A Total Synthesis of Paeoveitol

Transcription

1 A Total Synthesis of Paeoveitol Lun Xu, Fengyi Liu, Li-Wen Xu, Ziwei Gao, Yu-Ming Zhao* Key Laboratory of Applied Surface and Colloid Chemistry of MOE & School of Chemistry and Chemical Engineering, Shaanxi Normal University 620 West Chang an Ave, Xi an, , China Table of contents 1. General information s2 2. Experimental Procedures S3-S7 3. X-ray crystallography of 9 and S8-S24 4. DFT study s25-s Computational methods S Computed free energy surfaces of all species S25-S Cartesian computed coordinates and Gibbs free energies of all species s27-s52 5. References S53 6. Copies of 1 H and 13 C-NMR spectra of new compounds s54-s73 S1

2 1. General information Unless otherwise stated, all reactions were performed in oven-dried or flame-dried glassware under an atmosphere of dry nitrogen. Anhydrous dichloromethane was purified by distillation over calcium hydride. Anhydrous tetrahydrofuran was freshly distilled from sodium-benzophenone. Reactions were monitored by thin layer chromatography (TLC) (250 μm thickness, F-254 indicator) and visualized by UV irradiation and staining with p- anisaldehyde, phosphomolybdic acid, or potassium permanganate developing agents. Volatile solvents were removed under reduced pressure using a rotary evaporator. Flash column chromatography was performed over silica gel ( mesh) purchased from Qindao Haiyang Co., China. 1 H and 13 C NMR spectra were recorded on a Bruker AV 600 MHz NMR spectrometer using residue solvent peaks as an internal standard. Chemical shifts are reported in parts per million (ppm) with respect to the residual solvent signal. Peak multiplicities are reported as follows: s = singlet, bs = broad singlet, d = doublet, t = triplet, dd = doublet of doublets, td = triplet of doublets, m = multiplet. app = apparent. Melting points were determined using MEl-TEMP apparatus and are uncorrected. IR spectra were recorded on a Nicollet 170SX FT-IR spectrometer. High-resolution mass spectra (HRMS) were collected on a Bruker Maxis System. X-ray crystallographic analyses were performed on Bruker D8 Quest. S2

3 2. Experimental Procedures 2-(1-hydroxyethyl)phenol (6). NaBH4 (278 mg, 7.4 mmol, 0.5 equiv) was added to a solution of o-acetylphenol (2.0 g, 14.8 mmol, 1.0 equiv) in anhydrous methanol (20 ml) over a period of 5 min at 0 o C. The reaction mixture was slowly warmed to room temperature and stirred for an additional 1 hour. Cold water (10 ml) was slowly added at 0 o C and the reaction mixture stirred for 15 min. The aqueous phase was extracted with ethyl acetate (2 x 100 ml). The combined organic phases were washed with brine (50 ml), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/hexane) gave 6 (1.9 g, 94 %) as a colorless oil: 1 H NMR (600 MHz, CDCl3) δ 8.06 (s, 1H), 7.15 (m, 1H), 6.96 (dd, J = 7.5, 1.3 Hz, 1H), (m, 2H), (m, 1H), 3.07 (d, J = 3.9 Hz, 1H), 1.54 (d, J = 6.6 Hz, 3H); 13 C NMR (151 MHz, CDCl3) δ 155.2, 128.9, 128.6, 126.5, 120.0, 117.0, 71.4, 23.4; IR (thin film, cm -1 ) 3320, 2980, 2845, 1600, 1500, 1450, 1020, 760; HRMS (ESI) calcd. for [C8H10O2Na] + (M+Na) + : m/z , found Ethyl benzofuran-3-carboxylate (4). To a solution of salicyaldehyde (2.0 g, 16.4 mmol, 1.0 equiv) and HBF4 Et2O [0.3 ml, 1.64 mmol, 0.1 equiv; 54% (w/w)] in CH2Cl2 (10 ml) at room temperature was added ethyl diazoacetate (2.6 ml, 24.6mmol, 1.5 equiv) via syringe pump over 30 min at 5 o C. The reaction mixture was stirred for another 30 min at room temperature and concentrated in vacuo. Concentrated sulfuric acid (1.5 ml) was added and stirred for 30 min at room temperature. The reaction mixture was diluted with CH2Cl2 (50 ml) and the excess of acid was carefully quenched with saturated aqueous NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2 x 50 ml). The combined organic phase was washed with brine (40 ml), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/hexane) gave 4 (2.8 g, 90%) as a colorless liquid: 1 H NMR (600 MHz, CDCl3) δ 8.24 (s, 1H), (m, 1H), (m, 1H), (m, 2H), 4.40 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H); 13 C NMR (151 MHz, CDCl3) δ 163.4, 155.6, 150.9, 125.2, 124.7, 124.1, 122.1, 114.8, 111.7, S3

