Supporting Information

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1 Supporting Information First Total Syntheses of Tetracenomycins C and X Shogo Sato, Keiichiro Sakata, Yoshimitsu Hashimoto, Hiroshi Takikawa, and Keisuke Suzuki* anie_ _sm_miscellaneous_information.pdf

2 SUPPRTING INFRMATIN General Experimental Procedure All reactions utilizing air- or moisture-sensitive reagents were performed in dried glassware under an atmosphere of dry argon. THF, Et 2, and dichloromethane (anhydrous; Kanto Chemical Co., Inc.) were purified under argon using a solvent purification unit (Wako Pure Chemical Industries, Ltd). Toluene (anhydrous; Kanto Chemical Co., Inc.) was used as received. Et 3 N, DMF, CN, H, NMP, PhCl, and pyridine were distilled prior to use according to the standard protocols. Trimethyloxonium tetrafluoroborate was purified according to the literature procedure. [1] ther reagents were used without further purification. For thin-layer chromatography (TLC) analysis, rck pre-coated plates (silica gel 60 F254, 0.25 mm) were used. Silica-gel preparative thin-layer chromatography (PTLC) was performed using plates prepared from rck silica gel 60 PF254 (Art 7747). For flash column chromatography, silica gel 60N (spherical, neutral, µm) from Kanto Chemical was used. lting point (mp) determinations were performed using a Yanaco MP-500 instrument or a METTLER TLED M70 melting point system, and are uncorrected. 1 H- and 13 C-NMR were measured on a Bruker Avance III (600 MHz) spectrometer in the solvent indicated; Chemical shifts (δ) are expressed in parts per million (ppm) downfield from internal standard (tetramethylsilane; 0.00 ppm), and coupling constants are reported as hertz (Hz). Splitting patterns are indicated as follows: br, broad; s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet. Infrared (IR) spectra were recorded on a Thermo Scientific Nicolet is5 FT-IR spectrometer. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectra were recorded by using Thermo Scientific Nicolet is5 FT-IR spectrometer equipped with a universal ATR sampling accessory (id5 ATR). High-resolution mass spectra (HRMS) were obtained with Bruker Daltonics micrtf-q II. X-ray crystallographic data were recorded with a Rigaku RAXIS-RAPID diffractometer. [1] T. J. Curphey, rg. Synth. 1971, 51,

3 SUPPRTING INFRMATIN Synthesis of bis-tosylate S-1 H H H TsCl (2.8 equiv) K 2 C 3 (6.0 equiv) acetone, rt, 15 h then H, rt, 2 h To a mixture of phloroglucinol (5.00 g, 39.6 mmol) and K 2 C 3 (32.9 g, 238 mmol) in acetone (40 ml) was added TsCl (21.1 g, 111 mmol) at 0 C. After stirring for 4 h at room temperature, H (40 ml) was added to the mixture. After stirring for 2 h, the reaction mixture was quenched by adding conc. HCl, and organic solvents were removed by evaporation. The residue was dissolved in 1 M NaH at 0 C and the aqueous layer was washed with Et 2 (x3). The ph of the aqueous layer was adjusted to ca. 1 by conc. HCl, and the mixture was extracted with Et 2 (x3). The combined organic extracts were washed with 10% aqueous K 2 C 3 and the aqueous layer was extracted with toluene (x2). The combined organic extracts were dried (Na 2 S 4 ), and concentrated under reduced pressure to give bis-tosylate S-1 (12.9 g, 75%) as a white solid. R f 0.58 (hexane/etac = 1/1); 1 H NMR (600 MHz, CDCl 3 ) δ 2.46 (s, 6H), 5.36 (s, 1H), 6.21 (s, 1H), 6.46 (s, 2H), 7.33 (d, 4H, J = 8.1 Hz), 7.66 (d, 4H, J = 8.1 Hz); 13 C NMR (150 MHz, CDCl 3 ) δ 21.8, 108.8, 109.0, 128.4, 130.0, 131.7, 146.0, 150.2, 157.1; 75% Ts Spectral data matched the reported data. [2] H S-1 Ts Synthesis of bis-tosylate 13 H I 2 (2.0 equiv) 35% H 2 2 (4.0 equiv) I H I BnBr (1.05 equiv) K 2 C 3 (1.5 equiv) I Bn I Ts Ts H, rt, 32 h Ts Ts acetone, rt, 12 h Ts Ts S-1 S-2 74% for 2 steps 13 To a mixture of bis-tosylate S-1 (12.9 g, 29.6 mmol) and iodine (15.0 g, 59.1 mmol) in H (148 ml) was added aqueous H 2 2 [34.5% (w/v), 11.7 ml, 118 mmol] at 0 C. After stirring for 32 h, the reaction mixture was quenched by 20% aqueous NaHS 3, and products were extracted with CH 2 Cl 2 (x3). The combined organic extracts were washed with water (x2), brine, dried (Na 2 S 4 ) and concentrated in vacuo. The residue was dissolved into acetone (49 ml) and added K 2 C 3 (6.14 g, 44.4 mmol) and BnBr (3.73 ml, 31.2 mmol) at 0 C. After stirring for 12 h at room temperature, the reaction was quenched by adding 1 M HCl, and the products were extracted with CH 2 Cl 2 (x3). The combined organic extracts were washed with saturated aqueous NaHC 3, brine, dried (Na 2 S 4 ), and concentrated in vacuo. Recrystallization from EtAc afforded bis-tosylate 13 (1st crop: g, 51%; 2nd crop: 3.09 g, 13%) as a white solid. The mother liquor was concentrated in vacuo, and the residue was purified by trituration with a mixed solvent (hexane/etac = 1/1) to afford additional 13 as a white solid (2.14 g, 9%; total yield = 74%). [2] T. ikle, R. Stevens, J. Chem. Soc., Perkin Trans. 1, 1979,

4 SUPPRTING INFRMATIN S-2 R f 0.45 (hexane/etac = 1/1); mp C (CHCl 3 /hexane, colorless prisms); 1 H NMR (600 MHz, CDCl 3 ) δ 2.47 (s, 6H), 6.07 (s, 1H), 6.93 (s, 1H), 7.36 (d, 4H, J = 8.0 Hz), 7.82 (d, 4H, J = 8.0 Hz); 13 C NMR (150 MHz, CDCl 3 ) δ 21.8, 78.0, 108.7, 128.8, 130.1, 132.2, 146.3, 151.0, 156.2; IR (ATR) 3452, 1560, 1385, 1190, 1173, 1028, 771, 751 cm 1 ; HRMS (ESI) m/z Calcd for C 20 H 17 I 2 7 S 2 [M+H] + : ; found: R f 0.65 (hexane/etac = 1/1); mp C (EtAc, colorless prisms); 1 H NMR (600 MHz, CDCl 3 ) δ 2.47 (s, 6H), 4.90 (s, 2H), 7.20 (s, 1H), 7.36 (d, 4H, J = 8.3 Hz), (m, 3H), 7.58 (d, 2H, J = 6.8 Hz), 7.83 (d, 4H, J = 8.3 Hz); 13 C NMR (150 MHz, CDCl 3 ) δ 21.9, 74.6, 87.3, 113.0, 128.5, 128.7, 128.9, 130.1, 132.3, 135.4, 146.3, 151.5, (several signals overlapped); IR (ATR) 1594, 1369, 1352, 1191, 1176, 1033, 1010, 750, 660 cm 1 ; HRMS (ESI) m/z Calcd for C 27 H 22 I 2 7 S 2 [M+H] + : ; found: Synthesis of benzocyclobutene 14 I Ts Bn I Ts 13 + TBS 11 (1.1 equiv) n-buli (1.1 equiv) THF C, 1 h 73% I Ts Bn 14 TBS To a mixture of bis-tosylate 13 (1.00 g, 1.29 mmol) and ketene silylacetal 11 (309 mg, 1.42 mmol) in THF (12.9 ml) was added dropwise n-buli (1.57 M in hexane, 0.86 ml, 1.4 mmol) over 10 min at 95 C. After the reaction temperature was slowly raised to 20 C over 1 h, the reaction mixture was quenched by adding water, and the products were extracted with EtAc (x3). The combined extracts were washed with brine, dried (Na 2 S 4 ), and concentrated in vacuo. Trituration with hexane gave crude material, which was purified by flash column chromatography (silica gel, hexane/etac = 1/0 4/1) to afford benzocyclobutene 14 (599 mg, 67%) as a white solid. The mother liquor concentrated in vacuo, and the residue was purified by PTLC (toluene) to afford additional 14 (60 mg, 7%; total yield = 73%) as a white solid. R f 0.52 (hexane/etac = 2/1); mp C (CHCl 3 /hexane, colorless prisms); 1 H NMR (600 MHz, CDCl 3 ) δ 0.04 (s, 3H), 0.03 (s, 3H), 0.92 (s, 9H), 2.44 (s, 3H), 3.37 (s, 3H), 3.54 (s, 3H), 4.84 (s, 1H), 5.35 (d, 1H, J = 12.2 Hz), 5.40 (d, 1H, J = 12.2 Hz), 7.11 (s, 1H), 7.30 (d, 2H, J = 8.3 Hz), (m, 1H), 7.37 (dd, 2H, J = 7.3, 7.7 Hz), 7.47 (d, 2H, J = 7.3 Hz), 7.83 (d, 2H J = 8.3 Hz); 13 C NMR (150 MHz, CDCl 3 ) δ 3.8, 3.0, 18.4, 21.8, 26.0, 51.8, 57.3, 74.0, 85.1, 85.3, 103.9, 111.4, 127.3, 127.9, 128.4, 128.6, 128.9, 129.7, 132.8, 136.6, , 152.4, 154.7; IR (ATR) 2927, 1591, 1354, 1246, 1176, 1052, 736 cm 1 ; HRMS (ESI) m/z Calcd for C 30 H 37 INa 7 SSi [M+Na] + : ; found: CCDC contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via 4

