Studies toward the Total Synthesis of Caribbean Ciguatoxin C-CTX-1: Synthesis of the LMN-Ring Fragment through Reductive Olefin Cross-Coupling

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1 S1 Studies toward the Total Synthesis of Caribbean Ciguatoxin C-CTX-1: Synthesis of the LMN-Ring Fragment through Reductive lefin Cross-Coupling Makoto Sasaki,* Kotaro Iwasaki, Keisuke Arai Graduate School f Life Sciences, Tohoku University, Katahira, Aoba-ku, Sendai , Japan * masasaki@m.tohoku.ac.jp Supporting Information General Methods. 2 Synthetic Procedures and Characterization Data 3 References.. 23 NMR Spectra.. 24

2 S2 General Methods. All reactions sensitive to moisture and/or air were carried out under an atmosphere of argon in dry, freshly distilled solvents under anhydrous conditions using oven-dried glassware unless otherwise noted. Anhydrous dichloromethane (CH 2 Cl 2 ), ethyl acetate (EtAc), and 2-propanol (i-prh) were purchased from Kanto Chemical Co. Inc. and used directly without further drying. Anhydrous acetone was purchased from FUJIFILM Wako Pure Chemical Co. and used directly without further drying. Anhydrous tetrahydrofuran (THF), diethyl ether (Et 2 ), and toluene were purchased from FUJIFILM Wako Pure Chemical Co. and further purified by a Glass Contour solvent purification system under an atmosphere of argon immediately prior to use. Acetonitrile (MeCN), methanol (MeH), 2,6-lutidine, and triethylamine (Et 3 N) were distilled from calcium hydride under an atmosphere of argon. Dimethylformamide (DMF) was distilled from magnesium sulfate under reduced pressure. Hexamethylphosphoramide (HMPA) was distilled from calcium hydride under reduced pressure. All other chemicals were purchased at highest commercial grade and used directly. Analytical thin-layer chromatography (TLC) was performed using E. Merck silica gel 60 F 254 plates (0.25-mm thickness). Flash column chromatography was carried out using Kanto Chemical silica gel 60N ( mesh, spherical, neutral) or Fuji Silysia silica gel BW-300 ( mesh). ptical rotations were recorded on a JASC P-1020 digital polarimeter. IR spectra were recorded on a JASC FT/IR-4100 spectrometer. 1 H and 13 C NMR spectra were recorded on a JEL JNM ECA-600 spectrometer, and chemical shift values are reported in ppm (δ) downfield from tetramethylsilane with reference to internal residual solvent [ 1 H NMR, CHCl 3 (7.26), C 6 HD 5 (7.16), C 5 HD 4 N (7.21); 13 C NMR, CDCl 3 (77.0), C 6 D 6 (128.0), C 5 D 5 N (123.5)]. Coupling constants (J) are reported in hertz (Hz). The following abbreviations were used to designate the multiplicities: s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet or unresolved; br = broad signal. FAB mass spectra were recorded on a JEL JMS-700 spectrometer, and ESI-TF mass spectra were measured on a Bruker microtffocus spectrometer. Diastereomer ratio (dr) was estimated by 1 H NMR spectroscopic analysis (600 MHz), unless otherwise noted.

3 S3 Synthetic Procedures and Characterization Data H Kt-Bu, BnBr TBAI PMP THF, rt, 91% Bn H H Benzyl ether 14. To a solution of alcohol 13 1 (10.41 g, mmol) in THF (100 ml) was added Kt-Bu (97%, 9.19 g, 79.4 mmol), and the resultant solution was stirred at room temperature for 30 min. To this solution were sequentially added benzyl bromide (6.0 ml, 50.5 mmol) and n-bu 4 NI (1.28 g, 3.47 mmol), and the resultant solution was stirred at room temperature for 1 h 45 min. The reaction was quenched with saturated aqueous NH 4 Cl solution at 0 C. The mixture was diluted with EtAc, washed with H 2 and brine, dried over MgS 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 5% to 10% to 15% to 20% EtAc/hexanes) gave benzyl ether 14 (12.28 g, 91%) as a colorless solid: [α] D (c 1.29, CHCl 3 ); IR (neat) 2984, 2940, 2863, 1615, 1518, 1250, 1092, 1034, 829, 698 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 2H), (m, 5H), (m, 2H), 6.04 (dd, J = 17.4, 11.0 Hz, 1H), 5.48 (s, 1H), 5.34 (dd, J = 17.4, 1.4 Hz, 1H), 5.13 (dd, J = 11.0, 1.4 Hz, 1H), 4.61 (d, J = 11.9 Hz, 1H), 4.50 (d, J = 11.9 Hz, 1H), 4.27 (m, 1H), 3.80 (s, 3H), (m, 2H), 3.47 (m, 1H), 3.43 (dd, J = 11.5, 4.6 Hz, 1H), 2.41 (ddd, J = 11.9, 4.6, 4.1 Hz, 1H), 1.80 (ddd, J = 11.9, 11.5, 11.5 Hz, 1H), 1.41 (s, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 160.1, 142.6, 138.1, 130.0, (2C), 127.7, (2C), (2C), (2C), 113.5, 101.6, 79.0, 77.32, 77.29, 71.6, 70.0, 66.3, 55.3, 30.9, 15.9; HRMS (FAB) calcd for C 24 H [(M + H) + ] , found PMP Bn 1. 3, pyridine/meh CH 2 Cl 2 (2:3:4), 78 C Me 2 S, 78 C to rt H PMP 2. ( )-Ipc 2 BMe, allylmgbr Bn H THF, 78 C; aq NaH H 14 H 2 2, 73% (2 steps) dr 10:1 15 PMP Homoallylic alcohol 15. zone gas was bubbled through a solution of benzyl ether 14 (3.23 g, 8.15 mmol) in pyridine/ch 2 Cl 2 /MeH (1:3:4, v/v/v, 80 ml) at 78 C until a blue color persisted for 35 min. After passing 2 gas to remove excess 3, Me 2 S (1.0 ml, 13.5 mmol) was added to the reaction mixture. The resultant mixture was allowed

4 S4 to warm to room temperature for 2 h. The mixture was concentrated under reduced pressure to give crude aldehyde S1 (3.34 g) as a pale yellow oil, which was immediately used in the next reaction without purification. To a solution of ( )-Ipc 2 BMe (3.922 g, mmol) in Et 2 (60 ml) at 78 C was slowly added allylmagnesium bromide (1.0 M solution in Et 2, 12 ml, 12 mmol) over 5 min. After being stirred at 78 C for 15 min, the reaction mixture was allowed to warm to room temperature and vigorously stirred for 1 h. The resultant white suspension was cooled to 78 C, and a solution of the above aldehyde S1 (3.34 g, azeotropically dried three times with toluene) in THF (16 ml + 3 ml 2 rinse) was slowly added over 65 min. The resultant mixture was stirred at 78 C for 5 h and allowed to warm to 0 C. To the mixture at 0 C were carefully added 3 M aqueous NaH solution (20 ml) and 30% aqueous H 2 2 solution (15 ml), followed by saturated aqueous NaHC 3 solution (25 ml). The resultant mixture was vigorously stirred at room temperature for 15 h 45 min and heated to 70 C for 4 h. The mixture was cooled to room temperature, and the organic layer was separated. The aqueous layer was extracted twice with Et 2, and the combined organic layers were washed with H 2 and brine, dried over MgS 4, filtered, and concentrated under reduced pressure. After separation of isopinocampheol by sublimation at 65 C under reduced pressure (ca. 9 Torr) for 2.5 h, 2 the residue was purified by flash column chromatography (silica gel, first round: 10% to 20% to 30% EtAc/hexanes, second round: 10% to 20% to 25% to 30% EtAc/hexanes) to give homoallylic alcohol 15 (2.50 g, dr 10:1) as a colorless oil, along with the intermediary borinate ester (0.55 g). To a solution of the borinate ester (0.55 g) in THF/H 2 (1:1, v/v, 10 ml) was added NaB 3 4H 2 3 (0.77 g, 5.0 mmol), and the resultant solution was stirred at room temperature for 2.5 h. The reaction was quenched with saturated aqueous NH 4 Cl solution. The mixture was extracted with Et 2, washed with H 2 and brine, dried over MgS 4, filtered, and concentrated under reduced pressure. The residue was subjected to sublimation according to the process as described above and purified by flash column chromatography (silica gel, 10% 20% to 30% EtAc/hexanes) gave an additional homoallylic alcohol 15 (0.13 g, dr >20:1) as a colorless solid. Totally, 2.63 g (73% for the two steps, dr 10:1) of homoallylic alcohol 15 was obtained as a colorless oil: [α] 23.9 D 61.6 (c 1.06, CHCl 3 ); IR (neat) 3501, 2948, 2865, 2360, 2341, 1615, 1518, 1463, 1386, 1367, 1250, 1173, 1094, 1030, 829, 699 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 2H), (m, 2H),

