Direct ortho-c H Functionalization of Aromatic Alcohols Masked by Acetone Oxime Ether via exo-palladacycle

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Direct ortho-c H Functionalization of Aromatic Alcohols Masked by Acetone Oxime Ether via exo-palladacycle Kun Guo, Xiaolan Chen, Mingyu Guan, and Yingsheng Zhao* Key Laboratory of Organic Synthesis of Jiangsu Province College of Chemistry, Chemical Engineering and Materials Science Soochow University, Suzhou 215123 (PR China) Supporting Information Table of Contents 1. Reagents S2 2. Instruments S2 3. Preparation and Characterization of acetone oxime ether substrates S2 4. General olefination procedure and characterization of olefinated S8 compounds 5. General procedure for gram scale olefination reactions S23 6. General procedures for cleavage of N-O bond S24 7. Total syntheses of 3-deoxyisoochracinic acid S26 8. Synthesis of exo-palladacycle compound and X-ray crystallographic data S28 9. References S34 NMR spectra S1

1. Reagents: Unless otherwise noted, all commercial available reagents were purchased from Alfa Aesar, Acros, TCI, Adamas-beta or Accela and used as received. Hexane and tetrahydrofuran (THF) was distilled over sodium. 1,2-Dichloroethane (DCE) was distilled over CaH 2. Column chromatography purifications were performed using 300-400 mesh silica gel. 2. Instruments: 1 H and 13 C NMR spectra were recorded on Bruker AV 400, Varian Inova 400 (400 MHz and 101 MHz, respectively) and Agilent DD2 600 (600 MHz and 150 MHz, respectively) instruments. The peaks were internally referenced to TMS (0.00 ppm) or residual undeuterated solvent signal [CDCl 3 : 7.26 ppm ( 1 H NMR), 77.16 ppm ( 13 C NMR)]. The following abbreviations (or combinations thereof) were used to explain multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet, and br = broad singlet. High resolution mass spectra were recorded on a Bruker mass spectrometer using microtof-q III instrument. X-ray diffractions were recorded at X-Ray Facilities, Soochow University. 3. Preparation and Characterization of acetone oxime ether substrates General Procedure A: To a solution of alcohol (10 mmol, 1.0 equiv), N-hydroxyphthalimide (11 mmol, 1.1 equiv) and PPh 3 (11 mmol, 1.1 equiv) in 20 ml anhydrous THF was added diethyl azodicarboxylate (11 mmol, 1.1 equiv) dropwise over 5 minutes at room temperature. The reaction was monitored by TLC (silica gel, eluent: EtOAc/hexanes = 1: 2) and usually completed in 3 hours. Then hydrazine monohydrate (12 mmol, 1.2 equiv) wad added dropwise to the reaction mixture. The reaction was monitored by TLC (silica gel, eluent: EtOAc/hexanes = 1: 2) and usually completed in 30 minutes. Finally, acetone (12 mmol, 1.2 equiv) was added. The reaction was monitored by TLC (silica gel, eluent: EtOAc/hexanes = 1: 10 and 1: 2) twice and usually completed in 1 hour. On completion of the reaction, the mixture was filtered to remove precipitate and silica gel (7.0 g) was added to the filtrate. After removal of the solvent in vacuo, the residue was purified by flash column chromatography on silica gel (eluent: usually EtOAc/hexanes = 1: 10) to give the corresponding acetone oxime ether. All the yields are not optimized. Compound 1b: clear liquid. 1.33 g, 75% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.31 (d, J = 7.9 Hz, 2H), 7.20 (d, J = 7.8 Hz, 2H), 5.07 (s, 2H), 2.39 (s, 3H), 1.92 (s, 3H), 1.91 (s, 3H); 13 C NMR (101 MHz, S2

CDCl 3 ) δ 155.20, 137.41, 135.30, 129.09, 128.17, 75.26, 22.02, 21.31, 15.88; HRMS (ESI-TOF) m/z Calcd for C 11 H 16 NO + [M+H] + : 178.1226, found: 178.1228. Compound 1c: clear liquid. 1.73 g, 83% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.29 7.26 (m, 2H), 7.24 7.21 (m, 2H), 5.01 (s, 2H), 2.47 (s, 3H), 1.87 (s, 3H), 1.86 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 155.37, 137.78, 135.28, 128.65, 126.63, 74.89, 21.98, 16.00, 15.86; HRMS (ESI-TOF) m/z Calcd for C 11 H 16 NOS + [M+H] + : 210.0947, found: 210.0950. Compound 1d: clear liquid. 1.69 g, 77% yield. 1 H NMR (400 MHz, Chloroform-d) δ 7.40 7.35 (m, 2H), 7.30 (m, 2H), 5.04 (s, 2H), 1.88 (s, 3H), 1.87 (s, 3H), 1.32 (s, 9H); 13 C NMR (101 MHz, CDCl 3 ) δ 155.17, 150.60, 135.30, 127.84, 125.35, 75.21, 34.64, 31.48, 22.04, 15.91; HRMS (ESI-TOF) m/z Calcd for C 14 H 22 NO + [M+H] + : 220.1696, found: 220.1699. Compound 1f : clear liquid. 1.40 g, 86% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.35 7.29 (m, 2H), 7.05 6.99 (m, 2H), 5.02 (s, 2H), 1.87 (s, 3H), 1.87 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 162.44 (d, J C-F = 246.4 Hz), 155.52, 134.22 (d, J C-F = 3.0 Hz), 129.79 (d, J C-F = 8.1 Hz), 115.24 (d, J C-F = 21.2 Hz), 74.59, 21.97, 15.86; HRMS (ESI-TOF) m/z Calcd for C 10 H 14 NO + [M+H] + : 164.1070, found: 164.1069. Compound 1h: clear liquid. 1.41 g, 78% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.59 (d, J = 8.0 Hz, 2H), 7.48 7.42 (m, 2H), 5.11 (s, 2H), 1.91 (s, 3H), 1.87 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 155.96, 142.75, 130.26, 129.94, 129.62, 129.30, 127.84, 125.69, 125.42, 125.39, 125.35, 125.31, 122.99, 74.38, 21.96, 15.88; HRMS (ESI-TOF) m/z Calcd for C 10 H 13 FNO + [M+H] + : 182.0976, found: 182.0978. Compound 1i: clear liquid. 1.39 g, 63% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.04 7.99 (m, 2H), 7.43 7.38 (m, 2H), 5.11 (s, 2H), 3.90 (d, J = 1.1 Hz, 3H), 1.91 (s, 3H), 1.87 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 167.01, 155.74, 143.86, 129.67, 129.28, 127.37, 52.09, 21.86, 21.83, 15.81; HRMS (ESI-TOF) m/z Calcd for C 12 H 16 NO + 3 [M+H] + : 222.1125, found: 222.1123. S3

Compound 1j: clear liquid. 1.52 g, 86% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.34 7.31 (m, 1H), 7.23 7.14 (m, 3H), 5.08 (s, 2H), 2.35 (s, 3H), 1.88 (s, 6H); 13 C NMR (101 MHz, CDCl 3 ) δ 155.25, 136.93, 136.02, 130.21, 128.89, 127.96, 125.85, 73.82, 22.04, 19.06, 15.81; HRMS (ESI-TOF) m/z Calcd for C 11 H 16 NO + [M+H] + : 178.1226, found: 178.1227. Compound 1k: clear liquid. 1.66 g, 86% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.37 7.30 (m, 1H), 7.28 7.22 (m, 1.8 Hz, 1H), 6.96 6.91 (m, 0.9 Hz, 1H), 6.87 6.84 (m, 1H), 5.13 (s, 2H), 3.82 (s, 3H), 1.91 (s, 3H), 1.88 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 157.19, 155.09, 128.98, 128.64, 126.82, 120.38, 110.35, 70.27, 55.47, 22.01, 15.86; HRMS (ESI-TOF) m/z Calcd for C 11 H 16 NO + 2 [M+H] + : 194.1176, found: 194.1173. Compound 1l: clear liquid. 2.50 g, 93% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.46 7.39 (m, 2H), 7.41 7.24 (m, 4H), 7.27 7.17 (m, 1H), 7.00 6.91 (m, 1H), 6.94 6.86 (m, 1H), 5.22 (s, 2H), 5.08 (s, 2H), 1.90 (s, 3H), 1.87 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 156.26, 155.02, 137.35, 128.94, 128.59, 128.55, 127.80, 127.34, 127.13, 120.76, 111.78, 70.50, 69.95, 22.01, 15.87; HRMS (ESI-TOF) m/z Calcd for C 17 H 19 NO 2 Na + [M+Na] + : 292.1308, found: 292.1317. Compound 1m: clear liquid. 1.58 g, 80% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.42 7.38 (m, 1H), 7.36 7.32 (m, 1H), 7.27 7.18 (m, 2H), 5.18 (s, 2H), 1.93 (s, 3H), 1.88 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 155.78, 136.26, 133.05, 129.37, 129.22, 128.68, 126.71, 72.44, 21.98, 15.87; HRMS (ESI-TOF) m/z Calcd for C 10 H 13 ClNO + [M+H] + : 198.0680, found: 198.0676. Compound 1o: yellowish solid. 1.79 g, 86% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.10 8.02 (m, 1H), 7.66 7.57 (m, 2H), 7.47 7.38 (m, 1H), 5.47 (s, 2H), 1.96 (s, 3H), 1.87 (s, 3H); 13 C NMR (101 MHz, S4