4 60.5, 14.4; IR (thin film, cm -1 ) 2975, 2952, 2840, 1726, 1600, 1563, 1450, 1105, 1021, 754; HRMS (ESI) calcd. for [C11H10O3Na] + (M+Na) + : m/z , found Benzofuran-3-ylmethanol (5). To a solution of ester 4 (2.0 g, 10.5 mmol, 1.0 equiv) in CH2Cl2 (30 ml) at -78 o C was added a solution of diisobutylaluminium hydride (17.5 ml, 26.3 mmol, 2.5 equiv) in toluene (1.5 M) via syringe. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction was quenched with saturated aqueous NH4Cl solution. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (100 ml). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/hexane) gave 5 (1.4 g, 90%) as a white solid: m.p.=45-47 o C; 1 H NMR (600 MHz, CDCl3) δ 7.64 (d, J = 7.7 Hz, 1H), 7.57 (s, 1H), 7.48 (d, J = 8.2 Hz, 1H), (m, 1H), (m, 1H), 4.79 (s, 2H), 1.96 (s, 1H); 13 C NMR (151 MHz, CDCl3) δ 155.6, 142.4, 126.7, 124.7, 122.8, 120.4, 120.0, 111.6, 55.9; IR (thin film, cm -1 ) 3420, 2950, 2840, 1640, 1450, 1034, 750; HRMS (ESI) calcd. for [C9H8O2Na] + (M+Na) + : m/z , found Tetracyclic alcohol 7. A solution of 5 (44.7 mg, 0.30 mmol, 1.0 equiv) and 6 (50 mg, 0.36 mmol, 1.2 equiv) in CH2Cl2 (4 ml) was treated with anhydrous ZnCl2(8.5 mg, 0.06mmol, 0.2 equiv) at room temperature. After 12 hours, the reaction mixture was quenched with water (2 ml) and extracted with CH2Cl2 (25 ml). The organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/hexane) gave 7 (69.2 mg, 86%) as a White foam: m.p.= o C; 1 H NMR (600 MHz, CDCl3) δ 7.28 (d, J = 7.4 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 7.08 (m, 1H), 6.98 (m, 1H), 6.92 (m,, 1H), 6.80 (m, 1H), 6.67 (d, J = 7.8 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 5.11 (d, J = 3.1 Hz, 1H), 4.28 (dd, J = 11.8, 5.0 Hz, 1H), 3.95 (dd, J = 11.8, 8.8 Hz, 1H), (m, 1H), (m, 1H), 1.60 (d, J = 7.1 Hz, 3H); 13 C NMR (151 MHz, CDCl3) δ 160.7, 154.0, 131.2, 128.8, 127.4, 125.9, 125.9, 124.4, 122.9, 120.7, 117.9, 110.1, 89.4, 88.3, 67.5, 33.0, 13.2; IR (thin film, cm -1 ) 3425, 2930, 2840, 1610, 1480, 1233, 1030, 757; HRMS (ESI) calcd. for [C17H16O3Na] + (M+Na) + : m/z , found S4

5 Tetracyclic Ts-ester 9. To a solution of tetracyclic alcohol 7 (50mg, mmol, 1.0 equiv) in CH2Cl2 (2 ml) was added Et3N (80 ul, 0.57 mmol, 3.0 equiv), TsCl (53 mg, 0.28 mmol, 1.5 equiv), and DMAP (2.3 mg, mmol, 0.1 equiv) at 0 o C. The reaction mixture was warmed to room temperature and stirred overnight before water was added (1 ml). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (15 ml). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/hexane) gave Ts-ester 9 (73.9 mg, 94%) as a white solid : m.p.=95-97 o C; 1 H NMR (600 MHz, CDCl3) δ 7.77 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), (m, 2H), 7.09 (m, 1H), 6.96 (m, 1H), 6.91 (m, 1H), 6.79 (m, 1H), (m, 2H), 5.02 (d, J = 3.2 Hz, 1H), 4.69 (d, J = 10.5 Hz, 1H), 4.45 (d, J = 10.5 Hz, 1H), 3.09 (m, 1H), 2.41 (s, 3H), 1.57 (d, J = 7.1 Hz, 3H); 13 C NMR (151 MHz, CDCl3) δ 160.4, 153.4, 145.2, 132.7, 131.5, 129.9, , , 127.4, 125.8, 124.7, 124.2, 122.9, 120.9, 117.8, 110.3, 88.6, 85.8, 72.1, 32.3, 21.7, 13.2; IR (thin film, cm -1 ) 2940, 2845, 1600, 1480, 1360, 1180, 751, 551; HRMS (ESI) calcd. for [C24H22O5NaS] + (M+Na) + : m/z , found ,5-dihydroxy-4-methylbenzaldehyde 11. A solution of methylhydroquinone (500 mg, 4.03 mmol, 1.0 equiv) and hexamethylenetetramine (2.3 g, mmol, 4.0 equiv) in CF3COOH (8 ml) was heated to 80 o C for 4 hours. The reaction mixture was diluted with 0.4% HCl (40 ml ) and extracted with CH2Cl2 (3 x 30 ml ). The organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/hexane) gave aldehyde 11 (380 mg, 62 %) as a yellowish solid : m.p.= o C; 1 H NMR (600 MHz, MeOH-d 4 ) δ 9.82 (s, 1H), 6.94 (s, 1H), 6.68 (s, 1H), 4.89 (s, 2H), 2.22 (s, 3H); 13 C NMR (151 MHz, MeOH-d 4 ) δ 196.2, 156.1, 149.9, 138.3, 120.6, 119.8, 116.6, 17.2; IR (thin film, cm -1 ) 3392, 2980, 1756, 1634, 1480, 1250, 667; HRMS (ESI) calcd. for [C8H8O3Na] + (M+Na) + : m/z , found S5

