Supporting Information. Toward the Total Synthesis of Amphidinolide N: Synthesis of the C8 C29 Fragment

Transcript

1 Supporting Information Toward the Total Synthesis of Amphidinolide N: Synthesis of the C8 C29 Fragment Yuki Kawashima, Atsushi Toyoshima, Haruhiko Fuwa, * and Makoto Sasaki * Graduate School of Life Sciences, Tohoku University, Katahira, Aoba-ku, Sendai , Japan masasaki@m.tohoku.ac.jp, hfuwa@m.tohoku.ac.jp These authors contributed equally to this work. Table of Content Experimental General methods Experimental procedures and characterization data for all new compounds Modified Mosher analysis of compound 17 NMR spectra page S2 S3 S23 S24 S1

2 Experimental 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 ) was purchased from Kanto Chemical Co. Inc. and used directly without further drying unless otherwise noted. Anhydrous tetrahydrofuran (THF), diethyl ether (Et 2 ), and toluene were purchased from Wako Pure Chemical Industries, Ltd. and further purified by a Glass Contour solvent purification system under an atmosphere of argon immediately prior to use. Acetonitrile (CN), 2,6-lutidine, and H, and triethylamine (Et 3 N) were distilled from calcium hydride under an atmosphere of argon. Dimethylformamide (DMF) and dimethyl sulfoxide (DMS) were distilled from magnesium sulfate under reduced pressure. All other chemicals were purchased at highest commercial grade and used directly. Analytical thin-layer chromatography (TLC) was performed using E. rck 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 (7.24), C 6 HD 5 (7.15), CHD 2 CN (1.94); 13 C NMR, CDCl 3 (77.0), C 6 D 6 (128.0), CD 3 CN (118.26)]. 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. ESI-TF mass spectra were measured on a Bruker microtffocus spectrometer. Diastereomer ratio (dr) and E/Z isomer ratio were estimated by 1 H NMR spectroscopic analysis (600 MHz), unless otherwise noted. S2

3 Experimental procedures and characterization data for all new compounds TBDPS (Ph 2 Si) 2 Cu(CN)Li 2 TBDPS SiPh 2 THF, 78 to 0 C 9 10 NIS, CN 0 C to rt 83% (2 steps) E/Z >20:1 TBDPS 11 I Vinyl iodide11. To a suspension of CuCN (1.07 g, 11.9 mmol) in THF (10 ml) at 0 C was added Ph 2 SiLi (ca M solution in THF, 27 ml, 24 mmol), and the resultant mixture was stirred at 0 C for 30 min. To this mixture at 78 C was added a solution of alkyne 9 (1.34 g, 3.97 mmol) in THF (2.0 ml ml and 1.0 ml rinse), and the resultant solution was stirred at 78 C for 1.5 h and then allowed to warm to 0 C over a period of 2 h. The reaction was quenched with a 9:1 mixture of saturated aqueous NH 4 Cl solution and 30% NH 4 H solution, and the resultant mixture was stirred at room temperature for 5 h. 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, first round: 2% EtAc/hexanes; second round: hexanes) gave vinylsilane 10 (2.86 g), which was contaminated with some impurities and immediately used in the next reaction without further purification. To a solution of the above vinylsilane 10 (2.86 g) in CN (50 ml) at 0 C was added NIS (2.66 g, 11.8 mmol), and the resultant solution was stirred at room temperature for 11 h. The reaction was quenched with saturated aqueous Na 2 S 3 solution. 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, first round: 1% EtAc/hexanes; second and third rounds: hexanes) gave vinyl iodide 11 (1.54 g, 83% for the two steps, E/Z >20:1) as a colorless oil: [α] 23 D (c, CHCl 3 ); IR (film) 2929, 2857, 1427, 1256, 1110, 1048 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 4H), (m, 6H), 5.95 (dq, J = 10.1, 1.9 Hz, 1H), 3.47 (dd, J = 9.6, 5.9 Hz, 1H), 3.42 (dd, J = 9.6, 6.8 Hz, 1H), 2.61 (m, 1H), 2.32 (d, J = 1.9 Hz, 3H), 1.04 (s, 9H), 0.95 (d, J = 6.8 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 144.1, (2C), (2C), 133.7, 133.6, (2C), (4C), S3

4 94.5, 67.6, 38.3, 27.9, 26.8 (3C), 19.2, 16.5; HRMS (ESI) calcd for C 22 H 29 ISiNa [(M + Na) + ] , found TBDPS 11 I t-buli, THF, 78 C PMB 12 BF 3 Et 2 90 to 78 C, 65% TBDPS 13 H PMB PMB ether 13. To a solution of vinyl iodide 11 (494.8 mg, mmol) in toluene (8.0 ml) at 78 C was added t-buli (1.69 M solution in pentane, 1.30 ml, 2.20 mmol) dropwise, and the resultant solution was stirred at 78 C for 40 min. To this solution at 90 C were added a solution of epoxide 12 (405.2 mg, mmol) in toluene (1.0 ml ml rinse) and BF 3 Et 2 (0.28 ml, 2.2 mmol), and the resultant solution was allowed to warm to 78 C over a period of 10 min and then stirred at 78 C for 2 h. The reaction was quenched with saturated aqueous NaHC 3 solution. The mixture was extracted with EtAc, and the organic layer was washed with H 2 and brine, dried over Na 2 S 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 10% EtAc/hexanes, two rounds) gave PMB ether 13 (369.4 mg, 65%) as a colorless oil: [α] 24 D 1.7 (c, CHCl 3 ); IR (film) 3463, 2929, 2856, 1512, 1247, 1110, 822 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 4H), 7.41 (m, 2H), 7.36 (m, 4H), (m, 2H), (m, 2H), 4.97 (dq, J = 10.6, 0.9 Hz, 1H), 4.45 (s, 2H), 3.85 (m, 1H), 3.78 (s, 3H), (m, 3H), 3.32 (dd, J = 9.7, 6.9 Hz, 1H), 2.57 (m, 1H), (m, 2H), 1.69 (br s, 1H), 1.57 (d, J = 0.9 Hz, 3H), 1.02 (s, 9H), 0.92 (d, J = 6.9 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 159.2, (2C), (2C), (2C), 131.7, 131.3, 130.2, (2C), (2C), (4C), (2C), 73.7, 73.0, 68.5, 68.1, 55.3, 44.0, 35.4, 26.8 (3C), 19.2, 17.3, 16.5; HRMS (ESI) calcd for C 33 H 44 4 SiNa [(M + Na) + ] , found TBDPS 13 H PMB DDQ, 4Å MS CH 2 Cl 2, 0 C to rt 65% TBDPS S1 PMP p-thoxybenzylidene acetal S1. To a mixture of PMB ether 13 (313.4 mg, mmol) and 4 Å molecular sieves (320 mg) in CH 2 Cl 2 (6.0 ml) at 0 C was added DDQ (190.3 mg, mmol), and the resultant mixture was stirred at room temperature for 3 h. The reaction was S4