CDCl 3 ) δ 156.33, 147.60, 135.63, 133.56, 128.99, 128.00, 124.80, 71.96, 21.95, 15.92; HRMS (ESI-TOF) m/z Calcd for C 10 H 13 N 2 O 3 + [M+H] + : 209.0921, found: 209.0919. Compound 1p: clear liquid. 1.20 g, 68% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.34 7.30 (m, 4H), 7.27 7.21 (m, 1H), 5.19 (q, J = 6.6 Hz, 1H), 1.91 (s, 3H), 1.83 (s, 3H), 1.51 (d, J = 6.6 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 154.86, 144.15, 128.34, 127.26, 126.14, 80.23, 22.61, 22.05, 15.97; HRMS (ESI-TOF) m/z Calcd for C 11 H 16 NO + [M+H] + : 178.1226, found: 178.1226. Compound 1q: clear liquid. 0.84 g, 44% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.34 7.21 (m, 5H), 4.96 (t, J = 6.7 Hz, 1H), 1.92 (s, 3H), 1.95 1.87 (m, 1H), 1.81 (s, 3H), 1.80 1.72 (m, 1H), 0.90 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 154.83, 143.06, 128.19, 127.18, 126.59, 85.72, 29.66, 22.05, 15.93, 10.12; HRMS (ESI-TOF) m/z Calcd for C 12 H 18 NO + [M+H] + : 192.1383, found: 192.1387. Compound 1r: clear liquid. 1.17 g, 57%. yield 1 H NMR (400 MHz, CDCl 3 ) δ 7.34 7.20 (m, 5H), 5.03 (t, J = 6.7 Hz, 1H), 1.91 (s, 3H), 1.90 1.83 (m, 1H), 1.80 (s, 3H), 1.74 1.64 (m, 1H), 1.47 1.26 (m, 1H), 0.91 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 154.72, 143.50, 128.22, 127.16, 126.54, 84.35, 39.00, 22.05, 19.02, 15.95, 14.21; HRMS (ESI-TOF) m/z Calcd for C 13 H 20 NO + [M+H] + : 206.1539, found: 206.1533. Compound 1s: clear liquid. 1.90 g, 89% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.13 8.06 (m, 1H), 7.82 7.74 (m, 1H), 7.77 7.70 (m, 1H), 7.52 7.33 (m, 4H), 5.51 (s, 2H), 1.81 (s, 3H), 1.79 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 155.21, 133.68, 133.62, 131.87, 128.60, 128.49, 126.70, 126.06, 125.65, 125.27, 124.13, 73.82, 21.84, 15.66; HRMS (ESI-TOF) m/z Calcd for C 14 H 16 NO + [M+H] + : 214.1226, found: 214.1225. S5

Compound 1t: clear liquid. 1.89 g, 82% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.62 7.59 (m, 1H), 7.56 7.50 (m, 2H), 7.47 7.42 (m, 1H), 5.10 (s, 2H), 1.90 (s, 3H), 1.87 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 155.96, 139.64, 131.24, 131.10, 131.08, 130.92, 130.60, 130.28, 128.86, 128.36, 125.66, 124.59, 124.55, 124.51, 124.47, 124.43, 124.39, 122.95, 120.25, 74.44, 21.92, 15.86; HRMS (ESI-TOF) m/z Calcd for C 11 H 13 F 3 NO + [M+H] + : 232.0944, found: 232.0946. S6

Compound 5a: clear liquid. 1.20 g, 68% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.33 7.15 (m, 5H), 4.22 (t, J = 7.1 Hz, 2H), 2.96 (t, J = 7.1 Hz, 2H), 1.87 (s, 3H), 1.82 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 154.93, 139.03, 129.10, 128.38, 126.18, 73.95, 35.91, 21.96, 15.76; HRMS (ESI-TOF) m/z Calcd for C 11 H 16 NO + [M+H] + : 178.1226, found: 178.1233. Compound 5b: clear liquid. 1.30 g, 68% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.32 7.16 (m, 5H), 4.16 4.01 (m, 2H), 3.15 (q, J = 7.1 Hz, 1H), 1.86 (s, 3H), 1.78 (s, 3H), 1.29 (d, J = 7.0 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 154.88, 144.35, 128.36, 127.54, 126.33, 78.76, 39.39, 21.93, 18.07, 15.70; HRMS (ESI-TOF) m/z Calcd for C 12 H 18 NO + [M+H] + : 192.1383, found: 192.1394. Compound 5c: clear liquid. 1.01 g, 49% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.38 7.27 (m, 5H), 4.50 (dd, J = 7.9, 4.1 Hz, 1H), 4.20 (dd, J = 11.6, 7.9 Hz, 1H), 4.06 (dd, J = 11.6, 4.1 Hz, 1H), 3.30 (s, 3H), 1.88 (s, 3H), 1.85 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 155.41, 139.28, 128.50, 127.96, 127.16, 82.18, 77.52, 57.25, 21.99, 15.93; HRMS (ESI-TOF) m/z Calcd for C 12 H 17 NO 2 Na + [M+Na] + : 230.1151, found: 230.1157. General Procedure B: To the stirred mixture of benzyl bromide or benzyl chloride (20 mmol, 1.0 equiv) and acetone oxime (22 mmol, 1.1 equiv) in 25 ml DMSO, 10.0g of KOH in 10 ml H 2 O was added dropwise over 5 minutes at 0 C. Then the temperature of the reaction mixture rose to room temperature. The reaction was monitored by TLC (silica gel, eluent: EtOAc/hexanes = 1: 10) and usually completed in 1 hour. Extraction between ethyl acetate (80 ml) and brine (40 ml) followed by washing the organic layer with brine three times, dried over anhydrous Na 2 SO 4, filtered and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: EtOAc/hexanes = 1: 10) to give the corresponding acetone oxime ether. All the yields are not optimized. S7

Compound 1a: clear liquid. 2.51 g, 77% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.38 7.31 (m, 4H), 7.30 7.25 (m, 1H), 5.07 (s, 2H), 1.88 (s, 3H), 1.87 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 155.34, 138.43, 128.40, 127.97, 127.69, 75.34, 22.00, 15.89; HRMS (ESI-TOF) m/z Calcd for C 10 H 14 NO + [M+H] + : 164.1070, found: 164.1069. Match cited literature [1]. Compound 1g: clear liquid. 3.19 g, 81% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.32 7.24 (m, 4H), 5.01 (s, 2H), 1.87 (s, 3H), 1.85 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 155.68, 137.06, 133.47, 129.34, 128.59, 74.51, 22.01, 15.91; HRMS (ESI-TOF) m/z Calcd for C 10 H 13 ClNO + [M+H] + : 198.0680, found: 198.0682. O N Me Me MeO Compound 1e: clear liquid. 2.70 g, 70% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.33 7.27 (m, 2H), 6.90 6.84 (m, 2H), 4.99 (s, 2H), 3.79 (s, 3H), 1.86 (s, 3H), 1.86 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 159.33, 155.21, 130.48, 129.75, 113.84, 75.11, 55.38, 22.06, 15.91; HRMS (ESI-TOF) m/z Calcd for C 11 H 16 NO + 2 [M+H] + : 194.1176, found: 194.1171. Compound 1n: clear liquid. 2.82 g, 75% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.69 7.62 (m, 1H), 7.63 7.53 (m, 1H), 7.56 7.48 (m, 1H), 7.43 7.34 (m, 1H), 5.24 (s, 2H), 1.93 (s, 3H), 1.87 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 156.38, 142.26, 133.00, 132.78, 129.03, 128.09, 117.46, 111.67, 72.80, 21.92, 15.85; HRMS (ESI-TOF) m/z Calcd for C 11 H 12 N 2 ONa + [M+Na] + : 211.0842, found: 211.0847. 4. General olefination procedure and characterization of olefinated compounds General olefination procedure To a 20 ml sealed tube (with a Teflon cap) equipped with a magnetic stir bar was sequentially added Pd(OAc) 2 (2.2 mg, 0.01 mmol, 5 mol%), Ac-Val-OH (3.2 mg, 0.02 mmol, 10 mol%), AgOAc (83.5 mg, S8

