Copper-Catalyzed Oxidative Cyclization of Carboxylic Acids

Transcription

1 Copper-Catalyzed xidative Cyclization of Carboxylic Acids Supplementary material (51 pages) Shyam Sathyamoorthi and J. Du Bois * Department of Chemistry Stanford University Stanford, CA

2 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

3 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 (m, 5H), (m, 1H), (m, 3H), (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 (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 (m, 2H), (m, 2H), (m, 1H), 3.79 (s, 3H), (m, 3H), (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), (m, 1H), (m, 3H), (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), (m, 1H), (m, 3H), (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 found (MNa + ). S3

4 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), (m, 1H), 6.87 (d, 1H, J = 8.8 Hz), (m, 1H), 3.85 (s, 3H), (m, 3H), (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 found (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), (m, 1H), 3.98 (s, 3H), (m, 3H), (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 found (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 (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), (m, 1H), (m, 2H), (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), (m, 1H), (m, 2H), (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), (m, 3H), 5.87 (d, 1H, J = 7.2 Hz), (m, 2H), (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 found (MNa + ). S4

5 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), (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 (m, 5H), 5.18 (d, 1H, J = 6.4 Hz), (m, 1H), (m, 2H), (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 (m, 10H), 5.69 (dd, 1H, J = 10.0, 5.0 Hz), 5.45 (dd, 1H, J = 11.0, 6.0 Hz), (m, 1H), (m, 4H), (m, 2H), (m, 2H), (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 found 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), (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 found (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

6 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), (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 (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), (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 found (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), (m, 3H), 7.31 (d, 1H, J = 7.6 Hz), (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), (m, 2H), (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), (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

7 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 found (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 (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 found (MNa + ). CH 3 C 6 H 4 S 2 Me S 2 C 6 H 4 CH 3 Scheme 2E: Reaction performed on a 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), (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 found (MNa + ). c-hx N H SI Compound 1: Reaction performed on a 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), (m, 2H), (m, 1H), (m, 3H), (m, 2H), (m, 2H), (m, 2H), (m, 1H), (m, 2H), (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, ppm; IR (thin film) ν 3304, 2928, 1768, 1661, 1144, 937 cm -1 ; HRMS (ES + ) calcd for C 17 H 21 N 3 Na found (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

8 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), (m, 5H), (m, 1H), (m, 3H), (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 found (MNa + ). Me Me SI Compound 3: Reaction performed on a 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), (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 found (MNa + ). Me Me Me SI Compound 4: Reaction performed on a 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), (m, 2H), (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 found (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, mmol) in 5.0 ml of CH 3 CN was added potassium trimethylsilanoate (120 mg, 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 (br s, 1H), 7.44 (t, 1H, J = 8.0 Hz), 7.03 (d, 1H, J = 4.0 Hz), (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 found (MNa + ). S8

9 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, 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: :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 (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 found (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, 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: :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 (br s, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 2H), (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 found (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, mmol) in 2.0 ml of CH 2 Cl 2 was added BCl 3 (1 M in DCM, 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

10 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 (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 found (MNa + ). S10

11 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

12 Silver catalyzed decarboxylation of 2-indanylacetic acid (Figure 3) H 0.3 equiv AgN 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

13 1 H NMR of unpurified reaction mixture with added sample of 2-methyl-1-indanone (arrow indicates increase in Me-doublet signal) S13

14 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 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

15 Kinetic isotope effect measurements (Scheme 4) H D C 2 H K 2 S 2 8 (1.5 equiv) AcH/H 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

16 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

17 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

18 5-Hydroxy-5-phenylpentanoic acid (12) 5-xo-5-phenylpentanoic acid (13) S18

19 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

20 1 H NMR after spiking with authentic 4-phenylbutyrolactone n n = p-methoxy-4-phenylbutyrolactone = 4-phenylbutyrolactone S20

21 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

22 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

23 1 H and 13 C NMR spectra of products Table 2, Entry 1 S23

24 Me Me Table 2, Entry 1 S24

25 Me Table 2, Entry 2 S25

26 Br Table 2, Entry 2 S26

27 Me N H Table 2, Entry 2 S27

28 Br Me Table 2, Entry 3 S28

29 2 N Me Table 2, Entry 3 S29

30 Me Table 2, Entry 4 S30

31 Br Table 2, Entry 4 S31

32 Table 2, Entry 5 S32

33 Table 2, Entry 6 S33

34 Me Me Table 2, Entry 7 S34

35 C 2 H Table 2, Entry 8 S35

36 Me Me Sit BuMe 2 Table 2, Entry 9 S36

37 Me Me Me Me Table 2, Entry 10 S37

38 Me Me Table 2, Entry 10 S38

39 Me Me Table 2, Entry 11 S39

40 Ph Scheme 2A S40

41 Ph Scheme 2B S41

42 Scheme 2C S42

43 Me Me Me Me Scheme 2D S43

44 CH 3 C 6 H 4 S 2 Me S 2 C 6 H 4 CH 3 Scheme 2E S44

45 N H SI Compound 1 S45

46 SI Compound 2 S46

47 Me Me SI Compound 3 S47

48 Me Me Me SI Compound 4 S48

49 H Me H phyllodulcin S49

50 H H hydrangenol S50

51 H H H thunberginol G S51

52 H Me Me Me macrophyllol S52