5 S5 (m, 3H), (m, 2H), 5.88 (dddd, J = 17.0, 10.0, 6.9, 6.9 Hz, 1H), 5.48 (s, 1H), (m, 2H), 4.66 (d, J = 11.5 Hz, 1H), 4.45 (d, J = 11.5 Hz, 1H), 4.21 (m, 1H), 3.80 (s, 3H), 3.79 (dd, J = 11.5, 4.6 Hz, 1H), (m, 3H), 3.42 (m, 1H), 3.04 (br s, 1H), 2.54 (ddd, J = 11.5, 4.6, 4.1 Hz, 1H), 2.38 (br dd, J = 14.5, 6.2 Hz, 1H), 2.14 (m, 1H), 1.79 (ddd, J = 11.9, 11.5, 11.5 Hz, 1H), 1.34 (s, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 160.1, 137.3, 136.4, 129.8, (2C), 127.9, (2C), (2C), 116.5, (2C), 101.7, 78.5, 77.9, 77.3, 77.0, 70.2, 69.8, 66.2, 55.3, 35.4, 30.0, 12.6; HRMS (FAB) calcd for C 26 H [(M + H) + ] , found H Bn H 15 Bis-acetonide 16. To a solution of homoallylic alcohol 15 (22.1 mg, mmol) in MeH (1 ml) was added 10% Pd/C (11 mg), and the resultant mixture was stirred at room temperature under an atmosphere of H 2 (balloon) for 22 h. The mixture was filtered through a pad of Celite eluting with EtAc and MeH, and the filtrate was concentrated under reduced pressure to give crude tetraol (13.5 mg). To a solution of the above tetraol in CH 2 Cl 2 (1 ml) were added 2,2-dimethoxypropane (0.2 ml, 1.6 mmol) and PPTS (2.8 mg, mmol), and the resultant solution was stirred at room temperature for 17 h. The mixture was neutralized with Et 3 N (0.1 ml) and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 10% EtAc/hexanes) gave bis-acetonide 16 (12.3 mg, 78% for the two steps): [α] D (c 1.26, CHCl 3 ); IR (neat) 2991, 2958, 2873, 1466, 1269, 1200, 1120, 1104, 1069, 1041, 931, 903, 863, 755cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ 3.79 (dd, J = 10.6, 5.0 Hz, 1H), 3.68 (dd, J = 11.5, 4.1 Hz, 1H), ca (m, 1H, overlapped), 3.65 (dd, J = 10.6, 10.5 Hz, 1H), 3.52 (dd, J = 9.6, 2.3 Hz, 1H), 3.48 (ddd, J = 10.5, 10.1, 5.0 Hz, 1H), 1.92 (ddd, J = 11.5, 4.1, 4.1 Hz, 1H), 1.76 (ddd, J = 11.5, 11.5, 11.5 Hz, 1H), (m, 2H, overlapped), 1.49 (s, 3H), 1.47 (s, 3H), 1.41 (s, 3H), 1.40 (s, 3H), (m, 2H, overlapped), 1.24 (s, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 100.2, 99.4, 77.7, 74.0, 73.0, 70.7, 68.1, 63.5, 30.3, 29.9, 29.6, 29.2, 19.6, 19.3, 19.2, 14.0, 10.6; HRMS (FAB) calcd for C 17 H [(M + H) + ] , found PMP 1. H 2, Pd/C, MeH, rt 2. PPTS, Me 2 C(Me) 2 CH 2 Cl 2, rt 78% (2 steps) Me Me Me H 16 Me H Me

6 S6 H Bn PMP H 15 TIPSTf 2,6-lutidine DCE, 50 C 81%, dr 10:1 TIPS Bn PMP H 17 TIPS ether 17. To a solution of alcohol 15 (5.73 g, 13.0 mmol) in DCE (130 ml) were sequentially added 2,6-lutidine (4.5 ml, 38.9 mmol) and TIPSTf (4.4 ml, 16.4 mmol). The resultant solution was heated to 50 C for 3 h. The reaction was quenched with saturated aqueous NaHC 3 solution at 0 C. The resultant mixture was diluted with EtAc, washed with saturated aqueous NaHC 3 solution and brine, dried over MgS 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 3% to 5% EtAc/hexanes) gave TIPS ether 17 (6.25 g, 81%, dr 10:1) as a pale yellow oil, which was contaminated with a small amount of TIPSH. Data for 17: [α] 24.8 D 34.6 (c 1.24, CHCl 3 ); IR (neat) 2943, 2864, 1615, 1463, 1384, 1365, 1250, 1173, 1092, 1034, 883, 827, 678 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 2H), (m, 5H), (m, 2H), 5.85 (dddd, J = 17.0, 10.0, 6.9, 6.9 Hz, 1H), 5.44 (s, 1H), (m, 2H), 4.61 (d, J = 11.5 Hz, 1H), 4.51 (d, J = 11.5 Hz, 1H), 4.18 (m, 1H), 4.11 (dd, J = 11.5, 4.6 Hz, 1H), 3.84 (dd, J = 6.9, 4.6 Hz, 1H), 3.80 (s, 3H), (m, 2H), 3.40 (m, 1H), 2.64 (m, 1H), 2.43 (ddd, J = 11.5, 4.6, 4.6 Hz, 1H), 2.33 (m, 1H), 1.73 (ddd, J = 11.9, 11.9, 11.4 Hz, 1H), 1.28 (s, 3H), (m, 21H); 13 C NMR (150 MHz, CDCl 3 ) δ 160.1, 138.2, 137.6, 130.1, (2C), (2C), 127.6, (2C), 115.9, (2C), 101.7, 80.8, 79.0, 76.9, 73.0, 70.7, 69.9, 66.3, 55.3, 39.2, 30.8, 18.5 (3C), 18.4 (3C), 14.3, 13.3 (3C); HRMS (FAB) calcd for C 35 H 53 6 Si + [(M + H) + ] , found TIPS Bn Cy 2 BH, THF, rt aq NaH, H 2 2 TIPS rt, 79%, dr >20:1 H PMP Bn H Alcohol 18. To a solution of cyclohexene (3.6 ml, 35.5 mmol) in THF (70 ml) at 0 C was slowly added BH 3 THF (0.9 M solution in THF, 18 ml, 16.2 mmol), and the resultant solution was stirred at 0 C for 1 h. To the resultant white suspension was slowly added a solution of TIPS ether 17 (6.25 g, 10.5 mmol) in THF (15 ml + 3 ml 2 rinse) over 17 min. The resultant solution was stirred at room temperature for 1 h. To this solution at 0 C were slowly added 3 M aqueous NaH solution (20 ml) followed by 30% aqueous H 2 2 solution (20 ml). The resultant mixture was stirred at room PMP