0.5 mmol, 2.5 equiv), acetone oxime ether 1 (0.2 mmol, 1.0 equiv) and olefin 2 (0.3 mmol, 1.5 equiv). 1,4-Dioxane (1 ml) was carefully added to rinse the chemical on the inner side wall of the tube. The tube was then capped and submerged into a pre-heated oil bath at the specified temperature. The reaction was stirred for the indicated period of time and cooled down to room temperature. The crude reaction mixture was diluted with EtOAc (6 ml) and filtered through a short pad of Celite. The sealed tube and Celite pad were washed with an additional 10 ml of EtOAc. The filtrate was concentrated in vacuo, and the resulting residue was purified by flash column chromatography or preparative TLC using EtOAc/hexanes as the eluent. Characterization of olefinated compounds Compound 3a mono : clear liquid. 38.1 mg, 73% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.09 (d, J = 15.9 Hz, 1H), 7.65 7.59 (m, 1H), 7.44 7.31 (m, 3H), 6.39 (d, J = 15.9 Hz, 1H), 5.20 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.89 (s, 3H), 1.88 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.93, 155.89, 142.09, 137.05, 133.99, 129.94, 129.92, 128.44, 126.78, 120.06, 73.30, 60.55, 21.96, 15.81, 14.43; HRMS (ESI-TOF) m/z Calcd for C 15 H 20 NO + 3 [M+H] + : 262.1438, found: 262.1440. Compound 3a (o,o')di : white solid. 14.4 mg, 20% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.17 (d, J = 15.8 Hz, 2H), 7.58 (d, J = 7.8 Hz, 2H), 7.37 (t, J = 7.8 Hz, 1H), 6.35 (d, J = 15.8 Hz, 2H), 5.23 (s, 2H), 4.27 (q, J = 7.1 Hz, 4H), 1.87 (s, 3H), 1.81 (s, 3H), 1.34 (t, J = 7.1 Hz, 6H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.69, 156.15, 142.61, 136.39, 134.86, 128.97, 128.50, 121.77, 68.22, 60.70, 22.00, 15.71, 14.44; HRMS (ESI-TOF) m/z Calcd for C 20 H 26 NO + 5 [M+H] + : 360.1805, found: 360.1814. Compound 3b mono : clear liquid. 33.6 mg, 61% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.05 (d, J = 15.9 Hz, 1H), 7.45 7.40 (m, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.21 7.13 (m, 1H), 6.37 (d, J = 15.9 Hz, 1H), 5.14 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 2.36 (s, 3H), 1.87 (s, 3H), 1.85 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 167.03, 155.83, 142.31, 138.23, 134.13, 133.93, 130.75, 130.23, 127.41, S9

119.74, 73.15, 60.53, 22.01, 21.29, 15.83, 14.44; HRMS (ESI-TOF) m/z Calcd for C 16 H 21 NO 3 Na + [M+Na] + : 298.1414, found: 298.1413. Compound 3b (o,o')di : white solid. 23.9 mg, 32% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.14 (d, J = 15.9 Hz, 2H), 7.40 (s, 2H), 6.35 (d, J = 15.8 Hz, 2H), 5.19 (s, 2H), 4.27 (q, J = 7.1 Hz, 4H), 2.38 (s, 3H), 1.87 (s, 3H), 1.80 (s, 3H), 1.33 (t, J = 7.1 Hz, 6H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.73, 156.00, 142.71, 138.67, 136.22, 132.13, 129.22, 121.47, 67.97, 60.63, 21.99, 21.30, 15.68, 14.42; HRMS (ESI-TOF) m/z Calcd for C 21 H 27 NO 5 Na + [M+Na] + : 396.1781, found: 396.1788. Compound 3c mono : clear liquid. 35.6 mg, 58% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.02 (d, J = 16.0 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.23 (dd, J = 8.0, 2.0 Hz, 1H), 6.37 (d, J = 15.9 Hz, 1H), 5.12 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 2.50 (s, 3H), 1.86 (d, J = 7.2 Hz, 6H), 1.33 (t, J = 7.2 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.79, 155.98, 141.73, 139.03, 134.62, 133.82, 130.63, 127.70, 124.47, 120.51, 72.87, 60.66, 21.99, 15.82, 15.82, 14.42; HRMS (ESI-TOF) m/z Calcd for C 16 H 21 NO 3 SNa + [M+Na] + : 330.1134, found: 330.1145. Compound 3c (o,o')di : white solid. 11.3 mg, 14% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.12 (d, J = 15.9 Hz, 2H), 7.41 (s, 2H), 6.35 (d, J = 15.8 Hz, 2H), 5.16 (s, 2H), 4.27 (q, J = 7.1 Hz, 4H), 2.53 (s, 3H), 1.87 (s, 3H), 1.80 (s, 3H), 1.34 (t, J = 7.1 Hz, 6H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.58, 156.22, 142.33, 139.94, 136.89, 131.58, 125.75, 122.15, 67.92, 60.80, 22.02, 15.72, 15.63, 14.44; HRMS (ESI-TOF) m/z Calcd for C 21 H 27 NO 5 SNa + [M+Na] + : 428.1502, found: 428.1512. S10

Compound 3d mono : clear liquid. 36.1 mg, 57% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (d, J = 15.9 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.44 7.30 (m, 2H), 6.39 (d, J = 15.9 Hz, 1H), 5.16 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 1.88 (s, 3H), 1.86 (s, 3H), 1.38 1.30 (m, 12H); 13 C NMR (101 MHz, CDCl 3 ) δ 167.06, 155.79, 151.41, 142.80, 134.12, 133.58, 129.94, 127.23, 123.75, 119.64, 73.15, 60.55, 34.77, 31.36, 22.02, 15.85, 14.46; HRMS (ESI-TOF) m/z Calcd for C 19 H 27 NO 3 Na + [M+Na] + : 340.1883, found: 340.1878. Compound 3d (o,o')di : white solid. 24.1 mg, 29% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.17 (d, J = 15.8 Hz, 2H), 7.60 (s, 2H), 6.37 (d, J = 15.9 Hz, 2H), 5.20 (s, 2H), 4.28 (q, J = 7.1 Hz, 4H), 1.89 (s, 3H), 1.82 (s, 3H), 1.39 1.30 (m, 15H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.79, 156.08, 151.84, 143.21, 136.00, 132.03, 125.77, 121.41, 68.14, 60.69, 34.93, 31.27, 22.04, 15.75, 14.46; HRMS (ESI-TOF) m/z Calcd for C 24 H 33 NO 5 Na + [M+Na] + : 438.2251, found: 438.2248. Compound 3e mono : clear liquid. 32.6 mg, 56% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.05 (d, J = 15.9 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 2.7 Hz, 1H), 6.94 6.87 (m, 1H), 6.37 (d, J = 15.8 Hz, 1H), 5.11 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 1.87 (s, 3H), 1.84 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.92, 159.64, 155.81, 142.22, 135.45, 131.87, 129.44, 120.17, 115.60, 111.75, 72.91, 60.61, 55.46, 22.02, 15.82, 14.44; HRMS (ESI-TOF) m/z Calcd for C 16 H 21 NO 4 Na + [M+Na] + : 314.1363, found: 314.1369. S11