5 quenched with saturated aqueous NaHC 3 solution at 0 C. The mixture was filtered through a pad of Celite, and the filtrate was diluted with EtAc. The organic layer was washed with H 2 and brine, dried over Na 2 S 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 7% EtAc/hexanes) gave p-methoxybenzylidene acetal S1 (204.2 mg, 65%, dr 5:4) as a colorless oil: [α] 23 D 13.1 (c, CHCl 3 ); IR (film) 2927, 1512, 1248, 1111, 1077, 700 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 4H), (m, 10/9H), (m, 8/9H), (m, 6H), (m, 2H), 6.00 (s, 4/9H), 5.81 (s, 5/9H), 4.97 (m, 1H), 4.20 (dddd, J = 6.9, 6.8, 6.8, 6.8 Hz, 4/9H), 4.09 (dddd, J = 6.9, 6.4, 6.4, 6.4 Hz, 5/9H), 3.96 (dd, J = 8.2, 5.9 Hz, 4/9H), 3.76 (dd, J = 7.8, 6.8 Hz, 5/9H), (m, 14/9H), (m, 1H), 3.45 (dd, J = 7.7, 6.8 Hz, 4/9H), (s, 4/3H), (s, 5/3H), (m, 1H), (m, 1H), 2.10 (dd, J = 14.7, 6.9 Hz, 5/9H), 2.02 (dd, J = 13.8, 6.9 Hz, 4/9H), 1.52 (d, J = 1.3 Hz, 5/3H), 1.50 (d, J = 1.4 Hz, 4/3H), (s, 5H), (s, 4H), (m, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ (5/9C), (4/9C), (2C), (2C), (1C), (1C), (5/9C), (4/9C), (4/9C), (5/9C), (1C), (1C), (2C), (1C), (2C), (2C), (2C), (5/9C), (4/9C), 76.2 (5/9C), 75.2 (4/9C), 70.5 (5/9C), 69.6 (1C), 68.6 (4/9C), 54.7 (1C), 44.0 (5/9C), 43.6 (4/9C), 35.7 (1C), 27.1 (3C), 19.5 (1C), 17.6 (1C), 17.0 (5/9C), 16.9 (4/9C); HRMS (ESI) calcd for C 33 H 42 4 SiNa [(M + Na) + ] , found TBDPS S1 PMP DIBALH CH 2 Cl 2, 78 C 84% TBDPS 14 PMB H Primary alcohol 14. To a solution of p-methoxybenzylidene acetal S1 (204.2 mg, mmol) in CH 2 Cl 2 (3.5 ml) at 78 C was added DIBALH (1.02 M solution in n-hexane, 1.32 ml, 1.35 mmol), and the resultant solution was stirred at 78 C for 1 h. The reaction was quenched with H. The resultant mixture was diluted with EtAc and saturated potassium sodium tartrate solution and stirred vigorously until the layers became clear. The organic layer was washed with H 2 and brine, dried over Na 2 S 4, filtered, and concentrated under reduced pressure. Purification S5

