Total Syntheses of Aflavazole and 14-Hydroxyaflavinine

Transcription

1 Electronic Supporting Information Total Syntheses of Aflavazole and 14-Hydroxyaflavinine Hailong Li, Qifeng Chen, Zhaohong Lu, and Ang Li* State Key Laboratory of Bioorganic and Natural Products Chemistry, Collaborative Innovation Center of Chemistry for Life Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai , China I II III IV V Experimental Procedures and Spectroscopic Data of Compounds References HPLC Traces for Measuring Enantiomeric Excess 1 H and 13 C NMR Spectra of Compounds Comparison of the Spectra and Data of Natural and Synthetic Aflavazole and 14-Hydroxyaflavinine S1

2 I Experimental Procedures and Spectroscopic Data of Compounds General Procedures. All reactions were carried out under an argon atmosphere with dry solvents under anhydrous conditions, unless otherwise noted. Tetrahydrofuran (THF), diethyl ether (Et 2 O), and toluene were distilled immediately before use from sodium-benzophenoneketyl. Methylene chloride (CH 2 Cl 2 ), N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), hexamethylphosphoramide (HMPA), triethylamine (Et 3 N), pyridine, and 2,6-lutidine were distilled from calcium hydride and stored under an argon atmosphere. Methanol (MeOH) and ethanol (EtOH) were distilled from magnesium and stored under an argon atmosphere. Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated. Solvents for chromatography were used as supplied by Titan chemical. Reactions were monitored by thin layer chromatography (TLC) carried out on S mm E. Merck silica gel plates (60F-254) using UV light as visualizing agent and aqueous ammonium cerium nitrate/ammonium molybdate or basic aqueous potassium permanganate as developing agent. E. Merck silica gel (60, particle size mm) was used for flash column chromatography. Preparative thin layer chromatography separations were carried out on 0.25 or 0.50 mm E. Merck silica gel plates (60F-254). NMR spectra were recorded on Bruker AV III 400 or 600, or Agilent 500/54/ASP instrument and calibrated by using residual undeuterated chloroform (δ H = 7.26 ppm) and CDCl 3 (δ C = ppm), or undeuterated methanol (δ H = 3.31 ppm) and methanol-d 4 (δ C = ppm) as internal references. The following abbreviations are used to designate multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, quint = quintet, br = broad. IR spectra were recorded on a Thermo Scientific Nicolet 380 FT-IR spectrometer. Melting points (m.p.) are uncorrected and were recorded on a SGW X-4 apparatus. High-resolution mass spectra (HRMS) were recorded on a Bruker APEXIII 7.0 Tesla ESI-FT, a Waters Micromass GCT Premier EI, or an IonSpec 4.7 Tesla FT mass spectrometer. S2

3 Bicyclic enone 19: To a stirred solution of phosphoramidite ligand 1 (R,S,S)-22 (3.92 g, 7.26 mmol) in Et 2 O (280 ml) was added CuTC (693 mg, 3.63 mmol) at 22 C. The resultant mixture was stirred for 30 min before it was cooled to 30 C. Me 3 Al (109 ml, 2.0 M in hexane, 218 mmol) and a solution of 2-methylcyclohexenone 2 20 (20.0 g, 182 mmol) in Et 2 O (40 ml) were sequentially added at 30 C, and the reaction mixture was allowed to stir at that temperature for 2.5 h. To the mixture were sequentially added HMPA (81.4 g, 79.0 ml, 454 mmol) and MeLi (108 ml, 1.6 M in Et 2 O, 173 mmol) at 30 C. The resultant mixture was stirred at that temperature for 10 min before a solution of 3-trimethylsilyl-3-buten-2-one 3 (21, 38.7 g, 272 mmol) in THF (100 ml) was added by a syringe pump over a period of 1 h. The reaction mixture was allowed to stir at 30 C for 12 h, and then warmed to 10 C and stirred at that temperature for 4 h, before it was diluted with Et 2 O (800 ml) and quenched with saturated aq. NH 4 Cl (500 ml). The resultant mixture was filtered through a short plug of Celite. The organic layer was separated, and the aqueous layer was extracted with Et 2 O (3 500 ml). The combined organic phases were washed with brine (2 200 ml), dried over anhydrous Na 2 SO 4, and filtered. The volatile was evaporated under vacuum, and the crude α-silyl ketone was dissolved in MeOH (200 ml). To a stirred solution of NaOMe (24.5 g, 454 mmol) in MeOH (200 ml) was added the solution of the α-silyl ketone at 0 C. The resultant mixture was warmed to 60 C and allowed to stir at that temperature for 3 h, before it was cooled to 22 C and quenched with aq. HCl (150 ml, 3.0 M). The mixture so obtained was concentrated to a volume of ca. 200 ml and extracted with EtOAc (3 300 ml). The combined organic phases were washed with brine (2 100 ml), dried over anhydrous Na 2 SO 4, and filtered. After removal of the solvent under vacuum, the residue was subjected to flash column chromatography for purification using EtOAc/petroleum ether (1:20 1:8) as eluent to give bicyclic enone 19 (15.8 g, 49% for the two steps, 95 ee%) as a pale yellow oil. The spectra and physical properties of 19 are identical to those reported in the literature. 4 S3

4 Iodoacetal 23: This compound was prepared from bicyclic enone 19 through a three-step sequence reported by us previously. 5 The spectra and physical properties of 23 are identical to those reported. Bicyclic bis-enone 24: To a stirred solution of iodoacetal 23 (4.52 g, 11.5 mmol) in CH 2 Cl 2 (30 ml) were sequentially added Et 3 N (1.75 g, 2.40 ml, 17.3 mmol) and a solution of TMSOTf (2.82 g, 2.30 ml, 12.7 mmol) in CH 2 Cl 2 (10 ml) at 0 C. The reaction mixture was allowed to stir at that temperature for 1 h before it was quenched with saturated aq. NaHCO 3 (80 ml). The resultant mixture was extracted with CH 2 Cl 2 (3 100 ml). The combined organic phases were washed with brine (80 ml), dried over anhydrous Na 2 SO 4, and filtered. The solvent was evaporated under vacuum, and the crude silyl enol ether was dissolved in DMSO (2.0 ml). A suspension of IBX (3.86 g, 13.8 mmol) and 4-methoxypyridine N-oxide (MPO, 1.73 g, 13.8 mmol) in DMSO (23 ml) was stirred at 22 C for 30 min. To the stirred solution of the silyl enol ether was added the mixture of IBX and MPO at 0 C. The reaction mixture was warmed to 22 C and stirred at that temperature for 1 h before it was quenched with saturated aq. NaHCO 3 (80 ml). The resultant mixture was extracted with EtOAc (3 100 ml). The combined organic phases were washed with brine (50 ml), dried over anhydrous Na 2 SO 4, and filtered. After removal of the volatile under vacuum, the residue was purified by flash column chromatography with EtOAc/petroleum ether (1:15 1:6) to give bicyclic bis-enone 24 (3.06 g, 68%) as a pale yellow oil, along with recovered 23 (904 mg, 20%). 24: R f = 0.47 (silica, EtOAc:petroleum S4

