz, 2H), (m, 3H), (m, 3H), 6.90 (d, J = 8.7 Hz, 1H), 5.51 (m, 1H), 4.41 (m, 1H), 4.19 (q, J = 6.9 Hz, 2H), 3.69 (s, 3H), 3.40 (s, 1H), (m, 1H), (m, 1H), (m, 2H), 1.27 (t, J = 6.9 Hz, 3H); 13 C NMR (CDCl3, TMS, 75 MHz) 172.3, 170.4, 159.5, 146.0, 137.5, 134.9, 130.3, 129.7, 129.4, 127.2, 118.0, 116.4, 109.6, 62.9, 61.3, 55.0, 50.0, 31.6, 28.3, 14.0; HRMS Calcd. For C22H25O5N2 + : , found: The product was analyzed by HPLC to determine the enantiomeric excess: 96% ee (chiralpak ID, i-propanol/hexane = 30/70, flow rate 0.5 ml/min, λ = 254 nm); tr =18.24 and min. 6d Ethyl 2-((3R,4R)-2-benzoyl-6-(4-bromophenyl)-4-hydroxy-2,3,4,5-tetrahydropyridazin-3 -yl)acetate: Yield (73%); white solid, mp o C; [ ] 25 D = (c 1.43, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.68 (d, J = 7.2 Hz, 2H), (m, 7H), (m, 1H), 4.41 (m, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.49 (s, 1H), 3.04 (dd, J = 18.3, 6.0 Hz, 1H), 2.75 (dd, J = 15.0, 7.2 Hz, 1H), (m, 2H), 1.27 (t, J = 7.2 Hz, 3H); 13 C NMR (CDCl3, TMS, 100 MHz) 172.3, 170.4, 145.3, 135.0, 134.6, 131.6, 130.5, 129.7, 127.3, 126.9, 123.8, 62.7, 61.3, 50.0, 31.6, 28.2, 14.0; HRMS Calcd. For C21H22O4N2Br + : , found: The product was analyzed by HPLC to determine the enantiomeric excess: 97% ee (chiralpak ID, i-propanol/hexane = 30/70, flow rate 0.5 ml/min, λ = 254 nm); tr = and S10

11 17.48 min. 6e Propyl 2-((3R,4R)-2-benzoyl-4-hydroxy-6-phenyl-2,3,4,5-tetrahydropyridazin-3-yl)acetate: Yield (76%); white solid, mp o C; [ ] 25 D = (c 0.76, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.71 (d, J = 7.2 Hz, 2H), 7.59 (d, J = 4.2 Hz, 2H), (m, 6H), (m, 1H), 4.43 (m, 1H), 4.08 (t, J = 6.3 Hz, 2H), (m, 1H), 3.09 (dd, J = 18.0, 5.7 Hz, 1H), 2.78 (dd, J = 15.0, 6.9 Hz, 1H), (m, 2H), 1.66 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H); 13 C NMR (CDCl3, TMS, 75 MHz) 172.5, 170.3, 146.3, 136.1, 134.7, 130.5, 129.9, 129.5, 128.4, 127.3, 125.5, 66.9, 63.0, 49.9, 31.7, 28.4, 21.8, 10.3; HRMS Calcd. For C22H25O4N2 + : , found: The product was analyzed by HPLC to determine the enantiomeric excess: 95% ee (chiralpak ID, i-propanol/hexane = 30/70, flow rate 0.5 ml/min, λ = 254 nm); tr = and min. 6f Isopropyl 2-((3R,4R)-2-benzoyl-4-hydroxy-6-phenyl-2,3,4,5-tetrahydropyridazin-3-yl) acetate: Yield (72%); white solid, mp o C; [ ] 25 D = (c 0.73, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.72 (d, J = 6.9 Hz, 2H), 7.59 (s, 2H), (m, 6H), (m, 1H), (m, 1H), 4.43 (m, 1H), 3.60 (s, 1H), (m, 1H), (m, 3H), (m, 6H); 13 C NMR (CDCl3, TMS, 75 MHz) 171.9, 170.2, 146.4, 136.1, 134.7, 130.4, 129.9, 129.5, 128.4, 127.3, 125.5, 68.8, 63.0, 49.9, 32.0, 28.5, 21.7; HRMS Calcd. For C22H25O4N2 + : , found: The product was analyzed by HPLC to determine the enantiomeric excess: 91% ee (chiralpak ID, i-propanol/hexane = 30/70, flow rate 0.5 ml/min, λ = 254 nm); tr = and min. S11

