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

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...S78-133 S1

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, 0.0275 mmol) and Cu(MeCN)4BF4 (7.9 mg, 0.025 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, 0.022 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

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 178-180 o C; [ ] 25 D = -151.1 (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), 7.48-7.25 (m, 6H), 5.58-5.56 (m, 1H), 4.48-4.46 (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 + : 353.1492, found: 352.1423. 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 = 20.48 and 23.58 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 136-138 o C; [ ] 25 D = -120.7 (c 1.05, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.70 (d, J = 7.5 Hz, 2H), 7.50-7.40 (m, 7H), 5.53-5.52 (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

2.74 (dd, J = 14.7, 7.2 Hz, 1H), 2.60-2.47 (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 + : 431.0598, found: 430.0528. 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 = 18.32 and 20.44 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 194-196 o C; [ ] 25 D = -113.9 (c 0.71, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.72 (d, J = 6.6 Hz, 2H), 7.58-7.44 (m, 5H), 7.31-7.26 (m, 2H), 5.53-5.52 (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), 2.61-2.49 (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 + : 387.1103, found: 386.1033. 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 = 15.65 and 17.37 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 130-132 o C; [ ] 25 D = -99.4 (c 0.48, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.69 (d, J = 6.9 Hz, 2H), 7.35-7.25 (m, 7H), 5.51-5.50 (m, 1H), 4.43 (m, 1H), 3.74 (s, 3H), 3.58 (s, 1H), 2.91-2.81 (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

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 + : 387.1106, found: 386.1033. 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 = 17.31 and 20.17 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 168-169 o C; [ ] 25 D = -109.6 (c 0.55, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.71 (d, J = 6.9 Hz, 2H), 7.60-7.40 (m, 5H), 7.04-6.98 (m, 2H), 5.57-5.55 (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, 165.0 (d, JC-F = 252.9 Hz), 147.1, 135.6, 133.2, 131.5, 130.6, 128.3, 116.1 (d, JC-F = 22.0 Hz), 62.3, 51.8, 49.7, 30.2, 27.4; HRMS Calcd. For C20H20O4N2F + : 371.1397, found: 370.1329. 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 = 16.20 and 18.63 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 146-148 o C; [ ] 25 D = -119.6 (c 0.64, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.69 (d, J = 6.9 Hz, 2H), 7.48-7.26 (m, 5H), 7.08-7.02 (m, 2H), 5.50-5.48 (m, 1H), 4.40-4.38 (m, 1H), 3.74 (s, 3H), 3.49 (m, 1H), 3.04 (dd, J = 18.6, 5.7 Hz, 1H), 2.87-2.75 (m, 2H), 2.56 (dd, J = 15.0, 6.3 Hz, 1H); 13 C NMR (CDCl3, TMS, 75 MHz) δ 174.0, 170.7, 160.8 (d, JC-F = 249.5 Hz), 146.9, 133.9, 131.5 (d, JC-F = 8.3 Hz), 130.9, 129.8, S5

129.0, 127.5, 124.3, 116.3 (d, JC-F = 22.2 Hz), 74.1, 50.4, 36.2, 28.7, 28.6; HRMS Calcd. For C20H20O4N2F + : 371.1397, found: 370.1329. 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 = 16.32 and 18.40 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 146-148 o C; [ ] 25 D = -148.4 (c 0.88, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.73 (d, J = 6.9 Hz, 2H), 7.50-7.41 (m, 5H), 7.13 (d, J = 7.5 Hz, 2H), 5.50-5.53 (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), 2.61-2.45 (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 + : 367.1647, found: 366.1580. 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 = 17.96 and 20.65 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 183-184 o C; [ ] 25 D = -138.7 (c 0.73, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.75 (d, J = 6.9 Hz, 2H), 7.49-7.39 (m, 5H), 7.26-7.15 (m, 2H), 5.56-5.50 (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), 2.63-2.48 (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 + : 367.1647, found: S6