6 Benzofuran ester 12. To a solution of aldehyde 11 (2.0 g, mmol, 1.0 equiv) and HBF4 Et2O [0.24 ml, mmol, 0.1 equiv; 54% (w/w)] in CH2Cl2 (5 ml) at room temperature was added a solution of ethyl diazoacetate (7 ml, 58 mmol, 4.5 equiv) in CH2Cl2 (10 ml) via syringe pump over 30min. The reaction mixture was stirred for another 30 min and concentrated in vacuo. Concentrated sulfuric acid (1.5 ml) was added and stirred for 30 min at room temperature. The reaction mixture was diluted with CH2Cl2 (50 ml) and the excess of acid was carefully quenched with saturated aqueous NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2 x 50 ml). The combined organic phase was washed with brine (40 ml), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/hexane) gave benzofuran ester 12 (2.0g, 68%) as a white solid: m.p.= o C; 1 H NMR (600 MHz, acetone-d 6 ) δ 8.37 (s, 1H), 8.33 (s, 1H), 7.49 (s, 1H), 7.35 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H), 2.34 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H); 13 C NMR (151 MHz, acetone-d 6 ) δ 163.9, 153.7, 151.7, 150.9, , 124.0, 115.1, 113.5, 106.3, 60.9, 17.0, 14.7; IR (thin film, cm -1 ) 3380,2980, 2860, 1685,1550, 1460, 1280, 1152, 780, 640; HRMS (ESI) calcd. for [C12H12O4Na] + (M+Na) + : m/z , found Paeoveitol D (2). To a solution of ester 12 (1.5 g, 6.8 mmol, 1.0 equiv) in CH2Cl2 (25 ml) at -78 o C was added a solution of diisobutylaluminium hydride (11.4 ml, 17.0 mmol, 3.0 equiv) in toluene (1.5 M) via syringe. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction was quenched with saturated aqueous NH4Cl solution. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2 x 50 ml). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/hexane) gave paeoveitol D (2) (1.1 g, 88%) as a white solid: m.p.= o C ; 1 H NMR (600 MHz, MeOH-d 4 ) δ 7.53 (s, 1H), 7.16 (s, 1H), 6.99 (s, 1H), 4.88 (s, 2H), 4.66 (s, 2H), 2.28 (s, 3H); 13 C NMR (151 MHz, MeOH-d 4 ) δ 152.6, 151.6, 143.4, 126.6, 124.1, 121.6, 113.3, 104.9, 55.8, 17.1; IR (thin film, cm -1 ) 3500, 3200, 2960, 2860, 1480,1400, 1180, 995, 870, 810 ; HRMS (ESI) calcd. for [C10H10O3Na] + (M+Na) + : m/z , found S6

7 Diol 3. To a solution of ketone 13 [1] (800 mg, 4.8 mmol, 1.0 equiv) in THF (25 ml) at 0 o C was added a solution of BH3 (14.4 ml, 14.2 mmol, 3.0 equiv) in THF (1.0 M) via syringe. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour at same temperature. The reaction was quenched with water (5 ml). The organic layer was separated and the aqueous layer was extracted with Et2O (50 ml). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/hexane) gave diol 3 (694 mg, 86%) as a colorless oil: 1 H NMR (600 MHz, CDCl3) δ 7.65 (s, 1H), (m, 1H), 6.43 (s, 1H), 5.94 (s, 1H), 4.91 (q, J = 6.6 Hz, 1H), 3.71 (s, 1H), (m, 3H), 1.49 (d, J = 6.6 Hz, 3H); 13 C NMR (151 MHz, CDCl3) δ 148.2, 147.2, 127.2, 124.4, 118.8, 113.0, 70.2, 23.2, 15.6; IR (thin film, cm -1 ) 3382, 2978, 2928, 1634, 1506, 1420, 1190; HRMS (ESI) calcd. for [C9H12O3Na] + (M+Na) + : m/z , found Paeoveitol (1). A solution of 2 (1.1 g, 6.2 mmol, 1.0 equiv) and diol 3 (1.25 g, 7.4 mmol, 1.2 equiv) in CH2Cl2 (40 ml) was treated with anhydrous ZnCl2(85.0 mg, 0.62 mmol, 0.1 equiv) at room temperature. After 12 hours, the reaction mixture was quenched with water (2 ml) and extracted with CH2Cl2 (2 x 50 ml). The organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/hexane) gave paeoveitol (1) (1.34 g, 66%) as a White foam: m.p.= o C ; 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.75 (s, 1H), 8.70 (s, 1H), 6.68 (s, 1H), (m, 1H), 6.32 (s, 1H), 6.30 (s, 1H), (m, 1H), 4.97 (d, J = 3.0 Hz, 1H), 3.95 (dd, J = 11.5, 5.5 Hz, 1H), 3.77 (dd, J = 11.5, 6.7 Hz, 1H), 3.34 (d, J = 1.7 Hz, 3H), (m, 1H), 2.50 (p, J = 1.8 Hz, 3H), 1.97 (s, 3H), 1.93 (s, 3H), 1.41 (d, J = 7.0 Hz, 3H); 13 C NMR (151 MHz, DMSOd 6 ) δ 152.8, 150.1, 149.0, 146.0, 126.6, 126.4, 124.7, 121.5, 118.9, 112.1, 110.6, 110.0, 88.2, 87.9, 65.0, 31.6, 16.4, 15.6, 13.2; IR (thin film, cm -1 ) 3680, 2920, 2850, 1630, 1480, 1179; HRMS (ESI) calcd. for [C19H20O5Na] + (M+Na) + : m/z found S7

