Copper-Catalyzed xidative Cyclization of Carboxylic Acids Supplementary material (51 pages) Shyam Sathyamoorthi and J. Du Bois * Department of Chemistry Stanford University Stanford, CA 94305-5080
General. All reagents were obtained commercially unless otherwise noted. Reactions were performed using glassware that was oven-dried. Air- and moisture-sensitive liquids and solutions were transferred via syringe or stainless steel cannula. rganic solutions were concentrated under reduced pressure (~15 Torr) by rotary evaporation. Solvents were purified by passage under 12 psi through activated alumina columns. Chromatography was performed on Silicycle Silia-P Silica Gel (40-63 µm). Compounds purified by chromatography were typically applied to the adsorbent bed using the indicated solvent conditions with a minimum amount of added methylene chloride as needed for solubility. Thin layer chromatography was performed on either Whatman Partisil K6F Silica Gel 60 Å plates (250 µm) or EMD Chemicals Silica Gel (250 µm). Visualization of the developed chromatogram was accomplished by fluorescence quenching and/or by staining with butanolic ninhydrin, aqueous potassium permanganate, or aqueous ceric ammonium molybdate (CAM). Nuclear magnetic resonance (NMR) spectra were acquired on either a Varian Inova-600 operating at 600 and 150 MHz, a Varian Inova-300 operating at 300 and 75 MHz, a Varian Mercury-400 operating at 400 and 100 MHz, or a Varian Inova-500 operating at 500 and 125 MHz, and are referenced internally according to residual solvent signals. Data for NMR are recorded as follows: chemical shift (δ, ppm), multiplicity (s, singlet; br s, broad singlet; d, doublet; t, triplet; q, quartet; quint, quintet; sext, sextet; m, multiplet), integration, coupling constant (Hz). Data are reported in terms of chemical shift (δ, ppm). Infrared spectra were recorded on either a Thermo-Nicolet IR100 spectrometer or a Thermo-Nicolet IR300 spectrometer as thin films using NaCl salt plates and are reported in frequency of absorption. High-resolution mass spectra were obtained from the Vincent Coates Foundation Mass Spectrometry Laboratory at Stanford University. General procedure A for oxidative lactonization. A 5 ml reaction vial was charged with carboxylic acid substrate (0.5 mmol), Cu(Ac) 2 H 2 (0.05 mmol, 0.1 equiv), and K 2 S 2 8 (1 1.5 equiv, see below for specific oxidant loadings). To this mixture was added 2.4 ml of CH 3 CH and 2.4 ml of H 2. The vial was sealed and immersed into an oil bath pre-heated to 105 C, and the reaction mixture was stirred for 2 h. After cooling to room temperature, the reaction contents were transferred to a 100 ml Erlenmeyer flask. The solution was stirred and approximately 25 ml of 6.0 M aqueous NaH was added slowly until the ph was ~14. This mixture was then transferred to a 60 ml separatory funnel with 15 ml of CH 2 Cl 2. The organic layer was collected and the aqueous fraction was extracted with 2 x 10 ml of CH 2 Cl 2 and 2 x 10 ml of EtAc. The combined organic layers were dried over Na 2 S 4, filtered, and concentrated under reduced pressure. Pure material was obtained following chromatography on silica gel (conditions given below). General procedure B for oxidative lactonization. A 5 ml reaction vial was charged with carboxylic acid substrate (0.5 mmol), Cu(Ac) 2 H 2 (0.05 mmol, 0.1 equiv), and K 2 S 2 8 (1 1.5 equiv, see below for specific oxidant loadings). To this mixture was added 2.4 ml of CH 3 CN and 2.4 ml of H 2. The vial was sealed and immersed into an oil bath pre-heated to 85 C, and the reaction mixture was stirred for 2 h. After cooling to room temperature, the reaction contents were transferred to a 60 ml separatory funnel with 10 ml of CH 2 Cl 2 and 10 ml of H 2. The organic layer was collected and the aqueous fraction was extracted with 2 x 10 ml of CH 2 Cl 2 and 2 x 10 ml of EtAc. The combined organic layers were dried over Na 2 S 4, filtered, and concentrated under reduced