Supporting Information. Total Synthesis of Grandisine D. Haruaki Kurasaki, Iwao Okamoto, Nobuyoshi Morita, and Osamu Tamura*

Supporting Information Total Synthesis of Grandisine D Haruaki Kurasaki, Iwao Okamoto, Nobuyoshi Morita, and Osamu Tamura* Discovery Research Laboratories, Kyorin Pharmaceutical Co. Ltd. 2399-1, Nogi, Nogi-Machi, Shimotsuga-Gun, Tochigi 329-0114, Japan, and Showa Pharmaceutical University, 3-3165 Higashi-tamagawagakuen, Machida, Tokyo 194-8543, Japan tamura@ac.shoyaku.ac.jp Contents I. Experimental Section 1 II. 1 H and 13 C NMR Spectra 13 Experimental Section General. Melting points were determined with a Yanagimoto micro melting point apparatus and are uncorrected. Optical rotations were measured with a JASCO P-1020 auto digital polarimeter. Infrared spectra (IR) were recorded with PerkinElmer spectrum 100. Proton nuclear magnetic resonance ( 1 H NMR) spectra were recorded on a JEOL JNM-AL300 spectrometer. The chemical shifts are expressed in ppm downfield from tetramethylsilane (δ = 0) as an internal standard (CDCl 3 solution). Splitting patterns are indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak. Measurements of mass spectra (MS) and high resolution MS (HRMS) were performed with a JEOL JMS SX-102A or a JEOL JMS-T100LP mass spectrometer. HPLC analyses were conducted using a JASCO 880-PU with HITACHI 655A UV detection. Column chromatography was carried out on silica gel [silica gel 40-50 µm neutral, Kanto Chemical Co., Inc. or Chromatorex NH DM2035 (200-350 mesh Fuji Silysia Chemical, Ltd.)]. Merck precoated thin layer chromatography (TLC) plates (silica gel 60 F 254, 0.25 mm, Art 5715) were used for the TLC analysis. After extractive workup, organic layers were dried over anhydrous sodium sulfate or anhydrous magunesium sulfate and the solvent was removed by rotary evaporation under reduced pressure. (3S)-3-Acetoxy-1-(3-buten-1-yl)pyrrolidine-2,5-dione (12) A solution of L-malic acid (12.2 g, 91.1 mmol) in acetyl chloride (150 ml) was heated at reflux for 2 h. After evaporation of acetyl chloride, the residue was dissolved in CH 2 Cl 2 (70 ml). To the resulting solution was added dropwise a mixture of 4-amino-1-butene hydrochloride (22.1 g, 205 mmol) and triethylamine (28.5 ml, 205 mmol) in CH 2 Cl 2 (80 ml) at 0 o C and the mixture was 1

stirred at room temperature for 5 h. After evaporation of solvent, to the residue was added acetyl chloride (150 ml) and the mixture was heated at reflux for 1.5 h. After evaporation of acetyl chloride, the residue was dissolved in mixture of CH 2 Cl 2 (50 ml), water (50 ml), and a saturated aqueous NaHCO 3 (400 ml). The whole was extracted with CH 2 Cl 2 (50 ml x 2), washed with brine (50 ml), dried (Na 2 SO 4 ), and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (hexane-acoet, 1:1) to afford imide 12 as a colorless solid (17.4 g, 90%). mp 49.0-50.0 o C (hexane-acoet); [α] 24 D 19.0 (c 0.50, CHCl 3 ); IR (ATR) 2949, 1743, 1699 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 5.82-5.64 (m, 1H), 5.43 (dd, J = 8.8, 4.8 Hz, 1H), 5.14-5.02 (m, 2H), 3.64 (t, J = 7.2 Hz, 2H), 3.15 (dd, J = 18.3, 8.6 Hz, 1H), 2.65 (dd, J = 18.3, 5.0 Hz, 1H), 2.38 (br q, J = 7.1 Hz, 2H), 2.17 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 173.3, 173.1, 169.8, 134.0, 117.8, 67.3, 38.2, 35.7, 31.7, 20.5; MS (CI+) m/z 212 (MH + ); HRMS calcd for C 10 H 14 NO 4 212.0923, found 212.0922. The optical purity of 12 was measured to be 99.3% ee by chiral HPLC analysis (CHIRALPAK IA; 260 nm, 0.5 ml/min; hexane:etoh = 6:4; t R = 35.60 min, t S = 21.67 min) The corresponding enantiomer was prepared from D-malic acid by using the same procedure described above. (2R,3S)-1-Butenyl-2-ethoxy-5-oxopyrrolidin-3-yl acetate (trans-13) and (2S,3S)-1-Butenyl-2-ethoxy-5-oxopyrrolidin-3-yl acetate (cis-13) To a solution of imide 12 (10.0 g, 47.3 mmol) in EtOH (470 ml) was added NaBH 4 (8.96 g, 237 mmol) at -15 o C. After stirring for 15 min at -5 o C, the mixture was cooled to -52 o C, and