5 SUPPRTING INFRMATIN Synthesis of 1,4-epoxides 15 and 15 2 C 12 (1.5 equiv) + I Ts Bn 14 TBS Bn n-buli (1.25 equiv) 2 C THF, 78 C, 4 h 15, 15 56% (d.r. = 1:1) TBS To a mixture of benzocyclobutene 14 (899 mg, 1.29 mmol) and furan 12 (324 mg, 1.90 mmol) in THF (12.9 ml) was added dropwise n-buli (1.55 M in hexane, 0.87 ml, 1.4 mmol) over 5 min at 78 C. After stirring for 3 h, additional n-buli (0.17 ml, 0.26 mmol) was added to the reaction mixture. After stirring for 1 h, the reaction was quenched by adding water, and the products were extracted with EtAc (x3). The combined extracts were washed with brine, dried (Na 2 S 4 ), and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, hexane/etac = 9/1 to 7/3) to afford a diastereomeric mixture of 1,4-epoxides 15 and 15 (411 mg, 56%, d.r. = 1:1) as a white amorphous solid. A small portion of the mixture was further purified by column chromatography (silica gel, hexane/etac = 9/1) to give analytically pure samples of two diastereomers 15 and 15 both as a white amorphous solid. 15 (more polar) R f 0.60 (hexane/etac = 1/1); 1 H NMR (600 MHz, acetone-d 6 ) δ 0.02 (s, 3H), 0.03(s, 3H), 0.95 (s, 9H), 2.06 (s, 3H), 3.43 (s, 3H), 3.56 (s, 3H), 3.59 (s, 3H), 4.07 (s, 3H), 4.80 (s, 1H), 5.25 (d, 1H, J = 12.0 Hz), 5.38 (d, 1H, J = 12.0 Hz), 5.76 (s, 1H), 7.18 (s, 1H), 7.35 (t, 1H, J = 7.3 Hz), 7.43 (dd, 2H, J = 7.5, 7.3 Hz), 7.55 (d, 2H, J = 7.5 Hz); 13 C NMR (150 MHz, acetone-d 6 ) δ 3.5, 2.7, 18.6, 19.1, 26.5, 50.9, 52.1, 57.5, 60.4, 74.4, 80.2, 85.1, 92.5, 104.6, 111.6, 114.7, 128.3, 128.6, 129.2, 133.7, 138.6, 140.5, 144.4, 148.8, 154.1, 164.6, 182.9; IR (ATR) 2933, 1689, 1616, 1451, 1119, 1074, 1005, 840 cm 1 ; HRMS (ESI) m/z Calcd for C 31 H 40 Na 8 Si [M+Na] + : ; found: (less polar) R f 0.67 (hexane/etac = 1/1); 1 H NMR (600 MHz, acetone-d 6 ) δ 0.04 (s, 3H), 0.06 (s, 3H), 0.90 (s, 9H), 2.05 (s, 3H), 3.40 (s, 3H), 3.55 (s, 3H), 3.59 (s, 3H), 4.04 (s, 3H), 4.86 (s, 1H), 5.32 (d, 1H, J = 12.0 Hz), 5.35 (d, 1H, J = 12.0 Hz), 5.70 (s, 1H), 7.20 (s, 1H), 7.35 (t, 1H, J = 7.3 Hz), 7.44 (dd, 2H, J = 7.5, 7.3 Hz), 7.56 (d, 2H, J = 7.5 Hz); 13 C NMR (150 MHz, acetone-d 6 ) δ 3.6, 2.8, 18.5, 19.0, 26.5, 50.9, 52.3, 57.3, 60.5, 74.4, 80.4, 85.0, 92.5, 105.0, 111.5, 114.9, 128.3, 128.6, 129.3, 133.7, 138.6, 140.2, 144.4, 149.0, 154.2, 164.7, 182.6; IR (ATR) 2932, 2855, 1689, 1616, 1451, 1119, 1074, 839, 782 cm 1 ; HRMS (ESI) m/z Calcd for C 31 H 40 Na 8 Si [M+Na] + : ; found:

6 SUPPRTING INFRMATIN Synthesis of 1,4-epoxides 15 and 15 (one pot) I Ts Bn I Ts 13 TBS 11 (1.1 equiv) n-buli (1.1 equiv) THF C, 2 h 2 C 12 (1.5 equiv) n-buli (1.25 equiv) 78 C, 20 min 44% 2 C Bn 15, 15 (d.r. = 1:1) TBS To a mixture of bis-tosylate 13 (157 mg, mmol) and ketene silylacetal 11 (39 mg, 0.22 mmol) in THF (2.0 ml) was dropwise added n-buli (0.61 M in hexane, 0.37 ml, 0.22 mmol) over 5 min at 95 C. After the reaction temperature was slowly raised to 20 C over 2 h, furan 12 (48.1 mg, 0.22 mmol) in THF (1.0 ml) was added to the reaction mixture at 78 C to which was dropwise added n-buli (0.61 M in hexane, 0.37 ml, 0.22 mmol) over 5 min. After stirring for 20 min, the reaction was quenched by adding water, and the products were extracted with EtAc (x3). The combined extracts were washed with brine, dried (Na 2 S 4 ), and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, hexane/etac = 9/1 to 6/1) to afford a diastereomeric mixture of 1,4-epoxides 15 and 15 (51.0 mg, 44%, d.r. = 1:1) as a white amorphous solid. Synthesis of ketone 16 2 C Bn 15, 15 (d.r. = 1:1) TBS 1) TiCl 4 (5.1 equiv) Zn dust (10.2 equiv) THF, rt, 1 h 2) 46% HF (9.9 equiv) CN, 0 C, 1 h 78% for 2 steps 2 C 16 Bn To a suspension of Zn dust (1.07 g, 16.4 mmol) in THF (16.4 ml) was carefully added TiCl 4 (0.90 ml, 8.2 mmol) at 0 C, and the mixture was heated under reflux for 30 min. The reaction mixture was cooled to 0 C, to which was added dropwise 1,4-epoxides 15 and 15 (0.918 g, 1.61 mmol) in THF (4.0 ml). After stirring for 1 h, the reaction was quenched by adding 1 M HCl, and the products were extracted with EtAc (x3). The combined extracts were washed with brine, dried (Na 2 S 4 ), and concentrated in vacuo. The residue was dissolved into CN (16.1 ml) and added 46% aqueous HF (0.60 ml, 16 mmol) at 0 C. After stirring for 1 h at this temperature, the reaction was quenched by adding saturated NaHC 3 solution, and the aqueous layer was extracted with EtAc (x3). The combined organic extracts were washed with brine, dried (Na 2 S 4 ), and concentrated in vacuo. Trituration with a mixed solvent (hexane/et 2 = 1/1) gave ketone 16 (0.513 g, 78%) as an off-white solid. R f 0.30 (hexane/etac = 2/1); mp 159 C (decomp., CHCl 3 /hexane, yellow prisms); 1 H NMR (600 MHz, CDCl 3 ) δ 2.69 (s, 3H), 3.58 (s, 3H), 3.92 (s, 3H), 3.93 (s, 3H), 5.60 (s, 1H), 5.61 (d, 1H, J = 11.9 Hz), 5.75 (d, 1H, J = 11.9 Hz), 6.99 (s, 1H), 7.35 (t, 1H, J = 7.2 Hz), 7.38 (dd, 2H, J = 7.2, 7.2 Hz), 7.45 (s, 1H), 7.48 (d, 2H, J = 7.2 Hz); 13 C NMR (150 MHz, CDCl 3 ) δ 22.2, 52.5, 55.8, 56.6, 76.2, 91.0, 105.1, 113.8, 120.3, 126.2, 127.0, 128.2, 128.4, 128.6, 135.9, 137.5, 143.8, 147.3, 153.2, 156.1, 168.7, 186.5; IR (ATR) 2927, 1757, 1734, 1607, 6

7 SUPPRTING INFRMATIN 1557, 1263, 1202, 1095, 1064 cm 1 ; HRMS (ESI) m/z Calcd for C 24 H 22 Na 6 [M+Na] + : ; found: CCDC contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via Synthesis of oxime 17 2 C Bn NH 2 H HCl (10.0 equiv) 2 C Bn NH 16 H, pyridine (v/v = 1/1) 60 C, 18 h 17 88% To a solution of ketone 16 (250 mg, mmol) in a mixed solvent of pyridine (1.5 ml) and H (1.5 ml) was added NH 2 H HCl (428 mg, 6.16 mmol). After stirring for 18 h at 60 C, the reaction mixture was poured into 10% aqueous CuS 4 at 0 C, and the aqueous layer was extracted with EtAc (x3). The combined organic extracts were washed successively with 10% aqueous CuS 4 (x3), water, and brine, which was dried (Na 2 S 4 ) and concentrated in vacuo. The residue was purified by trituration with Et 2 to afford oxime 17 as a white solid (1st crop: 136 mg, 53%; 2nd crop: 41.2 mg, 16%). The mother liquor was concentrated in vacuo, and the residue was purified by PTLC (CHCl 3 /EtAc = 9/1) to afford additional 17 as a white solid (48 mg, 19%; total yield = 88%). R f 0.33 (CHCl 3 /EtAc = 10/1); mp 184 C (decomp., CHCl 3 /hexane, colorless needles); 1 H NMR (600 MHz, CDCl 3 ) δ 2.67 (s, 3H), 3.49 (s, 3H), 3.90 (s, 3H), 3.91 (s, 3H), 5.58 (d, 1H, J = 11.8 Hz), 5.71 (d, 1H, J = 11.8 Hz), 5,83 (s, 1H), 6.96 (s, 1H), 7.24 (brs, 1H), 7.32 (t, 1H, J = 7.4 Hz), 7.32 (s, 1H), 7.36 (dd, 2H, J = 7.4, 7.2 Hz), 7.45 (d, 2H, J = 7.2 Hz); 13 C NMR (150 MHz, CDCl 3 ) δ 22.2, 52.4, 55.2, 55.7, 74.2, 82.0, 105.1, 114.7, 118.1, 121.6, 126.7, 128.2, 128.3, 128.5, 135.8, 136.6, 141.0, 143.7, 152.1, 154.6, 155.2, 169.1; IR (ATR) 3286, 2950, 1731, 1607, 1570, 1245, 1221, 1079, 929 cm 1 ; HRMS (ESI) m/z Calcd for C 24 H 24 N 6 [M+H] + : ; found: Synthesis of nitrile oxide 18 2 C Bn NH NCS (2.4 equiv) Et 3 N (2.4 equiv) 2 C Bn C + N 17 H, CH 2 Cl 2 (v/v = 2/1) 0 C, 1 h 73% 18 To a mixture of oxime 17 (499 mg, 1.18 mmol) and Et 3 N (213 µl, 1.54 mmol) in a mixed solvent of H (8 ml) and CH 2 Cl 2 (4 ml) was added NCS (206 mg, 1.54 mmol) at 0 C. The reaction mixture was stirred for 30 min at 0 C before being added additional Et 3 N (180 µl, 1.30 mmol) and NCS (173 mg, 1.30 mmol). After stirring for 30 min at 0 C, the reaction was quenched by adding 10% aqueous Na 2 S 2 3, and the aqueous layer was extracted with EtAc (x3). The combined organic extracts were dried (Na 2 S 4 ) and concentrated in vacuo. 7