12 6g Methyl 2-((3R,4R)-2-benzoyl-4-ethyl-4-hydroxy-6-phenyl-2,3,4,5-tetrahydropyri-dazin- 3-yl)acetate: Yield (68%); yellow solid, mp o C; 1 H NMR (CDCl3, TMS, 300 MHz) 7.72 (d, J = 6.9 Hz, 2H), (m, 2H), (m, 3H), (m, 3H), (m, 1H), 3.73 (s, 3H), (m, 5H), 1.60 (q, J = 7.5 Hz, 2H), 1.02 (t, J = 7.5 Hz, 3H); 13 C NMR (CDCl3, TMS, 100 MHz) 173.0, 170.2, 145.7, 136.2, 134.7, 130.6, 129.9, 129.6, 128.5, 127.4, 125.5, 69.0, 52.3, 34.0, 32.5, 32.3, 29.7, 6.9; HRMS Calcd. For C22H25O4N2 + : , found: The product was analyzed by HPLC to determine the enantiomeric excess: 94% ee (chiralpak AD-H, i-propanol/hexane = 30/70, flow rate 0.5 ml/min, λ = 254 nm); tr = 8.65 and min. 6h Methyl 2-((3R,4R)-2-benzoyl-4-hydroxy-4-pentyl-6-phenyl-2,3,4,5-tetrahydro-pyridazin- 3-yl)acetate: Yield (70%); yellow solid, mp o C; [ ] 25 D = (c 0.42, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.71 (d, J = 7.5 Hz, 2H), (m, 2H), (m, 6H), (m, 1H), 3.73 (s, 3H), (m, 4H), 2.54 (dd, J = 15.6, 5.1 Hz, 1H), 1.53 (m, 2H), 1.26 (m, 6H), (m, 3H); 13 C NMR (CDCl3, TMS, 100 MHz) 172.9, 170.2, 145.8, 136.2, 134.7, 130.6, 129.8, 129.6, 128.5, 127.4, 125.5, 68.9, 52.6, 52.2, 39.7, 33.9, 32.9, 31.9, 22.4, 22.1, 13.9; HRMS Calcd. For C25H31O4N2 + : , found: The product was analyzed by HPLC to determine the enantiomeric excess: 92% ee (chiralpak ID, i-propanol/hexane = 30/70, flow rate 0.5 ml/min, λ = 254 nm); tr = and min. S12

13 6i Methyl 2-((3R,4R)-2-benzoyl-4-hydroxy-4-pentyl-6-(p-tolyl)-2,3,4,5-tetrahydropyridazin- 3-yl)acetate: Yield (65%); yellow solid, mp o C; [ ] 25 D = (c 1.42, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.71 (d, J = 6.9 Hz, 2H), (m, 5H), 7.14 (d, J = 7.8 Hz, 2H), (m, 1H), 3.72 (s, 3H), (m, 5H), 2.34 (s, 3H), 1.53 (m, 2H), 1.26 (m, 6H), (m, 3H); 13 C NMR (CDCl3, TMS, 100 MHz) 173.0, 170.1, 145.9, 139.8, 134.8, 133.5, 130.5, 129.9, 129.2, 127.4, 125.4, 68.9, 52.6, 52.2, 39.7, 33.9, 32.8, 31.9, 22.4, 22.1, 21.2, 13.9; HRMS Calcd. For C26H33O4N2 + : , found: The product was analyzed by HPLC to determine the enantiomeric excess: 93% ee (chiralpak AD-H, i-propanol/hexane = 30/70, flow rate 0.5 ml/min, λ = 254 nm); tr =9.85 and min. 6j Methyl 2-((3R,4R)-2-benzoyl-6-(4-bromophenyl)-4-hydroxy-4-pentyl-2,3,4,5-tetrahydropyridazin-3-yl)acetate: Yield (63%); yellow solid, mp o C; [ ] 25 D = (c 1.21, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.68 (d, J = 6.9 Hz, 2H), (m, 7H), 5.26 (m, 1H), 3.73 (s, 3H), (m, 4H), 2.53 (dd, J = 15.3, 4.8 Hz, 1H), 1.52 (m, 2H), 1.26 (m, 6H), (m, 3H); 13 C NMR (CDCl3, TMS, 100 MHz) 172.9, 170.2, 144.7, 135.1, 134.6, 131.7, 130.7, 129.8, 127.5, 127.0, 123.9, 68.8, 52.4, 52.3, 39.7, 33.9, 32.8, 31.9, 22.4, 22.1, 13.9; HRMS Calcd. For C25H30O4N2Br + : , found: The product was analyzed by HPLC to determine the enantiomeric excess: 94% ee (chiralpak AD-H, i-propanol/hexane = 30/70, flow rate 0.5 ml/min, λ = 254 nm); tr = 9.91 and min. S13