5 ether 1:4); [α] 26 D = (c = 1.0 in CHCl 3 ); IR (film): ν max = 2971, 2930, 1723, 1666, 1625, 1464, 1381, 1328, 1287, 1164, 1106, 1058, 1012, 891, 829 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ): δ = 7.06 (s, 0.46 H), 7.04 (s, 0.54 H), 6.24 (dd, J = 6.4, 1.9 Hz, 0.54 H), 6.22 (dd, J = 6.4, 1.9 Hz, 0.46 H), 6.17 (d, J = 6.4 Hz, 0.54 H), 6.15 (d, J = 6.4 Hz, 0.46 H), 4.68 (dd, J = 5.6, 4.4 Hz, 0.46 H), 4.48 (dd, J = 5.6, 4.4 Hz, 0.54 H), 4.41 (dd, J = 2.9, 2.9 Hz, 0.54 H), 4.32 (dd, J = 2.9, 2.9 Hz, 0.46 H), (m, 2 H), (m, 1.46 H), 3.15 (dd, J = 10.7, 4.2 Hz, 0.54 H), (m, 1 H), (m, 1 H), (m, 3 H), 1.32 (s, 1.38 H), 1.28 (s, 1.62 H), 1.26 (t, J = 7.1 Hz, 1.62 H), 1.17 (t, J = 7.0 Hz, 1.38 H), 1.10 (d, J = 6.6 Hz, 1.62 H), 1.09 (d, J = 6.6 Hz, 1.38 H) ppm; 13 C NMR (126 MHz, CDCl 3 ): δ = , , , , , , , , , , , 99.57, 78.68, 77.33, 61.96, 61.57, 44.20, 43.93, 41.52, 41.28, 33.55, 32.25, 25.67, 25.56, 18.73, 18.29, 16.19, 16.14, 15.35, 15.24, 5.98, 5.40 ppm; HRMS (m/z): [M + Na] + calcd for C 16 H 23 IO 3 Na , found Tricycle 18: A suspension of CuI (4.39 g, 23.1 mmol) and Zn dust (4.52 g, 69.1 mmol) in pyridine/water (132 ml, 1:10) was sonicated at 22 C for 10 min before a solution of bicyclic bis-enone 24 (3.00 g, 7.69 mmol) in pyridine (18 ml) was added at that temperature. The resultant mixture was sonicated at 22 C for 1.5 h and then diluted with EtOAc (100 ml). After stirring for 10 min, the mixture so obtained was filtered through a short plug of Celite. The filter cake was washed with EtOAc (100 ml). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 50 ml). The combined organic phases were sequentially washed with aq. citric acid (4 100 ml, 10 wt%) and brine (100 ml), dried over anhydrous Na 2 SO 4, and filtered. The solvent was evaporated under vacuum, and the crude tricycle was dissolved in EtOH (30 ml). To this solution was added a solution of MsOH (148 mg, 100 μl, 1.54 mmol) in EtOH (8.0 ml) at 22 C. The resultant mixture was stirred at S5

6 that temperature for 6 h before it was quenched with saturated aq. NaHCO 3 (50 ml). The mixture so obtained was extracted with EtOAc (3 100 ml). The combined organic phases were washed with brine (50 ml), dried over anhydrous Na 2 SO 4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using EtOAc/petroleum ether (1:15 1:9) as eluent to give tricycle 18 (1.59 g, 78%) as a colorless oil. 18: R f = 0.56 (silica, EtOAc:petroleum ether 1:4); [α] 26 D = 74.3 (c = 0.93 in CHCl 3 ); IR (film): ν max = 2972, 2931, 1686, 1461, 1397, 1376, 1101, 1063, 1040, 988, 943, 881, 863, 781, 733 cm 1 ; 1 H NMR (400 MHz, CDCl 3 ): δ = 6.58 (d, J = 10.3 Hz, 1 H), 5.93 (d, J = 10.3 Hz, 1 H), 5.01 (dd, J = 6.4, 3.4 Hz, 1 H), (m, 2 H), (m, 1 H), 2.79 (d, J = 16.5 Hz, 1 H), 2.42 (dd, J = 14.3, 6.0 Hz, 1 H), 2.07 (d, J = 16.5 Hz, 1 H), (m, 1 H), (m, 1 H), (m, 1 H), (m, 1 H), 1.53 (dd, J = 14.3, 3.7 Hz, 1 H), (m, 1 H), 1.18 (t, J = 7.1 Hz, 3 H), 1.11 (s, 3 H), 0.95 (d, J = 6.7 Hz, 3 H) ppm; 13 C NMR (101 MHz, CDCl 3 ): δ = , , , , 80.36, 63.67, 49.47, 44.09, 43.96, 40.92, 36.33, 25.41, 24.57, 16.62, 16.62, ppm; HRMS (m/z): [M + Na] + calcd for C 16 H 24 O 3 Na , found Boronic ester 26: To a stirred suspension of CuCl (603 mg, 6.09 mmol) in THF (40 ml) were sequentially added imidazolium salt 25 (975 mg, 3.05 mmol) and NaOt-Bu (1.17 g, 12.2 mmol) at 22 C. The resultant mixture was stirred at that temperature for 40 min before a solution of tricycle 18 (1.61 g, 6.09 mmol) and B 2 Pin 2 (2.01 g, 7.92 mmol) in THF (20 ml) was added. The reaction mixture was allowed to stir at 22 C for 3 h before it was quenched with saturated aq. NH 4 Cl (20 ml). The resultant mixture was extracted with EtOAc (3 100 ml). The combined organic phases were washed with brine (50 ml), dried over anhydrous Na 2 SO 4, and filtered. The solvent was evaporated under vacuum, and the residue was purified by flash column chromatography with Et 2 O/petroleum ether (1:10 1:4) to give S6

7 boronic ester 26 (1.82 g, 76%) as a white solid. 26: R f = 0.33 (silica, Et 2 O:petroleum ether 1:4); m.p.: C (EtOAc:hexane 1:1); [α] 26 D = 13.4 (c = 1.0 in CHCl 3 ); IR (film): ν max = 2956, 2921, 2854, 1721, 1463, 1378, 1323, 1143, 1058, 1001, 973, 847, 722 cm 1 ; 1 H NMR (400 MHz, CDCl 3 ): δ = 5.02 (dd, J = 6.0, 3.9 Hz, 1 H), (m, 2 H), (m, 1 H), 2.72 (dd, J = 14.2, 6.1 Hz, 1 H), 2.60 (d, J = 16.1 Hz, 1 H), 2.35 (dd, J = 16.4, 7.6 Hz, 1 H), 2.26 (dd, J = 16.4, 6.1 Hz, 1 H), 2.13 (d, J = 16.1 Hz, 1 H), (m, 1 H), (m, 1 H), (m, 2 H), (m, 1 H), 1.53 (dd, J = 14.2, 3.8 Hz, 1 H), 1.49 (m, 2 H), (m, 1 H), 1.23 (s, 12 H), 1.18 (t, J = 7.1 Hz, 3 H), 1.07 (s, 3 H), 0.96 (d, J = 6.7 Hz, 3 H) ppm; 13 C NMR (101 MHz, CDCl 3 ): δ = , , 83.61, 81.48, 63.48, 50.09, 47.28, 46.01, 39.44, 38.42, 36.74, 25.61, 25.10, 25.02, 24.71, 17.10, 16.85, ppm; HRMS (m/z): [M + Na] + calcd for C 22 H 37 BO 5 Na , found CCDC contains the supplementary crystallographic data of 26. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via Triflate 27: To a stirred solution of boronic ester 26 (1.45 g, 3.70 mmol) and PhNTf 2 (1.72 g, 4.80 mmol) in THF (37 ml) was added LiHMDS (9.20 ml, 1.0 M in THF, 9.20 mmol) at 78 C. The reaction mixture was warmed to 0 C and stirred at that temperature for 10 min before it was quenched with saturated aq. NH 4 Cl (50 ml). The resultant mixture was extracted with EtOAc (3 100 ml), and the combined organic phases were washed with brine (50 ml), dried over anhydrous Na 2 SO 4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography with EtOAc/petroleum ether (1:80 1:50) as eluent to give the desired triflate (1.51 g, 78%) as a white foam. This foam was dissolved in THF/water (36 ml, 1:1). To the stirred solution was added NaBO 3 (2.22 g, 14.4 mmol) at 22 C. The resultant mixture was allowed to stir at that temperature for 8 h before it was diluted with water (30 ml) and extracted with EtOAc (3 100 ml). The combined S7