8 SUPPRTING INFRMATIN The residue was purified by flash column chromatography (silica gel, hexane/etac = 3/1 to 0/1) to afford nitrile oxide 18 (307 mg, 57%) as a white solid. The fraction containing a mixture of 18 and impurity were further purified by PTLC (hexane/etac = 1/1) to afford 18 (88.0 mg, 15%; total yield = 73%) as a white solid. R f 0.67 (hexane/etac = 1/1); mp 141 C (decomp., CHCl 3 /hexane, colorless needles); 1 H NMR (600 MHz, CDCl 3 ) δ 2.76 (s, 3H), 3.42 (s, 6H), 3.93 (s, 3H), 3.96 (s, 3H), 5.06 (s, 2H), 5.55 (s, 1H), 7.07 (s, 1H), 7.39 (t, 1H, J = 7.2 Hz), 7.44 (dd, 2H, J = 7.3, 7.2 Hz), 7.52 (d, 2H, J = 7.3 Hz), 7.74 (s, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 19.4, 33.7, 52.6, 53.6, 55.9, 79.0, 101.3, 102.7, 105.5, 122.2, 123.0, , , , , , 133.3, 135.3, 137.4, 137.5, 155.4, 162.1, 168.5; IR (ATR) 2926, 2853, 2298, 1732, 1242, 1610, 1102, 1064 cm 1 ; HRMS (ESI) m/z Calcd for C 25 H 26 N 7 [M+H] + : ; found: Synthesis of triflate S-4 H C 2 Tf 2 (1.6 equiv) Et 3 N (2.4 equiv) Tf C 2 CH 2 Cl 2, rt, 4 h 98% S-4 To a mixture of methyl 3-hydroxy-2-naphthoate (4.04 g, 20.0 mmol) and Et 3 N (4.44 ml, 32.0 mmol) in CH 2 Cl 2 (200 ml) was dropwise added trifluoromethanesulfonic anhydride (5.25 ml, 32.0 mmol) at 0 C. After stirring for 4 h at room temperature, additional portion of Et 3 N was added (1st portion: 1.11 ml, 8.00 mmol, 2nd portion: 1.11 ml, 8.00 mmol; total = 6.66 ml, 48.0 mmol) with 1 h interval. The reaction was quenched by adding water, and the mixture was extracted with CH 2 Cl 2 (x3). The combined organic extracts were washed with brine, dried (Na 2 S 4 ), and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane/etac = 9/1) to afford triflate S-4 (6.53 g, 98%) as a white solid. R f 0.45 (hexane/etac = 4/1); mp C (CHCl 3 /hexane, colorless prisms); 1 H NMR (600 MHz, CDCl 3 ) δ 4.02 (s, 3H), 7.64 (dd, 1H, J = 2.0, 2.3 Hz), 7.70 (dd, 1H, J = 2.0, 2.3 Hz), 7.75 (s, 1H), 7.89 (d, 1H, J = 2.3 Hz), 8.00 (d, 1H, J = 2.3 Hz), 8.67 (s, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 52.7, (q, J CF = Hz), 121.1, 127.8, 128.1, 129.2, 129.3, 129.8, 131.4, 134.9, 135.0, 144.8, 164.4; IR (ATR) 1714, 1419, 1333, 1272, 1209, 1134, 1040 cm 1 ; HRMS (ESI) m/z Calcd for C 13 F 3 H 9 5 S [M+H] + : ; found: Synthesis of methyl 3-methyl-2-naphthoate (S-5) Tf C 2 MgBr (1.1 equiv) Fe(acac) 3 (10 mol%) C 2 THF, NMP (v/v = 3/1) rt, 4 h S-4 92% S-5 To a mixture of triflate S-4 (3.00 g, 8.97 mmol) and Fe(acac) 3 (317 mg, mmol) in THF (74 ml) and N- methylpyrrolidone (25 ml) was dropwise added MgBr (0.9 M in THF, 10.8 ml, 9.87 mmol) at 0 C. After stirring for 4 h at room temperature, the solution was diluted with Et 2, followed by adding 1 M HCl. The 8

9 SUPPRTING INFRMATIN mixture was extracted with EtAc (x3), and the combined organic extracts were washed with saturated aqueous NaHC 3, water, and brine. The organic layer was dried (Na 2 S 4 ), and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane/etac = 9/1) to afford methyl 3-methyl-2-naphthoate (S- 5) (1.65 g, 92%) as a white amorphous solid. R f 0.55 (hexane/etac = 9/1); 1 H NMR (600 MHz, CDCl 3 ) δ 2.74 (s, 3H), 3.95 (s, 3H), 7.46 (dd, 1H, J = 2.1, 2.3 Hz), 7.54 (dd, 1H, J = 2.1, 2.3 Hz), 7.67 (s, 1H), 7.76 (d, 1H, J = 2.3 Hz), 7.87 (d, 1H, J = 2.3 Hz), 8.48 (s, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 22.0, 52.0, 125.8, 126.9, 128.1, 128.7, 129.6, 131.0, 131.9, 135.1, 135.5, 168.1; IR (ATR) 1705, 1630, 1574, 1503, 1460, 1432, 1272, 1241, 1200, 1128, 1062 cm 1 ; HRMS (ESI) m/z Calcd for C 13 H 13 2 [M+H] + : ; found: Synthesis of aldehyde S-7 C 2 NBS (1.05 equiv) benzoyl peroxide (3 mol%) Br C 2 H (1.05 equiv) K 2 C 3 (1.3 equiv) C 2 CCl 4, reflux, 7 h DMF, rt, 3 h S-5 S-6 74% for 2 steps S-7 To a solution of methyl 3-methyl-2-naphthoate (S-5) (7.11 g, 35.5 mmol) in CCl 4 (35 ml) was added N- bromosuccinimide (6.64 g, 37.3 mmol) at room temperature. The mixture was degassed by sonication (x5), to which was added benzoyl peroxide (86.0 mg, mmol). After stirring for 4 h under reflux, additional portion of benzoyl peroxide was added (1st portion: 86.0 mg, mmol, 2nd portion: 86.0 mg, mmol, total = 1.07 mmol) with 7 h interval. The reaction was quenched by adding 10% aqueous Na 2 S 3, filtered through a Celite pad (washed with EtAc). The filtrate was extracted with EtAc (x3), and the combined organic extracts were washed with water and brine, dried (Na 2 S 4 ), and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane/etac = 11/1) to afford methyl 3-bromomethyl-2-naphthoate (S-6) contaminated with unreacted S-5 (9.75 g, S-6/S-5 = 91/9) as colorless syrup. The mixture was azeotropically dried with toluene (20 ml), and dissolved in DMF (71 ml), to which were added o-vanillin (4.86 g, 32.0 mmol) and K 2 C 3 (5.89 g, 42.6 mmol). After stirring for 3 h at room temperature, the reaction was quenched by adding water. The mixture was extracted with CHCl 3 (x3), and the combined organic extracts were dried (Na 2 S 4 ), and concentrated in vacuo. The residue was purified by trituration (hexane/etac = 4/1) followed by column chromatography (silica gel, hexane/etac = 5/1) to afford aldehyde S-7 [9.18 g, 74% (2 steps)] as a white solid. R f 0.20 (hexane/etac = 5/1); mp C (CHCl 3 /hexane, colorless needles); 1 H NMR (600 MHz, CDCl 3 ) δ (s, 3H), (s, 3H), 5.73 (s, 2H), (m, 2H), 7.44 (dd, 1H, J = 0.5, 2.1 Hz), 7.56 (dd, 1H, J = 2.1, 2.3 Hz), 7.61 (dd, 1H, J = 2.1, 2.3 Hz), 7.90 (d, 1H, J = 2.3 Hz), 7.93 (d, 1H, J = 2.3 Hz), 8.25 (s, 1H), 8.60 (s, 1H), 10.4 (s, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 57.0, 64.6, 73.6, 103.6, 109.2, 124.7, 126.6, 126.8, 127.7, 9

10 SUPPRTING INFRMATIN 127.8, 129.5, 130.9, , , 133.5, 134.2, 136.7, 150.7, 153.2; IR (ATR) 1722, 1690, 1586, 1482, 1439, 1281, 1200, 1129, 1062 cm 1 ; HRMS (ESI) m/z Calcd for C 21 H 18 Na 5 [M+Na] + : ; found: Synthesis of phenol S-8 H C 2 mcpba (1.2 equiv) CH 2 Cl 2, rt, 22 h then K 2 C 3, H C 2 S-7 94% S-8 To a solution of aldehyde S-7 (15.1 g, 43.1 mmol) in CH 2 Cl 2 (140 ml) was added mcpba (65% chemical purity, 2.80 g, 51.7 mmol) at 0 C. After stirring for 22 h at room temperature, K 2 C 3 (8.94 g, 64.7 mmol) and H (140 ml) were added to the mixture. After stirring for 3 h at room temperature, the reaction was quenched by adding 10% aqueous Na 2 S 2 3. The mixture was extracted with CH 2 Cl 2 (x3). The combined organic extracts were washed with water and brine, dried (Na 2 S 4 ), and concentrated under reduced pressure. The residue was purified by trituration (hexane/etac = 8/1) to afford phenol S-8 (10.2 g, 70%) as a white solid. The mother liquor was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/etac = 4/1) to afford additional S-8 (3.57 g, 24%; total yield = 94 %) as a white solid. R f 0.40 (hexane/etac = 3/1); mp C (EtAc/hexane, colorless prisms); 1 H NMR (600 MHz, CDCl 3 ) δ 3.92 (s, 3H), 4.02 (s, 3H), 5.38 (s, 2H), 6.49 (d, 1H, J = 2.0 Hz), 6.62 (d, 1H, J = 2.3 Hz), 6.96 (dd, 1H, J = 2.0, 2.3 Hz), 7.58 (dd, 1H, J = 2.0, 2.3 Hz), 7.63 (dd, 1H, J = 2.0, 2.3 Hz), 7.57(s, 1H), 7.91 (d, 1H, J = 2.3 Hz), 7.94 (d, 2H, J = 2.3 Hz), 8.04 (s, 1H) 8.65 (s, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 52.7, 56.0, 73.3, 103.5, 108.9, 124.6, 126.6, 127.2, 127.8, 128.8, 128.9, 131.4, 132.3, 133.1, 133.5, 134.3, 135.0, 151.2, 153.3, 168.3; IR (ATR) 3461, 2948, 1722, 1595, 1483, 1464, 1278, 1203, 1127, 1072 cm 1 ; HRMS (ESI) m/z Calcd for C 20 H 18 Na 5 [M+Na] + : ; found: Synthesis of alcohol S-9 H C 2 NaBH 4 (10 equiv) H THF, reflux, 1 h H H S-8 92% S-9 To a solution of phenol S-8 (13.7 g, 40.5 mmol) in THF (162 ml) was added portionwise NaBH 4 (7.66 g, 203 mmol) at 0 C. The mixture was stirred under reflux, to which was dropwise added H (18 ml) over 1 h. To the mixture was added an additional portion of NaBH 4 (7.66 g, 203 mmol) at 0 C, and the mixture was stirred 10

11 SUPPRTING INFRMATIN under reflux, to which was dropwise added H (18 ml) over 1 h. The reaction was quenched by adding 2 M HCl, filtered through a Celite pad (washed with EtAc) and extracted with EtAc (x3). The combined organic extracts were dried (Na 2 S 4 ), and concentrated in vacuo. The residue was triturated (Et 2 ), and the filtrate was purified by column chromatography (silica gel, hexane/etac = 2/1) to afford alcohol S-9 (11.4 g, 92%) as a white solid. R f 0.15 (hexane/etac = 3/1); mp C (CHCl 3 /hexane, colorless prisms); 1 H NMR (600 MHz, CDCl 3 ) δ2.72 (t, 1H, J = 1.6 Hz, H), 3.94 (s, 3H), 5.06 (d, 2H, J = 1.6 Hz), 5.26 (s, 2H), 6.50 (d, 1H, J = 2.3 Hz), 6.56 (d, 1H, J = 2.3 Hz), 6.95 (dd, 1H, J = 2.3, 2.3 Hz), 7.44 (s, 1H), (m, 2H), (m, 4H); 13 C NMR (150 MHz, CDCl 3 ) δ 56.0, 64.7, 73.6, 103.6, 109.1, 124.7, 126.7, 126.9, 127.7, 127.8, 129.5, 130.9, , , 133.5, 134.2, 136.7, 150.7, 153.2; IR (ATR) 3431, 3151, 1589, 1516, 1473, 1310, 1083, 1074, 1006 cm 1 ; HRMS (ESI) m/z Calcd for C 19 H 18 Na 4 [M+Na] + : ; found: Synthesis of o-quinone monoacetal 24d H H PhI(CCF 3 ) 2 (1.2 equiv) Na 2 C 3 (3.0 equiv) CH 2 Cl 2, rt, 2 h S-9 73% 24d To a mixture of alcohol S-9 (50.0 mg, mmol) and Na 2 C 3 (51.2 mg, mmol) in CH 2 Cl 2 (5.4 ml) was added bis(trifluoroacetoxy)iodobenzene (62.0 mg, mmol) at 0 C. After stirring for 2 h at room temperature, the reaction was quenched by adding 10% aqueous Na 2 S 2 3, and the mixture was extracted with EtAc (x3). The combined organic extracts were washed with water and brine, dried (Na 2 S 4 ), and concentrated in vacuo. The residue was purified by PTLC (hexane/etac = 3/2) to afford o-quinone monoacetal 24d (36.0 mg, 73%) as a yellow amorphous solid. R f 0.30 (hexane/etac = 2/1); 1 H NMR (600 MHz, CDCl 3 ) δ 3.77 (s, 3H), 5.30 (d, 1H, J = 2.0 Hz), 5.41 (d, 2H, J = 4.2 Hz), 5.60 (d, 2H, J = 4.2 Hz), 5.84 (d, 1H, J = 2.8 Hz), 6.98 (dd, 1H, J = 2.0, 2.8 Hz), 7.43 (dd, 2H, J = 0.9, 2.8 Hz), 7.56 (s, 2H), 7.76 (dd 2H, J = 0.9, 2.8 Hz); 13 C NMR (150 MHz, CDCl 3 ) δ 56.1, 68.3, 93.6, 94.9, 118.6, 124.9, 126.0, 127.4, 132.3, 135.7, 141.9, 165.0, 195.1; IR (ATR) 1670, 1635, 1558, 1450, 1357, 1267, 1236, 1129, 1083, 1038 cm 1 ; HRMS (ESI) m/z Calcd for C 19 H 16 Na 4 [M+Na] + : ; found:

12 SUPPRTING INFRMATIN Synthesis of isoxazoline S-10 2 C Bn C + N + PhCl 50 C, 3.5 h 2 C Bn N H H 18 76% S-10 24d (1.8 equiv) A suspension of nitrile oxide 18 (1.31 g, 2.90 mmol) and o-quinone monoacetal 24d (1.61 g, 5.22 mmol) in PhCl (5.8 ml) was stirred at room temperature for 3.5 h at 50 C. The reaction mixture was concentrated in vacuo, and the residue was purified by flash column chromatography (silica gel, hexane/etac = 2/1 to 5/3) to afford isoxazoline S-10 (1.68 g, 76%) as a white amorphous solid. R f 0.60 (hexane/etac = 1/1); 1 H NMR (600 MHz, acetone-d 6 ) δ 2.77 (s, 3H), 3.14 (s, 3H), 3.38 (s, 3H), 3.61 (s, 3H), 3.88 (s, 3H), 3.97 (s, 3H), 4.78 (d, 1H, J = 11.4 Hz), 4.99 (d, 1H, J = 15.2 Hz), 5.04 (d, 1H, J = 14.0 Hz), 5.05 (d, 1H, J = 9.9 Hz), 5.07 (d, 1H, J = 11.4 Hz), 5.14 (d, 1H, J = 14.0 Hz), 5.17 (d, 1H, J = 15.2 Hz), 5.24 (d, 1H, J = 2.6 Hz), 5.61 (dd, 1H, J = 2.6, 9.9 Hz), 5.68 (s, 1H), 7.39 (t, 1H, J = 7.3 Hz), 7.42 (s, 1H), (m, 4H), 7.51 (d, 1H, J = 7.4 Hz), 7.62 (s, 1H), 7.63 (s, 1H), 4.78 (m, 2H), 7.92 (s, 1H); 13 C NMR (150 MHz, acetone-d 6 ) δ 19.4, 52.4, 52.6, 54.0, 56.1, 56.3, 59.1, 68.4, 68.9, 77.8, 78.9, 98.9, 101.4, 102.0, 106.4, 119.9, 122.9, 123.7, 125.3, 125.8, 127.0, 128.2, 128.3, 128.5, , 129.5, 133.0, 133.2, 133.4, 136.1, 137.0, 137.5, 137.8, 138.2, 153.4, , , 157.5, 168.8, 195.0; IR (ATR) 2942, 2834, 1732, 1615, 1453, 1236, 1087, 1045, 879, 738 cm 1 ; HRMS (ESI) m/z Calcd for C 44 H 41 NNa 11 [M+Na] + : ; found: Synthesis of isoxazole S-11 2 C Bn N H H Ni 2 (20 equiv) CH 2 Cl 2, 0 C, 1 h 2 C Bn N S-10 S-11 82% To a solution of isoxazoline S-10 (1.59 g, 2.09 mmol) in CH 2 Cl 2 (42 ml) was portionwise added nickel peroxide (1.90 g, 20.9 mmol) at 0 C. The reaction mixture was stirred for 30 min at 0 C before being added additional nickel peroxide (1.90 g, 20.9 mmol). After stirring for 30 min at this temperature, the reaction mixture was filtered through a Celite pad (washed with EtAc) and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/etac = 1/1) to afford isoxazole S-11 (1.30 g, 82%) as an off-white amorphous solid. R f 0.47 (hexane/etac = 1/1); 1 H NMR (600 MHz, acetone-d 6 ) δ 2.75 (s, 3H), 2.98 (s, 3H), 3.40 (s, 3H), 3.88 (s, 3H), 3.97 (s, 3H), 3.99 (s, 3H), 4.80 (d, 1H, J = 11.3 Hz), 4.85 (d, 1H, J = 11.3 Hz), 5.22 (d, 1H, J = 15.4 Hz), 5.46 (d, 1H, J = 15.2 Hz), 5.49 (d, 1H, J = 15.4 Hz), 5.52 (d, 1H, J = 15.2 Hz), 5.66 (s, 1H), 7.27 (d, 2H, J =

13 SUPPRTING INFRMATIN Hz), 7.30 (t, 1H, J = 7.3 Hz), 7.35 (dd, 2H, J = 7.1, 7.3 Hz), (m, 2H), 7.60 (s, 1H), 7.64 (s, 1H), (m, 2H), 7.97 (s, 1H); 13 C NMR (150 MHz, acetone-d 6 ) δ 19.3, 50.9, 52.4, 54.4, 56.3, 57.7, 68.90, 68.94, 78.4, 88.2, 95.9, 100.5, 106.5, 109.6, 117.6, 123.0, 123.7, 125.3, 125.7, 126.9, 127.0, , , 128.7, 129.2, 129.4, , , , 136.8, 136.9, 137.0, 137.8, 138.4, 155.6, , , 168.8, 170.5, 176.8, (several signals overlapped); IR (neat) 3013, 2950, 2832, 1732, 1620, 1574, 1448, 1325, 1239, 1173, 1083, 1052 cm 1 ; HRMS (ESI) m/z Calcd for C 44 H 39 NNa 11 [M+Na] + : ; found: Synthesis of aldehyde 25 2 C Bn N 2 M H 2 S 4 THF, rt, 3 h 2 C Bn N S % To a solution of isoxazole S-11 (329 mg, mmol) in THF (4.3 ml) was added 2 M H 2 S 4 (4.3 ml) at 0 C. After stirring for 3 h at room temperature, the reaction mixture was poured into saturated aqueous NaHC 3, and the products were extracted with EtAc (x3). The combined extracts were washed with brine, dried (Na 2 S 4 ), and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/etac = 1/1) to afford aldehyde 25 (301 mg, 97%) as an off-white solid. R f 0.43 (hexane/1,4-dioxane = 1/1); mp 198 C (decomp.); 1 H NMR (600 MHz, CDCl 3 ) δ 2.78 (s, 3H), 3.90 (s, 3H), 3.95 (s, 3H), 3.96 (s, 3H), 4.71 (d, 1H, J = 11.4 Hz), 4.85 (d, 1H, J = 11.4 Hz), 5.19 (d, 1H, J = 15.1 Hz), 5.37 (d, 1H, J = 15.0 Hz), 5.45 (d, 1H, J = 15.1 Hz), 5.58 (d, 1H, J = 15.0 Hz), 5.90 (s, 1H), 7.21 (d, 2H, J = 7.3 Hz), 7.23 (s, 1H), (m, 3H), (m, 2H), 7.47 (s, 1H), 7.52 (s, 1H), (m, 2H), 8.19 (s, 1H), (s, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 19.3, 52.3, 56.0, 57.0, 68.5, 68.7, 78.2, 87.4, 95.0, 106.3, 109.0, 115.8, 124.8, 125.1, 125.5, , , 127.3, 127.4, 128.0, 128.4, 128.7, 130.2, 132.2, 133.5, 133.9, 135.2, 135.4, 136.4, 137.3, 155.1, 155.3, 157.5, 168.4, 169.3, 175.7, 184.6, (several signals overlapped); IR (ATR) 2947, 1731, 1695, 1614, 1568, 1453, 1323, 1241, 1222, 1172, 1090, 1045 cm 1 ; HRMS (ESI) Calcd for m/z C 42 H 34 N 10 [M+H] + : ; found:

14 SUPPRTING INFRMATIN Synthesis of α-ketol 26 2 C Bn N N N C N 6 F 5 23b (15 mol%) Et 3 N (15 mol%) THF, rt, 3 h + BF 4 2 C Bn N H 25 87%, >99% ee 26 A mixture of ketoaldehyde 25 (180 mg, mmol) and triazolium salt 23b (15.4 mg, 37.9 µmol) in THF (2.5 ml) was degassed by sonication under reduced pressure. To the mixture was dropwise added Et 3 N (5.3 µl, 38 µmol) at room temperature. After stirring for 3 h at this temperature, the reaction was quenched by adding saturated aqueous NH 4 Cl, and the products were extracted with EtAc (x3). The combined organic extracts were washed with brine, dried (Na 2 S 4 ), and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/etac = 13/7 to 9/11) to afford α-ketol (R)-26 (157 mg, 87%, >99% ee) as a pale yellow amorphous solid. R f 0.57 (CHCl 3 /CN = 20/1); 1 H NMR (600 MHz, CDCl 3 ) δ 2.78 (s, 3H), 3.58 (s, 3H), 3.93 (s, 1H), 3.95 (s, 3H), 3.96 (s, 3H), 4.99 (d, 1H, J = 13.8 Hz), 5.00 (d, 1H, J = 10.4 Hz), 5.04 (d, 1H, J = 16.3 Hz), 5.20 (d, 1H, J = 16.3 Hz), 5.21 (d, 1H, J = 10.4 Hz), 5.91 (s, 1H), 6.42 (d, 1H, J = 13.8 Hz), 7.19 (s, 1H), 7.36 (t, 1H, J = 7.3 Hz), 7.39 (s, 1H), 7.42 (dd, 2H, J = 7.3, 7.6 Hz), 7.46 (m, 2H), (m, 4H), 7.83 (dd, J = 3.4, 6.1 Hz), 8.43 (s, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 19.8, 52.6, 56.0, 56.1, 67.4, 70.3, 70.6, 77.1, 88.9, 103.7, 106.7, 106.8, 116.2, 122.4, 125.9, 126.2, 126.4, 127.1, 127.2, 127.7, 128.1, 128.4, 128.6, 130.2, 130.4, 132.1, 132.6, , , 135.3, 136.5, 137.4, 153.9, 155.0, 155.9, 162.0, 166.7, 168.5, (several signals overlapped); IR (ATR) 3505, 2946, 2869, 1731, 1703, 1591, 1564, 1513, 1455, 1321, 1240, 1153, 1053, 744 cm 1 ; HRMS (ESI) m/z Calcd for C 42 H 34 N 10 [M+H] + : ; found: ; ptical Rotation [α] 20 D (c 2.79, CHCl 3 ). Enantiomeric purity of (R)-26 was assessed by HPLC analysis on a chiral stationary phase [DAICEL CHIRALPAK ID (4.6 mm φ 250 mm), hexane/etac = 1/1, flow rate 1.0 ml/min, t R = 8.9 min for the (S)- isomer, 13.4 min for the (R)-isomer]. 14