7 S7 temperature for 1 h. The organic layer was separated, and the aqueous layer was extracted twice with Et 2. The combined organic layers were washed with brine, dried over MgS 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, first round: 20% to 30% EtAc/hexanes, second round: 2% to 30% t-bume/benzene) gave alcohol 18 (5.09 g, 79%, dr >20:1) as a pale yellow oil: [α] 25.1 D 37.4 (c 1.01, CHCl 3 ); IR (neat) 3433, 2943, 2865, 1615, 1518, 1464, 1384, 1366, 1250, 1173, 1033, 883, 829, 678 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 2H), (m, 5H), (m, 2H), 5.43 (s, 1H), 4.61 (d, J = 11.5 Hz, 1H), 4.46 (d, J = 11.5 Hz, 1H), 4.17 (m, 1H), 4.08 (dd, J = 11.5, 4.6 Hz, 1H), 3.80 (s, 3H), 3.72 (m, 1H), (m, 2H), (m, 2H), 3.40 (m 1H), 2.44 (ddd, J = 11.5, 4.6, 4.6 Hz, 1H), (m, 2H), 1.72 (ddd, J = 11.5, 11.5, 11.5 Hz, 1H), (m, 2H), 1.26 (s, 3H), (m, 21H), one proton missing due to H/D exchange; 13 C NMR (150 MHz, CDCl 3 ) δ 160.1, 138.3, 130.1, (2C), (2C), 127.6, (2C) (2C), 101.7, 80.8, 79.6, 76.9, 73.1, 70.8, 69.9, 66.4, 63.3, 55.3, 31.3, 30.8, 30.6, 18.6 (3C), 18.5 (3C), 14.3, 13.5 (3C); HRMS (FAB) calcd for C 35 H 54 7 SiNa + [(M + Na) + ] , found H TIPS Bn PMP Kt-Bu, BnBr THF, rt, 93% Bn TIPS Bn PMP Benzyl ether 19. To a solution of alcohol 18 (5.08 g, 8.26 mmol) in THF (80 ml) at 0 C was added Kt-Bu (2.87 g, 25.6 mmol), and the resultant solution was stirred at room temperature for 20 min. To this solution at 0 C was added benzyl bromide (1.6 ml, 13.5 mmol), and the resultant solution was stirred at room temperature for 75 min. The reaction was quenched with saturated aqueous NH 4 Cl solution at 0 C. The resultant mixture was diluted with EtAc, washed with H 2 and brine, dried over MgS 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 5% to 10% to 15% EtAc/hexanes) gave benzyl ether 19 (5.44 g, 93%) as a pale yellow oil: [α] 25.6 D 25.7 (c 1.69, CHCl 3 ); IR (neat) 2924, 2863, 1615, 1517, 1462, 1364, 1250, 1092, 1034, 883, 828, 734, 698, 678 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 2H), (m, 10H), (m, 2H), 5.43 (s, 1H), 4.58 (d, J = 11.9 Hz, 1H), (m, 2H, overlapped), 4.48 (d, J = 11.9 Hz, 1H), 4.17 (m, 1H), 4.08 (dd, J = 11.5, 4.6 Hz, 1H), 3.80 (s, 3H),

8 S (m, 1H), (m, 2H), (m, 3H), 3.42 (m, 1H), (m, 2H), 1.72 (ddd, J = 11.5, 11.5, 11.5 Hz, 1H), (m, 2H), 1.26 (s, 3H), (m, 21H); 13 C NMR (150 MHz, CDCl 3 ) δ 160.1, 138.7, 138.3, 130.1, (2C), (2C), (2C), (3C), (3C), (2C), 101.7, 80.8, 79.7, 76.9, 73.0, 72.8, 70.78, 70.71, 69.9, 66.3, 55.3, 31.0, 30.9, 28.4, 18.6 (3C), 18.5 (3C), 14.3, 13.4 (3C); HRMS (FAB) calcd for C 42 H 60 7 SiNa + [(M + Na) + ] , found Bn TIPS Bn PMP 19 DIBALH, CH 2 Cl 2 78 to 20 C Bn TIPS H + Bn Bn PMB TIPS PMB Bn H 20: 72% 21: 12% Alcohols 20 and 21. To a solution of p-methoxybenzylidene acetal 19 (5.42 g, 7.69 mmol) in CH 2 Cl 2 (70 ml) at 78 C was slowly added DIBALH (1.03 M solution in n-hexane, 38 ml, 39.1 mmol) over 10 min. The resultant solution was stirred at 78 C for 2 h, allowed to warm to 20 C over a period of 1 h, and stirred at 20 C for 20 h. The reaction was quenched with MeH. The resultant solution was diluted with saturated potassium sodium tartrate solution and EtAc and stirred at room temperature for 1 h. The organic layer was separated, and the aqueous layer was extracted twice with EtAc. The combined organic layers were washed with brine, dried over MgS 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, first round: 15% to 20% to 50% EtAc/hexanes; second round: 15% to 50% EtAc/hexanes) gave primary alcohol 20 (3.94 g, 72%) as a pale yellow oil, along with secondary alcohol 21 (0.648 g, 12%) as a colorless oil. Data for 20: [α] 24.7 D (c 1.32, CHCl 3 ); IR (neat) 3589, 3485, 2942, 2865, 1612, 1514, 1455, 1250, 1100, 1037, 883, 735, 698, 678 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 10H), (m, 2H), (m, 2H), 4.57 (d, J = 11.5 Hz, 1H), 4.54 (d, J = 11.0 Hz, 1H), (m, 2H), 4.46 (d, J = 11.0 Hz, 1H, overlapped), 4.35 (d, J = 11.5 Hz, 1H), 3.85 (dd, J = 11.9, 4.6 Hz, 1H), 3.81 (s, 3H), (m, 2H), (m, 2H), (m, 2H), 3.21 (m, 1H), 2.45 (ddd, J = 11.9, 4.6, 4.6 Hz, 1H), (m, 2H), (m, 2H), 1.54 (ddd, J = 11.9, 11.9, 11.5 Hz, 1H), 1.21 (s, 3H), (m, 21H); 13 C NMR (150 MHz, CDCl 3 ) δ 159.3, 138.6, 138.4, 130.0, (2C), (2C), (2C), (2C), (3C), 127.4, (2C), 79.9, 79.1, 73.5, 73.2, 72.8, 72.7, 70.9, 70.6, 70.4, 63.9, 55.3, 30.8, 30.5, 28.1, (3C), (3C), 14.0, 13.4 (3C); HRMS (FAB) calcd for C 42 H 62 7 SiNa + [(M + Na) + ]

9 S , found Data for 21: [α] 26.0 D 22.1 (c 1.98, CHCl 3 ); IR (neat) 3441, 2942, 2865, 1612, 1462, 1455, 1363, 1249, 1100, 1062, 883, 821, 735, 698, 678 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 12H), (m, 2H), 4.56 (d, J = 11.5 Hz, 1H), 4.51 (d, J = 11.5 Hz, 1H), (m, 3H), 4.44 (d, J = 11.5 Hz, 1H), 3.95 (dd, J = 11.5, 4.6 Hz, 1H), 3.81 (s, 3H), 3.68 (br d, J = 4.6 Hz, 1H), 3.62 (m, 1H), 3.58 (m, 1H), (m, 2H), (m, 2H), 3.29 (br s, 1H), 2.32 (m, 1H), (m, 2H), (m, 3H), 1.19 (s, 3H), (m, 21H); 13 C NMR (150 MHz, CDCl 3 ) δ 159.4, 138.7, 138.5, (2C), 129.4, (2C), (2C), (2C), (2C) , , (2C), 79.6, 79.5, 73.5, 73.1, 72.8, 72.6, 70.9, 70.80, 70.76, 70.4, 55.3, 33.1, 31.0, 28.3, (3C), (3C), 13.7, 13.4 (3C); HRMS (ESI) calcd for C 42 H 63 7 Si + [(M + H) + ] , found Bn TIPS H Bn PMB 20 Tf 2 2,6-lutidine CH 2 Cl 2 40 C Bn TIPS Tf Bn PMB S2 allylmgbr CuBr THF, 0 C to rt 89% (2 steps) Bn TIPS Bn PMB 22 lefin 22. To a solution of alcohol 20 (2.56 g, 3.62 mmol) and 2,6-lutidine (1.3 ml, 11.2 mmol) in CH 2 Cl 2 (40 ml) at 40 C was slowly added Tf 2 (0.9 ml, 5.4 mmol), and the resultant solution was stirred at 40 C for 55 min. The reaction mixture was poured into saturated aqueous NaHC 3 solution and extracted with EtAc. The organic layer was washed with H 2 and brine, dried over MgS 4, filtered, and concentrated under reduced pressure. The residue was roughly purified by flash column chromatography (silica gel, 15% EtAc/hexanes) to give triflate S2 (3.21 g) as a pale yellow oil, which was immediately used in the next reaction without further purification: 1 H NMR (600 MHz, CDCl 3 ) δ (m, 10H), (m, 2H), (m, 2H), 4.57 (dd, J = 10.1, 1.9 Hz, 1H), 4.56 (d, J = 11.5 Hz, 1H), 4.54 (d, J = 11.0 Hz, 1H), (m, 3H, overlapped), 4.48 (d, J = 11.5 Hz, 1H), 4.30 (d, J = 11.0 Hz, 1H), 3.93 (dd, J = 11.5, 4.6 Hz, 1H), 3.81 (s, 3H), (m, 2H), (m, 2H), 3.22 (ddd, J = 10.8, 10.1, 4.6 Hz, 1H), 2.49 (ddd, J = 12.4, 5.0, 4.6 Hz, 1H), (m, 2H), (m, 2H), 1.19 (s, 3H), (m, 21H). To a suspension of CuBr (223 mg, 1.58 mmol) in Et 2 (20 ml) at 0 C was slowly added allylmagnesium bromide (1.0 M solution in Et 2, 20 ml, 20 mmol) over 5 min, and the resultant solution was stirred at 0 C for 30 min. To the resultant black solution was slowly added a solution of the above triflate S2 (3.21 g) in Et 2 (10 ml + 3 ml 2