pressure. Pure material was obtained following chromatography on silica gel (conditions given below). General procedure C for oxidative lactonization. A 5 ml reaction vial was charged with carboxylic acid substrate (0.5 mmol), Cu(Ac) 2 H 2 (0.05 mmol, 0.1 equiv), and K 2 S 2 8 (1 1.5 equiv, see below for specific oxidant loadings). To this mixture was added 2.4 ml of CH 3 CH and 2.4 ml of H 2. The vial was sealed and immersed into an oil bath pre-heated to 105 C, and the reaction mixture was stirred for 2 h. After cooling to room temperature, the reaction contents were transferred to a 60 ml separatory funnel with 10 ml of CH 2 Cl 2 and 10 ml of 1.0 M aqueous HCl. The organic layer was collected and the aqueous fraction was extracted with 2 x 10 ml of CH 2 Cl 2 and 2 x 10 ml of EtAc. The combined organic layers were dried over Na 2 S 4, filtered, and concentrated under reduced pressure. Pure material was obtained following chromatography on silica gel (conditions given below). S2
Characterization data for lactone products (Table 2 and Scheme 2) Table 2, entry 1: Reaction performed according to general procedure A with 1.5 equiv K 2 S 2 8 (1.0 M aqueous NaH used in work-up); pale yellow oil (49 mg, 59%): TLC R f = 0.32 (3:1 hexanes/etac); 1 H NMR (CDCl 3, 300 MHz) δ 7.45-7.35 (m, 5H), 5.57-5.52 (m, 1H), 2.75-2.63 (m, 3H), 2.31-2.17 (m, 1H) ppm; 13 C NMR (CDCl 3, 75 MHz) δ 177.2, 139.6, 129.1, 128.7, 125.5, 81.5, 31.3, 29.3 ppm; IR (thin film) ν 1774, 1216, 1176, 1025, 940 cm -1. Me Me Table 2, entry 1:Reaction performed according to general procedure A with 1.5 equiv K 2 S 2 8 ; purified by chromatography on silica gel (3:1 hexanes/etac); white solid (54 mg, 57%): TLC R f = 0.45 (3:1 hexanes/etac); 1 H NMR (CDCl 3, 300 MHz) δ 7.44-7.34 (m, 5H), 5.48 (dd, 1H, J = 12.0, 6.0 Hz), 2.51 (dd, 1H, J = 13.5, 6.0 Hz), 2.10 (dd, 1H, J = 13.5, 12.0 Hz), 1.40 (s, 3H), 1.34 (s, 3H) ppm; 13 C NMR (CDCl 3, 100 MHz) δ 181.7, 139.5, 128.7, 128.3, 125.3, 77.6, 46.1, 40.8, 25.0, 24.2 ppm; IR (thin film) ν 2970, 1770, 1229, 1122, 925 cm -1. Me Table 2, entry 2: Reaction performed according to general procedure A with 1 equiv K 2 S 2 8 ; purified by chromatography on silica gel (3:1 hexanes/etac); white solid (73 mg, 75%): TLC R f = 0.20 (3:1 hexanes/etac); 1 H NMR (CDCl 3, 400 MHz) δ 7.25-7.23 (m, 2H), 6.91-6.87 (m, 2H), 5.45-5.42 (m, 1H), 3.79 (s, 3H), 2.65-2.54 (m, 3H), 2.21-2.12 (m, 1H) ppm; 13 C NMR (CDCl 3, 100 MHz) δ 177.1, 160.0, 131.4, 127.2, 114.3, 81.6, 55.5, 31.1, 29.4 ppm; IR (thin film) ν 1765, 1612, 1515, 1248, 1173, 1029, 935 cm 1. Br Table 2, entry 2: Reaction performed according to general procedure A with 1.5 equiv K 2 S 2 8 ; purified by chromatography on silica gel (3:1 hexanes/ EtAc); white solid (53 mg, 42%): TLC R f = 0.2 (3:1 hexanes/etac); 1 H NMR (CDCl 3, 400 MHz) δ 7.52 (d, 2H, J = 8.0 Hz), 7.21 (d, 2H, J = 8.0 Hz), 5.48-5.44 (m, 1H), 2.71-2.63 (m, 3H), 2.20-2.08 (m, 1H) ppm; 13 C NMR (CDCl 3, 100 MHz) δ 176.6, 138.4, 131.9, 127.0, 122.4, 80.5, 31.0, 28.9 ppm; IR (thin film) ν 1770, 1418, 1334, 1183, 1010, 943, 804 cm -1. Me N H Table 2, entry 2: Reaction performed according to general procedure B with 1.5 equiv K 2 S 2 8 ; purified by chromatography on silica gel (3:5 hexanes/etac); orange solid (46 mg, 46%): TLC R f = 0.13 (3:5 hexanes/etac); 1 H NMR (CDCl 3, 300 MHz) δ 7.93 (br s, 1H), 7.55 (d, 2H, J = 10.0 Hz), 7.25 (d, 2H, J = 10.0 Hz), 5.51-5.47 (m, 1H), 2.71-2.59 (m, 3H), 2.27-2.13 (m, 1H), 2.19 (s, 3H) ppm; 13 C NMR (CDCl 3, 100 MHz) δ 177.6, 169.1, 138.6, 134.9, 126.4, 120.4, 81.6, 31.1, 29.4, 24.8 ppm; IR (thin film) ν 3315, 1767, 1671, 1536, 1417, 1293, 1016, 841 cm -1. HRMS (ES + ) calcd for C 12 H 13 N 3 Na + 242.0788 found 242.0795 (MNa + ). S3