14 6k Methyl 2-((3R,4R)-2-benzoyl-4-hydroxy-4-isobutyl-6-phenyl-2,3,4,5-tetrahydropyridazin-3-yl)acetate: Yield (64%); yellow solid, mp o C; [ ] 25 D = (c 0.81, CHCl3); 1 H NMR (CDCl3, TMS, 400 MHz) 7.71 (d, J = 7.2 Hz, 2H), (m, 2H), (m, 3H), (m, 3H), 5.29 (m, 1H), 3.74 (s, 3H), (m, 1H), (m, 4H), (m, 1H), (m, 2H), (m, 6H); 13 C NMR (CDCl3, TMS, 100 MHz) 173.1, 170.2, 145.6, 138.8, 136.1, 134.7, 130.6, 129.8, 129.6, 128.5, 127.5, 125.4, 69.5, 52.3, 48.2, 34.1, 33.4, 24.7, 24.4, 23.6; HRMS Calcd. For C24H29O4N2 + : , found: The product was analyzed by HPLC to determine the enantiomeric excess: 84% ee (chiralpak ID, i-propanol/hexane = 30/70, flow rate 0.5 ml/min, λ = 254 nm); tr = and min. IV. Synthetic Transformations of the adduct 3a To a solution of 3a (141 mg, 0.4 mmol, 98% ee) in 3 ml THF was added NaBH4 (30.4 mg, 2.0 eq.), the mixture was stirred at this temperature for 5 h. Then, the solvent was evaporated and the residue was purified by column chromatography to give 7 in 85% yield, which was then directly analyzed by HPLC to determine the enantiomeric excess. S14

15 7 ((5R,6R)-5-hydroxy-6-(2-hydroxyethyl)-3-phenyl-5,6-dihydropyridazin-1(4H)-yl)(phenyl )methanone 7: Yield (85%); white solid, mp o C; [ ] 25 D = (c 1.01, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.74 (d, J = 7.8 Hz, 2H), (m, 2H), (m, 3H), (m, 3H), (m, 1H), 4.65 (brs, 1H), (m, 2H), (m, 1H), 3.68 (t, J = 10.8 Hz, 1H), 3.07 (dd, J = 18.0, 6.0 Hz, 1H), 2.66 (dd, J = 18.0, 10.8 Hz, 1H), (m, 1H), (m, 1H); 13 C NMR (CDCl3, TMS, 75 MHz) 171.6, 148.3, 135.9, 134.3, 130.8, 130.1, 129.7, 128.5, 127.5, 125.5, 62.9, 58.6, 50.5, 29.2, 27.5; HRMS Calcd. For C19H21O3N2 + : , found: The product was analyzed by HPLC to determine the enantiomeric excess: 98% ee (chiralpak AD-H, i-propanol/hexane = 30/70, flow rate 0.5 ml/min, λ = 254 nm); tr = 8.41 and 9.96 min. To a solution of 3a (141 mg, 0.4 mmol, 98% ee) in 20 ml CHCl3 was added NEt3 (60.6 mg, 1.5eq.), the mixture was refluxed overnight. Once starting material 3a was consumed, then the organic solvent was removed and the residue was purified by column chromatography to give the product 8 in 95% yield, which was then directly analyzed by HPLC to determine the enantiomeric excess. 8 S15