10 S10 rinse) over 10 min. The resultant solution was stirred at 0 C for 1 h, allowed to warm to room temperature, and stirred for 18.5 h. The reaction was quenched with saturated aqueous NH 4 Cl solution at 0 C. The mixture was filtered through a pad of Celite eluting with Et 2. The filtrate was diluted with Et 2, washed with H 2 and brine, dried over MgS 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 5 to 7 to 8% EtAc/hexanes) gave olefin 22 (2.37 g, 89% for the two steps) as a colorless oil: [α] 25.6 D (c 2.08, CHCl 3 ); IR (neat) 2943, 2865, 1612, 1513, 1463, 1455, 1249, 1100, 884, 734, 697, 678 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 12H), (m, 2H), 5.80 (dddd, J = 17.2, 10.3, 6.9, 6.9 Hz, 1H), 4.98 (dd, J = 17.2, 1.8 Hz, 1H), 4.93 (d, J = 10.3 Hz, 1H), 4.57 (d, J = 11.7 Hz, 1H), 4.54 (d, J = 11.0 Hz, 1H), (m, 3H), 4.36 (d, J = 11.0 Hz, 1H), 3.93 (dd, J = 12.4, 4.8 Hz, 1H), 3.81 (s, 3H), 3.72 (d, J = 5.5 Hz, 1H), (m, 3H), 3.00 (m, 1H), 2.43 (ddd, J = 11.7, 4.8, 4.8 Hz, 1H), 2.23 (m, 1H), 2.03 (m, 1H), 1.91 (m, 1H), (m, 2H), (m, 2H), 1.47 (ddd, J = 11.7, 11.7, 11.7 Hz, 1H), 1.28 (m, 1H), 1.15 (s, 3H), (m, 21H); 13 C NMR (150 MHz, CDCl 3 ) δ 159.2, 138.9, , , 130.4, (2C), (2C), (2C), (2C), (2C), (2C), 114.3, (2C), 79.7, 79.1, 76.4, 73.1, 72.8, 72.0, 70.8 (2C), 70.5, 55.3, 31.2, 31.0 (2C), 30.2, 28.3, 18.6 (3C), 18.5 (3C), 13.9, 13.4 (3C); HRMS (FAB) calcd for C 45 H 66 6 SiNa + [(M + Na) + ] , found Bn TIPS Bn PMB 22 DDQ, CH 2 Cl 2 ph 7 buffer, rt Bn TIPS Bn H S3 TPAP, NM 4 Å MS CH 2 Cl 2, rt 85% (2 steps) Bn TIPS Bn 23 Ketone 23. To a solution of PMB ether 22 (2.35 g, 3.21 mmol) in CH 2 Cl 2 /ph 7.0 phosphate buffer (10:1, v/v, 33 ml) at 0 C was added DDQ (0.89 g, 3.92 mmol), and the resultant solution was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous Na 2 S 3 solution. The mixture was extracted with EtAc, washed with saturated aqueous NaHC 3 solution and brine, dried over MgS 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 10% to 15% to 20% EtAc/hexanes) gave an inseparable 1:1 mixture of alcohol S3 and p-methoxybenzaldehyde (2.18 g) as a pale yellow oil, which was used in the next reaction without further purification: 1 H NMR

11 S11 (600 MHz, CDCl 3 ) δ (m, 10H), 5.80 (dddd, J = 16.9, 10.1, 6.8, 6.8 Hz, 1H), 5.00 (dd, J = 16.9, 1.8 Hz, 1H), 4.94 (dm, J = 10.1 Hz, 1H), 4.56 (d, J = 11.5 Hz, 1H), (m, 3H), 3.99 (dd, J = 10.6, 4.6 Hz, 1H), 3.71 (dd, J = 7.1, 3.0 Hz, 1H), (m, 2H), (m, 2H), (m, 2H), 2.06 (m, 1H), (m, 3H), (m, 4H), 1.38 (m, 1H), 1.17 (s, 3H), (m, 21H); 13 C NMR (150 MHz, CDCl 3 ) δ 138.7, 138.6, 138.5, (4C), (2C), (2C), , , 114.6, 79.5, 79.3, 72.63, 73.55, 72.8, 71.0, 70.8, 70.2, 34.4, 31.3, 30.9, 30.0, 28.3, 18.6 (3C), 18.5 (3C), 13.7, 13.4 (3C). To a suspension of the above alcohol S3 (2.18 g), NM (97%, 595 mg, 4.93 mmol), and 4 Å molecular sieves (3.29 g) in CH 2 Cl 2 (32 ml), and the resultant mixture was stirred at room temperature for 10 min. To this mixture was added TPAP (69.4 mg, mmol), and the resultant mixture was stirred at room temperature for 1 h. The mixture was directly purified by flash column chromatography (silica gel, 8% EtAc/hexanes) to give ketone 23 (1.67 g, 85% for the two steps) as a colorless oil: [α] 25.6 D (c 2.08, CHCl 3 ); IR (neat) 2943, 2865, 1612, 1513, 1463, 1455, 1249, 1100, 884, 734, 697, 678 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 10H), 5.77 (dddd, J = 17.2, 10.3, 6.8, 6.8 Hz, 1H), 5.01 (d, J = 17.2 Hz, 1H), 4.96 (d, J = 10.3 Hz, 1H), 4.54 (d, J = 11.7 Hz, 1H), 4.50 (s, 2H), 4.34 (d, J = 11.7 Hz, 1H), 4.22 (m, 1H), 3.97 (dd, J = 9.7, 3.5 Hz, 1H), 3.77 (dd, J = 5.5, 4.8 Hz, 1H), (m, 2H), 2.83 (dd, J = 15.1, 2.4 Hz, 1H), 2.66 (dd, J = 15.1, 4.1 Hz, 1H), 2.17 (m, 1H), 2.11 (m, 1H), (m, 2H), (m, 2H), (m, 2H), 1.26 (s, 3H), (m, 21H); 13 C NMR (150 MHz, CDCl 3 ) δ 212.3, 138.6, , , (4C), 127.6, (2C), (2C), , 115.2, 82.0, 77.0, 76.4, 75.4, 72.8, 71.3, 70.6, 39.8, 30.6, 29.6, 29.0, 27.8, 18.4 (3C), 18.3 (3C), 13.5, 13.3 (3C); HRMS (FAB) calcd for C 37 H 56 5 SiNa + [(M + Na) + ] , found Bn TIPS Bn 23 Me 3 Al, CH 2 Cl 2 78 to 15 C Bn TIPS Bn H H Me 24: 94% Bn TIPS 48 Bn H H Me 48-epi-24: 6% Alcohols 24 and 48-epi-24. To a solution of ketone 23 (1.84 g, 3.02 mmol) in CH 2 Cl 2 (30 ml) at 78 C was slowly added Me 3 Al (1.4 M solution in n-hexane, 7.6 ml, 10.6 mmol). After being stirred at 78 C for 6 h, the resultant solution was allowed to warm to 15 C over 15 min and stirred at 15 C for 15.5 h. The reaction was quenched with