Br Me Table 2, entry 3: Reaction performed according to general procedure A with 1.5 equiv K 2 S 2 8 ; purified by chromatography on silica gel (3:1 hexanes/etac); white solid (71 mg, 53%): TLC R f = 0.15 (3:1 hexanes/etac); 1 H NMR (CDCl 3, 400 MHz) δ 7.49 (d, 1H, J = 2.4 Hz), 7.24-7.21 (m, 1H), 6.87 (d, 1H, J = 8.8 Hz), 5.41-5.37 (m, 1H), 3.85 (s, 3H), 2.65-2.55 (m, 3H), 2.20-2.10 (m, 1H) ppm; 13 C NMR (CDCl 3, 100 MHz) δ 176.8, 156.2, 132.9, 130.8, 126.0, 112.2, 112.1, 80.5, 56.5, 31.1, 29.2 ppm; IR (thin film) ν 2946, 1774, 1606, 1441, 1213, 1139, 1019, 951, 849 cm -1 ; HRMS (ES + ) calcd for C 11 H 11 Br 3 Na + 292.9784 found 292.9784 (MNa + ). 2 N Me Table 2, entry 3: Reaction performed according to general procedure A with 1.5 equiv K 2 S 2 8 ; purified by chromatography on silica gel (1:1 hexanes/etac); light yellow oil (30 mg, 25%): TLC R f = 0.14 (1:1 hexanes/etac); 1 H NMR (CDCl 3, 400 MHz) δ 7.83 (s, 1H), 7.55 (d, 1H, J = 12.0 Hz), 7.13 (d, 1H, J = 12.0 Hz), 5.50-5.46 (m, 1H), 3.98 (s, 3H), 2.74-2.63 (m, 3H), 2.24-2.11 (m, 1H) ppm; 13 C NMR (CDCl 3, 100 MHz) δ 176.4, 153.2, 139.7, 131.9, 131.5, 123.2, 114.2, 79.8, 56.9, 31.0, 29.2 ppm; IR (thin film) ν 1775, 1533, 1355, 1019, 911 cm -1 ; HRMS (ES + ) calcd for C 11 H 11 N 5 Na + 260.0529 found 260.0535 (MNa + ). Me Table 2, entry 4: Reaction performed according to general procedure A with 1.5 equiv K 2 S 2 8 ; purified by chromatography on silica gel (3:1 hexanes/etac); clear oil (67 mg, 70%): TLC R f = 0.27 (3:1 hexanes/etac); 1 H NMR (CDCl 3, 400 MHz) δ 7.31-7.27 (m, 2H), 6.95 (t, 1H, J = 7.2 Hz), 6.88 (d, 1H, J = 8.4 Hz), 5.74 (t, 1H, J = 7.2 Hz), 3.83 (s, 3H), 2.74-2.67 (m, 1H), 2.61-2.57 (m, 2H), 2.14-2.05 (m, 1H) ppm; 13 C NMR (CDCl 3, 100 MHz) δ 177.8, 156.2, 129.5, 128.3, 125.8, 120.9, 110.7, 78.1, 55.6, 29.5, 28.8 ppm; IR (thin film) ν 2921, 1773, 1603, 1465, 1246, 1143, 1028 cm 1. Br Table 2, entry 4: Reaction performed according to general procedure A with 1.5 equiv K 2 S 2 8 ; purified by chromatography on silica gel (3:1 hexanes/etac); pale yellow oil (25 mg, 21%): TLC R f = 0.25 (3:1 hexanes/etac); 1 H NMR (CDCl 3, 400 MHz) δ 7.58 (d, 1H, J = 8.0 Hz), 7.41 (d, 1H, J = 8.0 Hz), 7.36 (t, 1H, J = 8.0 Hz), 7.21 (t, 1H, J = 8.0 Hz), 5.78 (t, 1H, J = 8.0 Hz), 2.92-2.83 (m, 1H), 2.65-2.61 (m, 2H), 2.11-2.02 (m, 1H) ppm; 13 C NMR (CDCl 3, 100 MHz) δ 177.0, 139.0, 133.0, 129.6, 127.9, 126.0, 120.6, 80.3, 29.7, 28.3 ppm; IR (thin film) ν 1778, 1441, 1141, 1019, 937 cm 1. Table 2, entry 5: Reaction performed according to general procedure A with 1 equiv K 2 S 2 8 ; purified by chromatography on silica gel (3:1 hexanes/etac); white solid (54 mg, 59%): TLC R f = 0.25 (3:1 hexanes/etac); 1 H NMR (CDCl 3, 400 MHz) δ 7.46 (d, 1H, J = 7.2 Hz), 7.35-7.23 (m, 3H), 5.87 (d, 1H, J = 7.2 Hz), 3.39-3.26 (m, 2H), 2.92-2.84 (m, 2H), 2.37 (dd, 1H, J = 18.4, 5.2 Hz) ppm; 13 C NMR (CDCl 3, 100 MHz) δ 177.1, 142.7, 139.0, 130.2, 127.8, 126.6, 125.5, 87.9, 38.1, 37.5, 35.9 ppm; IR (thin film) ν 2922, 1768, 1461, 1163, 1016, 950 cm 1 ; HRMS (ES + ) calcd for C 11 H 10 2 Na + 197.0573 found 197.0581 (MNa + ). S4
Table 2, entry 6: Reaction performed according to general procedure A with 1.5 equiv K 2 S 2 8 ; purified by chromatography on silica gel (10:3 hexanes/etac); white solid (57 mg, 60%): TLC R f = 0.49 (1:1 hexanes/etac); 1 H NMR (CDCl 3, 500 MHz) δ 7.43 (d, 1H, J = 10.0 Hz), 7.31 (t, 1H, J = 10.0 Hz), 7.05 (t, 1H, J = 10.0 Hz), 6.95 (d, 1H, J = 10.0 Hz), 5.51 (d, 1 H, J = 5.0 Hz), 4.23 (dd, 1H, J = 10.0, 5.0 Hz), 3.85 (dd, 1H, J = 15.0, 10.0 Hz), 3.08-3.01 (m, 1H), 2.90 (dd, 1H, J = 17.8, 8.5 Hz), 2.48 (dd, 1H, J = 20.0, 4.0 Hz) ppm; 13 C NMR (CDCl 3, 75 MHz) δ 175.6, 155.3, 131.7, 130.9, 122.2, 118.7, 117.7, 74.5, 65.1, 33.9, 31.4 ppm; IR (thin film) ν 1774, 1490, 1225, 1016 cm -1. Me Me Table 2, entry 7: Reaction performed according to general procedure A with 1.5 equiv K 2 S 2 8 ; purified by chromatography on silica gel (3:1 hexanes/etac); clear oil, crystallizes upon standing (48 mg, 45%, dr >20:1 trans/cis): TLC R f = 0.33 (3:1 hexanes/etac); 1 H NMR (CDCl 3, 400 MHz) δ 7.39-7.28 (m, 5H), 5.18 (d, 1H, J = 6.4 Hz), 2.70-2.64 (m, 1H), 2.45-2.36 (m, 2H), 1.86-1.78 (m, 1H), 0.97 (d, 3H, J = 6.8 Hz), 0.87 (d, 