8 3. X-ray crystallography 9 and X-ray crystal structure determination of 9 SI Table 1. Crystal data and structure refinement for 9. Identification code xl Empirical formula C24 H22 O5 S Formula weight Temperature 153(2) K Wavelength Å Crystal system Triclinic Space group P-1 Unit cell dimensions a = (3) Å = (10). b = (3) Å = (10). c = (3) Å = (10). Volume (5) Å 3 Z 2 Density (calculated) Mg/m 3 Absorption coefficient mm -1 F(000) 444 Crystal size 0.3 x 0.1 x 0.1 mm 3 Theta range for data collection to Index ranges -12<=h<=12, -13<=k<=13, -14<=l<=14 Reflections collected Independent reflections 4167 [R(int) = ] Completeness to theta = % Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 4167 / 0 / 271 Goodness-of-fit on F Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Extinction coefficient n/a Largest diff. peak and hole and e.å -3 S8

9 SI Table 2. Atomic coordinates (x 10 4 ) and equivalent isotropic displacement parameters (Å 2 x 10 3 ) for xl U(eq) is defined as one third of the trace of the orthogonalized U ij tensor. x y z U(eq) S(1) 2739(1) 6326(1) 3960(1) 20(1) O(3) 3235(1) 6764(1) 2439(1) 22(1) O(4) 4803(1) 6748(1) -1436(1) 24(1) O(5) 2128(1) 8706(1) 280(1) 19(1) O(1) 2604(1) 4881(1) 4450(1) 28(1) O(2) 3723(1) 6693(1) 4374(1) 29(1) C(7) 2545(2) 6360(2) 1727(1) 21(1) C(8) 1028(2) 7487(2) 4172(1) 20(1) C(9) 2608(2) 9770(1) -786(1) 18(1) C(10) 5047(2) 8332(2) -433(1) 22(1) C(11) 4522(2) 7032(2) -214(1) 20(1) C(12) -1441(2) 7860(2) 5201(2) 27(1) C(13) 2063(2) 12074(2) -2372(2) 26(1) C(14) 816(2) 8954(2) 3505(2) 27(1) C(15) 3515(2) 11990(2) -2808(2) 28(1) C(16) 4074(2) 9658(2) -1191(1) 19(1) C(17) 2888(2) 7239(1) 320(1) 18(1) C(18) -93(2) 6932(2) 5025(1) 24(1) C(19) 1594(2) 10953(2) -1360(1) 22(1) C(20) -536(2) 9856(2) 3690(2) 29(1) C(21) 2429(2) 6759(2) -555(1) 20(1) C(22) -1686(2) 9321(2) 4529(2) 26(1) C(23) 4512(2) 10782(2) -2223(2) 24(1) C(24) 3587(2) 6508(2) -1528(1) 22(1) C(25) 6645(2) 8112(2) -997(2) 32(1) C(26) 1120(2) 6576(2) -524(2) 26(1) C(27) 3506(2) 6045(2) -2486(2) 27(1) C(28) 2196(2) 5834(2) -2428(2) 30(1) C(29) 1013(2) 6102(2) -1472(2) 31(1) C(30) -3168(2) 10303(2) 4655(2) 37(1) S9

10 SI Table 3. Bond lengths [Å] and angles [ ] for xl S(1)-O(2) (11) S(1)-O(1) (11) S(1)-O(3) (10) S(1)-C(8) (15) O(3)-C(7) (17) O(4)-C(24) (18) O(4)-C(11) (16) O(5)-C(9) (16) O(5)-C(17) (16) C(7)-C(17) (19) C(8)-C(18) 1.387(2) C(8)-C(14) 1.392(2) C(9)-C(19) 1.384(2) C(9)-C(16) 1.393(2) C(10)-C(16) 1.511(2) C(10)-C(11) 1.523(2) C(10)-C(25) 1.525(2) C(11)-C(17) (19) C(12)-C(22) 1.387(2) C(12)-C(18) 1.388(2) C(13)-C(15) 1.386(2) C(13)-C(19) 1.391(2) C(14)-C(20) 1.381(2) C(15)-C(23) 1.391(2) C(16)-C(23) 1.391(2) C(17)-C(21) (19) C(20)-C(22) 1.397(2) C(21)-C(26) 1.386(2) C(21)-C(24) 1.387(2) C(22)-C(30) 1.503(2) C(24)-C(27) 1.384(2) C(26)-C(29) 1.392(2) C(27)-C(28) 1.390(2) S10