6 of the residue by flash column chromatography (silica gel, 10% EtAc/hexanes) gave primary alcohol 14 (171.5 mg, 84%) as a colorless oil: [α] 23 D 23.1 (c, CHCl 3 ); IR (film) 3419, 2928, 1512, 1247, 1110, 1077, 701 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 4H), (m, 2H), (m, 4H), (m, 2H), (m, 2H), 4.97 (dq, J = 9.6, 1.4 Hz, 1H), 4.54 (d, J = 11.0 Hz, 1H), 4.39 (d, J = 11.0 Hz, 1H), 3.77 (s, 3H), 3.60 (dd, J = 11.5, 3.7 Hz, 1H), 3.56 (m, 1H), (m, 3H), 2.56 (m, 1H), 2.30 (dd, J = 13.3, 5.0 Hz, 1H), 2.07 (dd, J = 13.3, 7.3 Hz, 1H), 1.71 (br s, 1H), 1.57 (d, J = 1.4 Hz, 3H), 1.03 (s, 9H), 0.95 (d, J = 6.4 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 159.3, (2C), (2C), (2C), 131.6, 130.9, 130.4, (2C), (4C), (4C), 77.7, 71.1, 68.4, 64.3, 55.3, 41.3, 35.5, 26.8 (3C), 19.3, 17.4, 16.8; HRMS (ESI) calcd for C 33 H 44 4 SiNa [(M + Na) + ] , found TBDPS H 1. S 3 pyridine, Et 3 N CH 2 Cl 2 /DMS, 0 C TBDPS C 2 H PMB 2. NaCl 2, NaH 2 P 4 PMB 2-methyl-2-butene 14 t-buh/h 2, 0 C to rt 7 94% (2 steps) Carboxylic acid 7. To a solution of alcohol 14 (75.9 mg, mmol) in CH 2 Cl 2 /DMS (1:1, v/v, 1.4 ml) at 0 C were added Et 3 N (0.10 ml, 0.72 mmol) and S 3 pyridine (92.4 mg, mmol), and the resultant mixture was stirred at 0 C for 30 min. The reaction mixture was diluted with t-bu and washed with 1 M aqueous HCl solution, saturated NaHC 3 solution, and brine. The organic layer was dried over MgS 4, filtered, and concentrated under reduced pressure to give crude aldehyde (123.2 mg), which was used in the next reaction without purification. To a solution of the above aldehyde in t-buh/h 2 (5:1, v/v, 1.2 ml) at 0 C were added sequentially 2-methyl-2-butene (180 µl), NaH 2 P 4 (26.4 mg, mmol), and NaCl 2 (80% purity, 39.0 mg, mmol), and the resultant mixture was stirred at room temperature for 1 h 15 min. The reaction mixture was acidified with saturated aqueous NH 4 Cl solution and extracted with EtAc. The organic layer was washed with brine, dried over Na 2 S 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 15 to 30% EtAc/hexanes) gave carboxylic acid 7 (72.9 mg, 94% for the two steps) as a colorless oil: S6

7 [α] 23 D +3.8 (c CHCl 3 ); IR (film) 1719, 1513, 1427, 1248, 1111, 822 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 4H), (m, 2H), (m, 4H), (m, 2H), (m, 2H), 5.01 (dd, J = 8.7, 1.4 Hz, 1H), 4.55 (d, J = 11.5 Hz, 1H), 4.36 (d, J = 11.5 Hz, 1H), 4.02 (dd, J = 8.2, 5.4 Hz, 1H), 3.76 (s, 3H), 3.50 (dd, J = 10.1, 5.9 Hz, 1H), 3.41 (dd, J = 10.1, 7.8 Hz, 1H), 2.58 (m, 1H), (m, 2H), 1.54 (d, J = 1.4 Hz, 3H), 1.05 (s, 9H), 0.97 (d, J = 6.9 Hz, 3H), one proton missing due to H/D exchange; 13 C NMR (150 MHz, CDCl 3 ) δ 177.3, 159.4, (2C), (2C), 134.0, 133.9, 131.4, 130.4, (2C), , , 128.9, (4C), (2C), 76.5, 72.2, 68.3, 55.2, 42.7, 35.5, 26.8 (3C), 19.2, 17.3, 16.4; HRMS (ESI) calcd for C 33 H 42 5 SiNa [(M + Na) + ] , found H H 15 PMB s 4, NM THF/H 2, rt 99% H H H H S2 PMB Diol S2. To a solution of olefin 15 (1.72 g, 5.40 mmol) in THF/H 2 (1:1, v/v, 50 ml) were added NM (4.8 M solution in H 2, 3.4 ml, 16 mmol) and s 4 (10 mg/ml solution in t-buh, 6.5 ml, 0.26 mmol), and the resultant mixture was stirred at room temperature for 13.5 h. The reaction was quenched with saturated aqueous Na 2 S 3 solution. The resultant mixture was stirred at room temperature for 1 h 10 min, and then extracted with EtAc. The organic layer was washed with saturated aqueous NaHC 3 solution and brine, dried over Na 2 S 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 40 to 80% EtAc/hexanes) gave diol S2 (1.89 g, 99%, dr 1:1) as a pale yellow oil: [α] 24 D +9.6 (c, CHCl 3 ); IR (film) 3408, 2953, 2934, 2870, 1514, 1248, 1083, 1035 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), 4.59 (d, J = 11.0 Hz, 0.5H), 4.57 (d, J = 11.0 Hz, 0.5H), 4.51 (d, J = 11.0 Hz, 0.5H), 4.49 (d, J = 11.0 Hz, 0.5H), 4.19 (m, 1H), 4.05 (m, 1H), 3.91 (m, 1H), 3.78 (s, 3H), 3.61 (m, 1H), 3.54 (dd, J = 11.0, 6.4 Hz, 0.5H), 3.48 (dd, J = 11.0, 5.5 Hz, 0.5H), 3.26 (m, 1H), 2.66 (br s, 2H), 2.09 (m, 0.5H), 2.01 (m, 0.5H), 1.91 (m, 1H), 1.80 (m, 0.5H), (m, 6.5H), (m, 3H), 0.86 (t, J = 7.3 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 159.1, (0.5C), (0.5C), , , , , 81.6 (0.5C), 81.5 (0.5C), 81.0 S7