3H, J = 6.8 Hz) ppm; 13 C NMR (CDCl 3, 100 MHz) δ 176.6, 139.6, 129.0, 128.8, 126.3, 85.0, 50.3, 32.0, 29.9, 21.0, 19.2 ppm; IR (thin film) ν 2960, 1777, 1458, 1270, 1206, 1149, 984 cm 1. C 2 H Table 2, entry 8: Reaction performed according to general procedure C with 1.5 equiv K 2 S 2 8 ; purified as an inseparable 1:1 mixture of diastereomers by chromatography on silica gel (10:3.5:0.1 hexanes/etac/ach); white solid (67 mg, 55%): TLC R f = 0.29 (1:1:0.1 hexanes/etac/ach); 1 H NMR (CDCl 3, 500 MHz) δ 7.44-7.32 (m, 10H), 5.69 (dd, 1H, J = 10.0, 5.0 Hz), 5.45 (dd, 1H, J = 11.0, 6.0 Hz), 3.24-3.18 (m, 1H), 3.11-2.91 (m, 4H), 2.76-2.69 (m, 2H), 2.64-2.54 (m, 2H), 2.10-2.02 (m, 1H) ppm; 13 C NMR (CDCl 3, 100 MHz) δ 178.2, 177.5, 176.6, 176.5, 139.7, 138.7, 129.1, 129.0, 128.9, 128.6, 125.9, 125.1, 80.1, 78.8, 38.2, 37.8, 35.9, 35.0, 34.5, 34.2 ppm; IR (thin film) ν 2942, 1770, 1453, 1407, 1332, 1015 cm -1 ; HRMS (ES + ) calcd for C 12 H 12 4 Na + 243.0628 found 243.0631. Me Me Sit BuMe 2 Table 2, entry 9: Reaction performed according to general procedure B with 1.5 equiv K 2 S 2 8 ; purified by chromatography on silica gel (3:1 hexanes/etac); clear oil, crystallizes upon standing (60 mg, 36%, dr > 20:1, stereochemistry unassigned): TLC R f = 0.36 (3:1 hexanes/etac); 1 H NMR (CDCl 3, 400 MHz) δ 7.24 (d, 2H, J = 8.8 Hz), 6.87 (d, 2H, J = 8.8 Hz), 5.10 (s, 1H), 3.80 (s, 3H), 2.73 (d, 1H, J = 16.8 Hz), 2.68 (d, 1H, J = 16.8 Hz), 1.47 (s, 3H), 0.70 (s, 9H), 0.01 (s, 3H), -0.25 (s, 3H) ppm; 13 C NMR (CDCl 3, 100 MHz) δ 175.2, 160.0, 128.8, 125.9, 113.4, 90.4, 78.8, 55.6, 45.5, 25.8, 24.2, 18.1, -2.3, -2.6 ppm; IR (thin film) ν 1786, 1516, 1253, 1174, 1020, 828 cm 1 ; HRMS (ES + ) calcd for C 18 H 28 4 SiNa + 359.1649 found 359.1647 (MNa + ). Me Me Me Me Table 2, entry 10: Reaction performed according to general procedure A with 1.5 equiv K 2 S 2 8 ; purified by chromatography on silica gel (5:1 hexanes/etac); white solid (25 mg, 35%): TLC (visualized by staining with S5
KMn 4 ) R f = 0.27 (5:1 hexanes/etac); 1 H NMR (CDCl 3, 300 MHz) δ 2.44 (s, 2H), 1.35 (s, 6H), 1.12 (s, 6H) ppm; 13 C NMR (CDCl 3, 100 MHz) δ 175.7, 88.6, 43.9, 41.1, 23.4, 23.0 ppm; IR (thin film) ν 2980, 1768, 1375, 1249, 1101, 921 cm -1. Me Me Table 2, entry 10: Reaction performed according to general procedure A with 1.5 equiv K 2 S 2 8 ; purified by chromatography on silica gel (5:1 hexanes/etac); clear oil (18 mg, 21%): TLC R f = 0.22 (10:1 hexanes/etac, visualized by staining with KMn 4 ); 1 H NMR (CDCl 3, 400 MHz) δ 2.40 (s, 2H), 1.85-1.70 (m, 8H), 1.11 (s, 6H) ppm; 13 C NMR (CDCl 3, 100 MHz) δ 176.1, 100.9, 44.9, 40.1, 32.8, 23.7, 23.1 ppm; IR (thin film) ν 2966, 1775, 1242, 1161, 1124, 983, 927 cm -1. Me Me Table 2, entry 11: Reaction performed according to general procedure B with 1.5 equiv K 2 S 2 8 ; purified by chromatography on silica gel (3:1 hexanes/etac); tan solid (22 mg, 16%): TLC R f = 0.21 (3:1 hexanes/etac); 1 H NMR (CDCl 3, 400 MHz) δ 7.76-7.70 (m, 3H), 7.38 (dd, 1H, J = 8.8, 2.0 Hz), 7.15 (dd, 1H, J = 8.8, 2.4 Hz), 7.11 (d, 1H, J = 2.4 Hz), 3.90 (s, 3H), 2.67-2.41 (m, 4H), 1.78 (s, 3H) ppm; 13 C NMR (CDCl 3, 100 MHz) δ 176.9, 158.2, 139.4, 134.0, 129.9, 128.6, 127.6, 123.2, 122.8, 119.6, 105.8, 87.3, 55.6, 36.3, 29.6, 29.2 ppm; IR (thin film) ν 1776, 1608, 1505, 1486, 1390, 1271, 1245, 1209, 1163, 1031, 944, 855 cm 1 ; HRMS (ES + ) calcd for C 16 H 16 3 Na + 279.0992 found 279.0994 (MNa + ). Ph Scheme 2A: Reaction performed according to general procedure A with 1.5 equiv K 2 S 2 8 ; purified by chromatography on silica gel (3:1 hexanes/etac); white solid (67 mg, 65%): TLC R f = 0.33 (3:1 hexanes/etac); 1 H NMR (CDCl 3, 400 MHz) δ 7.94 (d, 1H, J = 7.6 Hz), 7.63 (t, 1H, J = 7.6 Hz), 7.54 (t, 1H, J = 7.6 Hz), 7.38-7.34 (m, 3H), 7.31 (d, 1H, J = 7.6 Hz), 7.28-7.24 (m, 2H), 6.39 (s, 1H) ppm; 13 C NMR (CDCl 3, 100 MHz) δ 170.7, 149.9, 136.6, 134.5, 129.6, 129.5, 129.2, 127.2, 125.9, 125.8, 123.1, 82.9 ppm; IR (thin film) ν 1766, 1611, 