8 organic phases were washed with brine (50 ml), dried over anhydrous Na 2 SO 4, and filtered. The solvent was evaporated under vacuum, and the residue was subjected to flash column chromatography for purification using EtOAc/petroleum ether (1:10 1:6) as eluent to give triflate 27 (1.07 g, 90%) as a colorless oil. 27: R f = 0.34 (silica, EtOAc:petroleum ether 1:4); [α] 25 D = 74.3 (c = 1.6 in CHCl 3 ); IR (film): ν max = 3624, 3461, 2976, 2934, 1698, 1373, 1245, 1210, 1142, 1067, 1024, 993, 966, 897, 856, 804, 608 cm 1 ; 1 H NMR (400 MHz, CDCl 3 ): δ = 5.51 (d, J = 2.1 Hz, 1 H), 5.03 (dd, J = 5.7, 4.6 Hz, 1 H), (m, 1 H), (m, 1 H), (m, 1 H), (m, 1 H), 3.22 (dd, J = 14.8, 5.9 Hz, 1 H), 2.73 (ddd, J = 18.0, 3.8, 2.5 Hz, 1 H), 2.27 (dd, J = 18.0, 1.8 Hz, 1 H), (m, 1 H), 1.75 (d, J = 5.2 Hz, 1 H), (m, 2 H), 1.63 (dd, J = 14.8, 4.4 Hz, 1 H), (m, 1 H), (m, 1 H), 1.18 (t, J = 7.1 Hz, 3 H), 1.10 (s, 3 H), 0.85 (d, J = 6.8 Hz, 3 H) ppm; 13 C NMR (101 MHz, CDCl 3 ): δ = , , , , , , , 81.30, 74.12, 63.79, 49.09, 43.88, 39.80, 34.43, 33.59, 25.90, 25.19, 16.21, 15.38, ppm; HRMS (m/z): [M + Na] + calcd for C 17 H 25 F 3 O 6 SNa , found Triflate 28: To a stirred solution of triflate 27 (1.10 g, 2.65 mmol) in CH 2 Cl 2 (28 ml) were sequentially added NaHCO 3 (1.11 g, 13.2 mmol) and Dess Martin periodinane (1.35 g, 3.18 mmol) at 22 C. The reaction mixture was stirred at that temperature for 15 min before it was quenched with saturated aq. NaHCO 3 (80 ml). The resultant mixture was extracted with EtOAc (3 100 ml), and the combined organic phases were washed with brine (100 ml) and dried over anhydrous Na 2 SO 4. After filtration and evaporation of the solvent under vacuum, the residue was passed through a short plug of silica gel with EtOAc/petroleum ether (1:15 1:8) to give the desired ketone (1.01 g, 92%) as a colorless oil. This oil was dissolved in CH 2 Cl 2 (12 ml). To the stirred solution was added DIBAL-H (7.50 ml, 1.0 M in cyclohexane, 7.50 mmol) at 78 C. The reaction mixture was stirred at that temperature for 15 min S8

9 before it was quenched with saturated aq. potassium sodium tartrate (30 ml). The resultant mixture was diluted with EtOAc (100 ml) and stirred at 22 C for 30 min. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 50 ml). The combined organic phases were washed with brine (50 ml), dried over anhydrous Na 2 SO 4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using EtOAc/petroleum ether (1:10 1:5) as eluent to give triflate 28 (974 mg, 96%) as a colorless oil. 28: R f = 0.38 (silica, EtOAc:petroleum ether 1:4); [α] 25 D = 95.6 (c = 1.6 in CHCl 3 ); IR (film): ν max = 3468, 2980, 2934, 2870, 1693, 1420, 1361, 1246, 1212, 1141, 1042, 992, 905, 876, 829, 605 cm 1 ; 1 H NMR (400 MHz, CDCl 3 ): δ = 5.38 (s, 1 H), 5.05 (dd, J = 5.7, 4.3 Hz, 1 H), 3.87 (t, J = 2.8 Hz, 1 H), (m, 2 H), (m, 1 H), (m, 1 H), 2.38 (dd, J = 14.6, 5.9 Hz, 1 H), (m, 1 H), (m, 2 H), 1.71 (dd, J = 14.6, 4.2 Hz, 1 H), (m, 2 H), (m, 1 H), 1.20 (t, J = 7.1 Hz, 3 H), 1.09 (s, 3 H), 1.07 (d, J = 6.6 Hz, 3 H) ppm; 13 C NMR (101 MHz, CDCl 3 ): δ = , , , , , , , 80.97, 73.08, 63.83, 50.77, 44.68, 40.88, 33.27, 31.46, 26.27, 25.56, 18.67, 15.34, ppm; HRMS (m/z): [M + Na] + calcd for C 17 H 25 F 3 O 6 SNa , found Methyl ester 30: To a stirred solution of triflate 28 (1.06 g, 2.56 mmol) in THF (0.60 ml) was added 1-(trimethylsilyl)imidazole (29, 1.82 g, 1.90 ml, 13.0 mmol) at 22 C. The reaction mixture was stirred at that temperature for 1 h before EtOAc (50 ml) and brine (50 ml) were sequentially added. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 50 ml). The combined organic phases were washed with brine (30 ml), dried over anhydrous Na 2 SO 4, and filtered. The volatile was removed under vacuum, and the residue was passed through a short plug of silica gel with EtOAc/petroleum ether (1:50 1:20) to give the desired silyl ether (1.18 g, 95%) as a colorless oil. This oil was dissolved in DMF/MeOH (24 ml, 1:1). To the stirred solution were sequentially added S9

10 Et 3 N (488 mg, 670 μl, 4.82 mmol) and Pd(PPh 3 ) 4 (140 mg, mmol) at 22 C. The resultant mixture was stirred under a CO atmosphere (balloon) at 45 C for 2 h before it was cooled to 22 C and quenched with saturated aq. NaHCO 3 (50 ml). The mixture so obtained was extracted with EtOAc (3 50 ml). The combined organic phases were washed with brine (30 ml), dried over anhydrous Na 2 SO 4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography with EtOAc/petroleum ether (1:30 1:15) to give methyl ester 30 (703 mg, 73%) as a colorless oil. 30: R f = 0.63 (silica, EtOAc:petroleum ether 1:9); [α] 27 D = 171 (c = 1.3 in CHCl 3 ); IR (film): ν max = 2978, 2952, 2867, 1720, 1659, 1437, 1271, 1249, 1111, 1064, 1026, 998, 904, 841, 750 cm 1 ; 1 H NMR (400 MHz, CDCl 3 ): δ = 6.53 (d, J = 2.0 Hz, 1 H), 5.05 (dd, J = 5.6, 4.3 Hz, 1 H), 3.99 (d, J = 3.2 Hz, 1 H), (m, 1 H), 3.72 (s, 3 H), 3.57 (dd, J = 10.6, 5.3 Hz, 1 H), (m, 1 H), 2.46 (dd, J = 17.8, 5.2 Hz, 1 H), 2.32 (dd, J = 14.5, 6.0 Hz, 1 H), 2.27 (ddd, J = 17.8, 10.6, 4.4 Hz, 1 H), (m, 1 H), 1.73 (dd, J = 14.5, 4.2 Hz, 1 H), (m, 3 H), 1.20 (t, J = 7.1 Hz, 3 H), (m, 1 H), 1.00 (d, J = 6.0 Hz, 3 H), 0.96 (s, 3 H), 0.09 (s, 9 H) ppm; 13 C NMR (101 MHz, CDCl 3 ): δ = , , , , 81.39, 73.90, 63.74, 53.10, 51.84, 44.96, 40.43, 32.03, 30.83, 26.42, 25.94, 18.41, 15.41, 13.14, 0.34 ppm; HRMS (m/z): [M + Na] + calcd for C 21 H 36 O 5 SiNa , found Allyl iodide 17: To a stirred solution of methyl ester 30 (340 mg, mmol) in CH 2 Cl 2 (7.0 ml) was added DIBAL-H (5.00 ml, 1.0 M in cyclohexane, 5.00 mmol) at 78 C. The reaction mixture was stirred at that temperature for 20 min before it was quenched with saturated aq. potassium sodium tartrate (30 ml). The resultant mixture was diluted with EtOAc (50 ml) and stirred at 22 C for 30 min. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 50 ml). The combined organic phases were washed with brine (30 ml), dried over anhydrous Na 2 SO 4, filtered, and S10