8 (0.5C), 80.9 (0.5C), 79.0 (0.5C), 76.7 (0.5C), 72.6 (0.5C), 72.5 (0.5C), 71.7 (0.5C), 70.1 (0.5C), 66.7 (0.5C), 66.5 (0.5C), 55.3, 38.6 (0.5C), 37.8 (0.5C), 33.0 (0.5C), 32.3 (0.5C), (0.5C), (0.5C), 28.4 (0.5C), 28.0 (0.5C), (0.5C), (0.5C), 22.8, 14.0; HRMS (ESI) calcd for C 20 H 32 5 Na [(M + Na) + ] , found H H H H S2 PMB Pb(Ac) 4, Na 2 C 3 CH 2 Cl 2, 0 C to rt 87% HC H H 16 PMB Aldehyde 16. To a mixture of diol S2 (1.80 g, 5.11 mmol) and Na 2 C 3 (1.08 g, 10.2 mmol) in CH 2 Cl 2 (50 ml) at 0 ºC was added Pb(Ac) 4 (2.50 g, 5.64 mmol), and the resultant mixture was stirred at room temperature for 40 min. The reaction mixture was diluted with EtAc and filtered through a pad of Celite. The filtrate was washed with saturated aqueous NaHC 3 solution and brine, dried over Na 2 S 4, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 15% EtAc/hexanes) gave aldehyde 16 (1.43 g, 87%) as a pale yellow oil: [α] 24 D (c, CHCl 3 ); IR (film) 2954, 2870, 1725, 1612, 1513, 1248, 1083 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ 9.80 (dd, J = Hz, 1H), (m, 2H), (m, 2H), 4.60 (d, J = 11.0 Hz, 1H), 4.52 (d, J = 11.0 Hz, 1H), 4.40 (m, 1H), 4.05 (ddd, J = 8.7, 6.4, 6.4 Hz, 1H), 3.77 (s, 3H), 3.27 (ddd, J = 6.4, 6.4, 6.4 Hz, 1H), 2.69 (ddd, J = 16.0, 7.3, 2.3 Hz, 1H), 2.55 (ddd, J = 16.0, 5.0, 2.3 Hz, 1H), 2.14 (m, 1H), 1.94 (m, 1H), 1.68 (m, 1H), 1.53 (m, 1H), (m, 3H), (m, 3H), 0.86 (t, J = 7.3 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 201.4, 159.0, 131.2, (2C), (2C), 81.5, 80.9, 74.0, 72.5, 55.2, 49.6, 32.3, 30.5, 28.3, 27.8, 22.8, 14.0; HRMS (ESI) calcd for C 19 H 28 4 Na [(M + Na) + ] , found MgBr (+)-Ipc 2 B HC H H 16 PMB Et 2, 78 C 78%, dr >20:1 H H H 17 PMB Homoallylic alcohol 17. To a solution of (+)-Ipc 2 B (2.71 g, 8.57 mmol) in Et 2 (30 ml) at 78 ºC was added allylmagnesium bromide (1.0 M solution in Et 2, 7.6 ml, 7.6 mmol). The resultant solution was stirred at 78 ºC for 15 min and then at room temperature for 1 h. To this S8

9 solution at 78 ºC was added a solution of aldehyde 16 (1.43 g, 4.46 mmol) in Et 2 (4 ml + 2 ml rinse), and the resultant solution was stirred at 78 ºC for 2 h. The reaction was quenched with 3 M aqueous NaH solution/30% aqueous H 2 2 solution (1:1, v/v, 50 ml), and the resultant mixture was stirred at room temperature for 10 h 50 min. The mixture was extracted with EtAc, and the organic layer was washed with H 2 and brine, dried over Na 2 S 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, first round: 10 to 20% EtAc/hexanes; second round: 20% EtAc/hexanes) gave homoallylic alcohol 17 (1.27 g, 78%, dr >20:1) as a colorless oil: [α] 24 D +8.7 (c, CHCl 3 ); IR (film) 3443, 2954, 2933, 2870, 1514, 1248, 1068, 1037 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), 5.82 (dddd, J = 17.4, 10.5, 7.3, 7.3 Hz, 1H), (m, 2H), 4.62 (d, J = 11.0 Hz, 1H), 4.52 (d, J = 11.0 Hz, 1H), 4.23 (m, 1H), 4.05 (ddd, J = 8.2, 6.0, 6.0 Hz, 1H), 3.91 (m, 1H), 3.78 (s, 3H), 3.26 (ddd, J = 6.0, 6.0, 6.0 Hz, 1H), (m, 2H), 1.99 (m, 1H), 1.92 (m, 1H), (m, 4H), (m, 3H), (m, 4H), 0.86 (t, J = 7.3 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 159.0, 135.1, 131.2, (2C), 117.4, (2C), 81.5, 81.0, 76.8, 72.6, 68.7, 55.3, 41.9, 40.4, 32.1, 30.6, 28.4, 27.8, 22.8, 14.0; HRMS (ESI) calcd for C 22 H 34 4 SiNa [(M + Na) + ] , found H H H 17 PMB TESTf, 2,6-lutidine CH 2 Cl 2, 0 C, 94% TES H H S3 PMB TES ether S3. To a solution of homoallylic alcohol 17 (2.07 g, 5.71 mmol) in CH 2 Cl 2 (60 ml) at 0 C were added 2,6-lutidine ( ml, 8.63 mmol) and TESTf (1.50 ml, 6.63 mmol), and the resultant solution was stirred at 0 ºC for 1 h 45 min. The reaction was quenched with saturated aqueous NaHC 3 solution at 0 ºC. The resultant mixture was extracted with EtAc, and the organic layer was washed with H 2 and brine, dried over Na 2 S 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 S3 (2.57 g, 94%) as a pale red oil: [α] 24 D 1.6 (c, CHCl 3 ); IR S9