1495, 1210, 1014, 1000, 966 cm -1. Ph Scheme 2B: Reaction performed according to general procedure A with 1.5 equiv K 2 S 2 8 ; purified by chromatography on silica gel (3:1 hexanes/etac); white solid (76 mg, 65%): TLC R f = 0.20 (10:1 hexanes/etac); 1 H NMR (CDCl 3, 400 MHz) δ 8.15 (d, 1H, J = 8.0 Hz), 7.56 (dt, 1H, J = 8.0, 4.0 Hz), 7.50-7.45 (m, 2H), 7.45-7.35 (m, 4H), 7.28 (d, 1H, J = 8.0 Hz), 5.54 (dd, 1H, J = 12.0, 3.2 Hz), 3.33 (dd, 1H, J = 18.8, 12 Hz), 3.12 (dd, 1H, J = 16.4, 3.2 Hz) ppm; 13 C NMR (CDCl 3, 100 MHz) δ 165.3, 138.9, 138.6, 133.9, 130.4, 128.7, 128.6, 127.9, 127.4, 126.1, 125.1, 79.9, 35.6 ppm; IR (thin film) ν 1716, 1606, 1348, 1226, 1119, 1030 cm -1. Scheme 2C: Reaction performed according to general procedure A with 1.5 equiv K 2 S 2 8 ; purified by chromatography on silica gel (10:3 hexanes/etac); white foam (111 mg, 79%): TLC R f = 0.45 (1:1 hexanes/etac); 1 H NMR (CDCl 3, 400 MHz) δ 8.13 (d, 1H, J = 8.0 Hz), 7.58-7.53 (m, 1H), 7.41 (t, 1H, J = 8.0 Hz), 7.27 (d, 1H, J = 8.0 Hz), 6.98 (d, 1H, J = 2.0 Hz), 6.93 (dd, 1H, J = 8.0, 2.0 Hz), 6.87 (dd, 1H, J = 12.0 Hz), S6
5.43 (dd, 1H, J = 12.0, 4.0 Hz), 4.26 (s, 4H), 3.30 (dd, 1H, J = 16.0, 12.0 Hz), 3.08 (dd, 1H, J = 12.0, 4.0 Hz) ppm; 13 C NMR (CDCl 3, 100 MHz) δ 165.4, 143.8, 143.6, 138.9, 133.9, 131.7, 130.4, 127.8, 127.4, 125.1, 119.4, 117.4, 115.4, 79.6, 64.4, 64.3, 35.4 ppm; IR (thin film) ν 1723, 1592, 1277, 1067, 924 cm -1 ; HRMS (ES + ) calcd for C 17 H 14 4 Na + 305.0784 found 305.0790 (MNa + ). Me Me Me Me Scheme 2D: Reaction performed according to general procedure A with 1.5 equiv K 2 S 2 8 ; purified by chromatography on silica gel (20:7 hexanes/acetone); white foam (76 mg, 43%): TLC R f = 0.11 (10:3 hexanes/acetone); 1 H NMR (CDCl 3, 300 MHz) δ 7.54-7.49 (m, 1H), 6.98 (d, 1H, J = 6.0 Hz), 6.87 (d, 1H, J = 6.0 Hz), 6.70 (s, 2H), 5.36 (dd, 1H, J = 12.0, 3.0 Hz), 3.99 (s, 3H), 3.91 (s, 6H), 3.87 (s, 3H), 3.29 (dd, 1H, J = 18.0, 12.0 Hz), 3.07 (dd, 1H, J = 15.0, 3.0 Hz) ppm; 13 C NMR (CDCl 3, 100 MHz) δ 162.5, 161.6, 153.6, 141.9, 138.2, 134.9, 134.5, 119.4, 113.9, 111.3, 103.5, 79.5, 61.1, 56.5, 37.3 ppm; IR (thin film) ν 1726, 1595, 1476, 1233, 1084 cm -1 ; HRMS (ES + ) calcd for C 19 H 20 6 Na + 367.1152 found 367.1146 (MNa + ). CH 3 C 6 H 4 S 2 Me S 2 C 6 H 4 CH 3 Scheme 2E: Reaction performed on a 0.167 mmol scale according to general procedure A with 1.5 equiv K 2 S 2 8 and 1.0 ml of CH 3 CN to improve solubility; purified by chromatography on silica gel (gradient elution: 4:1 1:1hexanes/EtAc); white foam (51 mg, 51%): TLC R f = 0.19 (1:1 hexanes/ EtAc); 1 H NMR (CDCl 3, 400 MHz) δ 7.86 (d, 2H, J = 8.0 Hz), 7.73 (d, 2H, J = 8.0 Hz), 7.54 (t, 1H, J = 8.0 Hz), 7.35-7.29 (m, 6H), 7.22 (d, 1H, J = 8.0 Hz), 7.17 (d, 1H, J = 2.0 Hz), 6.85 (d, 1H, J = 8.0 Hz), 5.17 (dd, 1H, J = 12.0, 4.0 Hz), 3.56 (s, 3H), 3.18 (dd, 1H, J = 16.0, 12.0 Hz), 3.04 (dd, 1H, J = 17.7, 4.0 Hz), 2.44 (s, 6H) ppm; 13 C NMR (CDCl 3, 100 MHz) δ 160.3, 152.0, 148.9, 145.7, 145.3, 141.2, 138.1, 134.3, 132.9, 132.1, 130.3, 129.6, 129.4, 129.0, 128.6, 126.3, 125.9, 123.8, 122.2, 119.5, 112.7, 78.4, 55.7, 35.9, 21.8, 21.7 ppm; IR (thin film) ν 1736, 1515, 1373, 1021 cm -1 ; HRMS (ES + ) calcd for C 30 H 26 9 S 2 Na + 617.0910 found 617.0910 (MNa + ). c-hx N H SI Compound 1: Reaction performed on a 0.328 mmol scale according to general procedure B with 1.5 equiv K 2 S 2 8 ; purified by chromatography on silica gel (1:1 hexanes/etac); white solid (42 mg, 45%): TLC R f = 0.15 (1:1 hexanes/etac); 1 H NMR (CDCl 3, 400 MHz) δ 7.56 (d, 2H, J = 12.0 Hz), 7.40 (br s, 1H), 7.27-7.25 (m, 2H), 5.48-5.45 (m, 1H), 2.66-2.60 (m, 3H), 2.27-2.11 (m, 2H), 1.96-1.92 (m, 2H), 1.84-1.81 (m, 2H), 1.72-1.65 (m, 1H), 1.56-1.48 (m, 2H), 1.34-1.19 (m, 3H) ppm; 13 C NMR (CDCl 3, 100 MHz) δ 177.0, 174.6, 138.3, 134.7, 126.1, 119.9, 81.1, 46.5, 30.9, 29.6, 29.1 25.6 ppm; IR (thin film) ν 3304, 2928, 1768, 1661, 1144, 937 cm -1 ; HRMS (ES + ) calcd for C 17 H 21 N 3 Na + 310.1414 found 310.1418 (MNa + ). SI Compound 2: Reaction performed according to general procedure A with 1.5 equiv K 2 S 2 8 ; purified by chromatography on silica gel (10:3 hexanes/etac); white foam (111 mg, 67%): TLC R f = 0.41 (1:1 S7