11 concentrated under vacuum. The residue was subjected to a short plug of silica gel for purification using EtOAc/petroleum ether (1:6) as eluent to give the desired allylic alcohol (303 mg, 96%) as a colorless oil. This oil was dissolved in CH 2 Cl 2 (16 ml). To the stirred solution were sequentially added PPh 3 (280 mg, 1.07 mmol), imidazole (168 mg, 2.47 mmol), and I 2 (271 mg, 1.07 mmol) at 0 C. The reaction mixture was stirred at that temperature for 10 min before it was quenched with saturated aq. Na 2 SO 3 (20 ml). The resultant mixture was exacted with EtOAc (3 50 ml), and the combined organic phases were washed with saturated aq. NaI (15 ml), dried over anhydrous Na 2 SO 4, and filtered. The solvent was evaporated under vacuum, and the residue was purified by flash column chromatography with EtOAc/petroleum ether (1:50 1:30) to give allyl iodide 17 (385 mg, 98%) as a colorless oil. 17: R f = 0.58 (silica, EtOAc:petroleum ether 1:9); [α] 27 D = 178 (c = 1.1 in CHCl 3 ); IR (film): ν max = 2989, 2930, 2868, 1657, 1464, 1439, 1377, 1327, 1261, 1250, 1103, 1070, 993, 880, 840, 756 cm 1 ; 1 H NMR (400 MHz, CDCl 3 ): δ = 5.45 (d, J = 1.6 Hz, 1 H), 5.01 (dd, J = 5.7, 4.5 Hz, 1 H), 3.87 (d, J = 9.0 Hz, 1 H), 3.84 (d, J = 9.0 Hz, 1 H), (m, 1 H), (m, 1 H), 3.65 (dd, J = 10.6, 5.3 Hz, 1 H), (m, 1 H), 2.39 (ddd, J = 17.1, 10.6, 2.2 Hz, 1 H), 2.32 (dd, J = 14.5, 5.9 Hz, 1 H), 2.14 (dd, J = 17.1, 5.3 Hz, 1 H), (m, 1 H), (m, 1 H), 1.59 (dd, J = 14.5, 4.3 Hz, 1 H), (m, 2 H), 1.19 (t, J = 7.1 Hz, 3 H), (m, 1 H), 1.00 (d, J = 6.4 Hz, 3 H), 0.94 (s, 3 H), 0.10 (s, 9 H) ppm; 13 C NMR (101 MHz, CDCl 3 ): δ = , , , 81.36, 73.87, 63.73, 52.71, 44.50, 40.52, 33.84, 31.77, 26.53, 25.85, 18.51, 15.45, 13.20, 12.15, 0.38 ppm; HRMS (m/z): [M + Na] + calcd for C 20 H 35 IO 3 SiNa , found Homoallylic alcohol 31: To a stirred suspension of CrCl 2 (809 mg, 6.58 mmol), 4 Å molecular sieves (550 mg), and LiI (106 mg, mmol) in THF (8.0 ml) were sequentially added 2,6-lutidine (353 mg, 380 μl, 3.29 mmol), acetaldehyde (1.09 g, 1.00 ml, 24.7 mmol), and a solution of allyl iodide 17 (315 S11

12 mg, mmol) in THF (4.0 ml) at 22 C. The reaction mixture was allowed to stir at that temperature for 2 h before it was quenched with saturated aq. NH 4 Cl (40 ml). The resultant mixture was exacted with EtOAc (3 50 ml). The combined organic phases were washed with brine (30 ml), dried over anhydrous Na 2 SO 4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using EtOAc/petroleum ether (1:50 1:15) as eluent to give homoallylic alcohol 31 (193 mg, 74%) as a colorless oil. 31: R f = 0.41 (silica, EtOAc:petroleum ether 1:7); [α] 26 D = 47.5 (c = 1.6 in CHCl 3 ); IR (film): ν max = 3468, 2956, 1648, 1449, 1373, 1251, 1095, 1075, 1019, 987, 883, 840, 753 cm 1 ; 1 H NMR (400 MHz, CDCl 3 ): δ = 5.26 (s, 1 H), 5.02 (d, J = 5.3 Hz, 1 H), 4.94 (s, 1 H), (m, 2 H), (m, 1 H), 3.55 (d, J = 3.0 Hz, 1 H), (m, 2 H), (m, 2 H), (m, 4 H), (m, 2 H), (m, 2 H), 1.32 (d, J = 6.5 Hz, 3 H), 1.18 (t, J = 7.1 Hz, 3 H), 1.04 (d, J = 6.8 Hz, 3 H), 0.94 (s, 3 H), 0.07 (s, 9 H) ppm; 13 C NMR (101 MHz, CDCl 3 ): δ = , , , 79.40, 75.76, 66.57, 62.61, 51.69, 49.41, 44.45, 43.75, 38.61, 29.41, 27.48, 23.94, 22.18, 20.19, 16.67, 15.26, 0.43 ppm; HRMS (m/z): [M + Na] + calcd for C 22 H 40 O 4 SiNa , found Alcohol 32: To a stirred solution of homoallylic alcohol 31 (180 mg, mmol) in MeOH (18 ml) was added NiCl 2 6H 2 O (108 mg, mmol). The resultant mixture was cooled to 40 C before NaBH 4 (68.7 mg, 1.82 mmol) was added. The reaction mixture was stirred at that temperature for 30 min before NiCl 2 6H 2 O (108 mg, mmol) and NaBH 4 (68.0 mg, 1.80 mmol) were sequentially added again. The mixture so obtained was stirred at 40 C for 30 min before it was quenched with water (20 ml) and diluted with EtOAc (20 ml). The resultant mixture was filtered through a short plug of Celite, and the filter cake was washed with EtOAc (50 ml). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 50 ml). The combined organic phases were washed with S12

13 brine (20 ml), dried over anhydrous Na 2 SO 4, and filtered. The volatile was removed under vacuum, and the residue was purified by flash column chromatography with EtOAc/petroleum ether (1:15 1:7) to give alcohol 32 (168 mg, 93%) as a colorless oil. 32: R f = 0.34 (silica, EtOAc:petroleum ether 1:4); [α] 25 D = 54.8 (c = 0.80 in CHCl 3 ); IR (film): ν max = 3472, 2932, 1640, 1462, 1373, 1250, 1084, 892, 838, 801, 748 cm 1 ; 1 H NMR (400 MHz, CDCl 3 ): δ = 5.04 (dd, J = 6.1, 1.9 Hz, 1 H), (m, 2 H), (m, 2 H), (m, 1 H), 2.88 (d, J = 2.9 Hz, 1 H), 2.68 (dd, J = 14.8, 2.0 Hz, 1 H), (m, 1 H), 2.25 (dd, J = 14.8, 6.2 Hz, 1 H), (m, 1 H), (m, 1 H), (m, 2 H), (m, 1 H), (m, 1 H), (m, 1 H), 1.23 (d, J = 6.5 Hz, 3 H), 1.17 (t, J = 7.1 Hz, 3 H), 1.15 (d, J = 7.4 Hz, 3 H), 0.96 (d, J = 6.7 Hz, 3 H), 0.93 (s, 3 H), 0.06 (s, 9 H) ppm; 13 C NMR (101 MHz, CDCl 3 ): δ = , 75.79, 72.82, 68.11, 62.67, 50.74, 43.50, 42.20, 39.21, 38.17, 30.67, 28.86, 27.76, 24.38, 22.24, 19.08, 17.31, 15.35, 15.01, 0.51 ppm; HRMS (m/z): [M + Na] + calcd for C 22 H 42 O 4 SiNa , found Desilyl 32: To a stirred solution of alcohol 32 (12.0 mg, mmol) in THF (200 μl) was added TBAF (150 μl, 1.0 M in THF, mmol) at 22 C. The resultant mixture was allowed to stir at that temperature for 5 h before it was quenched with saturated aq. NaHCO 3 (5 ml). The mixture so obtained was extracted with EtOAc (3 10 ml). The combined organic phases were washed with brine (10 ml), dried over anhydrous Na 2 SO 4, filtered, and concentrated under vacuum. The residue was subjected to flash column chromatography for purification using EtOAc/petroleum ether (1:15 1:4) as eluent to give desilyl 32 (8.0 mg, 82%) as a white solid. Desilyl 32: R f = 0.21 (silica, EtOAc:petroleum ether 1:4); m.p.: C (EtOAc:hexane 1:1); [α] 25 D = 72.8 (c = 0.53 in CHCl 3 ); IR (film): ν max = 3408, 2962, 2922, 1456, 1449, 1306, 1145, 1065, 997, 922, 888, 559 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ): δ = 5.06 (dd, J = 6.0, 1.4 Hz, 1 H), (m, 2 H), 3.78 (d, J = 12.6 Hz, 1 H), (m, 1 H), S13