then a 1M solution of H 2 SO 4 in EtOH (215 ml) was added over 55 min. The mixture was allowed to warm to room temperature, and stirring was continued for 13 h. The mixture was poured into a saturated aqueous NaHCO 3 (1.5 L), and the whole was extracted with CH 2 Cl 2 (200 ml x 4), dried (Na 2 SO 4 ), and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (hexane-acoet, 1:1) to afford trans-13 as a colorless oil (9.60 g, 84%) and cis-13 as a colorless oil (1.11 g, 10%). trans-13: [α] 24 D 26.5 (c 0.50, CHCl 3 ); IR (ATR) 2977, 2934, 1742, 1702 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 5.78 (ddt, J = 17.1, 10.2, 6.9 Hz, 1H), 5.14-5.01 (m, 3H), 4.73 (s, 1H), 3.74 (dq, J = 9.6, 7.1 Hz, 1H), 3.67-3.53 (m, 2H), 3.17 (br dt, J = 13.8, 7.2 Hz, 1H), 2.88 (ddd, J = 17.9, 6.5, 0.8 Hz, 1H), 2.43-2.26 (m, 3H), 2.07 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H); 13 C NMR (75 MHz, CDCl 3,) δ 172.5, 170.3, 135.0, 116.9, 93.0, 70.5, 63.6, 39.7, 35.6, 32.2, 20.9, 15.2; MS (CI+) m/z 242 (MH + ); HRMS calcd for C 12 H 20 NO 4 242.1392, found, 242.1440. cis-13: [α] 24 D 57.7 (c 0.49, CHCl 3 ); IR (ATR) 2978, 2935, 1739, 1702 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 5.76 (ddt, J = 17.1, 10.5, 7.2 Hz, 1H), 5.20-5.04 (m, 4H), 3.72-3.51 (m, 3H), 3.13 (ddd, J = 2

14.1, 7.8, 6.3 Hz, 1H), 2.66 (dd, J = 16.8, 7.8 Hz, 1H), 2.60 (dd, J = 16.8, 7.8 Hz, 1H), 2.41-2.25 (m, 2H), 2.13 (s, 3H), 1.21 (t, J = 7.0 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 170.9, 170.7, 134.9, 117.2, 88.2, 67.7, 65.4, 39.9, 34.5, 32.1, 20.7, 15.5; MS (CI+) m/z 242 (MH + ); HRMS calcd for C 12 H 20 NO 4 242.1392, found 242.1389. (2R,3S)-2-Ethoxy-5-oxo-1-[(3E)-5-oxo-3-pentenyl]pyrrolidinyl acetate (11) A solution of trans-13 (4.43 g, 18.4 mmol), acrolein (3.68 ml, 55.1 mmol), and Grubbs-Hoveyda catalyst (1.15 g, 1.84 mmol) in CH 2 Cl 2 (50 ml) was stirred at room temperature for 2 h. After concentration, the crude product was purified by column chromatography on silica gel (hexane-acoet, 1:2) to afford aldehyde 11 as a brown oil (4.14 g, 84%). [α] 24 D 24.8 (c 0.47, CHCl 3 ); IR (ATR) 2978, 1741, 1684 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 9.51 (d, J = 7.9 Hz, 1H), 6.81 (dt, J = 15.6, 7.0 Hz, 1H), 6.13 (ddt, J = 15.6, 7.9, 1.5 Hz, 1H), 5.07 (d, J = 6.1 Hz, 1H), 4.67 (s, 1H), 3.76 (dq, J = 9.3, 6.9 Hz, 1H), 3.68-3.54 (m, 2H), 3.44 (br dt, J = 13.8, 6.6 Hz, 1H), 2.88 (dd, J = 17.8, 6.1 Hz, 1H), 2.75-2.57 (m, 2H), 2.32 (d, J = 17.8 Hz, 1H), 2.07 (s, 3H), 1.25 (t, J = 7.0 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 193.6, 172.7, 170.3, 154.0, 134.6, 93.4, 70.2, 63.7, 39.1, 35.5, 31.4, 20.9, 15.2; MS (CI+) m/z 270 (MH + ); HRMS calcd for C 13 H 20 NO 5 270.1341, found 270.1364. (1S,8aR)-8-Formyl-3-oxo-1,2,3,5,6,8a-hexahydroindolizin-1-yl acetate (trans-14) and (1S,8aS)-8-Formyl-3-oxo-1,2,3,5,6,8a-hexahydroindolizin-1-yl acetate (cis-14) To a solution of aldehyde 11 (4.00 g, 14.9 mmol) in CH 3 CN (75 ml) was added Me 2 S (1.64 ml, 22.3 mmol) and TfOH (3.29 ml, 37.1 mmol) at -35 o C. The resulting mixture was allowed to warm to room temperature and stirring was continued for 2 h. The reaction was quenched with a saturated aqueous NaHCO 3 (70 ml). After evaporation of CH 3 CN, the whole was extracted with CH 2 Cl 2 (30 ml x 3), dried (Na 2 SO 4 ), and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (MeOH-AcOEt, 1:20) to afford an inseparable mixture of trans-14 and cis-14 as a colorless solid (2.22 g, 67%, trans:cis = 96:4). IR (ATR) 2930, 2820, 1730, 1675 cm -1 ; MS (CI+) m/z 224 (MH + ); HRMS calcd for C 11 H 14 NO 4 224.0923, found 224.0924. trans-14: 1 H NMR (300 MHz, CDCl 3 ) δ 9.43 (s, 1H), 7.00-6.98 (m, 1H), 5.27 (ddd, J = 10.0, 5.0, 3.7 Hz, 1H), 4.54-4.51 (m, 1H), 4.39 (br dd, J = 13.3, 6.7 Hz, 1H), 2.86 (dd, J = 17.4, 8.4 Hz, 1H), 2.88-2.77 (m, 1H), 2.53 (ddd, J = 17.4, 6.3, 1.5 Hz, 1H), 2.64-2.35 (m, 2H), 2.16 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 191.3, 170.4, 170.3, 149.7, 140.2, 69.7, 58.8, 38.3, 35.2, 25.5, 21.0. cis-14: 1 H NMR (300 MHz, CDCl 3 ) δ 9.45 (s, 1H), 7.11-7.06 (m, 1H), 5.69 (t, J = 5.0 Hz, 1H), 4.64-4.59 (m, 1H), 4.38 (br, dd, J = 12.8, 5.7 Hz, 1H), 2.92-2.77 (m, 2H), 2.67-2.42 (m, 2H), 2.45 (d, J = 17.8 Hz, 1H), 1.91 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 191.0, 170.7, 169.6, 149.0, 137.5, 68.7, 3