10 (film) 2954, 2936, 2911, 2874, 1514, 1247, 1088, 1070, 743 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), 5.81 (dddd, J = 17.9, 10.5, 7.3, 7.3 Hz, 1H), (m, 2H), 4.69 (d, J = 11.0 Hz, 1H), 4.49 (d, J = 11.0 Hz, 1H), 4.08 (dddd, J = 9.2, 6.0, 3.7, 3.7 Hz, 1H), 3.98 (ddd, J = 9.1, 6.4, 6.4 Hz, 1H), 3.94 (m, 1H), 3.78 (s, 3H), 3.27 (m, 1H), (m, 2H), 2.00 (m, 1H), 1.88 (m, 1H), (m, 2H), (m, 5H), (m, 3H), 0.93 (t, J = 7.8 Hz, 9H), 0.86 (t, J = 7.3 Hz, 3H), 0.61 (q, J = 7.8 Hz, 6H); 13 C NMR (150 MHz, CDCl 3 ) δ 159.0, 135.0, 131.6, (2C), 117.0, (2C), 81.8, 81.1, 75.9, 72.6, 69.6, 55.3, 43.4, 43.0, 32.6, 30.7, 28.6, 27.9, 22.8, 14.1, 7.0 (3C), 5.1 (3C); HRMS (ESI) calcd for C 28 H 48 4 SiNa [(M + Na) + ] , found Cy 2 BH, THF, 0 C H TES H H S3 PMB then H 2 2, aq NaH rt, 95% TES H H 18 PMB Primary alcohol 18. To a solution of cyclohexene (2.2 ml, 22 mmol) in THF (40 ml) at 0 ºC was added BH 3 THF (0.9 M solution in THF, 9.0 ml, 8 mmol), and the resultant mixture was stirred at 0 C for 55 min. To the mixture was added a solution of TES ether S3 (2.57 g, 5.39 mmol) in THF (4 ml + 2 ml rinse), and the resultant mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0 C and treated with 3 M aqueous NaH solution/30% aqueous H 2 2 solution (1:1, v/v, 50 ml). The resultant mixture was stirred at room temperature for 2 h 10 min. The mixture was diluted with EtAc, and the organic layer was washed with H 2, saturated aqueous Na 2 S 3 solution, and brine, dried over Na 2 S 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, first round: 15 to 30% EtAc/hexanes; second round: 15% EtAc/hexanes to EtAc) gave primary alcohol 18 (2.53 g, 95%) as a pale yellow oil: [α] 24 D +2.5 (c, CHCl 3 ); IR (film) 3432, 2952, 2874, 1248, 1065, 1039, 742 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), 4.67 (d, J = 11.0 Hz, 1H), 4.50 (d, J = 11.0 Hz, 1H), 4.04 (dddd, J = 10.5, 10.5, 5.5, 5.5 Hz, 1H), (m, 2H), 3.78 (s, 3H), 3.62 (m, 1H), 3.56 (m, 1H), 3.27 (ddd, J = 6.0, 6.0, 6.0 Hz, 1H), 2.29 (br s, 1H), S10

11 2.01 (m, 1H), 1.88 (m, 1H), (m, 7H), (m, 4H), (m, 3H), 0.94 (t, J = 7.8 Hz, 9H), 0.86 (t, J = 7.3 Hz, 3H), 0.62 (q, J = 7.8 Hz, 6H); 13 C NMR (150 MHz, CDCl 3 ) δ 159.0, 131.5, (2C), (2C), 81.7, 81.1, 76.0, 72.5, 69.8, 63.2, 55.3, 43.0, 34.7, 32.7, 30.7, 28.6, 27.9, 27.8, 22.8, 14.1, 6.9 (3C), 5.0 (3C); HRMS (ESI) calcd for C 28 H 50 5 SiNa [(M + Na) + ] , found H TEMP, KBr NaCl, aq NaHC 3 HC Et 3 Si H H 18 PMB CH 2 Cl 2, 0 C 85% TES H H S4 PMB Aldehyde S4. To a solution of alcohol 18 (522.2 mg, mmol) in CH 2 Cl 2 (2 ml) at 0 C were added aqueous KBr solution (0.5 M, 0.20 ml, 0.1 mmol), TEMP (8.7 mg, 56 µmol), saturated aqueous NaHC 3 solution (0.60 ml), and aqueous NaCl solution (1.94 M, 0.65 ml, 1.3 mmol) and the resultant mixture was stirred at 0 C for 20 min. The reaction was quenched with saturated aqueous Na 2 S 3 solution. The resultant mixture was diluted with EtAc, and the organic layer was washed with H 2 and brine, dried over Na 2 S 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 8 to 15% EtAc/hexanes) gave aldehyde S4 (443.1 mg, 85%) as a colorless oil: [α] 24 D +7.7 (c, CHCl 3 ); IR (film) 2954, 2912, 2874, 1726, 1514, 1247, 1086, 744 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ 9.75 (dd, J = 1.4, 1.4 Hz, 1H), (m, 2H), (m, 2H), 4.65 (d, J = 11.0 Hz, 1H), 4.49 (d, J = 11.0 Hz, 1H), 4.02 (m, 1H), 3.98 (ddd, J = 8.7, 6.0, 6.0 Hz, 1H), 3.94 (dddd, J = 7.3, 5.5, 5.5, 5.5 Hz, 1H), 3.77 (s, 3H), 3.26 (ddd, J = 6.0, 6.0, 6.0 Hz, 1H), (m, 2H), 2.01 (m, 1H), (m, 2H), 1.74 (m, 1H), (m, 3H), (m, 4H), (m, 3H), 0.92 (t, J = 7.8 Hz, 9H), 0.86 (t, J = 7.3 Hz, 3H), 0.59 (q, J = 7.8 Hz, 6H); 13 C NMR (150 MHz, CDCl 3 ) δ 202.6, 159.0, 131.4, (2C), (2C), 81.7, 81.1, 75.9, 72.5, 69.1, 55.3, 43.5, 39.3, 32.7, 30.7, 30.0, 28.6, 27.9, 22.8, 14.1, 6.9 (3C), 5.0 (3C); HRMS (ESI) calcd for C 28 H 48 5 SiNa [(M + Na) + ] , found S11