15 SUPPRTING INFRMATIN Racemic 26 ptically active (R)-26 Synthesis of isoxazole S-12 2 C Bn N Bn*Br (5.2 equiv) NaH (4.0 equiv) 2 C Bn N 26 H DMF 20 0 C, 1 h 94% Bn* S-12 To the mixture of α-ketol 26 (161 mg, mmol) and benzyl bromide-d [3] 7 (0.140 ml, 1.18 mmol) in DMF (9.0 ml) was added NaH (63% dispersion in mineral oil, 34.4 mg, mmol) at 20 C. After stirring for 1 h at 0 C, the reaction was quenched by adding saturated aqueous NH 4 Cl, and the products were extracted with EtAc (x4). The combined organic extracts were washed with brine, dried (Na 2 S 4 ), and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/etac = 4/1 to 3/2) to afford isoxazole S-12 (172 mg, 94%) as an off-white amorphous solid. R f 0.67 (hexane/etac = 1/1); 1 H NMR (600 MHz, CDCl 3 ) δ 2.79 (s, 3H), 3.70 (s, 3H), 3.93 (s, 3H), 3.96 (s, 3H), 5.01 (d, 1H, J = 10.4 Hz), 5.04 (d, 1H, J = 15.7 Hz), 5.09 (d, 1H, J = 10.4 Hz), 5.13 (d, 1H, J = 14.6 Hz), 5.23 (d, 1H, J = 15.7 Hz), 5.89 (s, 1H), 6.62 (d, 1H, J = 14.6 Hz), 7.12 (s, 1H), (m, 5H), (m, 4H), (m, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 19.8, 52.6, 56.0, 56.5, 67.0, 68.0, 69.6, 76.1, 77.1, 88.1, 104.0, 104.9, 106.7, 115.7, 123.3, 125.8, 125.9, , , 127.1, , , , , , [3] A. ddour, J. Courtieu, Terrahedron: Asymmetry 2000, 11,

16 SUPPRTING INFRMATIN , , 128.2, 128.3, 128.4, 128.7, 130.1, 131.9, 132.3, 132.4, 134.4, 135.5, 136.0, 136.4, 137.5, 137.6, 154.1, 155.0, 155.5, 164.6, 167.3, 168.5, (several signals overlapped); IR (ATR) 2947, 1732, 1705, 1589, 1454, 1324, 1228, 1154, 1054, 908, 729 cm 1 ; HRMS (ESI) Calcd for m/z C 49 H 33 D 7 N 10 [M+H] + : ; found: ; ptical Rotation [α] 20 D (c 1.05, CHCl 3 ). Synthesis of isoxazolium salt 27 2 C Bn N 3 + BF 4 (1.4 equiv) MS4A (4 g/mmol) 2 C BF 4 Bn N + Bn* S-12 CH 2 Cl 2, rt, 14 h 97% 27 Bn* To a mixture of isoxazole S-12 (289 mg, mmol) and MS4A (1.43 g, 4 g/mmol) in CH 2 Cl 2 (10 ml) was added trimethyloxonium tetrafluoroborate (63.3 mg, mmol) at 0 C. The reaction mixture was stirred for 11 h at room temperature before being added additional trimethyloxonium tetrafluoroborate (10.6 mg, mmol). After stirring for 3 h at room temperature, the reaction was stopped by adding H. The mixture was filtered through a Celite pad (washed with EtAc) and concentrated in vacuo. The residue was purified by trituration (Et 2 /EtAc = 9/1) to afford isoxazolium salt 27 (314 mg, 97%) as a brown solid. R f 0.02 (hexane/etac = 1/1); mp 171 C (decomp.); 1 H NMR (600 MHz, CDCl 3 ) δ 2.89 (s, 3H), 3.84 (s, 3H), (s, 3H), (s, 3H), 4.30 (s, 3H), 4.60 (d, 1H, J = 11.2 Hz), 5.09 (d, 1H, J = 14.1 Hz), 5.15 (d, 1H, J = 16.3 Hz), 5.17 (d, 1H, J = 11.2 Hz), 5.20 (d, 1H, J = 16.3 Hz), 6.28 (s, 1H), 6.50 (d, 1H, J = 14.1 Hz), 7.11 (d, 2H, J = 7.3 Hz), 7.19 (dd, 2H, J = 7.3, 7.6 Hz), (m, 2H), 7.46 (m, 1H), 7.49 (s, 1H), 7.70 (s, 1H), (m, 1H), (m, 1H), 8.30 (s, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 19.3, 43.8, 52.9, 56.4, 58.3, 67.8, 68.5, 70.5, 74.9, 81.6, 87.1, 103.2, 107.5, 108.9, 110.1, 123.5, 124.9, 126.1, 126.4, 126.6, 127.3, 127.4, , , 127.6, 127.8, 128.0, 129.0, 129.1, , , 130.5, 131.3, 132.2, 132.5, 133.0, 134.6, 134.8, 134.9, 136.8, 140.0, 151.6, 157.1, 157.2, 167.5, 171.0, 172.7, (several signals overlapped); IR (ATR) 3638, 2949, 1728, 1604, 1556, 1526, 1317, 1247, 1214, 1183, 1047, 966, 750 cm 1 ; HRMS (ESI) Calcd for m/z C 50 H 35 D 7 N 10 [M BF 4 ] + : ; found: ; ptical Rotation [α] 20 D 19.1 (c 0.102, CHCl 3 ). 16

17 SUPPRTING INFRMATIN Synthesis of alcohol 29a 2 C BF 4 Bn N + ph 8.9 NaCl aq. (saturated with NaHC 3, 8 equiv) 2 C Bn H 27 Bn* acetone 40 C, 10 min 66% 29a Bn* To a solution of isoxazolium salt 27 (23.0 mg, 25.3 µmol) in acetone 16 ml was added 5% NaCl (saturated with NaHC 3, 0.30 ml, 0.20 mmol) at 40 C. After stirring for 10 min at this temperature, the reaction was quenched by adding 10% aqueous Na 2 S 2 3, and the products were extracted with EtAc (x3). The combined organic extracts were washed with brine, dried (Na 2 S 4 ), and concentrated in vacuo. The residue was purified by PTLC (hexane/acetone = 11/9) to afford alcohol 29a (13.8 mg, 66%) as a white solid. R f 0.63 (hexane/etac = 1/1); mp C (CHCl 3 /hexane, colorless needles); 1 H NMR (600 MHz, CDCl 3 ) δ 2.68 (s, 3H), 3.65 (s, 3H), 3.90 (s, 3H), 3.91 (s, 3H), 4.64 (s, 1H), 4.87 (d, 1H, J = 14.5 Hz), 4.91 (d, 1H, J = 15.9 Hz), 4.95 (d, 1H, J = 16.1 Hz), 4.97 (d, 1H, J = 16.1 Hz), 5.05 (d, 1H, J = 15.9 Hz), 5.37 (d, 1H, J = 14.5 Hz), 5.85 (s, 1H), 7.09 (s, 1H), 7.24 (s, 1H), (m, 5H), (m, 3H), (m, 1H), (m, 1H), 8.33 (s, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 20.4, 52.6, 56.0, 56.7, 67.4, 69.5, 70.3, 79.0, 85.9, 87.9, 101.9, 102.5, 106.6, 122.0, 123.2, 124.2, 126.0, 126.1, 126.5, 126.6, 126.7, 126.9, 127.1, 127.4, 127.6, 127.8, 128.4, 128.5, 128.8, 130.2, 132.0, 132.4, 133.8, 134.2, 134.3, 135.6, 136.0, 138.4, 139.0, 155.9, 160.6, 168.3, 171.7, 188.8, (several signals overlapped); IR (neat) 3406, 3013, 2947, 1735, 1705, 1672, 1609, 1326, 1245, 1231, 1153, 1110, 756 cm 1 ; HRMS (ESI) Calcd for m/z C 49 H 34 D 7 12 [M+H] + : ; found: ; ptical Rotation [α] 20 D +155 (c 1.19, CHCl 3 ). Synthesis of tetraketone 30a 2 C Bn H DDQ (8.0 equiv) 2,6-(tBu) 2 -pyridine (16 equiv) 2 C Bn H 29a Bn* 1,2-dichloroethane 80 C, 6 h 78% 30a Bn* To a mixture of alcohol 29a (107 mg, mmol) and 2,6-di-tert-butylpyridine (229 µl, 1.04 mmol) in 1,2- dichloroethane (5.2 ml) was added DDQ (118 mg, mmol) at room temperature. The reaction mixture was stirred for 2 h at 80 C before being added additional 2,6-di-tert-butylpyridine (114 µl, mmol) and DDQ (59.0 mg, mmol). The reaction mixture was stirred for 2 h before being added additional 2,6-di-tertbutylpyridine (114 µl, mmol) and DDQ (59.0 mg, mmol). After stirring for 2 h at 80 C, the reaction was quenched by adding aqueous 10% Na 2 S 2 3, and the products were extracted with EtAc (x3). The combined 17

18 SUPPRTING INFRMATIN organic extracts were washed with brine, dried (Na 2 S 4 ), and concentrated in vacuo. The residue was purified by Smart Flash EPCLC W-Prep 2XY system (ULTRA PACK, DIL-40B, hexane/etac = 3/1 to 3/2) to afford tetraketone 30a (66.5 mg, 78%) as a yellow amorphous solid. R f 0.57 (CHCl 3 /CN = 20/1); 1 H NMR (600 MHz, CDCl 3 ) δ 2.69 (s, 3H), 3.89 (s, 3H), 3.95 (s, 3H), 3.96 (s, 3H), 4.96 (d, 1H, J = 10.9 Hz), 5.05 (s, 1H), 5.21 (d, 1H, J = 10.9 Hz), 5.97 (s, 1H), 7.10 (s, 1H), 7.37 (t, J = 7.2 Hz), 7.41 (dd, J = 7.2, 7.2 Hz), 7.56 (d, J = 7.2 Hz), 8.03 (s, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 20.6, 52.7, 56.2, 57.3, 69.8, 79.6, 85.3, 89.2, 106.7, 110.3, 118.3, 125.5, 126.7, 127.3, , , , , 127.8, , , 130.5, 131.1, 136.0, 136.2, 136.6, 139.3, 156.6, 161.5, 165.2, 167.9, 187.7, 188.8, 190.6, (several signals overlapped); IR (neat) 3419, 3027, 2949, 1738, 1702, 1670, 1599, 1328, 1250, 1081, 1057, 723 cm 1 ; HRMS (ESI) Calcd for m/z C 37 H 23 D 7 Na 11 [M+Na] + 20 : ; found: ; ptical Rotation [α] D 207 (c 1.25, CHCl 3 ). Synthesis of β-alcohol 31 2 C Bn H NaBH 3 CN (4.0 equiv) 30a Bn* 2 C CH 2 Cl 2, AcH (v/v = 30/1) 0 C, 2 h Bn H 31 (63%) H Bn* + 2 C Bn H H Bn* 31 (15%) To a solution of tetraketone 30a (32.9 mg, 50.0 µmol) in a mixed solvent of CH 2 Cl 2 (3.0 ml) and AcH (0.1 ml) was added NaBH 3 CN (6.3 mg, 0.10 mmol) at 0 C. The reaction mixture was stirred for 1 h at 0 C before being added additional NaBH 3 CN (6.3 mg, 0.10 mmol). After stirring for 1 h at 0 C, the reaction was quenched by adding saturated aqueous NaHC 3, and the products were extracted with EtAc (x3). The combined organic extracts were washed with brine, dried (Na 2 S 4 ), and concentrated in vacuo. The residue was purified by Smart Flash EPCLC W-Prep 2XY system (ULTRA PACK, DIL-40A, hexane/etac = 7/3 to 1/1) to afford alcohols 31 (20.8 mg, 63%) and 31 (4.9 mg, 15%) both as a yellow solid. 31 R f 0.67 (CHCl 3 /EtAc = 9/1); mp C; 1 H NMR (600 MHz, CDCl 3 ) δ 2.70 (s, 3H), 3.89 (s, 3H), 3.94 (s, 3H), 3.95 (s, 3H), 4.34 (d, 1H, J = 11.1 Hz), 4.95 (d, 1H, J = 10.9 Hz), 5.25 (d, 1H, J = 11.1 Hz), 5.29 (d, 1H, J = 10.9 Hz), 5.43 (s, 1H), 5.47 (s, 1H), 7.14 (s, 1H), 7.36 (t, 1H, J = 7.3 Hz), 7.40 (dd, 2H, J = 7.2, 7.3 Hz), 7.56 (d, 2H, J = 7.2 Hz), 8.17 (s, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 20.6, 52.7, 56.1, 57.2, 65.7, 66.0, 79.7, 80.5, 82.6, 101.5, 106.6, 118.8, 125.6, 126.6, 127.0, 127.1, 127.3, 127.5, 127.7, 127.8, , , 128.5, 130.3, 130.9, 135.9, 136.2, 136.6, 139.3, 156.5, 161.1, 168.0, 178.2, , , (several signals overlapped); IR 18