56.9, 39.3, 35.0, 25.5, 20.8. The spectral data of trans-14 and cis-14 were measured after deprotection of the acetal of trans-15 and cis-15 obtained below by acid hydrolysis, respectively. (1S,8aR)-8-[1,3-Dioxolan-2-yl]-3-oxo-1,2,3,5,6,8a-hexahydroindolizin-1-yl acetate (trans-15) and (1S,8aS)-8-[1,3-Dioxolan-2-yl]-3-oxo-1,2,3,5,6,8a-hexahydroindolizin-1-yl acetate (cis-15) A solution of indolizidine 14 (350 mg, 1.57 mmol) (mixture of trans-14 and cis-14), ethylene glycol (393 µl, 7.06 mmol), and PTSA (3 mg, 0.016 mmol) in benzene (20 ml) was heated at reflux for 13 h. The reaction mixture was poured into a saturated aqueous NaHCO 3 (150 ml). The whole was extracted with CH 2 Cl 2 (200 ml x 4), dried (Na 2 SO 4 ), and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (AcOEt) to afford trans-15 as colorless crystals (347 mg, 88%) and cis-15 as a colorless oil (30.2 mg, 8%). trans-15: mp 90.0-91.0 o C (hexane-acoet); [α] 25 D 88.5 (c 0.50, CHCl 3 ); IR (ATR) 2937, 2883, 1738, 1674 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 6.15 (br d, J = 6.0 Hz, 1H), 5.46 (br dt, J = 9.2, 4.1 Hz, 1H), 5.23 (s, 1H), 4.39-4.37 (m, 1H), 4.27 (br dd, J = 13.2, 6.6 Hz, 1H), 4.05-3.84 (m, 4H), 2.92 (dd, J = 17.6, 8.2 Hz, 1H), 2.90-2.78 (m, 1H), 2.41 (ddd, J =17.6, 5.5, 1.5 Hz, 1H), 2.37-2.23 (m, 1H), 2.17-2.05 (m, 4H); 13 C NMR (75 MHz, CDCl 3 ) δ 170.6, 169.9, 132.6, 128.8, 103.8, 70.2, 64.9, 64.8, 60.0, 38.2, 36.0, 23.8, 20.9; MS (CI+) m/z 268 (MH + ); HRMS calcd for C 13 H 18 NO 5 268.1185, found 268.1147. cis-15: [α] 25 D +194 (c 0.45, CHCl 3 ); IR (ATR) 2887, 1735, 1686 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 6.24 (d, J = 6.2 Hz, 1H), 5.49 (t, J = 4.5 Hz, 1H), 5.17 (s, 1H), 4.52-4.46 (m, 1H), 4.26 (br dd, J = 12.9, 6.0 Hz, 1H), 4.00-3.81 (m, 4H), 2.84-2.71 (m, 2H), 2.41-2.13 (m, 3H), 1.98 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 170.8, 170.4, 130.6, 129.7, 104.4, 69.4, 65.0, 64.9, 57.6, 39.8, 35.7, 24.2, 21.0; MS (ESI+) m/z 268 (MH + ); HRMS calcd for C 13 H 18 NO 5 268.1185, found 268.1187. (1S,7aR)-7-Formyl-3-oxo-2,3,5,7a-tetrahydro-1H-pyrrolizidin-1-yl acetate (trans-18) and (1S,7aS)-7-Formyl-3-oxo-2,3,5,7a-tetrahydro-1H-pyrrolizidin-1-yl acetate (cis-18) An inseparable 91:9 mixture (58.7 mg, 36%, colorless oil) of trans-18 and cis-18 was obtained from aldehyde 16 (200 mg, 0.783 mmol) prepared from L-malic acid 1) by using procedure similar to that for 14. trans-18: 1 H NMR (300 MHz, CDCl 3 ) δ 9.80 (s, 1H), 6.94 (apparent q, J = 1.8 Hz, 1H), 5.35 (ddd, J = 9.3, 8.4, 6.6 Hz, 1H), 4.86-4.81 (m, 1H), 4.71-4.68 (m, 1H), 3.98-3.90 (m, 1H), 2.86 (dd, J = 16.5, 8.4 Hz, 1H), 2.75 (ddd, J = 16.2, 9.3, 0.9 Hz, 1H), 2.18 (s, 3H). cis-18: 1 H NMR (300 MHz, CDCl 3 ) δ 9.80 (s, 1H), 6.97 (apparent q, J = 2.1 Hz, 1H), 5.67 (t, J = 4.8 Hz, 1H), 5.09-5.07 (m, 1H), 4.77-4.75 (m, 1H), 4.04-3.96 (m, 1H), 3.03 (dd, J = 17.4, 4.8 Hz, 1H), 2.41 (d, J = 17.1 Hz, 1H), 1.92 (s, 3H). 4

These spectral data of trans-18 and cis-18 are identical with those reported. 1) For the preparation of trans-19 and cis-19 (3S)-3-Acetoxy-1-(4-penten-1-yl)pyrrolidine-2,5-dione This compound (3.89 g, 83%, colorless oil) was obtained from L-malic acid (2.80 g, 20.9 mmol) and 5-amino-1-pentene (4.00 g, 47.0 mmol) prepared from 3-butene-1-ol in three steps 2) by using procedure similar to that for 12. [α] 22 D 17.2 (c 0.50, CHCl 3 ); IR (ATR) 2944, 1749, 1705 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 5.79 (ddt, J = 17.1, 10.2, 6.6 Hz, 1H), 5.41 (dd, J = 8.8, 4.8 Hz, 1H), 5.10-4.97 (m, 2H), 3.57 (br t, J = 7.3 Hz, 2H), 3.15 (dd, J = 18.3, 8.8 Hz, 1H), 2.66 (dd, J = 18.3, 5.0 Hz, 1H), 2.17 (s, 