366.1580. 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 = 16.57 and 19.68 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 113-115 o C; [ ] 25 D = -134.8 (c 0.65, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.58 (d, J = 7.2 Hz, 2H), 7.38-7.29 (m, 4H), 7.21-7.14 (m, 3H), 5.53-5.51 (m, 1H), 4.42 (m, 1H), 3.74 (s, 3H), 3.47 (s, 1H), 2.91-2.80 (m, 2H), 2.67-2.54 (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: 334.1313, found: 334.1317. 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 = 16.54 and 17.97 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 185-186 o C; [ ] 25 D = -130.4 (c 0.56, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.72 (brs, 2H), 7.43 (brs, 3H), 7.25-7.16 (m, 3H), 6.91 (brs, 1H), 5.56 (m, 1H), 4.46 (m, 1H), 3.92 (s, 1H), 3.69 (s, 6H), 3.09-3.05 (m, 1H), 2.78-2.75 (m, 1H), 2.62-2.51 (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 + : 383.1597, found: 382.1529. The product was analyzed by HPLC to determine the enantiomeric excess: 98% ee (chiralpak ID, i-propanol/hexane = S7

30/70, flow rate 0.5 ml/min, λ = 254 nm); tr = 20.88 and 25.82 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 188-190 o C; [ ] 25 D = -123.9 (c 0.28, CHCl3); 1 H NMR (CDCl3, TMS, 400 MHz) 8.02 (s, 1H), 7.83-7.72 (m, 6H), 7.51-7.44 (m, 5H), 5.62-5.60 (m, 1H), 4.53-4.52 (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 + : 403.1647, found: 402.1580. 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 = 25.73 and 43.20 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 168-170 o C; [ ] 25 D = -121.3 (c 0.47, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.70 (d, J = 6.6 Hz, 2H), 7.48-7.26 (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), 2.53-2.37 (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 + : 379.1646, found: 378.1580. 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

ml/min, λ = 254 nm); tr = 20.40 and 27.61 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 136-138 o C; [ ] 25 D = -133.6 (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), 7.47-7.26 (m, 6H), 5.53-5.52 (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), 2.64-2.48 (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 + : 367.1647, found: 366.1580. 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 = 11.33 and 12.54 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 159-161 o C; [ ] 25 D = -127.5 (c 0.76, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.71 (d, J = 6.9 Hz, 2H), 7.49-7.37 (m, 5H), 7.12 (d, J = 7.8 Hz, 2H), 5.53-5.51 (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), 2.61-2.46 (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 + : 381.1807, found: 380.1736. 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

ml/min, λ = 254 nm); tr = 10.58 and 11.76 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 130-132 o C; [ ] 25 D = -109.3 (c 1.20, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.72 (d, J = 6.9 Hz, 2H), 7.43-7.40 (m, 3H), 7.26-7.15 (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), 3.11-3.04 (m, 1H), 2.79-2.72 (m, 1H), 2.63-2.57 (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 + : 397.1752, found: 396.1685. 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 21.95 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 118-120 o C; [ ] 25 D = -109.3 (c 1.43, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.68 (d, J = 7.2 Hz, 2H), 7.44-7.40 (m, 7H), 5.51-5.50 (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), 2.60-2.48 (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 + : 445.0757, found: 444.0685. 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 = 15.81 and S10

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 152-154 o C; [ ] 25 D = -129.0 (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), 7.47-7.26 (m, 6H), 5.54-5.52 (m, 1H), 4.43 (m, 1H), 4.08 (t, J = 6.3 Hz, 2H), 3.72-3.68 (m, 1H), 3.09 (dd, J = 18.0, 5.7 Hz, 1H), 2.78 (dd, J = 15.0, 6.9 Hz, 1H), 2.64-2.49 (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 + : 381.1803, found: 380.1736. 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 = 14.36 and 16.91 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 158-159 o C; [ ] 25 D = -119.7 (c 0.73, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.72 (d, J = 6.9 Hz, 2H), 7.59 (s, 2H), 7.43-7.26 (m, 6H), 5.54-5.52 (m, 1H), 5.07-5.02 (m, 1H), 4.43 (m, 1H), 3.60 (s, 1H), 3.13-3.06 (m, 1H), 2.77-2.49 (m, 3H), 1.26-1.24 (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 + : 381.1805, found: 380.1736. 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 = 13.37 and 15.29 min. S11