12 HC Ph 3 P + CH 2 CH 3 Br KHMDS TES H H S4 PMB THF, 0 C to rt quant, Z/E >20:1 TES H H PMB 19 lefin19. To a solution of Ph 3 P + CH 2 CH 3 Br (368.2 mg, mmol) in THF (4.0 ml) at 0 ºC was added KHMDS (0.5 M solution in toluene, 1.80 ml, 0.9 mmol), and the resultant mixture was stirred at 0 ºC for 50 min. To the resultant solution at 0 ºC was added a solution of aldehyde S4 (218.0 mg, mmol) in THF (0.5 ml ml rinse). The resultant solution was stirred at room temperature for 50 min. The reaction was quenched with saturated aqueous NH 4 Cl solution at 0 ºC. The resultant mixture was extracted with EtAc, and the organic layer was washed with H 2 and brine, dried over Na 2 S 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 3% EtAc/hexanes) gave olefin 19 (222.1 mg, quant, Z/E >20:1) as a colorless oil: [α] 23 D +4.5 (c, CHCl 3 ); IR (film) 2954, 2935, 2912, 2874, 1514, 1247, 1071 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), 5.41 (m, 1H), 5.35 (m, 1H), 4.69 (d, J = 11.0 Hz, 1H), 4.49 (d, J = 11.0 Hz, 1H), 4.07 (m, 1H), 3.98 (ddd, J = 9.2, 6.4, 6.4 Hz, 1H), 3.89 (m, 1H), 3.78 (s, 3H), 3.27 (ddd, J = 6.4, 6.4, 6.4 Hz, 1H), (m, 3H), 1.89 (m, 1H), (m, 11H), (m, 4H), 0.94 (t, J = 7.8 Hz, 9H), 0.86 (t, J = 7.4 Hz, 3H), 0.60 (q, J = 7.8 Hz, 6H); 13 C NMR (150 MHz, CDCl 3 ) δ 159.0, 131.6, 130.4, (2C), 123.9, (2C), 81.8, 81.1, 76.0, 72.6, 69.9, 52.3, 43.6, 38.1, 32.7, 30.7, 28.7, 28.0, 22.8, 22.5, 14.1, 12.7, 7.0 (3C), 5.2 (3C); HRMS (ESI) calcd for C 30 H 52 4 SiNa [(M + Na) + ] , found PPTS 16 TES H H PMB 19 CH 2 Cl 2 /H rt, 97% H 29 H H 8 PMB Alcohol 8. To a solution of olefin 19 (211.1 mg mmol) in H/CH 2 Cl 2 (1:1, v/v, 4 ml) was added PPTS (15.0 mg, 59.7 µmol), and the resultant solution was stirred at room temperature for 55 min. The reaction mixture was neutralized with Et 3 N at 0 ºC and concentrated under reduced S12

13 pressure. Purification of the residue by flash column chromatography (silica gel, 10 to 20% EtAc/hexanes) gave alcohol 8 (158.3 mg, 97%) as a colorless oil: [α] 24 D (c, CHCl 3 ); IR (film) 3446, 2954, 2933, 2861, 1514, 1248, 1083 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), 5.43 (m, 1H), 5.38 (m, 1H), 4.61 (d, J = 11.0 Hz, 1H), 5.51 (d, J = 11.0 Hz, 1H), 4.23 (m, 1H), 4.05 (ddd, J = 8.2, 6.4, 6.4 Hz, 1H), 3.85 (m, 1H), 3.78 (s, 3H), 3.26 (ddd, J = 6.4, 6.4, 6.4 Hz, 1H), 2.56 (br s, 1H), 2.18 (m, 1H), 2.10 (m, 1H), 1.97 (m, 1H), 1.92 (m, 1H), (m, 8H), (m, 4H), (m, 3H), 0.86 (t, J = 6.8 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 159.0, 131.2, 130.2, (2C), 124.1, (2C), 81.5, 81.0, 76.9, 72.6, 69.1, 55.2, 40.8, 37.0, 32.1, 30.6, 28.4, 27.8, 23.3, 22.8, 14.0, 12.7; HRMS (ESI) calcd for C 24 H 38 4 Na [(M + Na) + ] , found PMB TBDPS 7 C 2 H + H DCC, DMAP CH 2 Cl 2, rt, 91% H H PMB 8 PMB H H PMB 6 TBDPS Ester 6. To a solution of carboxylic acid 7 (535.4 mg, mmol) and alcohol 8 (324.0 mg, mmol) in CH 2 Cl 2 (9.0 ml) were added DCC (509.0 mg, mmol) and DMAP (203.1 mg, mmol), and the resultant solution was stirred at room temperature for 24 h. The mixture was diluted with t-bu and filtered to remove insoluble materials, and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 6% EtAc/hexanes) gave ester 6 (691.4 mg, 91%) as a colorless oil: [α] 23 D (c, CHCl 3 ); IR (film) 1744, 1613, 1513, 1247, 1111, 1036, 822 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 4H), (m, 2H), (m, 4H), (m, 2H), (m, 2H), (m, 2H), (m, 2H), (m, 2H), 5.11 (ddd, J = 6.4, 6.4, 6.4 Hz, 1H), 4.95 (d, J = 8.8 Hz, 1H), 4.67 (d, J = 11.5 Hz, 1H), 4.54 (d, J = 11.0 Hz, 1H), 4.49 (d, J = 11.5 Hz, 1H), 4.25 (d, J = 11.0 Hz, 1H), (m, 3H), 3.77 (s, 3H), 3.73 (s, 3H), 3.49 (dd, J = 9.6, 5.5 Hz, 1H), 3.37 (dd, J = 9.6, 8.3 Hz, 1H), 3.22 (dd, J = 11.5, 5.9 Hz, 1H), 2.57 (m, 1H), S13