14 (m, 1 H), 2.90 (s, 1 H), 2.71 (dd, J = 14.9, 1.8 Hz, 1 H), (m, 1 H), 2.27 (dd, J = 14.9, 6.1 Hz, 1 H), (m, 1 H), (m, 1 H), (m, 2 H), (m, 1 H), (m, 1 H), (m, 1 H), (m, 1 H), 1.25 (d, J = 6.5 Hz, 3 H), (m, 1 H), 1.18 (t, J = 7.1 Hz, 3 H), 1.17 (d, J = 7.4 Hz, 3 H), 1.08 (s, 3 H), 1.04 (d, J = 6.7 Hz, 3 H) ppm; 13 C NMR (126 MHz, CDCl 3 ): δ = , 75.65, 73.17, 68.14, 62.70, 50.72, 43.56, 42.28, 39.05, 37.33, 30.58, 28.85, 27.71, 24.45, 22.15, 19.30, 17.35, 15.37, ppm; HRMS (m/z): [M + Na] + calcd for C 19 H 34 O 4 Na , found CCDC contains the supplementary crystallographic data of desilyl 32. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via Ketone 15: To a stirred solution of alcohol 32 (168 mg, mmol) in CH 2 Cl 2 (14 ml) were sequentially added NMO (148 mg, 1.26 mmol) and TPAP (14.8 mg, mmol) at 22 C. The resultant mixture was stirred at that temperature for 30 min and then directly subjected to flash column chromatography for purification using EtOAc/petroleum ether (1:30 1:10) as eluent to give ketone 15 (148 mg, 89%) as a colorless oil. 15: R f = 0.50 (silica, EtOAc:petroleum ether 1:7); [α] 25 D = 18.0 (c = 0.95 in CHCl 3 ); IR (film): ν max = 3446, 2935, 2898, 1713, 1636, 1384, 1350, 1251, 1090, 1025, 891, 839, 749 cm 1 ; 1 H NMR (400 MHz, CDCl 3 ): δ = 5.04 (dd, J = 6.0, 4.0 Hz, 1 H), (m, 1 H), (m, 2 H), (m, 1 H), 3.29 (d, J = 4.4 Hz, 1 H), 3.03 (dd, J = 14.0, 3.8 Hz, 1 H), (m, 1 H), 2.18 (dd, J = 14.0, 6.1 Hz, 1 H), 2.14 (s, 3 H), (m, 1 H), (m, 2 H), (m, 2 H), (m, 1 H), (m, 1 H), 1.19 (t, J = 7.1 Hz, 3 H), 0.99 (d, J = 6.7 Hz, 3 H), 0.96 (d, J = 7.2 Hz, 3 H), 0.95 (s, 3 H), 0.08 (s, 9 H) ppm; 13 C NMR (126 MHz, CDCl 3 ): δ = , , 78.53, 71.97, 63.41, 51.88, 50.11, 43.01, 38.27, 36.85, 33.08, 30.74, 30.60, 27.51, S14

15 25.07, 18.78, 16.33, 15.41, 14.75, 0.42 ppm; HRMS (m/z): [M + Na] + calcd for C 22 H 40 O 4 SiNa , found Alkyne 12: To a stirred solution of ketone 15 (150 mg, mmol) and PhNTf 2 (270 mg, mmol) in THF (7.5 ml) was added NaHMDS (420 μl, 1.0 M in THF, mmol) at 78 C. The reaction mixture was warmed to 0 C and stirred at that temperature for 10 min before it was quenched with saturated aq. NH 4 Cl (20 ml). The resultant mixture was extracted with EtOAc (3 30 ml), and the combined organic phases were washed with brine (20 ml), dried over anhydrous Na 2 SO 4, and filtered. The volatile was removed under vacuum, and the crude triflate was dissolved in THF (1.0 ml). To the stirred solution was added TBAF (1.90 ml, 1.0 M in THF, 1.90 mmol) at 22 C. The reaction mixture was allowed to stir at that temperature for 5 h before it was quenched with saturated aq. NaHCO 3 (20 ml). The resultant mixture was extracted with EtOAc (3 30 ml). The combined organic phases were washed with brine (20 ml), dried over anhydrous Na 2 SO 4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography with EtOAc/petroleum ether (1:20 1:10) to give alkyne 12 (82.0 mg, 71%) as a pale yellow oil. 12: R f = 0.23 (silica, EtOAc:petroleum ether 1:4); [α] 25 D = 85.7 (c = 0.73 in CHCl 3 ); IR (film): ν max = 3479, 3306, 2932, 2117, 1462, 1381, 1332, 1262, 1159, 1082, 1003, 974, 927, 811, 631 cm 1 ; 1 H NMR (400 MHz, CDCl 3 ): δ = 5.05 (dd, J = 5.9, 4.2 Hz, 1 H), (m, 1 H), (m, 2 H), (m, 1 H), 3.10 (dd, J = 5.3, 2.5 Hz, 1 H), (m, 3 H), 2.13 (dd, J = 14.0, 4.1 Hz, 1 H), (m, 3 H), (m, 1 H), 1.62 (dd, J = 14.0, 3.4 Hz, 1 H), 1.33 (t, J = 6.5 Hz, 1 H), (m, 1 H), 1.20 (t, J = 7.1 Hz, 3 H), 1.11 (s, 3 H), 1.10 (d, J = 6.2 Hz, 3 H), 1.03 (d, J = 6.7 Hz, 3 H) ppm; 13 C NMR (101 MHz, CDCl 3 ): δ = , 84.42, 79.28, 73.86, 71.97, 63.37, 51.34, 41.92, 40.09, 34.80, 34.69, 33.02, 30.62, 27.63, 24.38, 18.89, 16.46, 15.42, ppm; HRMS (m/z): [M + Na] + calcd for C 19 H 30 O 3 Na , found S15

16 Alkenyl iodide 11: To a stirred suspension of AlI 3 (386 mg, mmol) in toluene (4.0 ml) was added a solution of alkyne 12 (58.0 mg, mmol) in toluene (2.0 ml) at 78 C. The resultant mixture was stirred at that temperature for 45 min before it was quenched with saturated aq. NaHCO 3 (20 ml). The mixture so obtained was extracted with EtOAc (3 30 ml), and the combined organic phases were washed with brine (10 ml), dried over anhydrous Na 2 SO 4, and filtered. The solvent was evaporated under vacuum, and the residue was subjected to flash column chromatography for purification using EtOAc/petroleum ether (1:20 1:10) as eluent to give alkenyl iodide 11 (50.0 mg, 68%) as a colorless oil. 11: R f = 0.35 (silica, EtOAc:petroleum ether 1:4); [α] 23 D = 79.7 (c = 0.90 in CHCl 3 ); IR (film): ν max = 3459, 2954, 2925, 2864, 1616, 1456, 1381, 1329, 1088, 1039, 1008, 934, 810, 738 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ): δ = 6.68 (d, J = 5.9 Hz, 1 H), (m, 1 H), 3.74 (dd, J = 13.0, 2.8 Hz, 1 H), 3.61 (dd, J = 12.1, 7.0 Hz, 1 H), (m, 2 H), (m, 2 H), (m, 1 H), 1.85 (dd, J = 11.2, 4.6 Hz, 1 H), 1.77 (d, J = 11.2 Hz, 1 H), 1.68 (dd, J = 12.3, 2.5 Hz, 1 H), (m, 2 H), (m, 2 H), 1.10 (s, 3 H), 1.04 (d, J = 4.8 Hz, 3 H), 1.02 (d, J = 5.2 Hz, 3 H) ppm; 13 C NMR (126 MHz, CDCl 3 ): δ = , , 84.68, 75.37, 74.29, 58.73, 51.45, 43.80, 34.81, 31.71, 31.61, 28.30, 26.39, 25.54, 18.05, 17.43, ppm; HRMS (m/z): [M] + calcd for C 17 H 25 IO , found S16