16 (4aR,7aR)-1-benzoyl-3-phenyl-4,4a,7,7a-tetrahydrofuro[3,2-c]pyridazin-6(1H)one 8: Yield (95%); white solid, mp o C; [ ] 25 D = (c 0.85, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.74 (d, J = 6.9 Hz, 2H), (m, 2H), (m, 6H), (m, 1H), (m, 1H), (m, 2H), (m, 2H); 13 C NMR (CDCl3, TMS, 75 MHz) 173.9, 170.7, 148.0, 135.4, 134.1, 130.9, 130.0, 129.9, 128.6, 127.5, 125.6, 74.0, 49.8, 35.9, 25.6; The product was analyzed by HPLC to determine the enantiomeric excess: 98% ee (chiralpak AD-H, i-propanol/hexane = 30/70, flow rate 0.5 ml/min, λ = 254 nm); tr = and min. V. Experiments to Confirm the Intermediate 4 with Other Trapping Agents as the Nucleophile MeO O Ph ROH + 1a + 2a O 4 Ph N N O Ph standard reaction conditions R = Me R = Et MeO MeO EtO MeO O O O N N N Ph N Ph 9, 60% yield, 96% ee Ph 10, 65% yield, 95% ee Under argon atmosphere, (S,S)- t Bu-Box (6.5 mg, mmol) and Cu(MeCN)4BF4 (6.3 mg, 0.02 mmol) were dissolved in 2.0 ml dry CH2Cl2, and stirred at room temperature for about 30 min. The reaction temperature was dropped to -40 o C and then -chloro N-benzoyl hydrazone 2a (0.2 mmol), Na2CO3 (0.3 mmol), 2-methoxyfuran 1a (0.3 mmol) and MeOH or EtOH (0.3 mmol) were added sequentially. Once starting material was consumed (monitored by TLC), the organic solvent was removed and the residue was purified by column chromatography to give the product (contaminated by around 10% yield of 3a), which was then directly analyzed by HPLC to determine the enantiomeric excess. S16

17 9 ((4aR,7aR)-6,6-dimethoxy-3-phenyl-4a,6,7,7a-tetrahydrofuro[3,2-c]pyridazin-1(4H)-yl)( phenyl)methanone: Yield (60%); yellow oil; [ ] 25 D = (c 0.78, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.73 (d, J = 6.9 Hz, 2H), (m, 2H), (m, 6H), (m, 1H), (m, 1H), 3.31 (s, 3H), 3.21 (s, 3H), 3.09 (dd, J = 16.8, 4.2 Hz, 1H), 2.82 (dd, J = 14.1, 7.5 Hz, 1H), 2.70 (dd, J = 16.8, 4.5 Hz, 1H), 2.31 (dd, J = 14.1, 5.1 Hz, 1H); 13 C NMR (CDCl3, TMS, 75 MHz) 170.6, 148.4, 136.3, 134.9, 130.4, 129.8, 129.5, 128.3, 127.3, 125.6, 121.4, 72.1, 52.2, 50.2, 49.5, 39.2, 26.0; HRMS Calcd. For C21H23O4N2 + : , found: The product was analyzed by HPLC to determine the enantiomeric excess: 96% ee (chiralpak ID, i-propanol/hexane = 30/70, flow rate 0.5 ml/min, λ = 254 nm); tr = and min. 10 ((4aR,6R,7aR)-6-ethoxy-6-methoxy-3-phenyl-4a,6,7,7a-tetrahydrofuro[3,2-c]pyridazin-1( 4H)-yl)(phenyl)methanone: Yield (65%); yellow oil; [ ] 25 D = (c 0.59, CHCl3); 1 H NMR (CDCl3, TMS, 400 MHz) (m, 2H), (m, 2H), (m, 3H), (m, 3H), (m, 1H), (m, 1H), (m, 2H), 3.21 (s, 3H), 3.08 (dd, J = 12.6, 3.6 Hz, 1H), 2.82 (dd, J = 10.5, 5.7 Hz, 1H), 2.70 (dd, J = 12.6, 3.6 Hz, 1H), 2.33 (dd, J = 10.5, 3.9 Hz, 1H), (m, 3H); 13 C NMR (CDCl3, TMS, 75 MHz) 170.5, 148.2, 136.2, 134.9, 130.3, 129.7, 129.3, 128.2, 127.2, 125.5, 121.1, 72.0, 57.7, 52.2, 49.9, 39.6, 26.0, 15.0; HRMS Calcd. For C22H25O4N2 + : , found: The product was analyzed by HPLC to determine the enantiomeric excess: 95% ee (chiralpak ID, i-propanol/hexane = 30/70, flow rate 0.5 ml/min, λ = 254 nm); tr = and min. S17