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 118-120 o C; 1 H NMR (CDCl3, TMS, 300 MHz) 7.72 (d, J = 6.9 Hz, 2H), 7.61-7.59 (m, 2H), 7.49-7.41 (m, 3H), 7.35-7.33 (m, 3H), 5.28-5.24 (m, 1H), 3.73 (s, 3H), 2.91-2.52 (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 + : 381.1805, found: 380.1736. 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 10.67 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 103-105 o C; [ ] 25 D = -61.9 (c 0.42, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.71 (d, J = 7.5 Hz, 2H), 7.61-7.59 (m, 2H), 7.49-7.26 (m, 6H), 5.28-5.25 (m, 1H), 3.73 (s, 3H), 2.91-2.65 (m, 4H), 2.54 (dd, J = 15.6, 5.1 Hz, 1H), 1.53 (m, 2H), 1.26 (m, 6H), 0.85-0.83 (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 + : 423.2271, found: 422.2206. 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 = 12.02 and 13.96 min. S12

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 120-122 o C; [ ] 25 D = -103.3 (c 1.42, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.71 (d, J = 6.9 Hz, 2H), 7.51-7.40 (m, 5H), 7.14 (d, J = 7.8 Hz, 2H), 5.28-5.24 (m, 1H), 3.72 (s, 3H), 2.90-2.50 (m, 5H), 2.34 (s, 3H), 1.53 (m, 2H), 1.26 (m, 6H), 0.86-0.82 (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 + : 437.2430, found: 436.2362. 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 14.44 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 138-140 o C; [ ] 25 D = -108.4 (c 1.21, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.68 (d, J = 6.9 Hz, 2H), 7.50-7.41 (m, 7H), 5.26 (m, 1H), 3.73 (s, 3H), 2.85-2.61 (m, 4H), 2.53 (dd, J = 15.3, 4.8 Hz, 1H), 1.52 (m, 2H), 1.26 (m, 6H), 0.87-0.83 (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 + : 501.1382, found: 500.1311. 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 14.40 min. S13

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 135-136 o C; [ ] 25 D = -64.1 (c 0.81, CHCl3); 1 H NMR (CDCl3, TMS, 400 MHz) 7.71 (d, J = 7.2 Hz, 2H), 7.60-7.59 (m, 2H), 7.52-7.42 (m, 3H), 7.35-7.33 (m, 3H), 5.29 (m, 1H), 3.74 (s, 3H), 2.93-2.88 (m, 1H), 2.78-2.60 (m, 4H), 1.93-1.88 (m, 1H), 1.50-1.43 (m, 2H), 1.02-0.96 (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 + : 409.2116, found: 408.2049. 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 = 12.76 and 13.76 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

7 ((5R,6R)-5-hydroxy-6-(2-hydroxyethyl)-3-phenyl-5,6-dihydropyridazin-1(4H)-yl)(phenyl )methanone 7: Yield (85%); white solid, mp 170-172 o C; [ ] 25 D = -230.4 (c 1.01, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.74 (d, J = 7.8 Hz, 2H), 7.61-7.59 (m, 2H), 7.53-7.40 (m, 3H), 7.34-7.31 (m, 3H), 5.21-5.18 (m, 1H), 4.65 (brs, 1H), 4.40-4.36 (m, 2H), 3.81-3.79 (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), 2.22-2.13 (m, 1H), 1.57-1.48 (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 + : 325.1544, found: 324.1474. 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