17 Aldehyde 34: To a stirred solution of alkenyl iodide 11 (49.0 mg, mmol) and stannane 33 (117 mg, mmol) in NMP (500 μl) were sequentially added Pd(PPh 3 ) 4 (14.6 mg, mmol) and CuTC (36.1 mg, mmol) at 22 C. The reaction mixture was stirred at that temperature for 10 min before it was diluted with EtOAc (10 ml) and quenched with saturated aq. NaHCO 3 (10 ml). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 10 ml). The combined organic phases were washed with brine (20 ml), dried over anhydrous Na 2 SO 4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography with EtOAc/petroleum ether (1:8 1:3) to give aldehyde 34 (55.0 mg, 78%, a mixture of two atropisomers) as a white foam. 34: R f = 0.26 (silica, EtOAc:petroleum ether 1:2); [α] 24 D = 96.3 (c = 0.97 in CHCl 3 ); IR (film): ν max = 3461, 2955, 2928, 1682, 1522, 1371, 1187, 1089, 915, 754, 669, 577 cm 1 ; 1 H NMR (400 MHz, CDCl 3 ): δ = (s, 0.78 H), (s, 0.22 H), 8.26 (d, J = 8.4 Hz, 1 H), 7.64 (s, 0.44 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.54 (t, J = 7.8 Hz, 1 H), 7.49 (d, J = 7.8 Hz, 1.56 H), 7.32 (t, J = 7.6 Hz, 1 H), 7.15 (s, 0.44 H), 7.12 (d, J = 7.7 Hz, 1.56 H), 6.25 (s, 0.22 H), 6.14 (d, J = 4.9 Hz, 0.78 H), 4.58 (t, J = 4.7 Hz, 1 H), 4.15 (dd, J = 12.0, 6.7 Hz, 0.78 H), 3.77 (s, 0.22 H), 3.70 (d, J = 12.1 Hz, 1 H), 3.37 (d, J = 3.7 Hz, 0.78 H), 3.12 (s, 0.22 H), 2.31 (s, 3 H), (m, 1 H), (m, 1 H), (m, 5 H), (m, 3 H), 1.15 (s, 3 H), 1.07 (d, J = 6.5 Hz, 3 H), (m, 0.66 H), 0.63 (d, J = 7.0 Hz, 2.34 H) ppm; 13 C NMR (101 MHz, CDCl 3 ): δ = , , , , , , , , , , , , , , , , , , , , , , 84.99, 82.96, 74.99, 74.74, 72.00, 71.82, 50.77, 49.61, 49.03, 44.04, 35.49, 31.27, 30.95, 29.82, 28.61, 28.37, 26.59, 25.77, 21.73, 18.23, 17.46, 17.01, ppm; HRMS (m/z): [M + H] + calcd for C 33 H 38 NO 5 S , found S17

18 Triene 10: To a stirred solution of N-phenyltetrazole sulfone 35 (56.3 mg, mmol) in DMF/HMPA (3.0 ml, 4:1) was added LiHMDS (240 μl, 1.0 M in THF, mmol) at 30 C. The resultant mixture was stirred at that temperature for 5 min before a solution of aldehyde 34 (44.0 mg, mmol) in DMF/HMPA (1.0 ml, 4:1) was added. The reaction mixture was stirred at 30 C for 15 min before it was warmed to 0 C and stirred at that temperature for 15 min. The mixture so obtained was quenched with saturated aq. NH 4 Cl (10 ml). The resultant mixture was extracted with EtOAc (3 20 ml). The combined organic phases were washed with brine (20 ml), dried over anhydrous Na 2 SO 4, and filtered. The volatile was removed under vacuum. The residue was subjected to flash column chromatography for purification using EtOAc/petroleum ether (1:15 1:5) as eluent to give triene 10 (38.7 mg, 86%) as a colorless oil. 10: R f = 0.35 (silica, EtOAc:petroleum ether 1:3); [α] 24 D = (c = 0.67 in CHCl 3 ); IR (film): ν max = 3453, 2968, 2926, 2890, 1639, 1598, 1449, 1378, 1263, 1229, 1174, 1090, 968, 812, 748, 669, 579 cm 1 ; 1 H NMR (400 MHz, CDCl 3 ): δ = 8.21 (d, J = 8.3 Hz, 1 H), 7.56 (d, J = 8.2 Hz, 2 H), 7.50 (d, J = 7.7 Hz, 1 H), (m, 1 H), (m, 1 H), 7.12 (d, J = 8.1 Hz, 2 H), 6.84 (d, J = 15.6 Hz, 1 H), 6.19 (d, J = 5.3 Hz, 1 H), 5.84 (dd, J = 15.6, 6.7 Hz, 1 H), (m, 1 H), (m, 1 H), 3.52 (dd, J = 11.2, 6.8 Hz, 1 H), 3.06 (d, J = 5.1 Hz, 1 H), 2.32 (s, 3 H), (m, 1 H), 1.94 (dd, J = 6.7, 1.8 Hz, 3 H), (m, 4 H), (m, 3 H), (m, 2 H), (m, 1 H), 1.13 (s, 3 H), 1.06 (d, J = 6.6 Hz, 3 H), 0.74 (d, J = 7.4 Hz, 3 H) ppm; 13 C NMR (101 MHz, CDCl 3 ): δ = , , , , , , , , , , , , , , , , , , 83.41, 75.02, 72.25, 49.35, 47.33, 43.90, 35.58, 31.87, 30.66, 28.41, 26.71, 25.74, 21.70, 18.61, 18.28, 17.51, 17.36, ppm; HRMS (m/z): [M + H] + calcd for C 35 H 42 NO 4 S , found S18

19 Heptacycle 36: A solution of triene 10 (20.0 mg, mmol) in toluene (10 ml) was heated to 90 C and allowed to stir at that temperature for 2 h before it was cooled to 22 C. The solvent was evaporated under vacuum, and the residue was dissolved in CH 2 Cl 2 (4.0 ml). To the stirred solution was added DDQ (15.9 mg, mmol) at 22 C. The resultant mixture was stirred at that temperature for 5 min and then directly passed through a short plug of Al 2 O 3 (neutral) using EtOAc/petroleum ether (1:15 1:5) as eluent to give heptacycle 36 (16.3 mg, 82%, a mixture of two conformers) as a colorless oil. 36: R f = 0.54 (silica, EtOAc:petroleum ether 1:4); [α] 24 D = (c = 1.0 in CHCl 3 ); IR (film): ν max = 3460, 2953, 2933, 2873, 1596, 1450, 1369, 1265, 1187, 1090, 811, 739, 670, 570 cm 1 ; 1 H NMR (400 MHz, CDCl 3 ): δ = 8.36 (d, J = 8.3 Hz, 0.41 H), 8.32 (d, J = 8.3 Hz, 0.59 H), 8.09 (d, J = 7.8 Hz, 0.59 H), 8.08 (s, 0.41 H), 8.02 (s, 0.59 H), 7.75 (d, J = 7.8 Hz, 0.41 H), 7.63 (d, J = 8.3 Hz, 2 H), (m, 1.41 H), (m, 0.59 H), (m, 2 H), 5.47 (d, J = 4.8 Hz, 0.41 H), 5.36 (d, J = 5.2 Hz, 0.59 H), 4.24 (d, J = 9.2 Hz, 0.59 H), (m, 0.41 H), (m, 1.59 H), 3.55 (dd, J = 12.0, 7.1 Hz, 0.41 H), (m, 1 H), 2.59 (s, 1.23 H), 2.56 (s, 1.77 H), (m, 4 H), (m, 2.41 H), (m, 0.59 H), (m, 4 H), (m, 1 H), (m, 1 H), 1.25 (s, 1.23 H), 1.17 (d, J = 6.5 Hz, 1.23 H), 1.07 (d, J = 6.4 Hz, 1.77 H), 0.96 (s, 1.77 H), 0.54 (d, J = 7.4 Hz, 1.23 H), 0.13 (d, J = 7.3 Hz, 1.77 H) ppm; 13 C NMR (101 MHz, CDCl 3 ): δ = , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 84.13, 81.00, 75.07, 74.78, 74.07, 73.67, 49.87, 49.65, 48.41, 44.23, 43.39, 41.62, 35.52, 34.36, 32.40, 31.23, 30.39, 28.68, 28.35, 27.06, 26.87, 26.77, 26.48, 25.72, 21.63, 20.53, 20.08, 19.20, 18.43, 18.07, 17.75, 17.36, ppm; HRMS (m/z): [M + Na] + calcd for C 35 H 39 NO 4 SNa , found S19