Compound 3e (o,o')di : white solid. 20.2 mg, 26% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.13 (d, J = 15.8 Hz, 2H), 7.10 (s, 2H), 6.35 (d, J = 15.8 Hz, 2H), 5.16 (s, 2H), 4.27 (q, J = 7.1 Hz, 4H), 3.85 (s, 3H), 1.88 (s, 3H), 1.81 (s, 3H), 1.34 (t, J = 7.0 Hz, 6H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.65, 159.48, 156.01, 142.63, 137.72, 127.64, 121.86, 113.75, 67.78, 60.74, 55.56, 22.03, 15.72, 14.43; HRMS (ESI-TOF) m/z Calcd for C 21 H 27 NO 6 Na + [M+Na] + : 412.1731, found: 412.1736. Compound 3f mono : clear liquid. 34.6 mg, 62% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.01 (dd, J H-H and H-F = 15.9, 1.5 Hz, 1H), 7.37 (dd, J H-H and H-F = 8.5, 5.8 Hz, 1H), 7.28 (dd, J H-H and H-F = 9.7, 2.8 Hz, 1H), 7.05 (td, J H-H and H-F = 8.3, 2.7 Hz, 1H), 6.35 (d, J = 15.9 Hz, 1H), 5.13 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 1.87 (s, 3H), 1.85 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.59, 162.64 (d, J C-F = 247.4), 156.07, 140.94 (d, J C-F = 2.0), 136.11 (d, J C-F = 8.1), 133.02 (d, J C-F = 3.0), 132.00 (d, J C-F = 9.1), 121.20, 116.66 (d, J C-F = 22.2), 113.32 (d, J C-F = 22.2), 72.56, 60.74, 21.96, 15.80, 14.41; HRMS (ESI-TOF) m/z Calcd for C 15 H 18 FNO 3 Na + [M+Na] + : 302.1163, found: 302.1168. Compound 3f (o,o')di : clear liquid. 16.6 mg, 22% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.11 (dd, J H-H and H-F = 15.9, 1.3 Hz, 2H), 7.27 (d, J = 9.2 Hz, 2H), 6.34 (d, J = 15.8 Hz, 2H), 5.17 (s, 2H), 4.27 (q, J = 7.1 Hz, 4H), 1.87 (s, 3H), 1.80 (s, 3H), 1.34 (t, J = 7.1 Hz, 6H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.36, 162.43 (d, J C-F = 248.5), 156.29, 141.52 (d, J C-F = 2.0), 138.64 (d, J C-F = 8.1), 131.14 (d, J C-F = 3.0), 122.78, 114.97 (d, J C-F = 22.2), 67.53, 60.87, 21.98, 15.69, 14.41; HRMS (ESI-TOF) m/z Calcd for C 20 H 25 FNO + 5 [M+H] + : 378.1711, found: 378.1707. Cl O N Me Me CO 2 Et Compound 3g mono : clear liquid. 33.0 mg, 56% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.98 (d, J = 15.8 Hz, 1H), 7.56 (d, J = 1.8 Hz, 1H), 7.35 7.29 (m, 2H), 6.36 (d, J = 15.9 Hz, 1H), 5.13 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.86 (s, 3H), 1.85 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.50, 156.10, 140.66, 135.62, 135.58, 134.26, 131.29, 129.66, 126.67, 121.30, 72.49, 60.72, 21.92, 15.78, 14.39; HRMS (ESI-TOF) m/z Calcd for C 15 H 18 ClNO 3 Na + [M+Na] + : 318.0867, found: 318.0873. S12

Compound 3g (o,o')di : pale yellow solid. 27.5 mg, 35% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.09 (d, J = 15.8 Hz, 2H), 7.53 (s, 2H), 6.35 (d, J = 15.8 Hz, 2H), 5.16 (s, 2H), 4.27 (q, J = 7.1 Hz, 4H), 1.86 (s, 3H), 1.80 (s, 3H), 1.34 (t, J = 7.1 Hz, 6H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.32, 156.34, 141.35, 138.09, 134.86, 133.43, 128.07, 122.85, 67.63, 60.85, 21.96, 15.67, 14.40; HRMS (ESI-TOF) m/z Calcd for C 20 H 25 ClNO + 5 [M+H] + : 394.1416, found: 394.1419. Compound 3h mono : clear liquid. 40.1 mg, 61% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.03 (d, J = 15.9 Hz, 1H), 7.84 7.79 (m, 1H), 7.64 7.56 (m, 1H), 7.56 7.49 (m, 1H), 6.43 (d, J = 15.9 Hz, 1H), 5.22 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.89 (s, 3H), 1.87 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.41, 156.38, 140.95, 140.48, 134.44, 130.78, 130.45, 129.96, 126.25, 126.22, 125.31, 123.67, 123.64, 122.61, 121.91, 72.51, 60.83, 21.92, 15.81, 14.39; HRMS (ESI-TOF) m/z Calcd for C 16 H 19 F 3 NO + 3 [M+H] + : 330.1312, found: 330.1301. Compound 3h (o,o')di : white solid. 12.8 mg, 15% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.16 (d, J = 15.9 Hz, 2H), 7.78 (s, 2H), 6.41 (d, J = 15.9 Hz, 2H), 5.23 (s, 2H), 4.29 (q, J = 7.1 Hz, 4H), 1.86 (s, 3H), 1.81 (s, 3H), 1.35 (t, J = 7.1 Hz, 6H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.23, 156.58, 141.37, 138.35, 137.36, 131.44, 131.12, 130.79, 124.97, 124.88, 124.85, 124.81, 124.77, 123.36, 67.82, 60.95, 21.97, 15.67, 14.42; HRMS (ESI-TOF) m/z Calcd for C 21 H 24 F 3 NO 5 Na + [M+Na] + : 450.1499, found: 450.1482. S13

Compound 3i mono : white solid. 42.7 mg, 67% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.29 8.23 (m, 1H), 8.07 7.97 (m, 2H), 7.48 (d, J = 8.0 Hz, 1H), 6.47 (d, J = 15.9 Hz, 1H), 5.23 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 1.89 (s, 3H), 1.87 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.61, 166.52, 156.25, 141.95, 140.86, 133.89, 130.61, 130.09, 129.52, 127.99, 121.31, 72.71, 60.70, 52.36, 21.91, 15.81, 14.40; HRMS (ESI-TOF) m/z Calcd for C 17 H 21 NO 5 Na + [M+Na] + : 342.1312, found: 342.1306. S14

112.28, 65.59, 60.49, 56.10, 22.03, 15.72, 14.40; HRMS (ESI-TOF) m/z Calcd for C 16 H 21 NO 4 Na + [M+Na] + : 314.1363, found: 314.1354. Compound 3l: white solid. 53.6 mg, 73% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.17 (d, J = 15.9 Hz, 1H), 7.47 7.41 (m, 2H), 7.39 7.32 (m, 2H), 7.33 7.19 (m, 3H), 6.98 6.92 (m, 1H), 6.37 (d, J = 15.9 Hz, 1H), 5.34 (s, 2H), 5.12 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 1.87 (s, 3H), 1.81 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.92, 157.51, 155.29, 143.01, 137.03, 136.85, 129.42, 128.58, 127.87, 127.18, 125.63, 120.47, 119.42, 113.96, 70.68, 65.78, 60.49, 21.99, 15.67, 14.41; HRMS (ESI-TOF) m/z Calcd for C 22 H 25 NO 4 Na + [M+Na] + : 390.1676, found: 390.1669. Compound 3m: clear liquid. 41.9 mg, 71% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.14 (d, J = 15.9 Hz, 1H), 7.50 7.45 (m, 1H), 7.45 7.40 (m, 1H), 7.30 7.26 (m, 1H), 6.35 (d, J = 15.9 Hz, 1H), 5.32 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 1.87 (s, 3H), 1.82 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.63, 156.16, 142.45, 137.65, 136.35, 133.84, 130.90, 129.55, 125.59, 121.59, 68.95, 60.72, 22.02, 15.69, 14.42; HRMS (ESI-TOF) m/z Calcd for C 15 H 18 ClNO 3 Na + [M+Na] + : 318.0867, found: 318.0862. Compound 3n: white solid. 37.2 mg, 65% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.12 (d, J = 15.9 Hz, 1H), 7.82 7.76 (m, 1H), 7.73 7.67 (m, 1H), 7.46 (t, J = 7.8 Hz, 1H), 6.39 (d, J = 15.9 Hz, 1H), 5.34 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.85 (s, 3H), 1.83 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.26, 156.54, 140.82, 139.60, 136.59, 134.03, 131.11, 129.10, 122.52, 117.48, 115.08, 70.09, 60.89, 21.93, 15.66, 14.40; HRMS (ESI-TOF) m/z Calcd for C 16 H 18 N 2 O 3 Na + [M+Na] + : 309.1210, found: 309.1203. S15