(4aR,7aR)-1-benzoyl-3-phenyl-4,4a,7,7a-tetrahydrofuro[3,2-c]pyridazin-6(1H)one 8: Yield (95%); white solid, mp 136-138 o C; [ ] 25 D = -295.7 (c 0.85, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.74 (d, J = 6.9 Hz, 2H), 7.61-7.58 (m, 2H), 7.51-7.35 (m, 6H), 5.30-5.22 (m, 1H), 5.15-5.09 (m, 1H), 3.30-3.18 (m, 2H), 2.90-2.82 (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 = 19.20 and 26.83 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, 0.022 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

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 = -219.5 (c 0.78, CHCl3); 1 H NMR (CDCl3, TMS, 300 MHz) 7.73 (d, J = 6.9 Hz, 2H), 7.62-7.60 (m, 2H), 7.47-7.26 (m, 6H), 4.99-4.93 (m, 1H), 4.82-4.79 (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 + : 367.1654, found: 366.1580. 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 = 28.88 and 32.51 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 = -240.4 (c 0.59, CHCl3); 1 H NMR (CDCl3, TMS, 400 MHz) 7.74-7.72 (m, 2H), 7.62-7.60 (m, 2H), 7.47-7.40 (m, 3H), 7.34-7.33 (m, 3H), 4.99-4.94 (m, 1H), 4.84-4.80 (m, 1H), 3.66-3.53 (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), 1.25-1.22 (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 + : 381.1808, found: 380.1736. 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 = 19.85 and 24.67 min. S17

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 136-138 o C; 1 H NMR (CDCl3, TMS, 300 MHz) 7.69-7.62 (m, 4H), 7.48-7.25 (m, 6H), 5.63-5.60 (m, 1H), 5.42-5.38 (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 = 21.36 and 24.44 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 = 386.82, T = 296 K, Monoclinic, space group P2(1), a = 11.4998(13), b = 6.3981(7), c = 13.1706(15) Å, V = 950.23(18) Å 3, Z = 2, 3302 unique reflections, final R1 = 0.1381 and wr2 = 0.3512 for 3769 observed [I>2σ(I)] reflections, Flack = -2.33(19). CCDC 1446798 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB21EZ, UK; fax: (+44) 1223-336-033; or deposit@ccdc.cam.ac.uk) S18

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, 8921. 2. G.M. Donald and E. D. Amstutz, J. Org. Chem. 1956, 21, 516. S19

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

3a S21

3b S22

3b S23

3c S24

3c S25

3d S26

3d S27

3e S28

3e S29

3f S30

3f S31

3g S32

3g S33

3h S34

3h S35

3i S36

3i S37

3j S38

3j S39

3k S40

3k S41

3l S42

3l S43

O Ph N N CO 2 Et OH 6a S44

O Ph N N CO 2 Et OH 6a S45

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

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

6c S48

6c S49

6d S50

6d S51

6e S52

6e S53

6f S54

6f S55

6g S56

6g S57

6h S58

6h S59

6i S60

6i S61

6j S62

6j S63

6k S64

6k S65

7 S66

7 S67

8 S68

8 S69

9 S70

9 S71

10 S72

10 S73

NOESY Spectra of 10 S74

12 S75

12 S76

12 S77

VII. HPLC Chromatograms 3a S78

3a S79

3b S80

3b S81

3c S82

3c S83

3d S84

3d S85

3e S86

3e S87

3f S88

3f S89

3g S90

3g S91

3h S92

3h S93

3i S94

3i S95

3j S96

3j S97

3k S98

3k S99

3l S100

3l S101

6a S102

6a S103

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

6b S105

6c S106

6c S107

6d S108

6d S109

6e S110

6e S111

6f S112

6f S113

6g S114

6g S115

6h S116

6h S117

6i S118

6i S119

6j S120

6j S121

6k S122

6k S123

7 S124

7 S125

8 S126

8 S127

9 S128

9 S129

10 S130

10 S131

12 S132

12 S133