14 (m, 2H), (m, 2H), 1.97 (m, 1H), 1.88 (m, 1H), (m, 2H), (m, 2H), (m, 4H), 1.50 (s, 3H), (m, 4H), (m, 3H), 1.03 (s, 9H), 0.97 (d, J = 6.4 Hz, 3H), 0.86 (t, J = 7.3 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 172.1, 159.2, 158.9, (2C), (2C), 134.0, 133.9, 131.4, 131.0, 130.6, (2C), (2C), , (2C), , (4C), 124.5, (2C), (2C), 81.5, 81.3, 77.0, 75.8, 73.0, 72.6, 71.7, 68.3, 55.2 (2C), 43.0, 40.4, 35.5, 34.4, 32.6, 30.7, 28.6, 27.8, 26.8 (3C), 22.8, 22.7, 19.2, 17.4, 16.4, 14.1, 12.8; HRMS (ESI) calcd for C 57 H 78 8 SiNa [(M + Na) + ] , found PMB R Tebbe THF, 0 C H H PMB 6 : R = 20: R = CH 2 sn Cl Cl Ru PCy 3 Ns G-II Ph toluene, 45 C 72% (2 steps) PMB H H H PMB 5 TBDPS TBDPS Dihydropyran 5. To a solution of ester 6 (24.8 mg, 27.0 µmol) in THF (0.7 ml) at 0 C was added Tebbe reagent (0.5 M solution in toluene, 0.27 ml, 0.14 mmol), and the resultant solution was stirred at 0 C for 30 min. The reaction was quenched with Et 3 N and H 2. The resultant mixture was diluted with t-bu and stirred at room temperature for 30 min. The reaction mixture was dried over Na 2 S 4, filtered through a pad of Celite, and concentrated under reduced pressure. The residue was roughly purified by column chromatography (silica gel, 10% EtAc/hexanes containing 1% Et 3 N) to give olefin 20 (28.7 mg) as a yellow oil, which was used directly in the next reaction without further purification. To a solution of the above olefin 20 (28.7 mg) in toluene (1.0 ml) was added a solution of the second-generation Grubbs catalyst (2.5 mg, 2.9 µmol) in toluene (1.7 ml), and the resultant solution was stirred at 45 C for 3 h. The reaction mixture was stirred at room temperature under air for 12 h and then concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 3 to 5% EtAc/hexanes) gave dihydropyran 5 (16.9 mg, 72% for the two steps) as a colorless oil: [α] 23 D (c, CHCl 3 ); IR (film) 1613, 1512, 1463, 1246, 1111, 1076, 1037, 822 cm 1 ; 1 H NMR (600 MHz, C 6 D 6 ) δ (m, 4H), (m, 2H), S14

15 (m, 2H), (m, 6H), (m, 2H), (m, 2H), 5.15 (dd, J = 8.7 Hz, 0.9 Hz, 1H), 4.85 (d, J = 11.5 Hz, 1H), 4.71 (m, 1H), 4.66 (d, J = 11.5 Hz, 1H), 4.62 (d, J = 11.5 Hz, 1H), 4.34 (d, J = 11.5 Hz, 1H), 4.31 (m, 1H), (m, 2H), 3.87 (dd, J = 6.9 Hz, 1H), 3.66 (dd, J = 10.1, 5.5 Hz, 1H), 3.51 (dd, J = 10.1, 7.8 Hz, 1H), (m, 7H), (m, 3H), 1.98 (m, 1H), 1.89 (m, 1H), (m, 2H), (m, 3H), 1.62 (d, J = 0.9 Hz, 3H), (m, 6H), (m, 3H), 1.19 (s, 9H), 1.09 (d, J = 6.8 Hz, 3H), 0.90 (t, J = 7.3 Hz, 3H); 13 C NMR (150 MHz, C 6 D 6 ) δ 159.5, 152.8, (2C), (2C), 134.4, 132.9, 132.3, 131.7, 130.2, , , (2C), (2C), (2C), (2C), (2C), (4C), 98.2, 81.9, 81.8, 79.1, 76.4, 73.8, 72.9, 70.1, 69.0, 54.72, 54.71, 44.4, 42.5, 35.9, 33.3, 31.2, 29.0, 28.8, 28.3, 27.1 (3C), 23.3, 20.7, 19.5, 17.9, 17.0, 14.3; HRMS (ESI) calcd for C 55 H 74 7 SiNa [(M + Na) + ] , found PMB TBDPS H H H PMB 5 1. m-cpba, NaHC 3 CH 2 Cl 2 /H, 0 C 2. PPTS, H, 45 C 3. DMP, NaHC 3 CH 2 Cl 2, 0 C to rt 42% (3 steps) TBDPS PMB H H H PMB 21 Ketone 21. To a solution of dihydropyran 5 (25.8 mg, 29.5 µmol) in CH 2 Cl 2 /H (1:1, v/v, 0.5 ml) at 20 C were added NaHC 3 (24.8 mg, mmol) and m-cpba (20.6 mg, mmol), and the resultant mixture was stirred at 20 C for 3.5 h. The reaction was quenched with a 1:1 mixture of saturated aqueous Na 2 S 2 3 solution and saturated aqueous NaHC 3 solution. The resultant mixture was extracted with EtAc. The organic layer was washed with saturated aqueous NaHC 3 solution and brine, dried over Na 2 S 4, filtered, and concentrated under reduced pressure. The residue was roughly purified by flash column chromatography (silica gel, 10 to 15 to 30% EtAc/hexanes) to give crude material (29.3 mg), which was directly used in the next reaction without further purification. To a solution of the above material in CH 2 Cl 2 /H (1:1, v/v, 0.5 ml) was added PPTS (3.4 mg, 14 µmol), and the resultant solution was stirred at 45 C for 4 h. The reaction mixture was S15