12 S12 MeH. The mixture was diluted with saturated aqueous potassium sodium tartrate solution and EtAc, and the resultant mixture was vigorously stirred at room temperature for 1 h. The mixture was extracted with EtAc, and the organic layer was washed with brine, dried over MgS 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 10% to 15% to 20% EtAc/hexanes) gave alcohol 24 (1.79 g, 94%) as a colorless oil, along with its 24.8 diastereomeric alcohol 48-epi-24 (114.6 mg, 6%) as a colorless oil. Data for 24: [α] D (c 1.02, CHCl 3 ); IR (neat) 3421, 2943, 2865, 2360, 1639, 1455, 1378, 1362, 1098, 1072, 883, 733, 697, 679 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 10H), 5.81 (dddd, J = 17.0, 10.1, 6.9, 6.9 Hz, 1H), 5.01 (dd, J = 17.0, 1.9 Hz, 1H), 4.95 (dd, J = 10.1, 1.0 Hz, 1H), 4.54 (d, J = 11.5 Hz, 1H), 4.48 (s, 2H), 4.45 (d, J = 11.5 Hz, 1H), 3.84 (dd, J = 9.6, 4.1 Hz, 1H), 3.72 (dd, J = 5.0, 5.0 Hz, 1H), 3.40 (dd, J = 6.8, 6.4 Hz, 2H), 3.36 (dd, J = 10.6, 1.4 Hz, 1H), 2.26 (m, 1H), 2.03 (m, 1H), (m, 2H), 1.82 (m, 1H), 1.71 (dd, J = 12.8, 10.1 Hz, 1H), (m, 2H), 1.55 (m, 1H), 1.33 (m, 1H), 1.21 (s, 3H), 1.13 (s, 3H), (m, 21H, overlapped), one proton missing due to H/D exchange; 13 C NMR (150 MHz, CDCl 3 ) δ 138.8, 138.7, 138.4, (2C), (2C), (2C), 127.5, (2C), , 114.5, 80.4, 78.1, 75.7, 74.8, 72.7, 71.3 (2C), 70.8, 40.5, 30.71, 30.66, 28.1, 27.9, 21.6, 18.4 (3C), 18.3 (3C), 13.6 (3C), 13.4; HRMS (FAB) calcd for C 38 H 60 5 SiNa + [(M + Na) + ] , found Data for 48-epi-24: [α] 24.4 D 5.38 (c 1.19, CHCl 3 ); IR (neat) 3579, 3480, 2944, 2866, 2360, 1639, 1455, 1362, 1097, 911, 883, 815, 734, 697, 679 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 10H), 5.73 (dddd, J = 17.3, 10.3, 7.6, 6.2 Hz, 1H), 5.00 (d, J = 17.3 Hz, 1H), 4.96 (d, J = 10.3 Hz, 1H), 4.56 (d, J = 11.7 Hz, 1H), (m, 2H), 4.42 (d, J = 11.7 Hz, 1H), 4.09 (dd, J = 11.6, 4.8 Hz, 1H), 3.76 (dd, J = 6.2, 4.1 Hz, 1H), (m, 3H), 2.37 (s, 1H), 2.25 (m, 1H), 2.16 (dd, J = 13.1, 5.5 Hz, 1H), 2.02 (m, 1H), 1.94 (m, 1H), 1.84 (m, 1H), (m, 5H), 1.16 (s, 3H), (m, 24H); 13 C NMR (150 MHz, CDCl 3 ) δ , (2C), (2C), (2C), (2C), (2C), , , 114.7, 79.9, 79.6, 74.8, 72.8, 71.3, 71.1, 70.6, 70.5, 39.6, 31.0, 30.2, 28.3, 27.2, 24.2, 18.4 (6C), 13.8 (3C), 13.6; HRMS (ESI) calcd for C 38 H 60 5 SiNa + [(M + Na) + ] , found

13 S13 Bn TIPS Bn H 24 H Me Cy 2 BH, THF, rt aq NaH, H 2 2 rt, quant Diol 25. To a solution of cyclohexene (3.0 ml, 29.6 mmol) in THF (50 ml) at 0 C was slowly added BH 3 THF (0.9 M solution in THF, 15 ml, 13.5 mmol), and the resultant solution was stirred at 0 C for 1 h. To the resultant white suspension was slowly added a solution of alcohol 24 (3.30 g, 5.28 mmol) in THF (15 ml + 4 ml 2 rinse) over 11 min. The resultant solution was stirred at room temperature for 1 h. To this solution at 0 C were slowly added 3 M aqueous NaH solution (25 ml) followed by 30% aqueous H 2 2 solution (25 ml). The resultant mixture was vigorously stirred at room temperature for 80 min. The organic layer was separated, and the aqueous layer was extracted twice with Et 2. The combined organic layers were washed with saturated aqueous Na 2 S 3 solution and brine, dried over MgS 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 40% to 50% to 60% EtAc/hexanes) gave diol 25 (3.74 g, quantitative) as a colorless oil: [α] D (c 1.13, CHCl 3 ); IR (neat) 3373, 2943, 2865, 1455, 1378, 1362, 1098, 1072, 883, 734, 697, 679 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 10H), 4.53 (d, J = 11.5 Hz, 1H), 4.47 (s, 2H), 4.44 (d, J = 11.5 Hz, 1H), 3.81 (dd, J = 9.6, 4.1 Hz, 1H), 3.71 (dd, J = 5.0, 5.0 Hz, 1H), (m, 2H), 3.39 (dd, J = 6.9, 6.4 Hz, 2H), 3.33 (d, J = 9.6 Hz, 1H), 1.94 (dd, J = 12.8, 4.1 Hz, 1H), 1.90 (m, 1H), 1.80 (m, 1H), 1.71 (dd, J = 12.8, 9.6 Hz, 1H), (m, 8H), 1.22 (s, 3H), 1.11 (s, 3H), (m, 21H), two protons missing due to H/D exchange; 13 C NMR (150 MHz, CDCl 3 ) δ 138.7, 138.4, (2C), (2C), (2C), 127.6, (2C), 127.4, 80.4, 77.9, 76.6, 74.9, 72.7, 71.4, 71.3, 70.8, 62.9, 40.4, 32.7, 30.6, 28.2, 28.1, 22.9, 21.6, 18.4 (3C), 18.3 (3C), 13.6 (3C), 13.4; HRMS (FAB) calcd for C 38 H 62 6 SiNa + [(M + Na) + ] , found Bn TIPS Bn H Me 25 H TIPS AZADL, PhI(Ac) 2 TIPS Bn Bn H Me 25 H CH 2 Cl 2, ph 7 buffer (1:1), rt, 88% Bn Bn H Me 26 C 2 H Carboxylic acid 26. To a solution of diol 25 (3.73 g, 5.28 mmol) in CH 2 Cl 2 /ph 7.0 phosphate buffer (1:1, v/v, 36 ml) at 0 C were sequentially added AZADL (82.2 mg, mmol) and PhI(Ac) 2 (5.12 g, 15.9 mmol). The resultant solution was stirred

14 S14 at room temperature for 3 h. The reaction was quenched with saturated aqueous Na 2 S 2 3 solution at 0 C. The mixture was extracted with EtAc, and the aqueous layer was extracted twice with EtAc. The combined organic layers were washed with brine, dried over MgS 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 40% to 50% to 60% EtAc/hexanes) gave carboxylic acid 26 (3.06 g, 88%) as a pale yellow oil: [α] 26.5 D 1.91 (c 1.49, CHCl 3 ); IR (neat) 3409, 2943, 2866, 1710, 1455, 1380, 1363, 1252, 1206, 1097, 883, 735, 697, 679 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 10H), 4.54 (d, J = 11.5 Hz, 1H), 4.48 (s, 2H), 4.44 (d, J = 11.5 Hz, 1H), 3.81 (dd, J = 10.1, 4.1 Hz, 1H), 3.72 (dd, J = 5.0, 5.0 Hz, 1H), 3.40 (dd, J = 6.4, 6.4 Hz, 2H), 3.35 (d, J = 10.1 Hz, 1H), (m, 2H), (m, 2H), (m, 2H), 1.72 (dd, J = 12.4, 10.1 Hz, 1H), (m, 3H), 1.53 (m, 1H), 1.26 (m, 1H), 1.23 (s, 3H), 1.11 (s, 3H), (m, 21H, overlapped), two proton missing due to H/D exchange; 13 C NMR (150 MHz, CDCl 3 ) δ 178.6, 138.6, 138.3, (2C), (2C), (2C), 127.6, (2C), 127.4, 80.5, 77.9, 76.4, 74.8, 72.7, 71.4, 71.3, 70.8, 40.3, 33.9, 30.5, 28.1, 27.7, 22.1, 21.5, 18.4 (3C), 18.3 (3C), 13.5 (3C), 13.4; HRMS (FAB) calcd for C 38 H 60 7 SiNa + [(M + Na) + ] , found TIPS 2,4,6-Cl 3 C 6 H 2 CCl Et 3 N, THF, rt TIPS Bn Bn H Me 26 C 2 H DMAP, toluene 100 C, 95% Bn Bn 12 Me Lactone 12. To a solution of carboxylic acid 26 (2.98 g, 4.54 mmol) and Et 3 N (1.9 ml, 13.6 mmol) in THF (45 ml) at 0 C was slowly added 2,4,6-trichlorobenzoyl chloride (1.0 ml, 6.4 mmol), and the resultant solution was stirred at room temperature for 70 min and diluted with toluene (180 ml). To a solution of DMAP (2.78 g, 22.8 mmol) in toluene (400 ml) at 100 C was slowly added the above mixture over 4 h. The resultant mixture was stirred at 100 C for further 30 min. The mixture was cooled to room temperature, diluted with EtAc, washed with cold 1 M aqueous HCl solution, saturated aqueous NaHC 3 solution, and brine, dried over MgS 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 10% to 20% to 30% EtAc/hexanes) gave lactone 12 (2.75 g, 95%) as a pale yellow oil: [α] 24.8 D 37.8 (c 1.40, CHCl 3 ); IR (neat) 2944, 2866, 1728, 1455, 1273, 1201, 1100, 1067, 1052, 884, 734, 697, 679 cm 1 ; 1 H NMR (600 MHz,