hexanes/etac); 1 H NMR (CDCl 3, 400 MHz) δ 8.00 (d, 2H, J = 8.0 Hz), 7.95 (d, 2H, J = 8.0 Hz), 7.60 (d, 2H, J = 8.0 Hz), 7.52-7.35 (m, 5H), 5.63-5.59 (m, 1H), 2.77-2.68 (m, 3H), 2.33-2.23 (m, 1H) ppm; 13 C NMR (CDCl 3, 100 MHz) δ 177.2, 156.4, 153.5, 139.0, 136.9, 129.4, 127.6, 126.9, 125.9, 125.3, 125.2, 124.3, 123.5, 123.1, 120.9, 120.2, 112.1, 81.3, 31.3, 29.2 ppm; IR (thin film) ν 1773, 1450, 1141, 939 cm -1 ; HRMS (ES + ) calcd for C 22 H 16 3 Na + 351.0992 found 351.0995 (MNa + ). Me Me SI Compound 3: Reaction performed on a 0.356 mmol scale according to general procedure A with 1.5 equiv K 2 S 2 8 ; purified by chromatography on silica gel (10:1 hexanes/etac to 1:1 hexanes/ EtAc); tan solid (53 mg, 47%): TLC R f = 0.25 (1:1 hexanes/etac); 1 H NMR (CDCl 3, 400 MHz) δ 7.47 (t, 1H, J = 8.0 Hz), 7.38 (d, 2H, J = 8.0 Hz), 6.95-6.90 (m, 3H), 6.83 (d, 1H, J = 8.0 Hz), 5.37 (dd, 1H, J = 12.0, 4.0 Hz), 3.96 (s, 3H), 3.81 (s, 3H), 3.27 (dd, 1H, J = 16.0, 12.0 Hz), 3.02 (dd, 1H, J = 20.0, 4.0 Hz) ppm; 13 C NMR (CDCl 3, 100 MHz) δ 162.7, 161.5, 160.0, 142.1, 134.8, 130.8, 127.9, 119.4, 114.2, 114.0, 111.2, 79.2, 56.4, 55.6, 36.9 ppm; IR (thin film) ν 1724, 1598, 1476, 1237, 1054 cm -1 ; HRMS (ES + ) calcd for C 17 H 16 4 Na + 307.047 found 307.0939 (MNa + ). Me Me Me SI Compound 4: Reaction performed on a 0.414 mmol scale according to general procedure A with 1 equiv K 2 S 2 8 ; purified by chromatography on silica gel (1:1 hexanes/etac); white foam (80 mg, 51%): TLC R f = 0.19 (1:1 hexanes/etac); 1 H NMR (CDCl 3, 500 MHz) δ 7.49 (t, 1H, J = 8.0 Hz), 7.03 (s, 1H), 6.98-6.95 (m, 2H), 6.88-6.85 (m, 2H), 5.37 (dd, 1H, J = 10.0, 5.0 Hz), 3.97 (s, 3H), 3.92 (s, 3H), 3.90 (s, 3H), 3.30 (dd, 1H, J = 15.0, 10.0 Hz), 3.04 (dd, 1H, J = 15.0, 5.0 Hz) ppm; 13 C NMR (CDCl 3, 125 MHz) δ 162.8, 161.5, 149.4, 149.3, 142.0, 134.9, 131.3, 119.5, 119.0, 114.0, 111.3, 111.1, 109.6, 79.4, 56.5, 56.3, 56.2, 37.0 ppm; IR (thin film) ν 1722, 1518, 1233, 1056 cm -1 ; HRMS (ES + ) calcd for C 18 H 18 5 Na + 337.1046 found 337.1041 (MNa + ). Synthesis of (±)-phyllodulcin (Figure 2) Ts Me 3 SiK H Me Ts CH 3 CN Me H To a solution of 9 (51 mg, 0.086 mmol) in 5.0 ml of CH 3 CN was added potassium trimethylsilanoate (120 mg, 0.860 mmol, 10 equiv). After stirring for 5 h, the reaction mixture was acidified to ph ~1 with 10 ml of 1.0 M aqueous HCl. The solution was transferred to a separatory funnel and extracted successively with 2 x 20 ml of CH 2 Cl 2 and 2 x 20 ml of EtAc. The combined organic fractions were dried over Na 2 S 4, filtered, and concentrated under reduced pressure to a red-orange oil. Purification of this material by preparatory thin layer chromatography (1:1 hexanes/etac) furnished the desired product as an off-white solid (13 mg, 51%). TLC R f = 0.18 (10:3 hexanes/etac); 1 H NMR (CDCl 3, 400 MHz) δ 11.00 (br s, 1H), 7.44 (t, 1H, J = 8.0 Hz), 7.03 (d, 1H, J = 4.0 Hz), 6.97-6.86 (m, 3H), 6.73 (d, 1H, J = 8.0 Hz), 5.50 (dd, 1H, J = 12.0, 4.0 Hz), 3.91 (s, 3H), 3.31 (dd, 1H, J = 12.0, 4.0 Hz), 3.08 (dd, 1H, J = 16.0, 4.0 HZ) ppm; 13 C NMR (CDCl 3, 100 MHz) δ 170.0, 162.5, 147.2, 146.0, 139.6, 136.6, 131.3, 118.5, 118.2, 116.6, 112.8, 110.8, 108.7, 80.9, 56.3, 35.3 ppm; IR (thin film) ν 3500, 1672, 1584, 1229, 1029 cm -1 ; HRMS (ES + ) calcd for C 16 H 14 5 Na + 309.0733 found 309.0737 (MNa + ). S8