3H), 2.14-2.03 (m, 2H), 1.71 (br quin, J = 7.3 Hz, 2H); 13 C NMR (75 MHz, CDCl 3 ) δ 173.4, 173.2, 169.9, 137.1, 115.5, 67.5, 38.7, 35.7, 30.9, 26.5, 20.5; MS (CI+) m/z 226 (MH + ); HRMS calcd for C 11 H 16 NO 4 226.1079, found 226.1090. (2R,3S)-1-(4-Pentenyl)-2-ethoxy-5-oxopyrrolidin-3-yl acetate (trans) and (2S,3S)-1-(4-Pentenyl)-2-ethoxy-5-oxopyrrolidin-3-yl acetate (cis) A trans-isomer as a colorless oil (2.07 g, 61%) and a cis-isomer as a colorless oil (607 mg, 18%) were obtained from imide (3.00 g, 13.3 mmol) prepared above by using procedure similar to that for 13. trans-isomer: [α] 23 D 33.5 (c 0.51, CHCl 3 ); IR (ATR) 2960, 2933, 1742, 1705 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 5.81 (ddt, J = 17.1, 10.2, 6.6 Hz, 1H), 5.10-4.96 (m, 3H), 4.69 (s, 1H), 3.74 (dq, J = 9.3, 7.0 Hz, 1H) 3.60 (dq, J = 9.3, 7.0 Hz, 1H) 3.55-3.46 (m, 1H) 3.15 (ddd, J = 13.5, 8.1, 5.4 Hz, 1H), 2.89 (ddd, J = 17.9, 6.5, 0.7 Hz, 1H), 2.32 (d, J = 18.0 Hz, 1H), 2.14-2.01 (m, 2H), 2.09 (s, 3H), 1.77-1.54 (m, 2H), 1.24 (t, J = 7.0 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 172.5, 170.3, 137.6, 115.2, 93.1, 70.6, 63.7, 40.1, 35.7, 30.9, 26.8, 21.0, 15.2; MS (CI+) m/z 256 (MH + ); HRMS calcd for C 13 H 22 NO 4 256.1549, found 256.1546. cis-isomer: [α] 23 D 51.3 (c 0.50, CHCl 3 ); IR (ATR) 2990, 2933, 1740, 1702 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 5.80 (ddt, J = 16.8, 10.5, 6.6 Hz, 1H), 5.17 (td, J = 8.3, 5.3 Hz, 1H), 5.09-4.96 (m, 2H), 5.04 (d, J = 5.3 Hz, 1H), 3.67-3.49 (m, 3H), 3.10 (ddd, J = 18.8, 8.4, 5.4 Hz, 1H), 2.67 (dd, J = 18.6, 8.1 Hz, 1H), 2.61 (dd, J = 18.3, 8.1 Hz, 1H), 2.15-2.02 (m, 2H), 2.13 (s, 3H), 1.77-1.59 (m, 2H), 1.20 (t, J = 6.9 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 170.9, 170.7, 137.4, 115.3, 88.1, 67.8, 65.5, 40.3, 34.5, 31.0, 26.8, 20.7, 15.5; MS (CI+) m/z 256 (MH + ); HRMS calcd for C 13 H 22 NO 4 256.1549, found 256.1548. (2R,3S)-2-Ethoxy-5-oxo-1-[(4E)-6-oxo-4-hexenyl]pyrrolidin-3-yl acetate (17) This compound (1.36 g, 82%, brown oil) was obtained from trans-aminal (1.50 g, 5.88 mmol) 5

prepared above by using procedure similar to that for 11. [α] 22 D 39.1 (c 0.50, CHCl 3 ); IR (ATR) 2990, 2934, 1741, 1685 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 9.52 (d, J = 7.7 Hz, 1H), 6.86 (dt, J = 15.6, 6.7 Hz, 1H), 6.14 (ddt, J = 15.6, 7.9, 1.5 Hz, 1H), 5.08 (d, J = 6.1 Hz, 1H), 4.68 (s, 1H), 3.75 (dq, J = 9.3, 7.1 Hz, 1H), 3.59 (dq, J = 9.3, 7.1 Hz, 1H), 3.47 (br dt, J = 13.8, 7.5 Hz, 1H), 3.30 (br ddd, J = 13.8, 7.5, 6.3 Hz, 1H), 2.90 (dd, J = 18.1, 6.5 Hz, 1H), 2.43-2.29 (m, 3H), 2.09 (s, 3H), 1.88-1.71 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 193.9, 172.7, 170.2, 157.1, 133.3, 93.4, 70.4, 64.0, 40.3, 35.7, 29.9, 26.2, 21.0, 15.2; MS (EI+) m/z 283 (M + ); HRMS calcd for C 14 H 21 NO 5 283.1420, found 283.1383. (1S,9aR)-9-Formyl-3-oxo-2,3,5,6,7,9a-hexahydro-1H-pyrrolo[1,2-a]azepin-1-yl acetate (trans-19) and (1S,9aS)-9-Formyl-3-oxo-2,3,5,6,7,9a-hexahydro-1H-pyrrolo[1,2-a]azepin-1-yl acetate (cis-19) An inseparable 66:34 mixture (107 mg, 64%, colorless oil) of trans-19 and cis-19 was obtained from aldehyde (200 mg, 0.706 mmol) prepared above by using procedure similar to that for 14. IR (ATR) 2943, 1739, 1677 cm -1 ; MS (CI+) m/z 238 (MH + ); HRMS calcd for C 12 H 16 NO 4 238.1079, found 238.1073. trans-19: 1 H NMR (300 MHz, CDCl 3 ) δ 9.40 (s, 1H), 6.98 (br ddd, J = 8.1, 5.7, 1.2 Hz, 1H), 5.35 (dt, J = 6.9, 2.7 Hz, 1H), 4.63 (s, 1H), 4.25 (ddd, J = 13.8, 8.1, 6.3 Hz, 1H), 2.97 (br dt, J = 14.1, 6.9 Hz, 1H), 2.74 (dd, J = 17.8, 7.0 Hz, 1H), 2.52-2.40 (m, 3H), 2.23-2.07 (m, 1H), 2.10 (s, 3H), 1.90-1.74 (m, 1H); 13 C NMR (75 MHz, CDCl 3 ) δ 192.9, 172.1, 170.2, 156.0, 142.1, 70.7, 64.4, 39.2, 37.2, 24.6, 24.2, 21.0. cis-19: 1 H NMR (300 MHz, CDCl 3 ) δ 9.36 (s, 1H), 7.02 (dd, J = 8.3, 5.9 Hz, 1H), 5.54 (apparent t, J = 5.0 Hz, 1H), 4.90 (dd, J = 4.8, 1.5 Hz, 1H), 4.17 (ddd, J = 14.4, 7.8, 1.5 Hz, 1H), 2.91-2.74 (m, 3H), 2.49 (d, J = 17.6 Hz, 1H), 2.45-2.33 (m, 1H), 2.24-2.07 (m, 1H), 1.96 (s, 3H), 1.86-1.72 (m, 1H); 13 C NMR (75 MHz, CDCl 3 ) δ 192.3, 172.0, 169.5, 154.1, 139.5, 69.4, 62.4, 38.2, 38.1, 23.5, 23.5, 20.9. The spectral data of trans-19 and cis-19 were measured after deprotection of the acetal of trans-20 and cis-20 obtained below by acid hydrolysis, respectively. (1S,9aR)-9-(1,3-Dioxolan-2-yl)-3-oxo-2,3,5,6,7,9a-hexahydro-1H-pyrrolo[1,2-a]azepin-1-yl acetate (trans-20) and (1S,9aS)-9-(1,3-Dioxolan-2-yl)-3-oxo-2,3,5,6,7,9a-hexahydro-1H-pyrrolo[1,2-a]azepin-1-yl acetate (cis-20) Trans-20 as colorless crystals (98.3 mg, 52%) and cis-20 as an orange oil (50.1 mg, 27%) were obtained from aldehyde (160 mg, 0.674 mmol) (mixture of trans-19 and cis-19) prepared above by using procedure similar to that for 15. 6

trans-20: mp 77.0-78.0 o C (hexane-acoet); [α] 24 D -54.9 (c 0.50, CHCl 3 ); IR (ATR) 2930, 2892, 1728, 1691 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 6.15 (br dd, J = 8.4, 6.9 Hz, 1H), 5.62 (dt, J = 6.5, 1.9 Hz, 1H), 5.19 (s, 1H), 4.38 (br s, 1H), 4.14 (ddd, J = 14.1, 8.1, 6.0 Hz, 1H), 4.08-4.02 (m, 2H), 3.95-3.87 (m, 2H), 3.00 (br dt, J = 13.8, 6.9 Hz, 1H), 2.83 (dd, J = 17.6, 6.6 Hz, 1H), 2.35 (dd, J =17.7, 1.4 Hz, 1H), 2.22-2.00 (m, 3H), 2.06 (s, 3H), 1.84-1.68 (m, 1H); 13 C NMR (75 MHz, CDCl 3 ) δ 172.4, 170.1, 135.0, 134.5, 105.6, 71.1, 66.0, 65.1, 64.9, 39.9, 37.3, 24.9, 23.2, 21.1; MS (ESI+) m/z 282 (MH + ); HRMS calcd for C 14 H 20 NO 5 282.1342, found 282.1343. cis-20: [α] 24 D +40.4 (c 0.50, CHCl 3 ); IR (ATR) 2944, 2874, 1738, 1681 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 6.20 (dd, J = 8.9, 6.1 Hz, 1H), 5.43 (t, J = 5.0 Hz, 1H), 5.11 (s, 1H), 4.52 (dd, J = 4.3, 1.0 Hz, 1H), 4.11-3.84 (m, 5H), 2.99 (ddd, J = 13.8, 10.8, 7.5 Hz, 1H), 2.75 (ddd, J = 17.4, 5.5, 0.7 Hz, 1H), 2.70-2.56 (m, 1H), 2.42 (d, J = 17.6 Hz, 1H), 2.13-1.96 (m, 2H), 2.00 (s, 3H), 1.70-1.57 (m, 1H); 13 C NMR (75 MHz, CDCl 3 ) δ 171.9, 169.9, 133.8, 132.5, 105.8, 70.5, 65.2, 65.1, 63.3, 38.9, 37.9, 23.2, 21.4, 21.1; MS (ESI+) m/z 282 (MH + ); HRMS calcd for C 14 H 20 NO 5 282.1342, found 282.1348. (1S,8aR)-8-(1,3-Dioxolan-2-yl)-1-hydroxy-1,5,6,8a-tetrahydro-2H-indolizin-3-one (21) To a solution of trans-15 (2.50 g, 9.95 mmol) in EtOH (6.5 ml) was added NaOEt (37.9 mg, 0.557 mmol) in EtOH (6.5 ml) at 4 o C, then the mixture was stirred at room temperature. After 1 h, a solution of NaOEt (37.9 mg, 0.557 mmol) in EtOH (2 ml) was added twice every 1 h. The mixture was poured into a saturated aqueous NH 4 Cl (100 ml), and the whole was extracted with CH 2 Cl 2 (40 ml x 2), dried (Na 2 SO 4 ), and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (MeOH-AcOEt, 1:20) to afford 21 as colorless crystals (1.57 g, 70%). mp 143.5-144.0 o C (hexane-acoet); [α] 25 D 126 (c 0.50, CHCl 3 ); IR (ATR) 3292, 2864, 1654 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 6.20 (d, J = 5.7 Hz, 1H), 5.29 (s, 1H), 4.32-3.96 (m, 7H), 3.82 (d, J = 2.4 Hz, 1H), 2.77-2.50 (m, 3H), 2.30-2.11 (m, 2H); 13 C NMR (75 MHz, CDCl 3 ) δ 170.3, 133.1, 128.5, 104.3, 72.3, 65.2, 64.5, 61.8, 39.4, 35.0, 24.6; MS (EI+) m/z 225 (MH + ); HRMS calcd for C 11 H 15 NO 4 225.1001, found 225.0972. (1S,8aR)-8-(1,3-Dioxolan-2-yl)-3-oxo-1,2,3,5,6,8a-hexahydro-indolizin-1-yl phenoxythiocarbonate A solution of 21 (1.55 g, 6.88 mmol), DMAP (1.26 g, 10.3 mmol), and phenyl chlorothionoformate (1.40 ml, 10.3 mmol) in CH 2 Cl 2 (44 ml) was heated at reflux for 24 h. After concentration, the crude product was purified by column chromatography on silica gel (hexane-acoet, 1:2) to afford the title compound as colorless crystals (2.48 g, quant.). mp 144.0-145.0 o C (hexane-acoet); [α] 25 D 30.0 (c 0.50, CHCl 3 ); IR (ATR) 2952, 2902, 2851, 1689 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.48-7.39 (m, 2H), 7.36-7.28 (m, 1H), 7.14-7.06 (m, 2H), 7