19 SUPPRTING INFRMATIN (neat) 3395, 2949, 1736, 1700, 1661, 1605, 1370, 1328, 1251, 1235, 1085, 1055, 752 cm 1 ; HRMS (ESI) Calcd for m/z C 37 H 25 D 7 Na 11 [M+Na] + : ; found: ; ptical Rotation [α] 20 D 215 (c 0.770, CHCl 3 ). 31 R f 0.43 (CHCl 3 /EtAc = 9/1); mp C; 1 H NMR (600 MHz, methanol-d 4 ) δ 2.62 (s, 3H), 3.80 (s, 3H), 3.90 (s, 3H), 3.96 (s, 3H), 4.47 (brs, 1H), 4.94 (d, 1H, J = 10.7 Hz), 5.03 (d, 1H, J = 10.7 Hz), 5.67 (brs, 1H), 7.31 (t, 1H, J = 7.3 Hz), 7.35 (dd, 2H, J = 7.3, 7.0 Hz), 7.45 (s, 1H), 7.52 (d, 2H, J = 7.0 Hz), 8.44 (brs, 1H); 13 C NMR (150 MHz, methanol-d 4 ) δ 20.7, 53.0, 56.7, 57.5, 71.3, 74.3, 79.9, 86.1, 86.2, 101.4, 108.1, 123.9, 124.7, 127.0, 127.9, 128.1, 128.2, , , , , 128.7, 128.8, 129.2, 129.3, 129.6, 131.5, 135.1, 136.2, 138.0, 140.0, 157.3, 161.2, 169.9, 176.1, 192.1, 195.6, (several signals overlapped); IR (neat) 3405, 3018, 2949, 1734, 1704, 1610, 1590, 1327, 1247, 1228, 1095, 1054, 754 cm 1 ; HRMS (ESI) Calcd for m/z C 37 H 25 D 7 Na 11 [M+Na] + : ; found: ; ptical Rotation [α] 20 D 60.7 (c 0.760, CHCl 3 ). Synthesis of tetraketone 30a 2 C Bn H 31 H Bn* To a solution of α-alcohol 31 (11.7 mg, 17.7 µmol) in CH 2 Cl 2 (1.5 ml) was added Dess Martin periodinane (15.0 mg, 35.5 µmol) at 0 C. After stirring for 2 h at room temperature, the reaction was quenched by adding 10% aqueous Na 2 S 2 3, and the products were extracted with EtAc (x3). The combined organic extracts were washed with brine, dried (Na 2 S 4 ), and concentrated in vacuo. The residue was purified by Smart Flash EPCLC W-Prep 2XY system (ULTRA PACK, DIL-40A, hexane/etac = 3/2 to 9/11) to afford tetraketone 30a (9.4 mg, 81%) as a yellow solid. Dess Martin periodinane (2.0 equiv) CH 2 Cl 2, rt, 2 h 81% 2 C Bn H Bn* 30a Synthesis of tetracenomycin C (1) 2 C Bn H H 2 (balloon) PdCl 2 (1.0 equiv) 2 C H H 31 H Bn* H, H 2, AcH (v/v/v = 8/2/1) rt, 1 h 70% H H tetracenomycin C (1) A mixture of β-alcohol 31 (24.5 mg, 37.1 µmol) and PdCl 2 (6.6 mg, 37 µmol) in a mixed solvent (H/H 2 /AcH = 8/2/1, 2.1 ml) was stirred under an atmosphere of hydrogen gas at room temperature. After stirring for 1 h at this temperature, the reaction mixture was filtered through a cotton pad and concentrated in vacuo. The residue was purified by Smart Flash EPCLC W-Prep 2XY system (ULTRA PACK, DIL-40A, hexane/etac = 1/1 to 1/4) to afford tetracenomycin C (1) (12.6 mg, 70%) as a yellow solid. 19

20 SUPPRTING INFRMATIN R f 0.50 (hexane/etac = 1/3); mp 238 C (decomp., H, yellow needles); 1 H NMR (600 MHz, CDCl 3 ) δ 2.85 (s, 3H), 2.91 (d, 1H, J = 9.7 Hz), 3.85 (s, 3H), 3.98 (s, 6H), 4.36 (s, 1H), 4.84 (s, 1H), 4.87 (d, 1H, J = 9.7 Hz), 5.69 (s, 1H), 7.15 (s, 1H), 7.96 (s, 1H), (s, 1H); 13 C NMR (150 MHz, DMS-d 6 ) δ 20.6, 52.6, 56.5, 56.7, 69.1, 83.3, 84.9, 99.5, 108.2, 108.9, , , 128.3, 128.4, 136.6, 140.1, 157.1, 165.8, 167.3, 174.1, 190.9, 193.7, 197.5; IR (neat) 3431, 2951, 1735, 1710, 1671, 1600, 1368, 1255, 1231, 1112, 1093 cm 1 ; HRMS (ESI) Calcd for m/z C 23 H [M+H] + : ; found: ; ptical Rotation [α] 24 D 22.2 (c 1.00, 1,4- dioxane), lit. [4] [α] 24 D 22 (c 1, 1,4-dioxane). Table 1. 1 H-NMR data of natural and synthetic 1 in CDCl 3 Table C-NMR data of natural and synthetic 1 in DMS-d 6 position natural 1 (200 MHz) [4] synthetic 1 (600 MHz) position natural 1 (25.2 MHz) [4] synthetic 1 (150 MHz) 1 H / ppm J / Hz 1 H / ppm J / Hz 13 C / ppm 13 C / ppm 2-H 5.70 d s 3-CH s 3.85 s 4-H 4.90 dd 1.5, d H 2.92 d ca d 9.7 4a-H 4.86 s 4.84 s 6-H 7.98 s 7.96 s 7-H 7.17 s 7.15 s 8-CH s 3.98 s 9-CH s 3.98 s 10-CH s 2.85 s 11-H s s 12a-H 4.86 s 4.84 s 2 C H H a 4a H H tetracenomycin C (1) C C C C 2 CH C C C C-5a C C-6a C-10a C-11a C C C C C-12a 84.9 C-4a 83.4 C ()-CH CH [4] a) W. Weber, H. Zähner, J. Siebers, K. Schröder, A. Zeeck, Arch. Microbiol. 1979, 121, : b) H. Drautz, P. Reuschenbach, H. Zähner, J. Rohr, A. Zeeck, J. Antibiot. 1985, 38,

21 SUPPRTING INFRMATIN Synthesis of ether S-13 2 C Bn H I (50 equiv) NaH (3.0equiv) 2 C Bn 29a Bn* DMF, 0 C, 30 min 90% Bn* S-13 To the mixture of alcohol 29a (78.3 mg, 94.6 µmol) and I (294 µl, 4.73 mmol) in DMF (4.3 ml) was added NaH (63% dispersion in mineral oil, 10.8 mg, mmol) at 0 C. After stirring for 30 min at 0 C, the reaction was quenched by adding saturated aqueous NH 4 Cl, and the products were extracted with EtAc (x3). The combined organic extracts were washed with brine, dried (Na 2 S 4 ), and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/etac = 1/5 to 2/5) to afford ether S-13 (71.7 mg, 90%) as an off-white amorphous solid. R f 0.63 (CHCl 3 /CN = 20/1); 1 H NMR (600 MHz, CDCl 3 ) δ 2.71 (s, 3H), 3.61 (s, 3H), 3.64 (s, 3H), 3.90 (s, 3H), 3.92 (s, 3H), 4.81 (d, 1H, J = 15.8 Hz), 4.86 (d, 1H, J = 14.6 Hz), 4.91 (d, 1H, J = 10.0 Hz), 5.14 (d, 1H, J = 15.8 Hz), 5.30 (d, 1H, J = 10.0 Hz), 5.37 (d, 1H, J = 14.6 Hz), 5.68 (s, 1H), 7.09 (s, 1H), 7.23 (s, 1H), (m, 5H), 7.51 (s, 1H), 7.60 (d, 2H, J = 7.3 Hz), 7.67 (d, 2H, J = 7.2 Hz), 7.73 (d, 1H, J = 7.3 Hz), 8.29 (s, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 20.1, 52.6, 56.0, 56.2, 56.4, 67.2, 69.2, 70.1, 70.2, 70.4, 78.9, 88.7, 91.1, 102.5, 104.2, 106.8, 122.2, 123.3, 124.1, 126.0, 126.1, 126.3, 126.6, 126.8, 126.9, 127.0, 127.1, 127.2, 127.4, 127.5, 127.7, 128.4, , , 130.2, 132.0, 132.2, 133.9, 134.2, 134.4, 135.6, 136.3, 138.7, 139.2, 156.0, 159.3, 168.2, 169.2, 189.5, 193.2, (several signals overlapped); IR (neat) 3013, 2944, 1736, 1703, 1618, 1609, 1245, 1152, 1071, 756 cm 1 ; HRMS (ESI) Calcd for m/z C 50 H 36 D 7 12 [M+H] + : ; found: ; ptical Rotation [α] 20 D +221 (c 1.51, CHCl 3 ). Synthesis of tetraketone 32 2 C Bn DDQ (8.0 equiv) 2,6-(tBu) 2 -pyridine (16 equiv) 2 C Bn Bn* S-13 1,2-dichloroethane 80 C, 4.5 h 75% 32 Bn* To a mixture of ether S-13 (101 mg, mmol) and 2,6-di-tert-butylpyridine (211 µl, mmol) in 1,2- dichloroethane (4.8 ml) was added DDQ (109 mg, mmol) at room temperature. The reaction mixture was stirred for 1.5 h at 80 C before being added additional 2,6-di-tert-butylpyridine (211 µl, mmol) and DDQ (109 mg, mmol). The reaction mixture was stirred for 1.5 h before being added additional 2,6-di-tertbutylpyridine (105 µl, mmol) and DDQ (54.3 mg, mmol). After stirring for 1.5 h at 80 C, the 21