15 S15 CDCl 3 ) δ (m, 10H), 4.53 (d, J = 11.5 Hz, 1H), (m, 2H), 4.43 (d, J = 11.5 Hz, 1H), 3.86 (dd, J = 11.9, 4.6 Hz, 1H), 3.73 (dd, J = 5.9, 4.1 Hz, 1H), 3.60 (dd, J = 11.0, 2.8 Hz, 1H), (m, 2H), 2.78 (m, 1H), 2.51 (m, 1H), 2.19 (dd, J = 12.6, 4.8 Hz, 1H), (m, 5H), (m, 4H), 1.44 (s, 3H), 1.21 (s, 3H), (m, 21H); 13 C NMR (150 MHz, CDCl 3 ) δ 174.0, 138.7, 138.1, (2C), (2C), (2C), 127.6, (2C), , 80.7, 80.0, 78.9, 73.5, 72.8, 72.1, 70.9, 70.7, 40.4, 36.8, 30.9 (2C), 28.3, 20.6, 19.1, 18.5 (3C), 18.4 (3C), 13.7, 13.6 (3C); HRMS (FAB) calcd for C 38 H 58 6 SiNa + [(M + Na) + ] , found Bn TIPS Bn Me 12 KHMDS (Ph) 2 P()Cl TIPS Bu 3 SnCH 2 H Pd(PPh 3 ) 4, LiCl TIPS HMPA, THF Bn Bn THF, reflux Bn 78 C, 95% Me Ph 83% Bn P Me 11 Ph 10 H Allylic alcohol 10. To a solution of lactone 12 (496.7 mg, mmol) in THF (8 ml) were added HMPA (0.4 ml, 2.3 mmol) and (Ph) 2 P()Cl (0.48 ml, 2.3 mmol). To this solution at 78 C was slowly added KHMDS (0.5 M solution in toluene, 4.0 ml, 2.0 mmol) over 4 min, and the resultant solution was stirred at 78 C for 1 h 20 min. The reaction was quenched with 3% NH 4 H. The resultant mixture was diluted with Et 2 and vigorously stirred at room temperature for 40 min. The mixture was extracted with EtAc, and the organic layer was washed with H 2 and brine, dried over MgS 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 10% to 15% EtAc/hexanes) gave enol phosphate 11 (645.1 mg, 95%) as a pale yellow oil, which was unstable and immediately used in the next reaction without further purification: 1 H NMR (600 MHz, CDCl 3 ) δ (m, 20H), 4.86 (m, 1H), 4.49 (d, J = 11.5 Hz, 1H), (m, 1H), 4.36 (d, J = 11.5 Hz, 1H), 3.82 (dd, J = 11.9, 4.6 Hz, 1H), 3.71 (dd, J = 5.9, 4.1 Hz, 1H), 3.51 (dd, J = 11.5, 2.8 Hz, 1H), (m, 2H), 2.09 (m 1H), (m, 2H), 1.90 (m, 1H), 1.79 (m, 1H), 1.76 (dd, J = 11.9, 11.9 Hz, 1H), (m, 2H), (m, 2H), 1.31 (s, 3H), 1.21 (s, 3H), (m, 21H). LiCl (99%, 97.8 mg, 2.28 mmol) was placed in a flask and dried with a heat gun under reduced pressure for 20 min. Pd(PPh 3 ) 4 (90.0 mg, mmol) and THF (4 ml) were added to the flask, and the resultant mixture was stirred at room temperature for 10 min. To the resultant clear yellow solution were slowly added a solution of the above enol phosphate 11 (645.1 mg, mmol) in THF (4 ml + 2 ml 2 rinse) followed

16 S16 by a solution of n-bu 3 SnCH 2 H 4 (479.5 mg, mmol) in THF (4 ml + 2 ml rinse). The resultant solution was heated to reflux for 3 h. The mixture was cooled to room temperature, diluted with EtAc, and washed with H 2 and brine, dried over MgS 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (10% w/w anhydrous K 2 C 3 -silica gel, 20% to 25% EtAc/hexanes) gave allylic alcohol 10 (401.3 mg, 83%) as a pale yellow oil: [α] 24.1 D 9.53 (c 1.29, CHCl 3 ); IR (neat) 3420, 2943, 2865, 1717, 1454, 1362, 1097, 735, 697, 679 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 10H), 5.15 (dd, J = 6.9, 5.0 Hz, 1H), 4.57 (d, J = 11.5 Hz, 1H), (m, 2H), 4.43 (d, J = 11.5 Hz, 1H), (m, 3H), 3.75 (dd, J = 6.0, 4.1 Hz, 1H), 3.56 (dd, J = 11.5, 3.2 Hz, 1H), (m, 2H), 2.15 (dd, J = 11.9, 5.0 Hz, 1H), (m, 2H), 1.94 (m, 1H), 1.86 (dd, J = 11.9, 11.9 Hz, 1H), 1.82 (m, 1H), (m, 3H), (m, 2H), 1.24 (s, 3H), 1.20 (s, 3H), (m, 21H); 13 C NMR (150 MHz, CDCl 3 ) δ 152.4, 138.7, 138.4, (2C), (2C), (2C), (3C), 127.4, 108.2, 79.9, 79.0, 77.9, 76.7, 72.9, 72.7, 70.8, 70.7, 65.2, 40.2, 30.9, 28.3, 27.1, 21.9, 18.5 (3C), 18.4 (3C), 16.4, 13.9, 13.6 (3C); HRMS (FAB) calcd for C 39 H 61 6 Si + [(M + H) + ] , found Bn TIPS Bn Me NC 6 H 4 SeCN Bu 3 P THF, 0 C, 95% H Bn TIPS Bn Me 9 Selenide 9. To a solution of allylic alcohol 10 (401.3 mg, mmol) and 2-nitrophenyl selenocyanate (98%, mg, mmol) in THF (7 ml) at 0 C was slowly added n-bu 3 P (0.23 ml, 0.93 mmol), and the resultant solution was stirred at 0 C for 70 min. The mixture was concentrated under reduced pressure, and the residue was directly purified by flash column chromatography (silica gel, 5% to 10% EtAc/hexanes) to give selenide 9 (489.4 mg, 95%) as a light yellow oil: [α] D (c 1.27, CHCl 3 ); IR (neat) 2942, 2865, 1515, 1454, 1331, 1303, 1098, 1066, 731, 697, 679 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ 8.28 (dd, J = 8.3, 1.4 Hz, 1H), 7.66 (dd, J = 8.2, 0.9 Hz, 1H), 7.48 (ddd, J = 8.3, 8.2, 1.4 Hz, 1H), (m, 11H), 5.24 (dd, J = 6.4, 5.5 Hz, 1H), 4.54 (d, J = 11.5 Hz, 1H), (m, 2H), 4.40 (d, J = 11.5 Hz, 1H), 3.83 (dd, J = 11.9, 5.0 Hz, 1H), 3.73 (dd, J = 5.9, 4.1 Hz, 1H), (m, 3H), (m, 2H), (m, 3H), 1.91 (m, 1H), 1.82 (dd, J = 12.4, 11.9 Hz, 1H), 1.81 (m, 1H), (m, 2H), (m, 2H), 1.22 (s, 3H), 1.21 (s, 3H), 1.11 Se N 2