6.19 (br d, J = 6.1 Hz, 1H), 5.83 (ddd, J = 8.2, 5.9, 4.8 Hz, 1H), 5.27 (s, 1H), 4.67-4.61 (m, 1H), 4.32 (br dd, J = 13.2, 6.6 Hz, 1H), 4.17-4.04 (m, 2H), 4.02-3.89 (m, 2H), 3.16 (dd, J = 17.5, 8.3 Hz, 1H), 2.88 (br td, J = 11.4, 4.8 Hz, 1H), 2.62 (ddd, J = 17.6, 5.9, 1.4 Hz, 1H), 2.42-2.26 (m, 1H), 2.21-2.08 (m, 1H); 13 C NMR (75 MHz, CDCl 3 ) δ 222.4, 198.3, 181.8, 161.0, 158.6, 158.1, 155.3, 150.3, 133.3, 108.1, 93.6, 93.5, 87.4, 66.2, 64.5, 52.5; MS (ESI+) m/z 362 (MH + ); HRMS calcd for C 18 H 20 NO 5 S 362.1062, found 362.1070. (8aS)-8-(1,3-Dioxolan-2-yl)-1,5,6,8a-tetrahydro-2H-indolizin-3-one (22) A solution of phenoxythiocarbonate derivative prepared above (2.45 g, 6.78 mmol), n Bu 3 SnH (5.39 ml, 20.3 mmol), and AIBN (55.7 mg, 0.339 mmol) in benzene (34 ml) was heated at reflux for 30 min. After concentration, the crude product was purified by column chromatography on silica gel containing 10%w/w KF 3) (MeOH-AcOEt, 1:20) to afford 22 as colorless crystals (1.33 g, 94%). mp 60.0-61.0 o C (hexane-acoet); [α] 25 D 212 (c 0.50, CHCl 3 ); IR (ATR) 3475, 2849, 1660 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 6.06 (br d, J = 5.7 Hz, 1H), 5.23 (s, 1H), 4.35-4.18 (m, 1H), 4.23 (dd, J = 12.6, 6.0 Hz, 1H), 4.08-3.86 (m, 4H), 2.76 (br td, J = 11.7, 4.8 Hz, 1H), 2.52-2.07 (m, 5H), 1.91-1.75 (m, 1H); 13 C NMR (75 MHz, CDCl 3 ) δ 173.2, 135.3, 126.4, 104.3, 65.1, 64.7, 54.5, 35.8, 31.9, 26.4, 24.4; MS (EI+) m/z 209 (M + ); HRMS calcd for C 11 H 15 NO 3 209.1052, found 209.1061. (8aS)-3-Oxo-1,2,3,5,6,8a-hexahydroindolizine-8-carbaldehyde (10) A solution of 22 (1.30 g, 6.21 mmol) and PTSA (1.18 g, 6.21 mmol) in acetone (62 ml) containing H 2 O (1.6 ml) was heated at reflux for 15 min. After concentration, the crude product was purified by column chromatography on silica gel (MeOH-AcOEt, 1:20) to afford 10 as a colorless oil (997 mg, 97%). [α] 25 D 424 (c 0.25, CHCl 3 ); IR (ATR) 3450, 2935, 2834, 1671 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 9.44 (s, 1H), 6.94-6.89 (m, 1H), 4.46-4.29 (m, 2H), 2.85-2.65 (m, 2H), 2.62-2.33 (m, 4H), 1.64-1.49 (m, 1H); 13 C NMR (75 MHz, CDCl 3 ) δ 191.7, 173.3, 147.7, 142.6, 53.6, 35.1, 31.5, 26.0, 25.9; MS (EI+) m/z 165 (M + ); HRMS calcd for C 9 H 11 NO 2 165.0790, found 165.0777. (8aS, 1 S, 6 S)-8-[(R)-Hydroxy(6-methyl-2 -oxo-cyclohex-3 -en-1-yl) methyl]-1,5,6,8atetrahydro-2h-indolizin-3-one (23) To a solution of (S)-5-methylcyclohexenone (9) 4) (500 mg, 4.54 mmol) in CH 2 Cl 2 (20 ml) was added dropwise successively i Pr 2 NEt (791 µl, 6.81 mmol), and n Bu 2 BOTf (1.0 M, 4.54 ml, 6.81 mmol) at -78 o C. After stirring at the same temperature for 1 h, a solution of aldehyde 10 (500 mg, 3.03 mmol) in CH 2 Cl 2 (10 ml) was added slowly at -78 o C. The mixute was allowed to warm to room temperature and stirring was continued for 1 h. The reaction was quenched by addition of MeOH (1.4 ml) and 30% H 2 O 2 (1.4 ml) at 4 o C, and then the mixture was poured into a saturated 8

aqueous NaHCO 3 (30 ml). The whole was extracted with CH 2 Cl 2 (20 ml x 2), washed with brine (20 ml), dried (Na 2 SO 4 ), and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (MeOH-AcOEt, 1:10) to afford 23 as colorless crystals (830 mg, quant.). mp 121-123 o C (hexane-etoh); [α] 22 D 100 (c 0.50, CHCl 3 ); IR (ATR) 3404, 2918, 1648 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 6.91 (dt, J = 10.1, 4.1 Hz, 1H), 6.05 (dt, J = 10.1, 1.9 Hz, 1H), 5.78 (d, J = 5.5 Hz, 1H), 4.37-4.19 (m, 3H), 2.73 (td, J = 12.1, 4.7 Hz, 1H), 2.63-2.05 (m, 10H), 1.94-1.80 (m, 1H), 1.14 (d, J = 7.0 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 201.1, 173.1, 148.4, 138.6, 128.6, 123.9, 73.0, 56.1, 55.3, 35.7, 31.9, 31.0, 30.7, 27.3, 24.7, 19.9; MS (ESI+) m/z 276 (MH + ); HRMS calcd for C 16 H 22 NO 3 276.1600, found 276.1591. Determination of Stereochemistry at C-10 of 23 Stereochemistry of 23 was determined by modified Mosher s method. Derivatization of 23 to the corresponding (R)- or (S)-MTPA esters was conducted according to a usual method, and 1 H NMR data are as follows. (R)-MTPA ester of 23: 1 H NMR (300 MHz, CDCl 3 ) δ 7.49-7.35 (m, 5H), 6.85-6.77 (m, 1H), 6.17 (d, J = 5.9 Hz, 