11 C(28)-C(29) 1.392(2) O(2)-S(1)-O(1) (7) O(2)-S(1)-O(3) (6) O(1)-S(1)-O(3) (6) O(2)-S(1)-C(8) (7) O(1)-S(1)-C(8) (7) O(3)-S(1)-C(8) (6) C(7)-O(3)-S(1) (9) C(24)-O(4)-C(11) (11) C(9)-O(5)-C(17) (10) O(3)-C(7)-C(17) (11) C(18)-C(8)-C(14) (14) C(18)-C(8)-S(1) (12) C(14)-C(8)-S(1) (11) C(19)-C(9)-O(5) (12) C(19)-C(9)-C(16) (13) O(5)-C(9)-C(16) (12) C(16)-C(10)-C(11) (12) C(16)-C(10)-C(25) (13) C(11)-C(10)-C(25) (13) O(4)-C(11)-C(10) (11) O(4)-C(11)-C(17) (11) C(10)-C(11)-C(17) (11) C(22)-C(12)-C(18) (14) C(15)-C(13)-C(19) (14) C(20)-C(14)-C(8) (14) C(13)-C(15)-C(23) (14) C(23)-C(16)-C(9) (13) C(23)-C(16)-C(10) (13) C(9)-C(16)-C(10) (12) O(5)-C(17)-C(21) (11) O(5)-C(17)-C(7) (11) C(21)-C(17)-C(7) (11) O(5)-C(17)-C(11) (11) S11

12 C(21)-C(17)-C(11) (11) C(7)-C(17)-C(11) (11) C(8)-C(18)-C(12) (14) C(9)-C(19)-C(13) (14) C(14)-C(20)-C(22) (15) C(26)-C(21)-C(24) (14) C(26)-C(21)-C(17) (13) C(24)-C(21)-C(17) (13) C(12)-C(22)-C(20) (15) C(12)-C(22)-C(30) (15) C(20)-C(22)-C(30) (15) C(15)-C(23)-C(16) (14) O(4)-C(24)-C(27) (14) O(4)-C(24)-C(21) (13) C(27)-C(24)-C(21) (15) C(21)-C(26)-C(29) (15) C(24)-C(27)-C(28) (15) C(27)-C(28)-C(29) (15) C(26)-C(29)-C(28) (16) Symmetry transformations used to generate equivalent atoms: S12

13 SI Table 4. Anisotropic displacement parameters (Å 2 x 10 3 ) for xl The anisotropic displacement factor exponent takes the form: -2 2 [ h 2 a* 2 U h k a* b* U 12 ] U 11 U 22 U 33 U 23 U 13 U 12 S(1) 23(1) 22(1) 14(1) -4(1) -2(1) -7(1) O(3) 24(1) 26(1) 14(1) -6(1) -1(1) -9(1) O(4) 23(1) 28(1) 20(1) -12(1) -1(1) -3(1) O(5) 20(1) 16(1) 19(1) -6(1) 1(1) -3(1) O(1) 33(1) 21(1) 23(1) -1(1) -4(1) -6(1) O(2) 28(1) 42(1) 22(1) -10(1) -5(1) -11(1) C(7) 26(1) 21(1) 16(1) -6(1) -3(1) -8(1) C(8) 23(1) 22(1) 17(1) -7(1) -2(1) -7(1) C(9) 21(1) 17(1) 16(1) -7(1) -2(1) -7(1) C(10) 19(1) 27(1) 19(1) -8(1) -4(1) -5(1) C(11) 21(1) 21(1) 16(1) -7(1) -3(1) -1(1) C(12) 26(1) 33(1) 26(1) -13(1) 3(1) -13(1) C(13) 31(1) 19(1) 27(1) -4(1) -10(1) -4(1) C(14) 28(1) 24(1) 26(1) -5(1) 0(1) -12(1) C(15) 34(1) 24(1) 23(1) -3(1) -3(1) -13(1) C(16) 21(1) 21(1) 18(1) -9(1) -3(1) -6(1) C(17) 21(1) 15(1) 17(1) -5(1) -2(1) -3(1) C(18) 29(1) 24(1) 20(1) -6(1) 0(1) -12(1) C(19) 21(1) 20(1) 24(1) -8(1) -4(1) -4(1) C(20) 34(1) 21(1) 31(1) -8(1) -4(1) -7(1) C(21) 27(1) 16(1) 16(1) -4(1) -4(1) -4(1) C(22) 27(1) 30(1) 26(1) -16(1) -3(1) -7(1) C(23) 24(1) 28(1) 22(1) -9(1) 0(1) -12(1) C(24) 27(1) 16(1) 18(1) -3(1) -5(1) -2(1) C(25) 20(1) 41(1) 34(1) -12(1) -4(1) -6(1) C(26) 30(1) 26(1) 22(1) -6(1) -2(1) -10(1) C(27) 37(1) 23(1) 18(1) -8(1) -5(1) -2(1) C(28) 48(1) 26(1) 22(1) -8(1) -11(1) -10(1) C(29) 38(1) 31(1) 28(1) -6(1) -9(1) -15(1) C(30) 30(1) 38(1) 44(1) -20(1) -4(1) -3(1) S13

14 SI Table 5. Hydrogen coordinates ( x 10 4 ) and isotropic displacement parameters (Å 2 x 10 3 ) for xl x y z U(eq) H(7A) H(7B) H(10A) H(11A) H(12A) H(13A) H(14A) H(15A) H(18A) H(19A) H(20A) H(23A) H(25A) H(25B) H(25C) H(26A) H(27A) H(28A) H(29A) H(30A) H(30B) H(30C) S14