17 S (m, 21H); 13 C NMR (150 MHz, CDCl 3 ) δ 149.2, 146.7, 138.7, 138.4, 134.5, 133.4, 129.5, (2C), (2C), (2C), (3C), 127.4, 126.2, 125.4, 110.5, 79.9, 79.0, 78.4, 76.4, 72.82, 72.76, 70.8, 70.6, 39.9, 32.8, 30.8, 28.3, 27.0, 22.6, 18.5 (3C), 18.4 (3C), 16.4, 13.9, 13.6 (3C); HRMS (ESI) calcd for C 45 H 63 N 7 SeSiNa + [(M + Na) + ] , found Bn TIPS Bn 9 Me Se N 2 H 2 2, DMAP THF 40 C to rt Bn TIPS exo-lefins 27 and 28. To a solution of selenide 9 (489.4 mg, mmol) and DMAP (359.6 mg, mmol) in THF (8 ml) at 40 C was slowly added 30% aqueous H 2 2 solution (0.7 ml, ca. 6.2 mmol). After being stirred at 40 C for 1 h, the reaction mixture was allowed to warm to room temperature and stirred for 16.5 h. The reaction was quenched with a 1:1 mixture of saturated aqueous NaHC 3 solution and saturated aqueous Na 2 S 2 3 solution. The mixture was extracted with EtAc, and the organic layer was washed with brine, dried over MgS 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 10% to 15% to 20% EtAc/hexanes) gave exo-olefin 27 (254.3 g, 67%) as a light yellow oil, along with its diastereomeric alcohol 28 (20.1 mg, 5 %) as a pale yellow oil. Data for 27: [α] D (c 0.86, CHCl 3 ); IR (neat) 3427, 2943, 2866, 1715, 1455, 1361, 1097, 1071, 883, 735, 697, 679 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 10H), 4.77 (d, J = 0.9 Hz, 1H), 4.63 (s, 1H), 4.56 (d, J = 11.5 Hz, 1H), (m, 2H), 4.41 (d, J = 11.5 Hz, 1H), 4.20 (m, 1H), 3.82 (dd, J = 11.5, 5.0 Hz, 1H), 3.72 (dd, J = 5.5, 4.6 Hz, 1H), 3.61 (dd, J = 10.6, 3.2 Hz, 1H), (m, 2H), 2.13 (dd, J = 12.4, 5.0 Hz, 1H), (m, 2H), 1.83 (dd, J = 11.9, 11.9 Hz, 1H), 1.81 (m, 1H), (m, 4H), 1.50 (m, 1H), 1.21 (s, 3H), 1.20 (s, 3H), (m, 21H), one proton missing due to H/D exchange; 13 C NMR (150 MHz, CDCl 3 ) δ 162.8, 138.7, 138.4, (2C), (2C), (2C), , (2C), , 97.3, 80.0, 78.9, 78.6, 73.4, 73.0, 72.7 (2C), 70.8, 70.7, 40.1, 32.8, 30.8, 28.3, 26.7, 19.0, 18.5 (3C), 18.4 (3C), 14.1, 13.6 (3C); HRMS (FAB) calcd for C 39 H 61 6 Si + [(M + H) + ] , found Data for 28:* [α] D (c 0.92, CHCl 3 ); IR (neat) 3444, 2943, 2866, 1715, 1455, 1380, 1362, 1208, 1097, 1070, 883, 734, 697, 679 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 10H), 4.64 (s, 1H), 4.61 (s, 1H), 4.57 (d, J = Bn Me 27: 67% H + Bn TIPS Bn Me 28: 5% H

18 S Hz, 1H), (m, 2H), 4.44 (m, 1H), 4.42 (d, J = 11.5 Hz, 1H), 3.85 (dd, J = 11.5, 5.0 Hz, 1H), 3.74 (dd, J = 5.5, 4.6 Hz, 1H), 3.55 (dd, J = 11.0, 2.8 Hz, 1H), (m, 2H), 2.15 (dd, J = 11.9, 5.0 Hz, 1H), (m, 4H), 1.81 (dd, J = 11.9, 11.9 Hz, 1H, overlapped), (m, 4H), 1.35 (s, 3H), 1.20 (s, 3H), (m, 21H), one proton missing due to H/D exchange; 13 C NMR (150 MHz, CDCl 3 ) δ 161.2, 138.7, 138.4, (2C), (2C), (2C), , (2C), , 100.9, 79.9, 78.9 (2C), 73.6, 73.1, 72.8, 71.1, 70.8, 70.7, 39.8, 30.83, 30.80, 28.3, 24.5, 18.8, 18.5 (3C), 18.4 (3C), 14.0, 13.6 (3C). *This compound was not further characterized due to its rapid decomposition. Bn TIPS Bn Me 27 H 4-2 NC 6 H 4 C 2 H DEAD, PPh 3 THF, 0 C, 72% Bn TIPS Bn Me 29 N 2 4-Nitrobenzoate 29. To a solution of alcohol 27 (352.5 mg, mmol) and PPh 3 (428.4 mg, mmol) in THF (5.5 ml) at 0 C were sequentially added 4-nitrobenzoic acid (271.5 mg, mmol) and DEAD (2.2 M solution in toluene, 0.74 ml, 1.63 mmol). The resultant solution was stirred at room temperature for 1 h. The reaction was quenched with saturated aqueous NaHC 3 solution at 0 C. The mixture was diluted with EtAc, washed with H 2 and brine, dried over MgS 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 10% to 20% Et 2 /hexanes) gave 4-nitrobenzoate 29 (310.1 mg, 72%) as a pale yellow oil: [α] 25.5 D 15.8 (c 1.09, CHCl 3 ); IR (neat) 2944, 2865, 1725, 1530, 1348, 1270, 1100, 1069, 1014, 883, 719, 697, 679 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), (m, 10H), 7.58 (m, 1H), (m, 2H), (m, 10H), 5.93 (br d, J = 5.5 Hz, 1H), 4.82 (s, 1H), 4.79 (s, 1H), 4.59 (d, J = 11.5 Hz, 1H), (m, 2H), 4.44 (d, J = 11.5 Hz, 1H), 3.88 (dd, J = 11.5, 5.0 Hz, 1H), 3.77 (dd, J = 5.5, 4.6 Hz, 1H), 3.65 (m, 1H), (m, 2H), 2.17 (dd, J = 11.9, 5.0 Hz, 1H), 2.09 (m, 1H), 1.96 (m, 1H), (m, 4H), 1.72 (m, 1H), 1.61 (m, 1H), 1.53 (m, 1H), 1.40 (s, 3H), 1.25 (s, 3H), (m, 21H); 13 C NMR (150 MHz, CDCl 3 ) δ 163.5, 156.6, 150.5, 138.7, 138.2, 135.7, (2C), (4C), (2C), 127.5, (2C), , (2C), 104.6, 80.0, 79.1, 78.9, 74.0, 73.9, 72.9, 72.7, 70.73, 70.66, 40.4, 30.8, 28.3, 27.3, 25.0, 18.5 (3C), 18.4 (3C), 18.0, 14.1, 13.6 (3C); HRMS (FAB) calcd for C 46 H 63 N 9 SiNa + [(M + Na) + ]

19 S , found Bn TIPS Bn Me 29 Alcohol 28. To a solution of 4-nitrobenzoate 29 (65.8 mg, mmol) in MeH/THF (1:1, v/v, 1.5 ml) at 0 C was added K 2 C 3 (34.4 mg, mmol). The resultant solution was stirred at room temperature for 45 min. The reaction was quenched with saturated aqueous NH 4 Cl solution. The mixture was diluted with EtAc and washed with H 2. The aqueous layer was extracted with EtAc, and the combined organic layers were washed with brine, dried over MgS 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 10% to 20% to 30% EtAc/hexanes) gave alcohol 28 (46.5 mg, 87%) as a pale yellow oil, which was unstable under both neutral and acidic conditions and immediately used in the next reaction. The spectroscopic data of 28 were identical to those described above. N 2 K 2 C 3 MeH, rt 87% Bn TIPS Bn Me 28 H Bn TIPS Bn Me 28 H TESCl, imidazole DMF, rt, 90% Bn TIPS Bn Me 8 TES TES ether 8. To a solution of alcohol 28 (414.5 mg, mmol) and imidazole (223.5 mg, mmol) in DMF (6 ml) at 0 C was slowly added TESCl (0.32 ml, 1.91 mmol), and the resultant solution was stirred at room temperature for 1 h. The reaction was quenched with saturated aqueous NaHC 3 solution at 0 C. The mixture was diluted with EtAc and washed with H 2 and brine, dried over MgS 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 3% to 5% EtAc/hexanes) gave TES ether 8 (436.1mg, 90%) as a colorless oil: [α] 25.7 D 13.6 (c 1.03, CHCl 3 ); IR (neat) 2946, 2868, 1456, 1379, 1240, 1099, 1069, 1011, 883, 734, 697, 679 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 10H), 4.56 (d, J = 11.5 Hz, 1H), 4.51 (s, 1H), (m, 2H), 4.43 (dd, J = 5.9, 2.3 Hz, 1H), (s, 1H), (d, J = 11.5 Hz, 1H), 3.81 (dd, J = 11.9, 5.0 Hz, 1H), 3.73 (dd, J = 5.9, 4.1 Hz, 1H), 3.50 (dd, J = 11.5, 2.8 Hz, 1H), (m, 2H), 2.15 (dd, J = 11.9, 5.0 Hz, 1H), (m, 2H), (m, 3H), 1.67