Compound 3o: yellow solid. 33.0 mg, 54% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.11 (d, J = 15.8 Hz, 1H), 7.75 7.69 (m, 2H), 7.47 (t, J = 7.9 Hz, 1H), 6.36 (d, J = 15.9 Hz, 1H), 5.34 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 1.81 (s, 3H), 1.77 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.15, 156.60, 151.75, 141.06, 137.41, 130.84, 130.37, 129.01, 124.75, 123.31, 67.05, 60.96, 21.90, 15.51, 14.39; HRMS (ESI-TOF) m/z Calcd for C 15 H 18 N 2 O 5 Na + [M+Na] + : 329.1108, found: 329.1098. Compound 3p mono : clear liquid. 47.3 mg, 86% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.17 (d, J = 15.8 Hz, 1H), 7.57 7.52 (m, 1H), 7.41 7.34 (m, 2H), 7.30 7.24 (m, 1H), 6.32 (d, J = 15.8 Hz, 1H), 5.52 (q, J = 6.6 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 1.93 (s, 3H), 1.83 (s, 3H), 1.51 (d, J = 6.6 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.93, 155.20, 143.18, 142.28, 132.40, 130.04, 127.51, 126.89, 126.63, 120.06, 77.83, 60.56, 22.38, 22.01, 15.96, 14.45; HRMS (ESI-TOF) m/z Calcd for C 16 H 21 NO 3 Na + [M+Na] + : 298.1414, found: 298.1407. Compound 3q mono : clear liquid. 37.6 mg, 65% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.19 (d, J = 15.8 Hz, 1H), 7.58 7.52 (m, 1H), 7.38 7.33 (m, 2H), 7.30 7.23 (m, 1H), 6.32 (d, J = 15.8 Hz, 1H), 5.32 (dd, J = 7.4, 5.8 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 1.95 (s, 3H), 1.93 1.85 (m, 1H), 1.82 (s, 3H), 1.80 1.72 (m, 1H), 1.34 (t, J = 7.1 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.97, 155.14, 142.49, 142.25, 132.61, 129.79, 127.46, 127.42, 126.86, 119.85, 83.34, 60.55, 29.62, 22.03, 15.94, 14.45, 10.28; HRMS (ESI-TOF) m/z Calcd for C 17 H 23 NO 3 Na + [M+Na] + : 312.1570, found: 312.1569. S16

Compound 3r mono : clear liquid. 44.2 mg, 73% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.20 (d, J = 15.8 Hz, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.37 7.32 (m, 2H), 7.29 7.22 (m, 1H), 6.32 (d, J = 15.8 Hz, 1H), 5.42 5.36 (m, 1H), 4.30 4.22 (m, 2H), 1.94 (s, 3H), 1.91 1.83 (m, 1H), 1.80 (s, 3H), 1.73 1.63 (m, 1H), 1.50 1.36 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.96, 155.04, 142.72, 142.47, 132.50, 129.83, 127.36, 127.31, 126.82, 119.81, 81.89, 60.53, 38.86, 22.00, 19.10, 15.94, 14.44, 14.10; HRMS (ESI-TOF) m/z Calcd for C 18 H 25 NO 3 Na + [M+Na] + : 326.1727, found: 326.1723. Compound 3s: white solid. 41.1 mg, 66% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.44 (d, J = 15.8 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.87 7.81 (m, 2H), 7.69 (d, J = 8.7 Hz, 1H), 7.62 7.50 (m, 2H), 6.52 (d, J = 15.8 Hz, 1H), 5.65 (s, 2H), 4.32 (q, J = 7.1 Hz, 2H), 1.92 (s, 3H), 1.82 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 167.00, 155.88, 142.77, 134.26, 133.04, 132.67, 132.59, 129.40, 128.45, 127.06, 126.78, 125.35, 123.79, 121.27, 67.82, 60.65, 22.03, 15.76, 14.46; HRMS (ESI-TOF) m/z Calcd for C 19 H 21 NO 3 Na + [M+Na] + : 334.1414, found: 334.1409. Compound 3t: clear liquid. 30.3 mg, 46% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.03 (d, J = 15.9 Hz, 1H), 7.71 7.64 (m, 2H), 7.62 7.55 (m, 1H), 6.42 (d, J = 15.9 Hz, 1H), 5.21 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.89 (s, 3H), 1.88 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.42, 156.50, 140.53, 137.96, 137.28, 131.62, 131.29, 127.26, 126.46, 126.42, 125.31, 125.10, 125.07, 122.43, 72.58, 60.89, 21.93, 15.84, 14.41; HRMS (ESI-TOF) m/z Calcd for C 16 H 19 F 3 NO + 3 [M+H] + : 330.1312, found: 330.1304. S17

Compound 3v: clear liquid. 29.3 mg, 51% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.05 (d, J = 16.1 Hz, 1H), 7.50 7.45 (m, 1H), 7.32 7.27 (m, 2H), 6.43 (d, J = 16.1 Hz, 1H), 5.77 (dd, J = 6.4, 3.2 Hz, 1H), 4.31 4.19 (m, 2H), 3.18 3.08 (m, 1H), 2.90 2.80 (m, 1H), 2.44 2.29 (m, 2H), 1.89 (s, 3H), 1.79 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 167.19, 155.54, 146.25, 142.53, 141.36, 132.56, 129.22, 126.51, 124.46, 119.36, 84.63, 60.45, 31.74, 30.41, 22.14, 15.80, 14.44; HRMS (ESI-TOF) m/z Calcd for C 17 H 21 NO 3 Na + [M+Na] + : 310.1414, found: 310.1408. Compound 3w: clear liquid. 39.4 mg, 65% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.01 (d, J = 15.9 Hz, 1H), 7.28 7.18 (m, 2H), 6.93 6.87 (m, 1H), 6.37 (d, J = 15.9 Hz, 1H), 5.23 (q, J = 1.8 Hz, 1H), 4.30 4.20 (m, 3H), 4.18 4.10 (m, 1H), 2.49 2.40 (m, 1H), 2.07 1.96 (m, 1H), 1.93 (s, 3H), 1.82 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.90, 156.15, 155.96, 141.98, 136.59, 129.78, 120.56, 119.47, 118.94, 118.88, 69.64, 61.52, 60.48, 27.65, 22.10, 16.03, 14.40; HRMS (ESI-TOF) m/z Calcd for C 17 H 21 NO 4 Na + [M+Na] + : 326.1363, found: 326.1353. Compound 3x: clear liquid. 40.3 mg, 67% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.07 (d, J = 15.9 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H), 7.19 7.13 (m, 1H), 6.32 (d, J = 15.9 Hz, 1H), 5.30 (t, J = 3.3 Hz, 1H), 4.29 4.17 (m, 2H), 2.91 2.81 (m, 1H), 2.78 2.65 (m, 1H), 2.50 2.38 (m, 1H), 1.93 (s, 3H), 1.91 1.81 (m, 1H), 1.78 (s, 3H), 1.77 1.75 (m, 1H), 1.74 1.71 (m, 1H), 1.32 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 167.02, 155.41, 143.12, 139.28, 135.94, 133.63, 130.99, 128.10, 124.50, 119.82, 73.93, 60.41, 30.12, 28.29, 22.11, 17.36, 15.93, 14.41; HRMS (ESI-TOF) m/z Calcd for C 18 H 23 NO 3 Na + [M+Na] + : 324.1570, found: 324.1564. S18

Compound 4a: white solid. 35.6 mg, 65% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (d, J = 15.2 Hz, 1H), 7.53 7.49 (m, 1H), 7.42 7.37 (m, 1H), 7.37 7.31 (m, 1H), 7.28 7.22 (m, 1H), 6.76 (d, J = 15.3 Hz, 1H), 5.54 (q, J = 6.6 Hz, 1H), 3.16 (s, 3H), 3.07 (s, 3H), 1.94 (s, 3H), 1.82 (s, 3H), 1.49 (d, J = 6.6 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.66, 155.01, 143.07, 140.07, 133.48, 129.37, 127.28, 126.80, 126.41, 119.83, 77.52, 37.52, 35.98, 22.32, 22.00, 15.97; HRMS (ESI-TOF) m/z Calcd for C 16 H 22 N 2 O 2 Na + [M+Na] + : 297.1573, found: 297.1581. Compound 4b: white solid. 44.1 mg, 73% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.96 (d, J = 15.3 Hz, 1H), 7.46 7.41 (m, 1H), 7.41 7.35 (m, 1H), 7.34 7.29 (m, 1H), 7.23 7.18 (m, 1H), 6.20 (d, J = 15.4 Hz, 1H), 5.64 (s, 1H), 5.57 5.50 (m, 1H), 1.92 (s, 3H), 1.81 (s, 3H), 1.49 (d, J = 6.7 Hz, 3H), 1.43 (s, 9H); 13 C NMR (101 MHz, CDCl 3 ) δ 165.18, 155.00, 143.06, 137.64, 132.96, 129.29, 127.25, 126.68, 126.30, 124.31, 77.42, 51.51, 28.97, 22.33, 21.99, 15.96; HRMS (ESI-TOF) m/z Calcd for C 18 H 26 N 2 O 2 Na + [M+Na] + : 325.1886, found: 325.1894. Compound 4c: white solid. 46.3 mg, 75% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.22 (d, J = 15.3 Hz, 1H), 7.98 7.92 (m, 2H), 7.65 7.59 (m, 1H), 7.58 7.52 (m, 2H), 7.46 7.42 (m, 1H), 7.41 7.37 (m, 2H), 7.29 7.22 (m, 1H), 6.77 (d, J = 15.3 Hz, 1H), 5.47 (q, J = 6.7 Hz, 1H), 1.95 (s, 3H), 1.84 (s, 3H), 1.51 (d, J = 6.7 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 155.58, 143.63, 140.91, 140.56, 133.44, 130.97, 130.45, 129.43, 128.76, 127.76, 127.73, 127.33, 127.26, 78.15, 22.27, 22.04, 16.05; HRMS (ESI-TOF) m/z Calcd for C 19 H 21 NO 3 SNa + [M+Na] + : 366.1134, found: 366.1134. S19