15 3.2. X-ray crystal structure determination of 1 SI Table 6. Crystal data and structure refinement for 1. Identification code xl Empirical formula C19 H20 O5 Formula weight Temperature K Wavelength Å Crystal system Monoclinic Space group C2/c Unit cell dimensions a = (9) Å = 90. b = (4) Å = (2). c = (8) Å = 90. Volume (2) Å 3 Z 8 Density (calculated) Mg/m 3 Absorption coefficient mm -1 F(000) 1392 Crystal size 0.5 x 0.4 x 0.3 mm 3 Theta range for data collection to Index ranges -25<=h<=25, -11<=k<=11, -23<=l<=23 Reflections collected Independent reflections 3621 [R(int) = ] Completeness to theta = % Absorption correction Semi-empirical from equivalents Max. and min. transmission and Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 3621 / 0 / 223 Goodness-of-fit on F Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Largest diff. peak and hole and e.å -3 S15

16 SI Table 7. Atomic coordinates (x 10 4 ) and equivalent isotropic displacement parameters (Å 2 x 10 3 ) for xl U(eq) is defined as one third of the trace of the orthogonalized U ij tensor. x y z U(eq) O(2) 6978(1) 2780(1) 4081(1) 22(1) O(1) 5328(1) 1511(1) 4201(1) 22(1) O(4) 6292(1) -933(1) 1728(1) 27(1) O(5) 4915(1) 7446(1) 3523(1) 33(1) O(3) 5887(1) -236(2) 5417(1) 33(1) C(6) 6325(1) 879(2) 3517(1) 19(1) C(3) 6990(1) 1140(2) 2225(1) 20(1) C(7) 6842(1) 1922(2) 3457(1) 19(1) C(4) 6468(1) 68(2) 2292(1) 20(1) C(5) 6130(1) -67(2) 2931(1) 20(1) C(2) 7175(1) 2080(2) 2822(1) 21(1) C(15) 4695(1) 3379(2) 3476(1) 22(1) C(14) 5222(1) 3002(2) 4005(1) 19(1) C(16) 4559(1) 4877(2) 3305(1) 22(1) C(13) 5637(1) 4068(2) 4381(1) 21(1) C(9) 6054(1) 1029(2) 4264(1) 20(1) C(17) 4984(1) 5944(2) 3670(1) 23(1) C(10) 6554(1) 2213(2) 4643(1) 20(1) C(11) 6177(1) 3512(2) 4970(1) 22(1) C(18) 5517(1) 5548(2) 4200(1) 24(1) C(1) 7343(1) 1277(2) 1523(1) 30(1) C(12) 6675(1) 4698(2) 5302(1) 28(1) C(8) 6052(1) -436(2) 4682(1) 25(1) C(19) 3970(1) 5303(2) 2744(1) 31(1) S16

17 SI Table 8. Bond lengths [Å] and angles [ ] for xl O(2)-C(7) (18) O(2)-C(10) (18) O(1)-C(14) (18) O(1)-C(9) (18) O(4)-H(4) O(4)-C(4) (18) O(5)-H(5) O(5)-C(17) (19) O(3)-H(3) O(3)-C(8) 1.412(2) C(6)-C(7) 1.380(2) C(6)-C(5) 1.388(2) C(6)-C(9) 1.504(2) C(3)-C(4) 1.406(2) C(3)-C(2) 1.396(2) C(3)-C(1) 1.506(2) C(7)-C(2) 1.378(2) C(4)-C(5) 1.389(2) C(5)-H(5A) C(2)-H(2) C(15)-H(15) C(15)-C(14) 1.378(2) C(15)-C(16) 1.400(2) C(14)-C(13) 1.388(2) C(16)-C(17) 1.390(2) C(16)-C(19) 1.507(2) C(13)-C(11) 1.511(2) C(13)-C(18) 1.384(2) C(9)-C(10) 1.555(2) C(9)-C(8) 1.520(2) C(17)-C(18) 1.392(2) C(10)-H(10) C(10)-C(11) 1.525(2) S17

18 C(11)-H(11) C(11)-C(12) 1.523(2) C(18)-H(18) C(1)-H(1A) C(1)-H(1B) C(1)-H(1C) C(12)-H(12A) C(12)-H(12B) C(12)-H(12C) C(8)-H(8A) C(8)-H(8B) C(19)-H(19A) C(19)-H(19B) C(19)-H(19C) C(7)-O(2)-C(10) (11) C(14)-O(1)-C(9) (11) C(4)-O(4)-H(4) C(17)-O(5)-H(5) C(8)-O(3)-H(3) C(7)-C(6)-C(5) (14) C(7)-C(6)-C(9) (13) C(5)-C(6)-C(9) (14) C(4)-C(3)-C(1) (14) C(2)-C(3)-C(4) (14) C(2)-C(3)-C(1) (14) O(2)-C(7)-C(6) (13) O(2)-C(7)-C(2) (13) C(2)-C(7)-C(6) (14) O(4)-C(4)-C(3) (14) O(4)-C(4)-C(5) (13) C(5)-C(4)-C(3) (14) C(6)-C(5)-C(4) (14) C(6)-C(5)-H(5A) C(4)-C(5)-H(5A) S18