18 12 ((4aR,7aR)-6-methyl-3-phenyl-4a,7a-dihydrofuro[3,2-c]pyridazin-1(4H)-yl)(phenyl)meth anone: Yield (65%); white solid, mp o C; 1 H NMR (CDCl3, TMS, 300 MHz) (m, 4H), (m, 6H), (m, 1H), (m, 1H), 5.07 (m, 1H), 3.41 (dd, J = 15.9, 2.1 Hz, 1H), 2.58 (dd, J = 15.9, 3.9 Hz, 1H), 1.72 (s, 3H); 13 C NMR (CDCl3, TMS, 100 MHz) 170.8, 159.3, 154.1, 136.4, 135.1, 130.5, 129.9, 129.8, 128.5, 127.4, 125.9, 97.4, 78.8, 59.0, 27.0, 13.4; The product was analyzed by HPLC to determine the enantiomeric excess: 86% ee (chiralpak ID, i-propanol/hexane = 30/70, flow rate 0.5 ml/min, λ = 254 nm); tr = and min. VI. The absolute configuration determination of (3R,4R)-3c Figure 1. X-ray structure of (3R,4R)-3c Crystal data for (3R,4R)-3c: C24H25ClN2O4, Mr = , T = 296 K, Monoclinic, space group P2(1), a = (13), b = (7), c = (15) Å, V = (18) Å 3, Z = 2, 3302 unique reflections, final R1 = and wr2 = for 3769 observed [I>2σ(I)] reflections, Flack = -2.33(19). CCDC contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via (or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB21EZ, UK; fax: (+44) ; or deposit@ccdc.cam.ac.uk) S18

19 VII. Proposed Working Model for the Stereochemistry of this Multicomponent Cascade IEDDA/Nucleophilic Addition/Ring-Opening Reaction VII. References 1. a) Chen, J.-R.; Dong, W.-R.; Candy, M.; Pan, F.-F.; Jörres, M.; Bolm C. J. Am. Chem. Soc. 2012, 134, 6924; b) South, M. S.; Jakuboski, T. L.; Westmeyer, M. D.; Dukesherer, D. R. J. Org. Chem. 1996, 61, G.M. Donald and E. D. Amstutz, J. Org. Chem. 1956, 21, 516. S19

20 VI. 1 H NMR and 13 C NMR Spectra 3a S20

21 3a S21

22 3b S22

23 3b S23

24 3c S24

25 3c S25

26 3d S26

27 3d S27

28 3e S28

29 3e S29

30 3f S30

31 3f S31

32 3g S32

33 3g S33

34 3h S34

35 3h S35

36 3i S36

37 3i S37

38 3j S38

39 3j S39

40 3k S40

41 3k S41

42 3l S42

43 3l S43

44 O Ph N N CO 2 Et OH 6a S44

45 O Ph N N CO 2 Et OH 6a S45

46 O Ph N N CO 2 Et OH Me 6b S46

47 O Ph N N CO 2 Et OH Me 6b S47

48 6c S48

49 6c S49

50 6d S50

51 6d S51

52 6e S52

53 6e S53

54 6f S54

55 6f S55

56 6g S56

57 6g S57

58 6h S58

59 6h S59

60 6i S60

61 6i S61

62 6j S62

63 6j S63

64 6k S64

65 6k S65

66 7 S66

67 7 S67

68 8 S68

69 8 S69

70 9 S70

71 9 S71

72 10 S72

73 10 S73

74 NOESY Spectra of 10 S74

75 12 S75

76 12 S76

77 12 S77

78 VII. HPLC Chromatograms 3a S78

79 3a S79

80 3b S80

81 3b S81

82 3c S82

83 3c S83

84 3d S84

85 3d S85

86 3e S86

87 3e S87

88 3f S88

89 3f S89

90 3g S90

91 3g S91

92 3h S92

93 3h S93

94 3i S94

95 3i S95

96 3j S96

97 3j S97

98 3k S98

99 3k S99

100 3l S100

101 3l S101

102 6a S102

103 6a S103

104 O Ph N N CO 2 Et OH Me 6b S104

105 6b S105

106 6c S106

107 6c S107

108 6d S108

109 6d S109

110 6e S110

111 6e S111

112 6f S112

113 6f S113

114 6g S114

115 6g S115

116 6h S116

117 6h S117

118 6i S118

119 6i S119

120 6j S120

121 6j S121

122 6k S122

123 6k S123

124 7 S124

125 7 S125

126 8 S126

127 8 S127

128 9 S128

129 9 S129

130 10 S130

131 10 S131

132 12 S132

133 12 S133