22 SUPPRTING INFRMATIN reaction was quenched by adding aqueous 10% Na 2 S 2 3, and the products were extracted with EtAc (x3). The combined organic extracts were washed with brine, dried (Na 2 S 4 ), and concentrated in vacuo. The residue was purified by Smart Flash EPCLC W-Prep 2XY system (ULTRA PACK, DIL-40B, hexane/etac = 4/1 to 1/1) to afford tetraketone 32 (60.5 mg, 75%) as a yellow amorphous solid. The 1 H NMR of 32 showed the presence of two components in equilibrium with the ratio solvent-dependent, major:minor = 5.3:1 in CDCl 3, 12.9:1 in acetone-d 6, 5.0:1 in toluene-d 8, and 10.3:1 in DMS-d 8. R f 0.57 (CHCl 3 /CN = 20/1); 1 H NMR (600 MHz, CDCl 3, the major component) δ 2.67 (s, 3H), 3.70 (s, 3H), 3.90 (s, 3H), 3.93 (s, 3H), 3.94 (s, 3H), 5.01 (d, 1H, J = 10.7 Hz), 5.25 (d, 1H, J = 10.7 Hz), 5.87 (s, 1H), 7.03 (s, 1H), (m, 3H), 7.59 (d, 2H, J = 7.1 Hz), 7.91 (s, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 20.6, 52.7, 56.1, 56.4, 57.4, 70.1, 79.5, 90.0, 90.7, 106.5, 108.8, 120.3, 125.3, 126.9, 127.2, 127.4, 127.6, 127.7, 127.9, 128.4, 128.6, 128.7, 130.1, 130.9, , , 136.4, 138.6, 156.1, 160.5, 165.4, 168.1, 187.4, 188.5, 190.4, (several signals overlapped); IR (neat) 3020, 2948, 1739, 1716, 1667, 1598, 1327, 1248, 1079, 1063, 753 cm 1 ; HRMS (ESI) Calcd for m/z C 38 H 25 D 7 Na 11 [M+Na] + : ; found: ; ptical Rotation [α] 20 D 195 (c 1.06, CHCl 3 ). Synthesis of β-alcohol 33 2 C Bn NaBH 3 CN (6.0 equiv) 32 Bn* 2 C CH 2 Cl 2, AcH (v/v = 30/1) 0 C, 3 h Bn 33 (69%) H Bn* + 2 C Bn H Bn* 33 (14%) To a solution of tetraketone 32 (19.7 mg, 29.3 µmol) in a mixed solvent of CH 2 Cl 2 (1.8 ml) and AcH (60 µl) was added NaBH 3 CN (3.7 mg, 58.7 µmol) at 0 C. The reaction mixture was stirred for 1 h at 0 C before being added additional NaBH 3 CN (7.4 mg, 117 µmol). After stirring for 2 h at 0 C, the reaction was quenched by adding saturated aqueous NaHC 3, and the products were extracted with EtAc (x3). The combined organic extracts were washed with brine, dried (Na 2 S 4 ), and concentrated in vacuo. The residue was purified by Smart Flash EPCLC W-Prep 2XY system (ULTRA PACK, DIL-40A, hexane/etac/ch 2 Cl 2 = 14/3/3 to 4/3/3) to afford alcohols 33 (13.6 mg, 69%) and 33 (2.8 mg, 14%) both as a yellow solid. The 1 H NMR of 33 showed the presence of two components in equilibrium with the ratio solvent-dependent, major:minor = 13.9:1 in CDCl 3 and 3.6:1 in toluene-d R f 0.73 (CHCl 3 /EtAc = 9/1); mp C; 1 H NMR (600 MHz, CDCl 3 ) δ 2.68 (s, 3H), 3.71 (s, 3H), 3.88 (s, 3H), 3.93 (s, 3H), 3.94 (s, 3H), 4.44 (d, 1H, J = 11.0 Hz), 4.99 (d, 1H, J = 10.9 Hz), 5.28 (d, 1H, J = 11.0 Hz), 22

23 SUPPRTING INFRMATIN 5.33 (d, 1H, J = 10.9 Hz), 5.39 (s, 1H), 7.08 (s, 1H), 7.35 (t, 1H, J = 7.3 Hz), 7.39 (dd, 2H, J = 7.1, 7.3 Hz), 7.58 (d, 2H, J = 7.1 Hz), 8.07 (s, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 20.7, 52.6, 55.9, 56.0, 57.2, 65.9, 66.1, 79.4, 81.9, 101.2, 106.4, 120.8, 125.2, 126.8, 127.0, 127.2, 127.3, 127.4, 127.6, 127.7, 128.3, 128.5, 128.7, 129.9, 130.7, 136.0, 136.3, 136.5, 138.6, 155.9, 160.1, 168.2, 178.8, 190.0, 190.4, (several signals overlapped); IR (neat) 3477, 2946, 1736, 1716, 1692, 1658, 1605, 1248, 1234, 1090, 1065, 754 cm 1 ; HRMS (ESI) Calcd for m/z C 38 H 27 D 7 Na 11 [M+Na] + : ; found: ; ptical Rotation [α] 20 D 267 (c 0.585, CHCl 3 ). 33 R f 0.60 (CHCl 3 /EtAc = 9/1); mp C; 1 H NMR (600 MHz, CDCl 3, the major component) δ 2.67 (s, 3H), 3.68 (s, 3H), 3.89 (s, 3H), 3.92 (s, 3H), 3.93 (s, 3H), 4.35 (d, 1H, J = 11.8 Hz), 5.00 (d, 1H, J = 10.9 Hz), 5.32 (d, 1H, J = 10.9 Hz), 5.33 (s, 1H), 5.55 (d, 1H, J = 11.8 Hz), 7.08 (s, 1H), 7.35 (t, 1H, J = 7.3 Hz), 7.40 (dd, 2H, J = 7.3, 7.3 Hz), 7.58 (d, 2H, J = 7.3 Hz), 8.08 (s, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 20.6, 52.6, 55.8, 56.0, 57.5, 69.4, 70.4, 79.5, 85.1, 90.3, 100.7, 106.4, 121.2, 125.3, 127.0, 127.3, 127.4, 127.5, 127.6, 127.8, 127.9, 128.2, 128.3, 128.5, 128.7, 128.9, 130.5, 130.8, 136.2, 136.5, 136.9, 138.4, 155.9, 159.9, 168.1, 179.4, 190.6, 190.9, (several signals overlapped); IR (neat) 3405, 3018, 2949, 1734, 1704, 1610, 1590, 1327, 1247, 1228, 1095, 1054, 754 cm 1 ; HRMS (ESI) Calcd for m/z C 37 H 25 D 7 Na 11 [M+Na] + : ; found: ; ptical Rotation [α] 20 D 119 (c 0.820, CHCl 3 ). Synthesis of tetraketone 32 2 C Bn Dess Martin periodinane (2.0 equiv) 2 C Bn 33 H Bn* CH 2 Cl 2, rt, 1 h 90% 32 Bn* To a solution of α-alcohol 33 (14.5 mg, 21.5 µmol) in CH 2 Cl 2 (1.8 ml) was added Dess Martin periodinane (18.3 mg, 43.0 µmol) at 0 C. After stirring for 1 h at room temperature, the reaction was quenched by adding 10% aqueous Na 2 S 2 3, and the products were extracted with EtAc (x3). The combined organic extracts were washed with brine, dried (Na 2 S 4 ), and concentrated in vacuo. The residue was purified by Smart Flash EPCLC W-Prep 2XY system (ULTRA PACK, DIL-40A, hexane/etac = 4/1 to 2/3) to afford tetraketone 32 (13.0 mg, 90%) as a yellow amorphous solid. Synthesis of tetracenomycin X (2) 2 C Bn H 2 (balloon) PdCl 2 (1.0 equiv) 2 C H 33 H Bn* H, H 2, AcH (v/v/v = 8/2/1) rt, 3 h 76% H H tetracenomycin X (2) 23

24 SUPPRTING INFRMATIN A mixture of β-alcohol 33 (27.9 mg, 41.4 µmol) and PdCl 2 (7.3 mg, 41 µmol) in a mixed solvent (H/H 2 /AcH = 8/2/1, 3.3 ml) was stirred under an atmosphere of hydrogen gas at room temperature. After stirring for 3 h at this temperature, the reaction mixture was filtered through a cotton pad and concentrated in vacuo. The residue was purified by Smart Flash EPCLC W-Prep 2XY system (ULTRA PACK, DIL-40A, hexane/etac = 1/1 to 7/13) to afford tetracenomycin X (2) (15.4 mg, 76%) as a yellow solid. R f 0.50 (hexane/etac = 1/3); mp 158 C (decomp.); 1 H NMR (600 MHz, CDCl 3 ) δ 2.83 (d, 1H, J = 9.4 Hz), 2.87 (s, 3H), 3.64 (s, 3H), 3.79 (s, 3H), 3.99 (s, 6H), 4.37 (s, 1H), 4.78 (d, 1H, J = 9.4 Hz), 5.55 (s, 1H), 7.17 (s, 1H), 7.95 (s, 1H), (s, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 21.0, 52.8, 56.3, 56.6, 56.9, 69.7, 83.8, 87.0, 101.8, 107.4, 109.0, 121.2, 126.7, 129.4, 139.0, 140.6, 158.2, 167.1, 167.8, 170.9, 190.6, 193.1, 195.6; IR (neat) 3464, 2949, 1733, 1711, 1688, 1603, 1370, 1262, 1231 cm 1 ; HRMS (ESI) Calcd for m/z C 24 H 22 Na 11 [M+H] + : ; found: ; ptical Rotation [α] 20 D 105 (c 0.290, H), lit. [5] [α] 20 D (c 0.66, H). Table 3. 1 H-NMR data of natural and synthetic 2 in CDCl 3 Table C-NMR data of natural and synthetic 2 in CDCl 3 position natural 2 (500 MHz) [5] synthetic 2 (600 MHz) position natural 2 (125 MHz) [5] synthetic 2 (150 MHz) 1 H / ppm J / Hz 1 H / ppm J / Hz 13 C / ppm 13 C / ppm 2-H 5.54 s 5.55 s 3-CH s 3.79 s 4-H 4.78 d d H 4.46 d d 9.1 4a-H brs 6-H 7.94 s 7.95 s 7-H 7.16 s 7.17 s 8-CH s 3.99 s 9-CH s 3.99 s 10-CH s 2.87 s 11-H s s 12a-CH s 3.64 s 2 C H a 4a H H tetracenomycin X (2) C C C-1 C 2 CH C-3 C-11 C C-5a C C-6a C-10a C-11a C-6 C-9 C-7 C-2 C-12a C-4a C-4 CH CH 3-12a CH C 2 CH CH [5] B. Liu, Y. Tan, M. Gan, H. Zhou, Y. Wang, Y. Ping, B. Li, Z. Yang, C. Xiao, Acta. Pharm. Sin. 2014, 14,