19 C(3)-C(2)-H(2) C(7)-C(2)-C(3) (14) C(7)-C(2)-H(2) C(14)-C(15)-H(15) C(14)-C(15)-C(16) (14) C(16)-C(15)-H(15) C(15)-C(14)-O(1) (13) C(15)-C(14)-C(13) (14) C(13)-C(14)-O(1) (13) C(15)-C(16)-C(19) (14) C(17)-C(16)-C(15) (14) C(17)-C(16)-C(19) (15) C(14)-C(13)-C(11) (14) C(18)-C(13)-C(14) (14) C(18)-C(13)-C(11) (14) O(1)-C(9)-C(6) (12) O(1)-C(9)-C(10) (12) O(1)-C(9)-C(8) (12) C(6)-C(9)-C(10) (12) C(6)-C(9)-C(8) (12) C(8)-C(9)-C(10) (13) O(5)-C(17)-C(16) (15) O(5)-C(17)-C(18) (14) C(16)-C(17)-C(18) (15) O(2)-C(10)-C(9) (11) O(2)-C(10)-H(10) O(2)-C(10)-C(11) (12) C(9)-C(10)-H(10) C(11)-C(10)-C(9) (13) C(11)-C(10)-H(10) C(13)-C(11)-C(10) (12) C(13)-C(11)-H(11) C(13)-C(11)-C(12) (13) C(10)-C(11)-H(11) C(12)-C(11)-C(10) (13) S19

20 C(12)-C(11)-H(11) C(13)-C(18)-C(17) (15) C(13)-C(18)-H(18) C(17)-C(18)-H(18) C(3)-C(1)-H(1A) C(3)-C(1)-H(1B) C(3)-C(1)-H(1C) H(1A)-C(1)-H(1B) H(1A)-C(1)-H(1C) H(1B)-C(1)-H(1C) C(11)-C(12)-H(12A) C(11)-C(12)-H(12B) C(11)-C(12)-H(12C) H(12A)-C(12)-H(12B) H(12A)-C(12)-H(12C) H(12B)-C(12)-H(12C) O(3)-C(8)-C(9) (13) O(3)-C(8)-H(8A) O(3)-C(8)-H(8B) C(9)-C(8)-H(8A) C(9)-C(8)-H(8B) H(8A)-C(8)-H(8B) C(16)-C(19)-H(19A) C(16)-C(19)-H(19B) C(16)-C(19)-H(19C) H(19A)-C(19)-H(19B) H(19A)-C(19)-H(19C) H(19B)-C(19)-H(19C) S20

21 SI Table 9. Anisotropic displacement parameters (Å 2 x 10 3 ) for xl The anisotropic displacement factor exponent takes the form: -2 2 [ h 2 a* 2 U h k a* b* U 12 ] U 11 U 22 U 33 U 23 U 13 U 12 O(2) 23(1) 22(1) 22(1) -4(1) 3(1) -6(1) O(1) 18(1) 17(1) 31(1) 1(1) 5(1) 0(1) O(4) 31(1) 25(1) 23(1) -5(1) -1(1) -3(1) O(5) 30(1) 19(1) 50(1) 5(1) -5(1) 1(1) O(3) 33(1) 40(1) 26(1) 4(1) 4(1) -9(1) C(6) 18(1) 17(1) 21(1) 1(1) 3(1) 2(1) C(3) 18(1) 21(1) 22(1) 2(1) 2(1) 3(1) C(7) 17(1) 16(1) 23(1) -2(1) -1(1) 2(1) C(4) 20(1) 18(1) 21(1) -2(1) -1(1) 2(1) C(5) 19(1) 16(1) 25(1) 1(1) 1(1) -2(1) C(2) 17(1) 19(1) 26(1) 1(1) 2(1) -2(1) C(15) 18(1) 22(1) 26(1) -3(1) 4(1) -3(1) C(14) 18(1) 16(1) 24(1) 0(1) 6(1) 1(1) C(16) 17(1) 25(1) 25(1) 0(1) 3(1) 0(1) C(13) 20(1) 20(1) 22(1) -2(1) 3(1) 1(1) C(9) 20(1) 17(1) 22(1) -1(1) 2(1) 0(1) C(17) 22(1) 17(1) 30(1) 1(1) 5(1) 2(1) C(10) 21(1) 20(1) 20(1) 0(1) 1(1) -1(1) C(11) 25(1) 22(1) 21(1) -2(1) 2(1) 2(1) C(18) 23(1) 18(1) 29(1) -4(1) 1(1) -1(1) C(1) 32(1) 33(1) 25(1) -1(1) 8(1) -6(1) C(12) 28(1) 30(1) 26(1) -7(1) -2(1) 2(1) C(8) 29(1) 21(1) 25(1) 3(1) 3(1) 0(1) C(19) 24(1) 30(1) 37(1) 3(1) -5(1) 1(1) S21

22 SI Table 10. Hydrogen coordinates (x 10 4 ) and isotropic displacement parameters (Å 2 x 10 3 ) for xl x y z U(eq) H(4) H(5) H(3) H(5A) H(2) H(15) H(10) H(11) H(18) H(1A) H(1B) H(1C) H(12A) H(12B) H(12C) H(8A) H(8B) H(19A) H(19B) H(19C) S22