Compound 4d: clear liquid. 36.3 mg, 70% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (d, J = 16.1 Hz, 1H), 7.60 7.54 (m, 1H), 7.44 7.34 (m, 2H), 7.32 7.26 (m, 1H), 6.62 (d, J = 16.0 Hz, 1H), 5.52 (q, J = 6.7 Hz, 1H), 2.70 (q, J = 7.3 Hz, 2H), 1.92 (s, 3H), 1.84 (s, 3H), 1.52 (d, J = 6.6 Hz, 3H), 1.17 (t, J = 7.3 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 201.07, 155.22, 143.20, 140.03, 132.68, 130.15, 127.99, 127.62, 126.83, 126.71, 77.81, 33.85, 22.14, 22.00, 15.96, 8.37; HRMS (ESI-TOF) m/z Calcd for C 16 H 21 NO 2 Na + [M+Na] + : 282.1465, found: 282.1471. Compound 4e: clear liquid. 31.4 mg, 68% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 9.71 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 15.8 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.47 7.39 (m, 2H), 7.32 (m, 1H), 6.64 (dd, J = 15.8, 7.8 Hz, 1H), 5.53 (q, J = 6.7 Hz, 1H), 1.92 (s, 3H), 1.84 (s, 3H), 1.55 (d, J = 6.6 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 193.96, 155.44, 150.57, 143.26, 131.94, 131.09, 130.12, 127.82, 127.16, 127.01, 77.71, 22.14, 22.01, 15.99; HRMS (ESI-TOF) m/z Calcd for C 14 H 18 NO + 2 [M+H] + : 232.1332, found: 232.1328. Compound 4f: clear liquid. 35.8 mg, 65% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.44 7.39 (m, 1H), 7.33 7.27 (m, 1H), 7.25 7.18 (m, 2H), 6.96 (d, J = 15.9 Hz, 1H), 6.19 (d, J = 15.8 Hz, 1H), 5.30 (t, J = 6.5 Hz, 1H), 1.98 (br, 1H), 1.94 (s, 3H), 1.87 1.83 (m, 1H), 1.82 (s, 3H), 1.80 1.77 (m, 1H), 1.42 (s, 6H), 0.91 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 154.83, 140.13, 139.74, 135.29, 127.27, 127.15, 126.57, 126.33, 124.13, 82.74, 71.24, 29.97, 29.84, 28.94, 22.03, 15.97, 10.21; HRMS (ESI-TOF) m/z Calcd for C 17 H 25 NO 2 Na + [M+Na] + : 298.1778, found: 298.1776. S20

Compound 4g: yellow solid. 29.1 mg, 59% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.29 (d, J = 15.8 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.44 7.36 (m, 2H), 7.34 7.27 (m, 1H), 6.34 (d, J = 15.8 Hz, 1H), 5.60 5.51 (m, 1H), 1.95 (s, 3H), 1.85 (s, 3H), 1.53 (d, J = 6.7 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 171.90, 155.69, 144.55, 143.43, 132.03, 130.52, 127.64, 127.10, 126.79, 119.10, 77.89, 22.46, 22.00, 16.08; HRMS (ESI-TOF) m/z Calcd for C 14 H 17 NO 3 Na + [M+Na] + : 270.1101, found: 270.1104. Compound 4h: white solid. 44.8 mg, 77% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.21 (d, J = 15.8 Hz, 1H), 7.57 7.52 (m, 1H), 7.42 7.35 (m, 2H), 7.30 7.24 (m, 1H), 6.36 (d, J = 15.8 Hz, 1H), 5.52 (q, J = 6.6 Hz, 1H), 4.37 4.31 (m, 2H), 3.92 3.85 (m, 2H), 2.51 (s, 1H), 1.93 (s, 3H), 1.83 (s, 3H), 1.50 (d, J = 6.6 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 167.22, 155.44, 143.21, 143.14, 132.21, 130.25, 127.58, 126.90, 126.68, 119.32, 77.69, 66.32, 61.33, 22.32, 21.96, 15.98; HRMS (ESI-TOF) m/z Calcd for C 16 H 21 NO 4 Na + [M+Na] + : 314.1363, found: 314.1372. Compound 4i: clear liquid. 28.7 mg, 50% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.20 (d, J = 15.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.42 7.34 (m, 2H), 7.31 7.25 (m, 1H), 6.36 (d, J = 15.8 Hz, 1H), 6.07 5.92 (m, 1H), 5.52 (q, J = 6.7 Hz, 1H), 5.41 5.34 (m, 1H), 5.30 5.24 (m, 1H), 4.73 4.70 (m, 2H), 1.93 (s, 3H), 1.83 (s, 3H), 1.51 (d, J = 6.7 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.57, 155.29, 143.24, 142.79, 132.41, 132.31, 130.18, 127.56, 126.92, 126.69, 119.60, 118.32, 77.85, 65.29, 22.38, 22.04, 16.00; HRMS (ESI-TOF) m/z Calcd for C 17 H 21 NO 3 Na + [M+Na] + : 310.1414, found: 310.1418. S21

Compound 6a mono : clear liquid. 35.2 mg, 64% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (d, J = 15.8 Hz, 1H), 7.60 7.54 (m, 1H), 7.35 7.23 (m, 3H), 6.37 (d, J = 15.8 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 4.20 (t, J = 6.8 Hz, 2H), 3.11 (t, J = 6.8 Hz, 2H), 1.88 (s, 3H), 1.79 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 167.05, 155.20, 142.36, 138.88, 133.78, 130.78, 130.06, 126.90, 126.63, 119.80, 73.60, 60.56, 33.03, 21.96, 15.79, 14.46; HRMS (ESI-TOF) m/z Calcd for C 16 H 21 NO 3 Na + [M+Na] + : 298.1414, found: 298.1413. Compound 6a (o,o')di : white solid. 14.9 mg, 20% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.12 (d, J = 15.8 Hz, 2H), 7.58 (d, J = 7.8 Hz, 2H), 7.33 7.25 (m, 1H), 6.35 (d, J = 15.7 Hz, 2H), 4.29 (q, J = 7.1 Hz, 4H), 4.18 (t, J = 6.5 Hz, 2H), 3.27 (t, J = 6.5 Hz, 2H), 1.88 (s, 3H), 1.78 (s, 3H), 1.36 (t, J = 7.1 Hz, 6H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.77, 155.42, 142.57, 137.95, 135.33, 128.53, 127.17, 121.26, 73.11, 60.69, 29.04, 21.97, 15.84, 14.47; HRMS (ESI-TOF) m/z Calcd for C 21 H 27 NO 5 Na + [M+Na] + : 396.1781, found: 396.1776. Compound 6b mono : clear liquid. 38.1 mg, 66% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.15 (d, J = 15.7 Hz, 1H), 7.53 (dd, J = 7.9, 1.3 Hz, 1H), 7.39 7.30 (m, 2H), 7.25 7.20 (m, 1H), 6.32 (d, J = 15.8 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 4.12 (d, J = 2.7 Hz, 1H), 4.10 (d, J = 2.8 Hz, 1H), 3.61 (h, J = 7.0 Hz, 1H), 1.85 (s, 3H), 1.72 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H), 1.29 (d, J = 7.0 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 167.04, 155.25, 143.93, 142.77, 133.75, 130.18, 126.84, 126.56, 126.54, 120.20, 78.55, 60.55, 34.31, 21.94, 18.20, 15.70, 14.48; HRMS (ESI-TOF) m/z Calcd for C 17 H 23 NO 3 Na + [M+Na] + : 312.1570, found: 312.1566. S22