1H), 5.97 (dd, J = 10.3, 2.9 Hz, 1H), 5.85 (d, J = 10.6 Hz, 1H), 4.24 (dd, J = 13.0, 6.4 Hz, 1H), 4.16-4.05 (m, 1H), 3.40 (d, J = 0.7 Hz, 3H), 2.75-2.55 (m, 3H), 2.43-2.06 (m, 7H), 1.64-1.48 (m, 1H), 1.10 (d, J = 7.2 Hz, 3H). (S)-MTPA ester of 23: 1 H NMR (300 MHz, CDCl 3 ) δ 7.48-7.29 (m, 5H), 6.88-6.79 (m, 1H), 6.13 (d, J = 5.5 Hz, 1H), 6.00 (dd, J = 10.3, 2.8 Hz, 1H), 5.81 (d, J = 11.4 Hz, 1H), 4.16 (dd, J = 12.7, 5.4 Hz, 1H), 3.99-3.88 (m, 1H), 3.58 (d, J = 1.7 Hz, 3H), 2.73-2.51 (m, 3H), 2.28-1.83 (m, 7H), 1.10 (d, J = 7.2 Hz, 3H), 0.78-0.63 (m, 1H). MTPA -0.042-0.173 O O H C 10 0.032 O N H 0.022-0.075-0.036 0.001 Fig. 1 Modified Mosher s method: differences of the chemical shifts ( δ = (δ S -δ R ), CDCl 3 ) between (R)- and (S)-MTPA esters of 23. (8aS,1 R,6 S)-8-[6 -Methyl-2 -oxo-cyclohex-3 -enecarbonyl]-1,5,6,8a-tetrahydro-2h-indolizin-3 -one (8) To a solution of 23 (500 mg, 1.82 mmol) in CH 2 Cl 2 (18 ml) was added a solution of Dess-Martin periodinane (15%w/w, 7.76 ml, 3.63 mmol) in CH 2 Cl 2 at 4 o C, and then the mixute was allowed to 9

warm to room temperature and stirring was continued for 3 h. The mixture was poured into a saturated aqueous NaHCO 3 (30 ml) and the whole was extracted with CH 2 Cl 2 (20 ml x 3), dried (Na 2 SO 4 ), and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (MeOH-AcOEt, 1:20) to afford 8 as a colorless syrup (436 mg, 88%). [α] 24 D 57.6 (c 0.50, CHCl 3 ); IR (ATR) 2906, 1685, 1671, 1642, 1625 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.02 (ddd, J = 10.2, 5.7, 2.7 Hz, 1H), 6.95-6.89 (m, 1H), 6.07 (dd, J = 10.1, 2.7, 1.3 Hz, 1H), 4.62-4.52 (m, 1H), 4.29 (br dd, J = 12.0, 6.0 Hz, 1H), 3.81 (d, J = 11.2 Hz, 1H), 2.87-2.66 (m, 3H), 2.62-2.30 (m, 5H), 2.17 (ddt, J = 19.1, 10.3, 2.8 Hz, 1H), 1.51-1.37 (m, 1H), 0.98 (d, J = 6.6 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 197.7, 196.3, 173.2, 150.0, 142.8, 140.0, 129.3, 60.5, 54.6, 34.8, 33.2, 33.0, 31.5, 26.7, 25.6, 19.9; MS (ESI+) m/z 274 (MH + ); HRMS calcd for C 16 H 20 NO 3 274.1443, found 274.1446. (8aS,1 R,2 S,3 S)-8-[2 -Methyl-6 -oxo-4 -phenylsulfanyl-cyclohexanecarbonyl]-1,5,6,8a-tetrahy dro-2h-indolizin-3-one (24) To a solution of 8 (100 mg, 0.366 mmol) and PhSH (112 µl, 1.10 mmol) in MeOH (5 ml) was added 60% HClO 4 (36.8 µl, 0.366 mmol) at room temperature, and stirring was continued at the same temperature for 2 h. After concentration in vacuo, the crude product was purified by column chromatography on silica gel (MeOH-AcOEt, 1:20) to afford sulfide 24 as a colorless syrup (132 mg, 94% yield). [α] 22 D -185 (c 0.30, CHCl 3 ); IR (ATR) 2930, 1709, 1655 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.47-7.39 (m, 2H), 7.37-7.28 (m, 3H), 6.85 (br d, J = 5.3 Hz, 1H), 4.58-4.48 (m, 1H), 4.29 (dd, J = 13.0, 6.4 Hz, 1H), 3.82-3.73 (m, 1H), 3.70 (d, J = 8.3 Hz, 1H), 2.95-2.26 (m, 9H), 2.17 (dt, J = 14.4, 4.8 Hz, 1H), 1.91 (ddd, J = 14.4, 9.6, 3.9 Hz, 1H), 1.53-1.37 (m, 1H), 0.96 (d, J = 6.8 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 205.3, 195.8, 173.5, 141.4, 139.2, 133.1, 132.9, 129.1, 127.8, 63.9, 54.6, 45.9, 43.9, 36.0, 34.9, 32.2, 31.5, 26.6, 25.4, 20.3; MS (ESI+) m/z 384 (MH + ); HRMS calcd for C 22 H 26 N 2 O 3 S 384.1633, found 384.1638. (8aS,1 R,3 S,5 S)-(3-Methyl-5-phenylsulfanyl)-2-(3-thioxo-1,2,3,5,6,8a-hexahydro-indolizine-8- carbonyl)-cyclohexanone (25) A mixture of 24 (110 mg, 0.287 mmol) and Lawesson s reagent (63.7 mg, 0.158 mmol) in toluene-ch 2 Cl 2 (2:1, 6 ml) was stirred at 65 o C for 15 min. After concentration, the crude product was purified by column chromatography on silica gel (hexane-acoet, 1:1) to afford thioamide 25 as a colorless syrup (92.6 mg, 81%). [α] 23 D -263 (c 0.30, CHCl 3 ); IR (ATR) 2929, 1709, 1663 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.46-7.38 (m, 2H), 7.37-7.28 (m, 3H), 6.90 (br d, J = 4.2 Hz, 1H), 5.07 (dd, J = 12.8, 5.7 Hz, 1H), 4.81-4.71 (m, 1H), 3.83-3.74 (m, 1H), 3.69 (d, J = 8.8 Hz, 1H), 3.10-2.43 (m, 9H), 2.22-2.12 (m, 10