23 SI Table 11. Torsion angles [ ] for xl O(2)-C(7)-C(2)-C(3) (13) O(2)-C(10)-C(11)-C(13) 69.57(15) O(2)-C(10)-C(11)-C(12) (16) O(1)-C(14)-C(13)-C(11) 0.7(2) O(1)-C(14)-C(13)-C(18) (13) O(1)-C(9)-C(10)-O(2) (13) O(1)-C(9)-C(10)-C(11) 8.62(17) O(1)-C(9)-C(8)-O(3) (16) O(4)-C(4)-C(5)-C(6) (13) O(5)-C(17)-C(18)-C(13) (14) C(6)-C(7)-C(2)-C(3) -0.9(2) C(6)-C(9)-C(10)-O(2) 8.06(15) C(6)-C(9)-C(10)-C(11) (13) C(6)-C(9)-C(8)-O(3) (13) C(3)-C(4)-C(5)-C(6) -0.7(2) C(7)-O(2)-C(10)-C(9) -7.86(15) C(7)-O(2)-C(10)-C(11) (12) C(7)-C(6)-C(5)-C(4) 0.0(2) C(7)-C(6)-C(9)-O(1) (13) C(7)-C(6)-C(9)-C(10) -5.60(16) C(7)-C(6)-C(9)-C(8) (14) C(4)-C(3)-C(2)-C(7) 0.2(2) C(5)-C(6)-C(7)-O(2) (13) C(5)-C(6)-C(7)-C(2) 0.8(2) C(5)-C(6)-C(9)-O(1) -63.9(2) C(5)-C(6)-C(9)-C(10) (15) C(5)-C(6)-C(9)-C(8) 53.3(2) C(2)-C(3)-C(4)-O(4) (13) C(2)-C(3)-C(4)-C(5) 0.6(2) C(15)-C(14)-C(13)-C(11) (14) C(15)-C(14)-C(13)-C(18) -1.4(2) C(15)-C(16)-C(17)-O(5) (14) C(15)-C(16)-C(17)-C(18) -1.5(2) S23

24 C(14)-O(1)-C(9)-C(6) (15) C(14)-O(1)-C(9)-C(10) 40.78(16) C(14)-O(1)-C(9)-C(8) (12) C(14)-C(15)-C(16)-C(17) 1.9(2) C(14)-C(15)-C(16)-C(19) (15) C(14)-C(13)-C(11)-C(10) 46.90(18) C(14)-C(13)-C(11)-C(12) (14) C(14)-C(13)-C(18)-C(17) 1.8(2) C(16)-C(15)-C(14)-O(1) (13) C(16)-C(15)-C(14)-C(13) -0.5(2) C(16)-C(17)-C(18)-C(13) -0.4(2) C(9)-O(1)-C(14)-C(15) (14) C(9)-O(1)-C(14)-C(13) (18) C(9)-C(6)-C(7)-O(2) 1.04(18) C(9)-C(6)-C(7)-C(2) (13) C(9)-C(6)-C(5)-C(4) (15) C(9)-C(10)-C(11)-C(13) (17) C(9)-C(10)-C(11)-C(12) (13) C(10)-O(2)-C(7)-C(6) 4.47(17) C(10)-O(2)-C(7)-C(2) (14) C(10)-C(9)-C(8)-O(3) 56.18(18) C(11)-C(13)-C(18)-C(17) (14) C(18)-C(13)-C(11)-C(10) (16) C(18)-C(13)-C(11)-C(12) -8.3(2) C(1)-C(3)-C(4)-O(4) 3.3(2) C(1)-C(3)-C(4)-C(5) (15) C(1)-C(3)-C(2)-C(7) (14) C(8)-C(9)-C(10)-O(2) (13) C(8)-C(9)-C(10)-C(11) (15) C(19)-C(16)-C(17)-O(5) -2.8(2) C(19)-C(16)-C(17)-C(18) (15) S24

25 4. DFT study 4.1. Computational Methods The geometries of reactants, transition states, intermediates and products of 5 + cis/trans-o-qm reaction were optimized with M06-2X functional and polarized triple-ζ G(d,p) basis sets. Vibrational analyses were performed at same level to verify the stationary points and to obtain their Gibbs free energies (at K). For multicomponent reactions, the free energies considering entropy effect is more reasonable than electronic potential energy, therefore in the current study, Gibbs free energy is used to evaluate the reaction energy as well as barrier height. Intrinsic reaction coordinate (IRC) calculations were done to ensure the connectivity between TS and minimum structures. During geometry optimization, the polarizable continuum model (PCM) was employed in order to consider the solvent (dichloromethane) contribution to both energy and geometry Computed free energy surfaces SI Figure 1. Free energy surfaces for oxa-michael Addition. S25

26 SI Figure 2. Free energy surfaces for [4+2]-cycloaddition. S26

27 4.3. Cartesian coordinates and Gibbs free energies of all specie SI Table 12. Cartesian Coordinates (Angstrom) and Gibbs Free Energies (Hartree) of All Involved Minima and Transition States cis-o-qm S27

28 trs-o-qm RC S28

29 RCc S29

30 TS S30

31 TS S31

32 TS0c S32

33 TS0c S33

34 endo-ts S34

35 endo-ts2 endo-ts S35

36 endo-ts S36

37 exo-ts S37

38 exo-ts S38

39 exo-ts S39

40 exo-ts S40

41 MP S41

42 MP S42

43 MP0c S43