Compound 6b (o,o')di : white solid. 16.3 mg, 21% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.17 (d, J = 15.7 Hz, 2H), 7.46 (d, J = 7.7 Hz, 2H), 7.24 (t, J = 7.7 Hz, 1H), 6.22 (d, J = 15.6 Hz, 2H), 4.32 4.24 (m, 6H), 3.77 (h, J = 7.3 Hz, 1H), 1.83 (s, 3H), 1.68 (s, 3H), 1.40 (d, J = 7.4 Hz, 3H), 1.34 (t, J = 7.2 Hz, 6H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.71, 155.54, 144.40, 142.16, 129.58, 127.05, 121.37, 121.03, 77.19, 60.70, 35.86, 21.94, 17.80, 15.70, 14.47; HRMS (ESI-TOF) m/z Calcd for C 22 H 29 NO 5 Na + [M+Na] + : 410.1938, found: 410.1939. Compound 6c mono : clear liquid. 41.5 mg, 68% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.15 (d, J = 15.8 Hz, 1H), 7.59 7.54 (m, 1H), 7.54 7.49 (m, 1H), 7.44 7.37 (m, 1H), 7.34 7.26 (m, 1H), 6.37 (d, J = 15.8 Hz, 1H), 4.94 (dd, J = 7.2, 4.4 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 4.21 (dd, J = 11.7, 7.2 Hz, 1H), 4.03 (dd, J = 11.7, 4.4 Hz, 1H), 3.30 (s, 3H), 1.89 (s, 3H), 1.81 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.79, 155.49, 141.62, 138.69, 133.68, 130.16, 127.99, 127.14, 126.83, 120.58, 78.62, 77.13, 60.55, 57.29, 21.89, 15.78, 14.42; HRMS (ESI-TOF) m/z Calcd for C 17 H 23 NO 4 Na + [M+Na] + : 328.1519, found: 328.1517. 5. General procedure for gram scale olefination reaction To a 50 ml sealed tube (with a Teflon cap) equipped with a magnetic stir bar was sequentially added Pd(OAc) 2 (56.1 mg, 0.25 mmol, 5 mol%), Ac-Val-OH (80.0 mg, 0.50 mmol, 10 mol%), AgOAc (2.50 g, 15.0 mmol, 3.0 equiv), acetone oxime ether 1 (5.0 mmol, 1.0 equiv) and olefin 2 (7.5 mmol, 1.5 equiv). 1,4-Dioxane (20 ml) was carefully added to rinse the chemical on the inner side wall of the tube. The tube was then capped and submerged into a pre-heated 90 C oil bath. The reaction was stirred for 24 h and cooled down to room temperature. The crude reaction mixture was diluted with EtOAc (30 ml) and filtered through a short pad of Celite. The sealed tube and Celite pad were washed with an S23

additional 20 ml of EtOAc. The filtrate was concentrated in vacuo, and the resulting residue was purified by flash column chromatography or preparative TLC using EtOAc/hexanes as the eluent. Compound 7: pale yellow oil. 1.52 g, 71% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.22 (d, J = 15.9 Hz, 1H), 7.46 7.28 (m, 10H), 7.27 7.24 (m, 1H), 7.23 7.20 (m, 1H), 7.00 6.92 (m, 1H), 6.42 (d, J = 15.9 Hz, 1H), 5.34 (s, 2H), 5.25 (s, 2H), 5.13 (s, 2H), 1.83 (s, 3H), 1.76 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.76, 157.55, 155.42, 143.70, 140.65, 137.07, 136.79, 136.28, 129.48, 128.69, 128.64, 128.29, 127.94, 127.24, 125.77, 120.08, 119.49, 114.15, 70.78, 66.37, 65.80, 22.02, 15.70; ; HRMS (ESI-TOF) m/z Calcd for C 27 H 28 NO + 4 [M+H] + : 430.2013, found: 430.2010. 6. General procedures for cleavage of N-O bond 6.1 Reduction of carbon-carbon double bonds and N-O bond reserved To a solution of compound 3a (52.2 mg, 0.20 mmol) in EtOAc (2 ml), Pd/C (5.2 mg, 10 wt%) was added. A balloon with hydrogen gas was then attached to the reaction vial, and the reaction was stirred at room temperature overnight. Then the Pd/C was filtered off using a short pad of Celite and solvent was removed in vacuo to give the purified product. Clear liquid. 52.1 mg, 99% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.41 7.36 (m, 1H), 7.30 7.21 (m, 3H), 5.13 (s, 2H), 4.16 (q, J = 7.1 Hz, 2H), 3.08 3.02 (m, 2H), 2.68 2.61 (m, 2H), 1.90 (s, 3H), 1.89 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 173.01, 155.10, 139.70, 135.58, 129.98, 129.20, 128.36, 126.45, 73.57, 60.43, 35.76, 27.79, 21.97, 15.81, 14.30; HRMS (ESI-TOF) m/z Calcd for C 15 H 21 NO 3 Na + [M+Na] + : 286.1414, found: 286.1417. 6.2 Selectively cleavage of N-O bond S24

Following a literature procedure [2], to a mixture of compound 3a (52.2 mg, 0.20 mmol) in acetonitrile (4 ml) containing water (0.5 ml), molybdenum hexacarbonyl (52.8 mg, 0.20 mmol) was added. The flask was evacuated and backfilled with Ar three times and then heated at reflux. The reaction was monitored by TLC (silica gel, eluent: EtOAc/hexanes = 1: 5). On completion of the reaction, silica gel (0.4 g) is added to the cooled mixture. After removal of the solvent in vacuo, the residue was purified by flash column chromatography on silica gel (eluent: EtOAc/hexanes = 1: 3) to give the corresponding product. Compound 8: clear liquid. 33.0 mg, 80% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.01 (d, J = 15.8 Hz, 1H), 7.61 7.55 (m, 1H), 7.45 7.41 (m, 1H), 7.39 7.28 (m, 2H), 6.37 (d, J = 15.9 Hz, 1H), 4.79 (s, 2H), 4.24 (q, J = 7.1 Hz, 2H), 2.63 (s, 1H), 1.32 (t, J = 7.2 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 167.16, 141.55, 139.73, 133.13, 130.20, 128.77, 128.23, 126.85, 120.19, 62.82, 60.74, 14.38; HRMS (ESI-TOF) m/z Calcd for C 12 H 14 O 3 Na + [M+Na] + : 229.0835, found: 229.0841. Match cited literature [4]. Compound 9: clear liquid. 49.3 mg, 79% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.09 (d, J = 15.9 Hz, 1H), 7.45 7.32 (m, 5H), 7.27 (t, J = 7.1 Hz, 1H), 7.19 (dd, J = 8.0, 1.2 Hz, 1H), 6.99 (dd, J = 8.2, 1.1 Hz, 1H), 6.37 (d, J = 15.8 Hz, 1H), 5.12 (s, 2H), 4.88 (d, J = 4.7 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 2.28 (t, J = 5.9 Hz, 1H), 1.33 (t, J = 7.2 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.78, 157.43, 141.77, 136.53, 135.45, 129.23, 128.87, 128.50, 128.35, 127.46, 121.71, 119.86, 113.38, 70.73, 60.71, 56.60, 14.44; HRMS (ESI-TOF) m/z Calcd for C 19 H 20 O 4 Na + [M+Na] + : 335.1254, found: 335.1259. Compound 10: clear liquid. 50.9 mg, 68% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.15 (d, J = 15.8 Hz, 1H), 7.44 7.32 (m, 10H), 7.30 7.25 (m, 1H), 7.19 (dd, J = 7.9, 1.0 Hz, 1H), 7.00 (dd, J = 8.2, 1.0 Hz, 1H), 6.43 (d, J = 15.8 Hz, 1H), 5.25 (s, 2H), 5.12 (s, 2H), 4.87 (s, 2H), 2.20 (s, 1H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.60, 157.46, 142.40, 136.52, 136.13, 135.33, 129.28, 128.90, 128.72, 128.58, S25

128.45, 128.39, 127.49, 121.31, 119.90, 113.52, 70.77, 66.56, 56.65; HRMS (ESI-TOF) m/z Calcd for C 24 H 22 O 4 Na + [M+Na] + : 397.1410, found: 397.1406. 6.3 Cleavage of N-O bond and reduction of carbon-carbon double bonds Following a literature procedure [3], compound 3a (52.2 mg, 0.20 mmol) was dissolved in THF (6 ml) and MeOH (6 ml). B(OH) 3 (53.8 mg, 0.87 mmol) was dissolved in water (2 ml), and the solution was added to the stirring mixture along with Raney Ni(~ 1 ml, 50% in water). The system was purged and stirred rapidly under an atmosphere of H 2 for 6 hours. The mixture was diluted with EtOAc (16 ml) and filtered through a plug of Celite. The eluent was washed with water (50 ml), washed with brine (50 ml), dried with anhydrous Na 2 SO 4, filtered and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: EtOAc/hexanes = 1: 3) to give the corresponding product. Compound 11: clear liquid. 39.5 mg, 95% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.39 7.33 (m, 1H), 7.26 7.18 (m, 3H), 4.72 (d, J = 3.7 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 3.02 (t, J = 7.6 Hz, 2H), 2.68 (t, J = 7.6 Hz, 2H), 2.37 (s, 1H), 1.22 (t, J = 7.2 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 173.41, 138.92, 138.66, 129.17, 129.14, 128.31, 126.79, 63.34, 60.74, 35.53, 27.04, 14.29; HRMS (ESI-TOF) m/z Calcd for C 12 H 16 O 3 Na + [M+Na] + : 231.0992, found: 231.0988. 7. Total syntheses of 3-deoxyisoochracinic acid To a solution of compound 12 (2.14 g, 10 mmol, 1.0 equiv), N-hydroxyphthalimide (1.96 g, 12 mmol, 1.2 equiv) and PPh 3 (3.15 g, 12 mmol, 1.2 equiv) in 30 ml anhydrous THF was added diethyl S26