20 S (m, 2H), (m, 2H), 1.38 (s, 3H), 1.20 (s, 3H), (m, 21H), 0.96 (t, J = 8.0 Hz, 9H), 0.61 (q, J = 8.0 Hz, 6H); 13 C NMR (150 MHz, CDCl 3 ) δ 162.3, 138.7, 138.5, (2C), (2C), (2C), (2C), , , 98.9, 79.6, 79.0, 78.8, 74.4, 73.0, 72.7, 71.1, 70.8, 70.5, 40.7, 31.7, 30.8, 28.3, 24.7, 18.5 (3C), 18.4 (3C), 18.1, 14.0, 13.6 (3C), 6.8 (3C), 4.8 (3C); HRMS (FAB) calcd for C 45 H 74 6 Si 2 Na + [(M + Na) + ] , found Bn TIPS Bn Me 8 TES 7 TBS Fe(dibm) 3, Na 2 HP 4 Ph(i-Pr)SH 2 EtH/i-PrH (1:1) rt, 65% Bn TIPS Bn Me Me 5 TES TBS Ketone 5. To a mixture of TES ether 8 (48.6 mg, mmol), vinyl ketone 7 5 (46.0 mg, mmol), Na 2 HP 4 (9.3 mg, mmol), and Fe(dibm) 3 (3.8 mg, mmol) in EtAc/i-PrH (1:1, v/v, 0.5 ml) was added Ph(i-Pr)SiH 2 (0.04 ml, 0.22 mmol), and the resultant mixture was stirred at room temperature for 3 h. The reaction was quenched with brine. The mixture was extracted four times with EtAc, and the combined organic layers were washed with brine, dried over MgS 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, first round: 10% Et 2 /hexanes, second round: 5% to 7% to 10% Et 2 /hexanes) gave ketone 5 (39.9 mg, 65%) as a colorless oil: [α] 26.3 D 7.6 (c 1.03, CHCl 3 ); IR (neat) 2952, 2866, 1720, 1463, 1378, 1362, 1254, 1102, 1070, 1005, 839, 735, 697, 678 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 10H), 4.54 (d, J = 11.5 Hz, 1H), (m, 2H), 4.37 (d, J = 11.5 Hz, 1H), (m, 2H), 3.79 (dd, J = 11.9, 4.6 Hz, 1H), 3.75 (d, J = 5.9 Hz, 1H), 3.70 (dd, J = 6.4, 4.1 Hz, 1H), (m, 2H), 3.20 (dd, J = 11.5, 3.7 Hz, 1H), 2.78 (ddd, J = 17.9, 10.1, 5.5 Hz, 1H), 2.52 (ddd, J = 17.9, 10.1, 5.0 Hz, 1H), 1.93 (dd, J = 12.4, 4.6 Hz, 1H), ca (m, 1H, overlapped), (m, 3H), 1.76 (m, 1H), 1.67 (m, 1H), 1.58 (m, 1H), 1.51 (dd, J = 12.4, 11.9 Hz, 1H), ca (m, 1H, overlapped), 1.41 (s, 3H), (m, 2H), 1.19 (s, 3H), 1.15 (s, 3H), (m, 21H), 0.96 (t, J = 7.8 Hz, 9H), 0.93 (s, 9H), 0.60 (q, J = 7.8 Hz, 6H), (s, 3H), (s, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 211.8, (2C), (2C), (2C), (2C), (2C), , , 80.6, 79.4, 79.3, 77.2, 76.4, 76.3, 72.8, 72.7, 70.9, 70.3, 69.3, 42.0, 37.1, 33.8, 30.9, 28.4, 27.4, 25.8 (3C), 24.0, 23.5, 18.5 (3C), 18.4 (3C), 18.2, 17.6, 14.2, 13.7 (3C), 6.9 (3C),

21 S (3C), 5.5 (2C); HRMS (FAB) calcd for C 55 H 97 8 Si 3 + [(M + H) + ] , found Bn TIPS Bn Me Me 5 CSA TES CH 2 Cl 2 /MeH rt, 85% TBS Bn TIPS L M Bn Me Me 30 H N Me H Methyl acetal 30. To a solution of ketone 5 (28.7 mg, mmol) in CH 2 Cl 2 /MeH (1:1, v/v, 2.0 ml) was added CSA (5.7 mg, mmol), and the resultant solution was stirred at room temperature for 20 h. The mixture was neutralized with Et 3 N (0.1 ml) at 0 C and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 30% to 40% EtAc/hexanes) gave methyl acetal 30 (19.0 mg, 85%) as a colorless oil: [α] 25.7 D 63.2 (c 0.99, CHCl 3 ); IR (neat) 3464, 2944, 2866, 1456, 1379, 1115, 1071, 883, 735, 697, 679 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 10H), 4.54 (d, J = 11.5 Hz, 1H), (m, 2H), 4.37 (d, J = 11.5 Hz, 1H), 3.78 (dd, J = 11.9, 5.0 Hz, 1H), 3.71 (dd, J = 6.0, 4.1 Hz, 1H), (m, 2H), 3.51 (dd, J = 11.5, 5.5 Hz, 1H), 3.46 (dd, J = 11.5, 6.4 Hz, 1H), (m, 2H), 3.24 (s, 3H), 2.06 (dd, J = 12.4, 5.0 Hz, 1H), 1.88 (m, 1H), (m, 7H), (m, 5H), 1.50 (m, 1H), 1.29 (s, 3H), 1.25 (s, 3H), 1.19 (s, 3H), (m, 21H); 13 C NMR (150 MHz, CDCl 3 ) δ 138.7, 138.6, (2C), (2C), (2C), (2C), , , 97.7, 79.5, 78.9, 77.9, 76.1, 72.9, 72.8, 72.7, 72.6, 70.9, 70.4, 64.2, 48.3, 41.6, 35.9, 30.8, 28.9, 28.2, 24.7, 24.3, 20.6, (3C), 18.48, (3C), 13.9, 13.6 (3C); HRMS (FAB) calcd for C 44 H 70 8 SiNa + [(M + Na) + ] , found Bn TIPS L M Bn Me Me 30 H N Me H Sc(Tf) 3 acetone, rt, 73% Bn TIPS L M Bn Me Me 4 H N Me Me LMN-ring fragment 4. To a solution of methyl acetal 30 (61.1 mg, mmol) in acetone (5.0 ml) was added Sc(Tf) 3 (7.8 mg, mmol), and the resultant solution was stirred at room temperature for 30 min. The reaction was quenched with Et 3 N (0.1 ml). The resultant mixture was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 5% to 10% to 20%

22 S EtAc/hexanes) gave LMN-ring fragment 4 (45.8 mg, 73%) as a colorless oil: [α] D 60.4 (c 0.74, CHCl 3 ); IR (neat) 2944, 2866, 1455, 1381, 1114, 1067, 1036, 984, 883, 734, 697, 679 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 10H), 4.54 (d, J = 11.5 Hz, 1H), (m, 2H), 4.37 (d, J = 11.5 Hz, 1H), 3.93 (d, J = 8.3 Hz, 1H), 3.91 (dd, J = 10.6, 5.0 Hz, 1H), 3.78 (dd, J = 11.9, 4.6 Hz, 1H), 3.70 (dd, J = 5.9, 4.1 Hz, 1H), 3.69 (d, J = 8.3 Hz, 1H), 3.67 (dd, J = 11.0, 4.6 Hz, 1H), (m, 2H), 2.06 (dd, J = 12.4, 4.6 Hz, 1H), (m, 2H), (m, 4H), (m, 6H), 1.50 (s, 3H), 1.50 (m, 1H, overlapped), 1.40 (s, 3H), 1.26 (s, 3H), 1.19 (s, 3H), (m, 21H); 13 C NMR (150 MHz, CDCl 3 ) δ 138.7, 138.6, (2C), (2C), (2C), (2C), , , 111.1, 103.0, 79.5, 79.0, 77.9, 76.0, 74.6, 73.5, 72.8, 72.7, 72.6, 70.9, 70.4, 41.6, 37.1, 30.9, 30.4, 28.3, 27.2, 26.8, 24.7, 24.5, 20.6, 18.6, 18.5 (3C), 18.4 (3C), 14.0, 13.6 (3C); HRMS (FAB) calcd for C 46 H 72 7 SiNa + [(M + Na) + ] , found