20 Aflavazole (6): To a stirred solution of heptacycle 36 (12.0 mg, mmol) and Et 3 SiH (124 mg, 170 μl, 1.06 mmol) in CH 2 Cl 2 (2.0 ml) was added TiCl 4 (210 μl, 1.0 M in CH 2 Cl 2, mmol) at 78 C. The reaction mixture was warmed to 30 C and stirred at that temperature for 1 h before it was quenched with saturated aq. NaHCO 3 (10 ml). The resultant mixture was extracted with EtOAc (3 20 ml). The combined organic phases were washed with brine (10 ml), dried over anhydrous Na 2 SO 4, filtered, and concentrated under vacuum. The residue was passed through a short plug of silica gel using EtOAc/petroleum ether (1:15 1:5) as eluent to give N-Ts-aflavazole as a colorless oil (9.6 mg, 80%). This oil was dissolved in MeOH (4.0 ml). To the solution was added Mg powder (4.1 mg, 0.17 mmol) at 22 C. The resultant mixture was sonicated at that temperature for 1 h before it was quenched with saturated aq. NH 4 Cl (8 ml). The mixture so obtained was extracted with EtOAc (3 10 ml), and the combined organic phases were washed with brine (10 ml), dried over anhydrous Na 2 SO 4, and filtered. After removal of the solvent under vacuum, the residue was purified by flash column chromatography with EtOAc/petroleum ether (1:10 1:5) as eluent to give aflavazole (6, 6.7 mg, 96 %) as a white solid. 6: R f = 0.34 (silica, EtOAc:petroleum ether 1:3); [α] 23 D = 20.2 (c = 0.35 in MeOH); 6 m.p.: C (EtOAc:hexane 1:1); IR (film): ν max = 3399, 3274, 2931, 1626, 1609, 1455, 1378, 1263, 1042, 1000, 972, 930, 873, 736 cm 1 ; 1 H NMR (400 MHz, methanol-d 4 ): δ = 7.96 (d, J = 8.0 Hz, 1 H), 7.41 (d, J = 8.0 Hz, 1 H), (m, 1 H), (m, 1 H), 7.11 (s, 1 H), 4.23 (d, J = 4.9 Hz, 1 H), 4.20 (dd, J = 13.9, 4.4 Hz, 1 H), (m, 1 H), (m, 3 H), (m, 1 H), (m, 2 H), 2.35 (s, 3 H), (m, 1 H), (m, 2 H), 1.67 (dd, J = 12.7, 2.1 Hz, 1 H), (m, 1 H), 1.34 (s, 3 H), (m, 1 H), 1.20 (d, J = 6.7 Hz, 3 H), 0.67 (d, J = 7.5 Hz, 3 H) ppm; 1 H NMR (400 MHz, CDCl 3 ): δ = 8.01 (d, J = 8.0 Hz, 1 H), 7.94 (s, 1 H), 7.42 (d, J = 7.4 Hz, 1 H), 7.38 (dd, J = 7.4, 7.4 Hz, S20

21 1 H), (m, 1 H), 7.08 (s, 1 H), (m, 2 H), 3.87 (d, J = 3.2 Hz, 1 H), (m, 2 H), (m, 1 H), (m, 1 H), (m, 1 H), 2.42 (dd, J = 12.7, 7.1 Hz, 1 H), 2.36 (s, 3 H), (m, 1 H), (m, 1 H), (m, 1 H), 1.71 (dd, J = 12.7, 2.1 Hz, 1 H), (m, 2 H), 1.39 (s, 3 H), (m, 1 H), 1.23 (d, J = 6.7 Hz, 3 H), 1.20 (d, J = 4.0 Hz, 1 H), 0.65 (d, J = 7.5 Hz, 3 H) ppm; 13 C NMR (101 MHz, methanol-d 4 ): δ = , , , , , , , , , , , , 72.42, 71.41, 45.15, 44.91, 39.98, 36.33, 32.76, 32.58, 30.74, 28.71, 25.18, 23.03, 20.68, 19.85, 19.37, ppm; 13 C NMR (101 MHz, CDCl 3 ): δ = , , , , , , , , , , , , 72.39, 71.04, 44.06, 43.82, 38.94, 35.47, 31.52, 31.45, 30.41, 27.39, 24.53, 22.03, 20.73, 19.59, 19.20, ppm; HRMS (m/z): [M] + calcd for C 28 H 35 NO , found CCDC contains the supplementary crystallographic data of 6. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via Homoallylic alcohol 37: This compound was synthesized by using the protocol for preparing 31. Homoallylic alcohol 37 (218 mg) was obtained as a colorless oil from allyl iodide 17 (270 mg, mmol) and isovaleraldehyde (482 mg, 600 μl, 5.59 mmol) in 88% yield. 37: R f = 0.33 (silica, EtOAc:petroleum ether 1:12); [α] 27 D = 27.8 (c = 0.50 in CHCl 3 ); IR (film): ν max = 3473, 2954, 2870, 1647, 1457, 1250, 1098, 1075, 893, 840, 751 cm 1 ; 1 H NMR (400 MHz, CDCl 3 ): δ = 5.27 (s, 1 H), 5.03 (d, J = 5.5 Hz, 1 H), 4.93 (s, 1 H), 4.44 (t, J = 5.8 Hz, 1 H), (m, 1 H), (m, 1 H), (m, 3 H), 2.36 (d, J = 15.2 Hz, 1 H), 2.30 (dd, J = 11.9, 11.9 Hz, 1 H), (m, 3 H), 2.10 (dd, J = 15.2, 6.0 Hz, 1 H), (m, 3 H), (m, 1 H), (m, 3 H), 1.19 (t, J = 7.1 Hz, 3 H), 1.05 (d, J = 6.8 Hz, 3 H), 0.95 (s, 3 H), 0.91 (d, J = 6.6 Hz, 3 H), 0.89 (d, J = 6.5 Hz, 3 S21

22 H), 0.08 (s, 9 H) ppm; 13 C NMR (101 MHz, CDCl 3 ): δ = , , , 79.68, 75.57, 69.07, 62.63, 51.75, 48.11, 45.16, 44.66, 43.92, 38.74, 29.52, 27.60, 25.71, 24.10, 23.23, 22.79, 20.25, 16.76, 15.32, 0.48 ppm; HRMS (m/z): [M + Na] + calcd for C 25 H 46 O 4 SiNa , found Ketone 16: This compound was synthesized by using the protocol for preparing 15. Ketone 16 (122 mg) was obtained as a white foam from homoallylic alcohol 37 (160 mg, mmol) in 77% overall yield for the two steps (80% yield for the hydrogenation and 96% for the oxidation). 16: R f = 0.47 (silica, EtOAc:petroleum ether 1:12); [α] 27 D = 18.8 (c = 0.92 in CHCl 3 ); IR (film): ν max = 2956, 2872, 1711, 1463, 1402, 1285, 1251, 1093, 1047, 1025, 891, 840, 750 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ): δ = (m, 1 H), (m, 3 H), (m, 1 H), 3.18 (d, J = 4.2 Hz, 1 H), 3.09 (dd, J = 13.9, 3.3 Hz, 1 H), 2.35 (dd, J = 16.8, 7.2 Hz, 1 H), (m, 4 H), (m, 1 H), (m, 2 H), (m, 2 H), (m, 1 H), (m, 1 H), 1.18 (t, J = 7.0 Hz, 3 H), 0.98 (d, J = 6.6 Hz, 3 H), 0.95 (d, J = 7.0 Hz, 3 H), 0.94 (s, 3 H), 0.87 (d, J = 6.3 Hz, 3 H), 0.84 (d, J = 6.3 Hz, 3 H), 0.06 (s, 9 H) ppm; 13 C NMR (126 MHz, CDCl 3 ): δ = , , 78.46, 72.05, 63.41, 54.74, 51.99, 49.97, 43.05, 38.44, 36.92, 30.66, 30.61, 27.54, 25.08, 23.74, 22.68, 22.49, 18.80, 16.41, 15.45, 14.77, 0.44 ppm; HRMS (m/z): [M + Na] + calcd for C 25 H 46 O 4 SiNa , found Alkyne 13: This compound was synthesized by using the protocol for preparing 12. Alkyne 13 (42.5 mg) was obtained as a colorless oil from ketone 16 (60.0 mg, mmol) in 89% yield. 13: R f = 0.29 (silica, S22