25 H Ts Ts S-1 1 H NMR (600 MHz, CDCl 3 ) NAME SS2 ditos EXPN 50 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

26 H Ts Ts S-1 13 C NMR (150 MHz, CDCl 3 ) NAME SS2 ditos EXPN 60 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zgpg30 SLVENT CDCl3 NS 512 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

27 I H I Ts Ts S-2 1 H NMR (600 MHz, CDCl 3 ) NAME SS2 diiodo ditos EXPN 30 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

28 I H I Ts Ts S-2 13 C NMR (150 MHz, CDCl 3 ) NAME SS2 diiodo ditos EXPN 40 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zgpg30 SLVENT CDCl3 NS 512 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

29 I Bn I Ts Ts 13 1 H NMR (600 MHz, CDCl 3 ) NAME SS EXPN 10 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

30 I Bn I Ts Ts C NMR (150 MHz, CDCl 3 ) NAME SS EXPN 20 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zgpg30 SLVENT CDCl3 NS 256 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

31 I Bn TBS Ts 14 1 H NMR (600 MHz, CDCl 3 ) NAME SS EXPN 20 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

32 I Bn TBS Ts C NMR (150 MHz, CDCl 3 ) NAME SS EXPN 21 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zgpg30 TD SLVENT CDCl3 NS 1024 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

33 2 C Bn TBS 15 (more polar) 1 H NMR (600 MHz, acetone-d 6 ) NAME SS2 morepolar EXPN 20 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT Acetone NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

34 2 C Bn TBS 15 (more polar) 13 C NMR (150 MHz, acetone-d 6 ) NAME SS2 morepolar EXPN 21 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zgpg30 SLVENT Acetone NS 1024 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

35 2 C Bn TBS 15 (less polar) 1 H NMR (600 MHz, acetone-d 6 ) NAME SS2 lesspolar EXPN 20 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT Acetone NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

36 2 C Bn TBS 15 (less polar) 13 C NMR (150 MHz, acetone-d 6 ) NAME SS2 lesspolar EXPN 21 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zgpg30 SLVENT Acetone NS 1024 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

37 2 C Bn 16 1 H NMR (600 MHz, CDCl 3 ) NAME SS EXPN 10 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

38 2 C Bn C NMR (150 MHz, CDCl 3 ) NAME SS EXPN 11 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zgpg30 SLVENT CDCl3 NS 512 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

39 2 C Bn NH 17 1 H NMR (600 MHz, CDCl 3 ) NAME SS2 oxime EXPN 30 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

40 2 C Bn NH C NMR (150 MHz, CDCl 3 ) NAME SS2 oxime EXPN 41 PRCN 1 Date_ Time 0.23 PRBHD 5 mm CPPBB BB PULPRG zgpg30 SLVENT CDCl3 NS 512 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

41 2 C Bn C + N 18 1 H NMR (600 MHz, CDCl 3 ) NAME SS2 N10 EXPN 10 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

42 2 C Bn C + N C NMR (150 MHz, CDCl 3 ) NAME SS2 10 EXPN 10 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zgpg30 SLVENT CDCl3 NS 512 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

43 Tf C 2 S-4 1 H NMR (600 MHz, CDCl 3 ) NAME KS1 1 TM 1H EXPN 10 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

44 Tf C 2 S-4 1 H NMR (600 MHz, CDCl 3 ) NAME KS1 1 TM EXPN 11 PRCN 1 Date_ Time 7.07 PRBHD 5 mm CPPBB BB PULPRG zgpg30 TD SLVENT CDCl3 NS 1024 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

45 C 2 S-5 1 H NMR (600 MHz, CDCl 3 ) NAME SS EXPN 10 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

46 C 2 S-5 13 C NMR (150 MHz, CDCl 3 ) NAME SS EXPN 20 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zgpg30 SLVENT CDCl3 NS 512 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

47 C 2 S-7 1 H NMR (600 MHz, CDCl 3 ) NAME KS1 86 pt EXPN 20 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

48 C 2 S-7 13 C NMR (150 MHz, CDCl 3 ) NAME KS1 14 TM EXPN 21 PRCN 1 Date_ Time 8.58 PRBHD 5 mm CPPBB BB PULPRG zgpg30 SLVENT CDCl3 NS 1024 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

49 H C 2 S-8 1 H NMR (600 MHz, CDCl 3 ) NAME KS1 15 pt EXPN 22 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

50 H C 2 S-8 13 C NMR (150 MHz, CDCl 3 ) NAME KS1 15 pt EXPN 32 PRCN 1 Date_ Time 9.44 PRBHD 5 mm CPPBB BB PULPRG zgpg30 SLVENT CDCl3 NS 1024 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

51 H H S-9 1 H NMR (600 MHz, CDCl 3 ) NAME KS EXPN 40 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

52 H H S-9 13 C NMR (150 MHz, CDCl 3 ) NAME KS EXPN 11 PRCN 1 Date_ Time 0.55 PRBHD 5 mm CPPBB BB PULPRG zgpg30 SLVENT CDCl3 NS 1024 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

53 S-10 1 H NMR (600 MHz, CDCl 3 ) NAME SS2 QM EXPN 22 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

54 S C NMR (150 MHz, CDCl 3 ) NAME KS EXPN 11 PRCN 1 Date_ Time 0.02 PRBHD 5 mm CPPBB BB PULPRG zgpg30 SLVENT CDCl3 NS 1024 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

55 2 C Bn N H S-10 1 H NMR (600 MHz, acetone-d 6 ) H NAME SS EXPN 20 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT Acetone NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

56 2 C Bn N H S C NMR (150 MHz, acetone-d 6 ) H NAME SS EXPN 30 PRCN 1 Date_ Time 5.58 PRBHD 5 mm CPPBB BB PULPRG zgpg30 TD SLVENT Acetone NS 7168 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

57 2 C Bn N S-11 1 H NMR (600 MHz, acetone-d 6 ) NAME SS EXPN 20 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT Acetone NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG 17.5 DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

58 2 C Bn N S C NMR (150 MHz, acetone-d 6 ) NAME SS EXPN 21 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zgpg30 SLVENT Acetone NS 1024 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

59 2 C Bn N 25 1 H NMR (600 MHz, CDCl 3 ) NAME SS EXPN 20 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

60 2 C Bn N C NMR (150 MHz, CDCl 3 ) NAME SS EXPN 31 PRCN 1 Date_ Time 8.26 PRBHD 5 mm CPPBB BB PULPRG zgpg30 TD SLVENT CDCl3 NS 4096 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

61 2 C Bn N 26 1 H NMR (600 MHz, CDCl 3 ) H NAME SS EXPN 31 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

62 2 C Bn N C NMR (150 MHz, CDCl 3 ) H NAME SS EXPN 21 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zgpg30 SLVENT CDCl3 NS 1024 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

63 2 C Bn N S-12 1 H NMR (600 MHz, CDCl 3 ) Bn* NAME SS EXPN 10 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

64 2 C Bn N S C NMR (150 MHz, CDCl 3 ) Bn* NAME SS EXPN 31 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zgpg30 TD SLVENT CDCl3 NS 6144 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

65 2 C BF 4 Bn N H NMR (600 MHz, CDCl 3 ) Bn* NAME SS EXPN 20 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

66 2 C BF 4 Bn N C NMR (150 MHz, CDCl 3 ) Bn* NAME SS EXPN 32 PRCN 1 Date_ Time 9.48 PRBHD 5 mm CPPBB BB PULPRG zgpg30 SLVENT CDCl3 NS 8192 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

67 2 C Bn H 29a 1 H NMR (600 MHz, CDCl 3 ) Bn* NAME SS EXPN 10 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

68 2 C Bn H 29a 13 C NMR (150 MHz, CDCl 3 ) Bn* NAME SS EXPN 21 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zgpg30 TD SLVENT CDCl3 NS 6144 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

69 2 C Bn H Bn* 30a 1 H NMR (600 MHz, CDCl 3 ) NAME SS EXPN 30 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

70 2 C Bn H Bn* 30a 13 C NMR (150 MHz, CDCl 3 ) NAME SS EXPN 40 PRCN 1 Date_ Time 3.11 PRBHD 5 mm CPPBB BB PULPRG zgpg30 TD SLVENT CDCl3 NS 3584 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

71 2 C Bn H H Bn* 31 1 H NMR (600 MHz, CDCl 3 ) NAME SS EXPN 20 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

72 2 C Bn H H Bn* C NMR (150 MHz, CDCl 3 ) NAME SS EXPN 21 PRCN 1 Date_ Time 6.49 PRBHD 5 mm CPPBB BB PULPRG zgpg30 TD SLVENT CDCl3 NS 8192 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

73 2 C Bn H H Bn* 31 1 H NMR (600 MHz, methanol-d 4 ) NAME SS EXPN 30 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT D NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

74 2 C Bn H H Bn* C NMR (150 MHz, methanol-d 4 ) NAME SS EXPN 31 PRCN 1 Date_ Time 9.52 PRBHD 5 mm CPPBB BB PULPRG zgpg30 TD SLVENT D NS 8192 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

75 2 C H H H H tetracenomycin C (1) 1 H NMR (600 MHz, CDCl 3 ) NAME SS EXPN 10 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

76 2 C H H H H tetracenomycin C (1) 13 C NMR (150 MHz, DMS-d 6 ) NAME SS EXPN 41 PRCN 1 Date_ Time 5.03 PRBHD 5 mm CPPBB BB PULPRG zgpg30 TD SLVENT DMS NS 6144 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

77 2 C Bn S-13 1 H NMR (600 MHz, CDCl 3 ) Bn* NAME SS EXPN 30 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

78 2 C Bn S C NMR (150 MHz, CDCl 3 ) Bn* NAME SS EXPN 40 PRCN 1 Date_ Time 9.40 PRBHD 5 mm CPPBB BB PULPRG zgpg30 SLVENT CDCl3 NS 512 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

79 2 C Bn Bn* 32 1 H NMR (600 MHz, CDCl 3 ) NAME SS EXPN 20 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

80 2 C Bn Bn* C NMR (150 MHz, CDCl 3 ) NAME SS EXPN 21 PRCN 1 Date_ Time PRBHD 5 mm CPPBB BB PULPRG zgpg30 SLVENT CDCl3 NS 2048 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

81 2 C Bn H Bn* 33 1 H NMR (600 MHz, CDCl 3 ) NAME SS EXPN 10 PRCN 1 Date_ Time 9.25 PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

82 2 C Bn H Bn* C NMR (150 MHz, CDCl 3 ) NAME SS EXPN 11 PRCN 1 Date_ Time 9.23 PRBHD 5 mm CPPBB BB PULPRG zgpg30 SLVENT CDCl3 NS 1024 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm

83 2 C Bn H Bn* 33 1 H NMR (600 MHz, CDCl 3 ) NAME SS EXPN 10 PRCN 1 Date_ Time 4.42 PRBHD 5 mm CPPBB BB PULPRG zg30 SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec SF MHz NUC1 1H P usec PLW W SI SF MHz LB 0.30 Hz PC ppm

84 2 C Bn H Bn* C NMR (150 MHz, CDCl 3 ) NAME SS EXPN 52 PRCN 1 Date_ Time 8.03 PRBHD 5 mm CPPBB BB PULPRG zgpg30 TD SLVENT CDCl3 NS 6036 DS 4 SWH Hz FIDRES Hz AQ sec RG DW usec DE usec D sec D sec SF MHz NUC1 13C P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W SI SF MHz LB 1.00 Hz PC ppm