azodicarboxylate (1.90 ml, 12 mmol, 1.2 equiv) dropwise over 5 minutes at room temperature. The reaction was monitored by TLC (silica gel, eluent: EtOAc/hexanes = 1: 2) and usually completed in 3 hours. Then hydrazine monohydrate (0.74 ml, 13 mmol, 1.3 equiv) wad added dropwise to the reaction mixture. The reaction was monitored by TLC (silica gel, eluent: EtOAc/hexanes = 1: 2) and usually completed in 30 minutes. Finally, acetone (0.75 ml, 14 mmol, 1.4 equiv) was added. The reaction was monitored by TLC (silica gel, eluent: EtOAc/hexanes = 1: 10 and 1: 2) twice and usually completed in 1 hour. On completion of the reaction, the mixture was filtered to remove precipitate and silica gel (7.0 g) was added to the filtrate. After removal of the solvent in vacuo, the residue was purified by flash column chromatography on silica gel (eluent: usually EtOAc/hexanes = 1: 10) to give the corresponding acetone oxime ether 1l. To a 50 ml sealed tube (with a Teflon cap) equipped with a magnetic stir bar was sequentially added Pd(OAc) 2 (56.1 mg, 0.25 mmol, 5 mol%), Ac-Val-OH (80.0 mg, 0.50 mmol, 10 mol%), AgOAc (2.50 g, 15.0 mmol, 3.0 equiv), 1l (1.35 g, 5.0 mmol, 1.0 equiv) and benzyl acrylate (1.22 g, 7.5 mmol, 1.5 equiv). 1,4-Dioxane (20 ml) was carefully added to rinse the chemical on the inner side wall of the tube. The tube was then capped and submerged into a pre-heated 90 C oil bath. The reaction was stirred for 24 h and cooled down to room temperature. The crude reaction mixture was diluted with EtOAc (30 ml) and filtered through a short pad of Celite. The sealed tube and Celite pad were washed with an additional 20 ml of EtOAc. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluent: usually EtOAc/hexanes = 1: 15) to give the olefinated product 7. Following a literature procedure [2], to a mixture of compound 7 (85.9 mg, 0.20 mmol) in acetonitrile (4 ml) containing water (0.5 ml), molybdenum hexacarbonyl (52.8 mg, 0.20 mmol) was added. The flask was evacuated and backfilled with Ar three times and then heated at reflux. The reaction was monitored by TLC (silica gel, eluent: EtOAc/hexanes = 1: 5). On completion of the reaction, silica gel (0.4 g) is added to the cooled mixture. After removal of the solvent in vacuo, the residue was purified by flash column chromatography on silica gel (eluent: EtOAc/hexanes = 1: 3) to give the selectively cleavage of N-O bond product 10. Following a literature procedure [5], to a solution of compound 10 (28.5 mg, 0.076 mmol, 1.0 equiv) in anhydrous THF (15 ml), NaH (9.1 mg, 0.228 mmol, 3.0 equiv) was added at -50 C and mixture was warmed up to room temperature. After completion of the reaction (TLC monitoring), the mixture was filtered through Celite and the filtrate was washed by brine. The organic layer was dried over anhydrous Na 2 SO 4, filtered and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: EtOAc/hexanes = 1: 6) to give the cyclized product 13. Following a literature procedure [6], to a solution of compound 13 (25.5 mg, 0.068 mmol) in EtOAc (2 ml), Pd/C (2.5 mg, 10 wt%) was added. A balloon with hydrogen gas was then attached to the reaction vial, and the reaction was stirred at room temperature overnight. Then the Pd/C was filtered off using a short pad of Celite and solvent was removed in vacuo to give the purified product 14. S27

Compound 13: white solid. 25.6 mg, 90% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.42 7.37 (m, 4H), 7.37 7.30 (m, 6H), 7.22 7.17 (m, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.74 (d, J = 7.5 Hz, 1H), 5.75 5.64 (m, 1H), 5.18 (d, J = 1.4 Hz, 2H), 5.16 (d, J = 3.0 Hz, 1H), 5.12 5.10 (m, 1H), 5.09 (s, 2H), 2.88 2.76 (m, 2H); 13 C NMR (101 MHz, CDCl 3 ) δ 170.76, 153.40, 142.86, 136.86, 135.91, 129.48, 128.73, 128.67, 128.43, 128.37, 128.16, 127.60, 127.38, 113.68, 110.90, 80.96, 71.54, 70.05, 66.63, 41.76; HRMS (ESI-TOF) m/z Calcd for C 24 H 22 O 4 Na + [M+Na] + : 397.1410, found: 397.1405. Compound 14: white solid. 13.1 mg, 99% yield. 1 H NMR (400 MHz, Acetone-d 6 ) δ 7.14 (t, J = 7.7 Hz, 1H), 6.81 (d, J = 7.5 Hz, 1H), 6.76 (d, J = 7.9 Hz, 1H), 5.59 5.52 (m, 1H), 5.06 (dd, J = 12.2, 2.8 Hz, 1H), 4.95 (dd, J = 12.1, 1.6 Hz, 1H), 2.80 (dd, J = 15.6, 4.8 Hz, 1H), 2.63 (dd, J = 15.6, 8.1 Hz, 1H); 13 C NMR (101 MHz, Acetone-d 6 ) δ 172.09, 152.52, 144.53, 130.06, 126.33, 115.09, 113.32, 81.74, 71.20, 41.97; HRMS (ESI-TOF) m/z Calcd for C 10 H 9 O - 4 [M-H] - : 193.0506, found: 193.0498. Match cited literature [6, 7]. 8. Synthesis of exo-palladacycle compound and X-ray crystallographic data Synthesis of exo-palladacycle compound Pd(OAc) 2 (80.8 mg, 0.36 mmol) and 1a (48.9 mg, 0.3 mmol) were added to chloroform (2 ml). The reaction was stirred at room temperature for 5 h, and then the solvent was removed in vacuum. To the crude product, dichloromethane (0.5 ml) was added, followed by hexane (6 ml), and then some unknown black substance precipitated. Filtered and the filtrate was transferred into a thin bottle. The next day afternoon, some fine orange-red crystals were formed and attached to the inner side wall of the bottle away from the mother liquor. At the bottom of the mother liquor, more unknown black substance precipitated. The fine orange-red crystals were confirmed to be the palladacycle compound by X-ray. X-ray crystallographic data of exo-palladacycle S28

Me O N Me Me Pd O O O OMe Pd MeO O Me O O Pd Me Me N O Table 1 Crystal data and structure refinement for g140929c. Identification code g140929c Empirical formula C 28 H 36 N 2 O 10 Pd 3 S29

Formula weight 879.79 Temperature/K 223.00(10) Crystal system monoclinic Space group P2 1 /c a/å 8.2684(4) b/å 13.1049(5) c/å 14.9823(6) α/ 90 β/ 98.209(4) γ/ 90 Volume/Å 3 1606.80(12) Z 2 ρ calc g/cm 3 1.818 µ/mm -1 1.716 F(000) 872.0 Crystal size/mm 3 0.3 0.2 0.2 Radiation MoKα (λ = 0.71073) 2Θ range for data collection/ 5.87 to 53.988 Index ranges -9 h 10, -16 k 16, -19 l 17 Reflections collected 9785 Independent reflections 3504 [R int = 0.0271, R sigma = 0.0311] Data/restraints/parameters 3504/0/199 Goodness-of-fit on F 2 1.085 Final R indexes [I>=2σ (I)] R 1 = 0.0288, wr 2 = 0.0694 Final R indexes [all data] R 1 = 0.0367, wr 2 = 0.0733 Largest diff. peak/hole / e Å -3 0.92/-0.67 Table 2 Fractional Atomic Coordinates ( 10 4 ) and Equivalent Isotropic Displacement Parameters (Å 2 10 3 ) for g140929c. U eq is defined as 1/3 of of the trace of the orthogonalised U IJ tensor. Atom x y z U(eq) Pd1-534.0(3) 2053.8(2) 5729.8(2) 29.41(9) Pd2 0 0 5000 28.78(10) O1 1044(3) 3364.4(18) 4439.2(15) 45.0(6) O2-2249(3) 1142.1(16) 6189.6(14) 38.3(5) S30

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