Additional examples of 3,4-dihydroisocoumarin natural products synthesis Me H BBr 3 (±)-hydrangenol Me CH 2 Cl 2 H To a 78 C solution of 8-methoxy-3-(4-methoxyphenyl)isochroman-1-one (53 mg, 0.186 mmol) in 1.3 ml of CH 2 Cl 2 was added BBr 3 (1.0 M in CH 2 Cl 2, 670 µl, 3.6 equiv) dropwise. The reaction mixture was warmed to room temperature over the course of 2 h. Following this time, the solution was cooled to 0 C and the reaction was quenched by dropwise addition of 2 ml of H 2 and 0.5 ml of 1.0 M aqueous NaH. The mixture was acidified to ph ~1 with 5 ml of 1.0 M aqueous HCl, transferred to a separatory funnel, and extracted with 2 x 20 ml of CH 2 Cl 2 and 2 x 20 ml of EtAc. The combined organic fractions were dried over Na 2 S 4, filtered, and concentrated under reduced pressure to a red-orange solid. Purification of this material by reversed-phase HPLC (Alltima C18, 10µm, 22 x 250 mm, eluting with gradient flow over 40 min of 0:100 100:0 MeCN/H 2, 254 nm UV detection) furnished the desired product as a white solid (21 mg, 45%). At a flow rate of 12 ml/min, the product had a retention time of 25 min. TLC R f = 0.2 (10:3 hexanes/etac); 1 H NMR (CDCl 3, 400 MHz) δ 10.99 (s, 1H), 7.45 (t, 1H, J = 8.0 Hz), 7.33 (d, 2H, J = 8.0 Hz), 6.93 (d, 1H, J = 8.0 Hz), 6.88 (d, 2H, J = 8.0 Hz), 6.74 (d, 1H, J = 8.0 Hz), 5.54 (dd, 1H, J = 12.8, 3.2 Hz), 5.10 (br s, 1H), 3.33 (dd, 1H, J = 16.0, 12.0 Hz), 3.10 (dd, 1H, J = 16.0, 4.0 Hz) ppm; 13 C NMR (CDCl 3, 100 MHz) δ 169.9, 162.2, 156.2, 139.4, 136.4, 130.0, 127.9, 117.9, 116.4, 115.6, 108.4, 80.8, 35.0 ppm; IR (thin film) ν 3357, 1666, 1519, 1229, 1031 cm -1 ; HRMS (ES + ) calcd for C 15 H 12 4 Na + 279.0634 found 279.0630 (MNa + ). Me H BBr 3 (±)-thunberginol G Me Me CH 2 Cl 2 H H To a 78 C solution of 3-(3,4-dimethoxyphenyl)-8-methoxyisochroman-1-one (0.080 g, 0.254 mmol) in 2.0 ml of CH 2 Cl 2 was added BBr 3 (1.0 M in CH 2 Cl 2, 1.0 ml, 4.0 equiv) dropwise. The reaction mixture was warmed to room temperature over the course of 1.25 h. Following this time, the solution was cooled to 0 C, and the reaction was quenched by dropwise addition of 2 ml of H 2 and 0.5 ml of 1.0 M aqueous NaH. The mixture was acidified to ph ~1 with 5 ml of 1.0 M aqueous HCl, transferred to a separatory funnel, and extracted with 2 x 20 ml of CH 2 Cl 2 and 2 x 20 ml of EtAc. The combined organic fractions were dried over Na 2 S 4, filtered, and concentrated under reduced pressure to a red-orange solid. Purification of this material by reversed-phase HPLC (Alltima C18, 10µm, 22 x 250 mm, eluting with gradient flow over 40 min of 0:100 100:0 MeCN/H 2, 254 nm UV detection) furnished the desired product as a tan solid (16 mg, 23%). TLC R f = 0.3 (1:1 hexanes/etac); 1 H NMR (CD 3 CN, 400 MHz) δ 11.02 (br s, 1H), 7.53-7.49 (m, 1H), 6.99-6.97 (m, 1H), 6.92-6.89 (m, 1H), 6.88-6.87 (m, 2H), 6.84-6.82 (m, 1H), 5.54 (d, 1H, J = 12.0, 2.0 Hz), 3.35 (dd, 1H, J = 16.0, 12.0 Hz), 3.13 (dd, 1H, J = 16.0, 4.0 Hz) ppm; 13 C NMR (CD 3 CN, 100 MHz) δ 170.0, 161.8, 145.1, 144.6, 140.5, 136.4, 130.5, 118.7, 118.2, 115.5, 115.3, 113.7, 108.6, 80.9, 34.1 ppm; IR (thin film) ν 3269, 1665, 1461, 1229, 1030 cm -1 ; HRMS (ES + ) calcd for C 15 H 12 5 Na + 295.0577 found 295.0584 (MNa + ). Me Me Me Me BCl 3 CH 2 Cl 2 H Me Me Me (±)-macrophyllol To a 0 C solution of 8-methoxy-3-(3,4,5-trimethoxyphenyl)isochroman-1-one (0.052 g, 0.150 mmol) in 2.0 ml of CH 2 Cl 2 was added BCl 3 (1 M in DCM, 0.150 ml, 1.0 equiv) dropwise. The reaction mixture was warmed to room temperature over the course of 1.5 h. Following this time, the solution was cooled to 0 C and an additional 150 µl of BCl 3 was added dropwise. The reaction was warmed to room temperature and stirred for an additional 12 h. The reaction was then quenched by dropwise addition of 2 ml of H 2 and 0.5 ml of 1.0 M aqueous NaH. The mixture was acidified to ph ~1 with 5 ml of 1.0 M aqueous HCl, transferred to a separatory funnel, and extracted with 2 x S9
20 ml of CH 2 Cl 2 and 2 x 20 ml of EtAc. The combined organic fractions were dried over Na 2 S 4, filtered, and concentrated under reduced pressure to a yellow oil. Purification of this material by chromatography on silica gel (10:3 hexanes/acetone) furnished the desired product as an off-white solid (14 mg, 29%). TLC R f = 0.39 (10:3 hexanes/acetone); 1 H NMR (CDCl 3, 400 MHz) δ 10.97 (br s, 1H), 7.46 (t, 1H, J = 8.0 Hz), 6.94 (d, 1H, J = 8.0 Hz), 6.75 (d, 1H, J = 8.0 Hz), 6.67 (s, 2H), 5.52 (dd, 1H, J = 12.0, 4.0 Hz), 3.89 (s, 6H), 3.86 (s, 3H), 3.31 (dd, 1H, J = 16.0, 12.0 Hz), 3.12 (dd, 1H, J = 12.0, 4.0 Hz) ppm; 13 C NMR (CDCl 3, 100 MHz) δ 169.9, 162.6, 153.7, 139.4, 138.5, 136.7, 133.8, 118.2, 116.8, 108.6, 103.4, 81.2, 61.2, 56.5, 35.7 ppm; IR (thin film) ν 1674, 1593, 1424, 1127 cm -1 ; HRMS (ES + ) calcd for C 18 H 18 6 Na + 353.0996 found 353.0994 (MNa + ). S10