23 acetone/petroleum ether 1:9); [α] 24 D = 65.4 (c = 1.1 in CHCl 3 ); IR (film): ν max = 3486, 2929, 1725, 1675, 1462, 1380, 1343, 1319, 1284, 1081, 1022, 979, 932, 804 cm 1 ; 1 H NMR (400 MHz, CDCl 3 ): δ = 5.02 (dd, J = 5.1, 4.9 Hz, 1 H), 4.31 (d, J = 2.4 Hz, 1 H), (m, 2 H), (m, 1 H), 3.00 (dd, J = 5.1, 1.7 Hz, 1 H), (m, 1 H), (m, 3 H), (m, 1 H), 1.93 (d, J = 13.2 Hz, 1 H), 1.87 (dd, J = 12.8, 5.4 Hz, 1 H), (m, 3 H), (m, 2 H), 1.18 (t, J = 7.9 Hz, 3 H), 1.17 (d, J = 1.7 Hz, 3 H), 1.15 (d, J = 1.7 Hz, 3 H), 1.10 (s, 3 H), 1.07 (d, J = 7.4 Hz, 3 H), 1.02 (d, J = 6.7 Hz, 3 H) ppm; 13 C NMR (126 MHz, CDCl 3 ): δ = , 91.82, 79.58, 79.30, 72.16, 63.04, 51.92, 41.92, 39.99, 34.90, 34.59, 33.25, 30.62, 27.76, 24.47, 23.52, 23.48, 20.85, 18.93, 16.58, 15.47, ppm; HRMS (m/z): [M + Na] + calcd for C 22 H 36 O 3 Na , found Alkenyl iodides 14 and 38: To a stirred suspension of AlI 3 (212 mg, mmol) in toluene (4.0 ml) was added a solution of alkyne 13 (30.2 mg, mmol) in toluene (2.0 ml) at 78 C. The resultant mixture was stirred at that temperature for 45 min before it was quenched with saturated aq. NaHCO 3 (10 ml). The mixture so obtained was extracted with EtOAc (3 20 ml). The combined organic phases were washed with brine (10 ml), dried over anhydrous Na 2 SO 4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography with EtOAc/petroleum ether (1:20 1:10) as eluent to give alkenyl iodide 14 (21.6 mg, 58%) as a white foam and alkenyl iodide 38 (7.1 mg, 19%) as a white solid. 14: R f = 0.22 (silica, EtOAc:petroleum ether 1:8); [α] 24 D = 77.5 (c = 0.80 in CHCl 3 ); IR (film): ν max = 3467, 2958, 2926, 2867, 1622, 1462, 1381, 1286, 1262, 1042, 931, 804, 751, 577 cm 1 ; 1 H NMR (400 MHz, CDCl 3 ): δ = 4.54 (d, J = 4.9 Hz, 1 H), (m, 1 H), 3.59 (dd, J = 12.2, 6.9 Hz, 1 H), (m, 1 H), (m, 1 H), 2.53 (d, J = 5.6 Hz, 1 H), (m, 2 H), (m, 1 H), 1.88 (dd, J = 11.2, 5.1 Hz, 1 H), (m, 1 H), 1.73 (d, J = 11.2 Hz, 1 H), (m, 2 H), (m, 2 H), 1.11 (s, 3 H), 1.08 (d, J = 6.9 Hz, 3 H), 1.03 (d, J = 6.6 Hz, 3 S23

24 H), 0.96 (d, J = 7.6 Hz, 3 H), 0.94 (d, J = 7.0 Hz, 3 H) ppm; 13 C NMR (126 MHz, CDCl 3 ): δ = , , 84.90, 75.56, 72.12, 59.15, 51.92, 43.63, 39.68, 34.89, 32.47, 32.10, 28.31, 26.57, 25.69, 20.81, 19.57, 18.07, 17.62, ppm; HRMS (m/z): [M] + calcd for C 20 H 31 IO , found : R f = 0.44 (silica, EtOAc:petroleum ether 1:8); m.p.: C (acetone:hexane 1:1); [α] 27 D = 79.1 (c = 0.25 in CHCl 3 ); IR (film): ν max = 3396, 2999, 2925, 2867, 1640, 1456, 1376, 1260, 1194, 1091, 1013, 965, 798, 738 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ): δ = 4.74 (s, 1 H), 3.62 (s, 1 H), 3.50 (dd, J = 12.2, 3.9 Hz, 1 H), (m, 2 H), (m, 1 H), (m, 1 H), (m, 1 H), 1.90 (d, J = 10.4 Hz, 1 H), (m, 2 H), (m, 2 H), 1.58 (d, J = 10.4, 1 H), (m, 2 H), 0.98 (d, J = 6.5 Hz, 6 H), 0.93 (d, J = 5.3 Hz, 3 H), 0.91 (d, J = 5.0 Hz, 3 H), 0.86 (s, 3 H) ppm; 13 C NMR (101 MHz, CDCl 3 ): δ = , , 80.14, 75.78, 73.54, 53.60, 52.67, 39.88, 38.93, 35.33, 33.36, 28.77, 26.78, 25.51, 24.95, 23.88, 23.79, 20.16, 17.82, ppm; HRMS (m/z): [M] + calcd for C 20 H 31 IO , found CCDC contains the supplementary crystallographic data of 38. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via Hexacycle 40: This compound was synthesized by using the protocol for preparing 34. Hexacycle 40 (20.3 mg, a mixture of two atropisomers) was obtained as a white foam from alkenyl iodide 14 (17.5 mg, mmol) and stannane 39 (26.6 mg, mmol) in 87% yield. 40: R f = 0.31 (silica, EtOAc:petroleum ether 1:3); [α] 24 D = (c = 0.75 in CHCl 3 ); IR (film): ν max = 3455, 2957, 2926, 2859, 1598, 1446, 1371, 1264, 1127, 1088, 1042, 960, 811, 748, 572 cm 1 ; 1 H NMR (400 MHz, methanol-d 4 ): δ = 8.06 (d, J = 8.6 Hz, 0.78 H), 8.02 (s, 0.22 H), 7.74 (s, 0.44 H), 7.70 (d, J = 8.2 Hz, 1.56 H), 7.55 (s, 0.22 H), (m, 2 H), (m, 3.78 H), (m, 1 H), 3.83 (dd, J = S24

25 11.9, 6.9 Hz, 0.78 H), 3.79 (s, 0.22 H), 3.73 (dd, J = 12.8, 2.5 Hz, 1 H), 2.63 (d, J = 4.3 Hz, 0.22 H), 2.52 (d, J = 5.5 Hz, 0.78 H), (m, 1 H), 2.33 (s, 3 H), (m, 0.22 H), (m, 0.78 H), (m, 2 H), 1.82 (d, J = 11.2 Hz, 1 H), (m, 3 H), (m, 1 H), (m, 1 H), 1.42 (d, J = 12.8 Hz, 1 H), 1.12 (s, 3 H), 1.07 (d, J = 7.3 Hz, 2.34 H), (m, 0.66 H), 1.00 (d, J = 7.5 Hz, 3 H), 0.99 (d, J = 7.6 Hz, 2.34 H), 0.84 (d, J = 6.9 Hz, 3 H), 0.80 (d, J = 7.2 Hz, 0.66 H) ppm; 13 C NMR (101 MHz, CDCl 3 ): δ = , , , , , , , , , , , , , , , , , , , 85.24, 75.27, 71.67, 55.73, 50.50, 49.84, 49.72, 43.75, 35.34, 34.88, 31.71, 31.29, 30.47, 30.27, 29.84, 28.38, 26.76, 26.05, 22.46, 21.70, 21.36, 20.83, 20.42, 18.13, 17.49, 16.99, ppm; HRMS (m/z): [M + H] + calcd for C 35 H 44 NO 4 S , found Hydroxyaflavinine (8): To a stirred solution of hexacycle 40 (17.3 mg, mmol) and Et 3 SiH (175 mg, 240 μl, 1.50 mmol) in CH 2 Cl 2 (5.0 ml) was added TiCl 4 (300 μl, 1.0 M in CH 2 Cl 2, mmol) at 78 C. The reaction mixture was warmed to 30 C and stirred at that temperature for 1 h before it was quenched with saturated aq. NaHCO 3 (10 ml). The resultant mixture was extracted with EtOAc (3 20 ml). The combined organic phases were washed with brine (10 ml), dried over anhydrous Na 2 SO 4, filtered, and concentrated under vacuum. The residue was passed through a short plug of silica gel using EtOAc/petroleum ether (1:15 1:5) as eluent to give N-Ts-14-hydroxyaflavinine as a colorless oil (15.4 mg, 89%). This oil was dissolved in MeOH (5.0 ml). To the solution were sequentially added NH 4 Cl (2.2 mg, mmol) and Mg powder (6.5 mg, 0.27 mmol) at 22 C. The resultant mixture was sonicated at that temperature for 1 h before it was quenched with saturated aq. NH 4 Cl (8 ml). The mixture so obtained was extracted with EtOAc (3 10 ml), and S25