1H), 1.91 (ddd, J = 14.1, 9.6, 3.9 Hz, 1H), 1.54-1.42 (m, 1H), 0.95 (d, J = 6.6 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 205.1, 200.0, 195.6, 140.8, 138.9, 133.1, 133.0, 129.1, 127.9, 64.2, 61.9, 45.8, 44.3, 43.9, 39.9, 36.0, 32.1, 28.3, 25.1, 20.3; MS (ESI+) m/z 400 (MH + ); HRMS calcd for C 22 H 26 NO 2 S 2 400.1405, found 400.1415. Grandisine D trifluoroacetic acid salt (5 TFA) To a solution of 25 (50.0 mg, 0.125 mmol) in CH 3 CN (1.2 ml) was added Me 3 OBF 4 (55.5 mg, 0.375 mmol) at 4 o C and then the mixture was stirred at room temperature for 1 h. After concentration, the residue (50.0 mg, 0.125 mmol) was dissolved in MeOH (1.2 ml), and NaBH 3 CN (15.7 mg, 0.250 mmol) was added to the solution. The mixture was stirred at room temperature for 1 h, and then was poured into a saturated aqueous NaHCO 3 (5 ml), and extracted with CH 2 Cl 2 (5 ml x 3), dried (Na 2 SO 4 ), and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (28% NH 3 -MeOH-AcOEt, 1:10:50) to afford 5 as a colorless oil (20.6 mg, 63% yield). A solution of 5 in CH 2 Cl 2 (1 ml) at 4 o C was added TFA (6.0 µl, 0.0806 mmol) and then the resulting mixture was allowed to warm to room temperature and stirring was continued for 1 h and concentrated in vacuo to afford 5 TFA. [α] 23 D +65.7 (c 0.09, MeOH); IR (ATR) 2955, 2926, 2873, 2795, 1675, 1655 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 10.15 (br s, 1H), 7.34 (apparent t, J = 3.8 Hz, 1H), 7.19-7.11 (m, 1H), 5.96 (dd, J = 10.0, 2.1 Hz, 1H), 4.45-4.35 (m, 1H), 4.32 (d, J = 11.6 Hz, 1H), 3.63-3.47 (m, 1H), 3.40-3.27 (m, 2H), 3.19-3.03 (m, 1H), 2.67-2.56 (m, 2H), 2.53-2.35 (m, 3H), 2.27-2.12 (m, 1H), 2.09-1.92 (m, 2H), 1.72-1.55 (m, 1H), 0.85 (d, J = 6.2 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 198.4, 196.8, 151.8, 140.2, 137.3, 128.4, 59.3, 58.0, 53.0, 43.1, 33.0, 32.7, 28.1, 23.0, 20.3, 19.2; MS (ESI+) m/z 260 (MH + ); HRMS calcd for C 16 H 22 NO 2 260.1651, found 260.1652. We attribute the difference in the optical rotation data [found, [α] 23 D +65.7 (c 0.09, MeOH), previously reported, [α] 23 D +34.6 (c 0.09, MeOH)] to the synthetic 5 having a much higher level of purity. 11

17 1 2 11 O 9 16 H H 3 15 10 8 N 14 12 O 7 13 6 Grandisine D 5 O H H N O Synthetic (5) 1 H-NMR (DMSO-d 6 ) (, multiplicity, J (Hz)) Reported 5) (600 MHz) Observed (Synthetic) (300 MHz) 1α 1.62 dddd (8.4, 9.6, 9.6, 9.6) 1.64 m 1β 2.40 dddd (8.4, 9.6, 9.6, 9.6) 2α 2.00 t (7.8) 2.01 m 2β 2.00 t (7.8) 2.01 m 3α 3.28 m 3.34 m 3β 3.48 ddd (10.8, 10.8, 10.8) 3.55 m 4 10.25 bs 10.15 bs 5α 3.28 m 3.34 m 5β 3.09 ddd (6.6, 6.6, 12.6) 3.11 m 6α 2.60 m 6β 2.60 m 7 7.30 bdd (4.0, 4.0) 7.34 dd (3.8, 3.8) 9 4.32 dd (8.4, 8.4) 4.39 bs 11 4.29 d (11.4) 4.32 d (11.6) 13 5.94 d (9.6) 5.96 dd (10.0, 2.1) 14 7.13 ddd (5.4, 9.6, 9.6) 7.15 m 15α 2.20 dd (11.4, 19.8) 2.20 m 15β 2.45 m 16 2.40 ddq (6.6, 6.6, 11.4) 17 0.84 d (6.6) 0.85 d (6.2) 13 C-NMR (DMSO-d 6 ) (, multiplicity) Reported 5) (125 MHz) Observed (Synthetic) (75.5 MHz) 1 28.2, CH 2 28.1, CH 2 2 20.3, CH 2 20.3, CH 2 3 52.9, CH 2 53.0, CH 2 5 43.2, CH 2 43.1, CH 2 6 23.0, CH 2 23.0, CH 2 7 140.1, CH 140.2, CH 8 137.7, qc 137.3, qc 9 58.0, CH 58.0, CH 10 198.3, qc 198.4, qc 11 59.3, CH 59.3, CH 12 196.6, qc 196.8, qc 13 128.4, CH 128.4, CH 14 151.6, CH 151.8 CH 15 32.6, CH 2 32.7, CH 2 16 33.0, CH 33.0, CH 17 19.1, CH 3 19.2, CH 3 References 1) Myers, E. L.; De Vries, J. G.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2007, 46, 1893-1896. 2) Zabawa, T. P.; Chemler, S. R. Org. Lett. 2007, 9, 2035-2038. 3) Harrowven, D. C.; Guy, I. L. Chem. Commun. 2004, 1968-1969. 4) (a) Katsuhara, J. J. Org. Chem. 1967, 32, 797-799. (b) Mutti, S.; Daubié, C.; Decalogne, F.; Fournier, R.; Rossi, P. Tetrahedron Lett. 1996, 37, 3125-3128. (c) Caine, D.; Procter, K.; Cassell, R. A. J. Org. Chem. 1984, 49, 2647-2648. (d) Oppolzer, W.; Petrzilka, M. Helv. Chim. Acta 1978, 61, 2755-2762. 5) Katavic, P. L.; Venables, D. A.; Forster, P. I.; Guymer, G.; Carroll, A. R. J. Nat. Prod. 2006, 69, 1295-1299. 12