Evaluation of stereospecificity (entry 11, Table 2) H Me Me 99.9% ee 10 mol% Cu(Ac)2 K 2S 28 (1.5 equiv) H 2/CH3CN 85 C, 2 h HPLC Trace of Racemic Lactone Me Me racemic HPLC Trace of Reaction Product S11
Silver catalyzed decarboxylation of 2-indanylacetic acid (Figure 3) H 0.3 equiv AgN 3 3.0 equiv K 2 S 2 8 Me 4 H 2 /CH 3 CN 50 C, 16 h 5 6% 6 12% 1 H NMR of unpurified reaction mixture (CDCl 3, 300 MHz) Arrow indicates characteristic doublet of 2-methyl-1-indanone S12
1 H NMR of unpurified reaction mixture with added sample of 2-methyl-1-indanone (arrow indicates increase in Me-doublet signal) S13
Kinetic isotope effect measurements (Scheme 4) H D C 2 H 10 mol% Cu(Ac) 2 K 2 S 2 8 (1.5 equiv) AcH/H 2 105 C, 2 h D k H/ k D = 1.9 ± 0.1 H 1 H NMR of unpurified reaction mixture (CDCl 3, 400 MHz) Quantitative 13 C NMR of unpurified reaction mixture (CDCl 3, 100 MHz, 1 H decoupled without NE, d1 = 90, at = 1.5) S14
Kinetic isotope effect measurements (Scheme 4) H D C 2 H K 2 S 2 8 (1.5 equiv) AcH/H 2 105 C, 2 h D k H/ k D = 2.1 ± 0.1 H Quantitative 13 C NMR of unpurified reaction mixture (CDCl 3, 125 MHz, 1 H decoupled without NE, d1 = 90, at = 1.5) S15
Kinetic isotope effect measurements (Scheme 4) H H C 2 H D D C 2 H 10 mol% Cu(Ac) 2 K 2 S 2 8 (1.5 equiv) 1 equiv AcH/H 2 H 105 C, 2 h 1 equiv k H/ k D = 2.2 ± 0.2 D 1 H NMR of unpurified reaction mixture (CDCl 3, 500 MHz) Quantitative 13 C NMR of unpurified reaction mixture (CDCl 3, 100 MHz, 1 H decoupled without NE, d1 = 90, at = 1.5) S16
Product distribution with 5-phenylvaleric acid as substrate (Scheme 5) Ph C 2 H 10 mol% Cu(Ac) 2 C H 2 H C 2 H K 2 S 2 8 (1.5 equiv) Ph Ph AcH/H 2, 105 C 12 25% 13 30% 1 H NMR of unpurified reaction mixture (CDCl 3, 400 MHz) * = p-nitrotoluene standard S17
5-Hydroxy-5-phenylpentanoic acid (12) 5-xo-5-phenylpentanoic acid (13) S18
Competition experiments between 4-arylbutanoic acids (Scheme 6) C 2 H C 2 H K 2 S 2 8 Me AcH/H 2 Ph 105 C, 2 h 1 1 equiv 14 1 equiv 2 Ar 15 w/ 10 mol% Cu(Ac) 2 w/o Cu(Ac) 2 ratio 2/15 = 1:6 = 1:4 1 H NMR integration of the unpurified reaction mixture (reaction w/ 10 mol% Cu(Ac) 2 ) (CDCl 3, 500 MHz) n = p-methoxy-4-phenylbutyrolactone = 4-phenylbutyrolactone S19
1 H NMR after spiking with authentic 4-phenylbutyrolactone n n = p-methoxy-4-phenylbutyrolactone = 4-phenylbutyrolactone S20
1 H NMR integration of the unpurified reaction mixture (reaction w/o Cu(Ac) 2 ) (CDCl 3, 400 MHz) n = p-methoxy-4-phenylbutyrolactone = 4-phenylbutyrolactone S21
1 H NMR of Cu-catalyzed oxidation of methyl 4-phenylbutanoate (CDCl 3, 600 MHz) C 2 Me 10% Cu(Ac) 2 K 2 S 2 8 (1.5 eq) C 2 Me H Ph 2 /CH 3 CN Ph 80 C, 2 h 23% 36% = starting material n = lactone product u = ketone product * = p-nitrotoluene standard S22
1 H and 13 C NMR spectra of products Table 2, Entry 1 S23
Me Me Table 2, Entry 1 S24
Me Table 2, Entry 2 S25
Br Table 2, Entry 2 S26
Me N H Table 2, Entry 2 S27
Br Me Table 2, Entry 3 S28
2 N Me Table 2, Entry 3 S29
Me Table 2, Entry 4 S30
Br Table 2, Entry 4 S31
Table 2, Entry 5 S32
Table 2, Entry 6 S33
Me Me Table 2, Entry 7 S34
C 2 H Table 2, Entry 8 S35
Me Me Sit BuMe 2 Table 2, Entry 9 S36
Me Me Me Me Table 2, Entry 10 S37
Me Me Table 2, Entry 10 S38
Me Me Table 2, Entry 11 S39
Ph Scheme 2A S40
Ph Scheme 2B S41
Scheme 2C S42
Me Me Me Me Scheme 2D S43
CH 3 C 6 H 4 S 2 Me S 2 C 6 H 4 CH 3 Scheme 2E S44
N H SI Compound 1 S45
SI Compound 2 S46
Me Me SI Compound 3 S47
Me Me Me SI Compound 4 S48
H Me H phyllodulcin S49
H H hydrangenol S50
H H H thunberginol G S51
H Me Me Me macrophyllol S52