16 neutralized with Et 3 N and concentrated under reduced pressure. The residue was roughly purified by flash column chromatography (silica gel, 10 to 15% EtAc/hexanes) to give crude material (19.9 mg), which was directly used in the next reaction without further purification. To a solution of the above material in CH 2 Cl 2 (0.5 ml) at 0 C were added NaHC 3 (25.0 mg, mmol) and Dess Martin periodinane (38.7 mg, mmol), and the resultant mixture was stirred at room temperature for 1.5 h. The reaction was quenched with a 1:1 mixture of saturated aqueous Na 2 S 3 solution and saturated aqueous NaHC 3 solution. The resultant mixture was extracted with t-bu. 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, first round: 10 to 12% EtAc/hexanes; second round: 12% EtAc/hexanes) gave ketone 21 (11.4 mg, 42% for the three steps) as a pale yellow oil: [α] 22 D 5.6 (c, CHCl 3 ); IR (film) 2932, 1731, 1613, 1513, 1247, 1071cm 1 ; 1 H NMR (600 MHz, C 6 D 6 ) δ (m, 4H), (m, 2H), (m, 8H), (m, 2H), (m, 2H), 5.15 (d, J = 8.7 Hz, 1H), (m, 2H), 4.57 (d, J = 11.5 Hz, 1H), 4.54 (d, J = 10.6 Hz, 1H), 4.34 (m, 1H), 4.21 (m, 1H), (m, 2H), 3.67 (dd, J = 9.6, 5.0 Hz, 1H), 3.47 (m, 4H), (m, 8H), 2.83 (dd, J = 14.2, 10.1 Hz, 1H), 2.71 (m, 1H), 2.59 (d, J = 13.7 Hz, 1H), 2.38 (m, 1H), 2.32 (ddd, J = 10.1, 6.8, 3.7 Hz, 1H), 1.84 (m, 1H), (m, 9H), (m, 15H), 1.11 (d, J = 6.4 Hz, 3H), 0.90 (t, J = 7.3 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 203.4, 159.6, 159.5, (2C), (2C), , , 133.7, 132.0, 131.7, 130.1, (2C), (2C), 128.5, (4C), 128.0, (2C), (2C), 101.5, 81.8, 81.3, 80.3, 75.8, 74.4, 72.7, 68.9, 68.5, 54.7 (2C), 49.9, 42.7, 41.6, 36.4, 36.1, 33.0, 31.7, 31.2, 28.8, 28.3, 27.1 (3C), 23.3, 19.5, 17.8, 16.9, 14.3; HRMS (ESI) calcd for C 56 H 76 9 SiNa [(M + Na) + ] , found H PMB H H H PMB 21 L-Selectride THF, 40 C 91%, dr >20:1 PMB H H H PMB 22 TBDPS TBDPS S16

17 Alcohol 22. To a solution of ketone 21 (11.4 mg, 12.4 µmol) in THF (0.5 ml) at 40 C was added L-Selectride (1.02 M solution in THF, ml, mmol), and the resultant solution was stirred at 40 C for 1 h. The reaction was quenched with saturated aqueous NaHC 3 solution. The resultant mixture was extracted with EtAc. The organic layer was washed with H 2 and brine, dried over Na 2 S 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 10% EtAc/hexanes) gave alcohol 22 (10.4 mg, 91%, dr >20:1) as a colorless oil: [α] 24 D 30.6 (c 0.25, CHCl 3 ); IR (film) 3444, 1730, 1613, 1513, 1247, 1111, 1070, 1036, 702 cm 1 ; 1 H NMR (600 MHz, CDCl 3 ) δ (m, 4H), (m, 2H), (m, 4H), (m, 2H), (m, 2H), (m, 2H), (m, 2H), 4.98 (d, J = 9.2 Hz, 1H), 4.82 (m, 1H), 4.75 (d, J = 10.1 Hz, 1H), 4.62 (d, J = 11.5 Hz, 1H), 4.48 (d, J = 11.5 Hz, 1H), 4.29 (m, 1H), 4.23 (d, J = 10.1 Hz, 1H), 4.02 (ddd, J = 8.8, 6.0, 6.0 Hz, 1H), 3.87 (m, 1H), (m, 4H), (m, 5H), 3.52 (dd, J = 9.6, 5.5 Hz, 1H), 3.38 (dd, J = 9.6, 8.7 Hz, 1H), 3.21 (s, 3H), 2.58 (m, 1H), 2.22 (d, J = 14.2 Hz, 1H), 2.13 (dd, J = 14.2, 12.8 Hz, 1H), 2.05 (m, 1H), (m, 3H), (m, 5H), (m, 5H), (m, 5H), 1.03 (s, 9H), (d, J = 6.9 Hz, 3H), 0.86 (t, J = 7.3 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 159.2, 159.0, (2C), (2C), , 133.9, 132.4, 131.3, 130.0, (2C), (2C), (2C), (2C), (2C), (4C), 98.2, 81.6, 80.7, 80.6, 77.2, 75.6, 74.9, 72.5, 68.5, 68.4, 66.7, 55.2 (2C), 47.4, 42.8, 39.8, 35.6, 30.6, 29.7, 28.5, 27.9, 26.9 (3C), 26.3, 25,2, 22.9, 19.3, 17.6, 16.9, 14.1; HRMS (ESI) calcd for C 56 H 78 9 SiNa [(M + Na) + ] , found H PMB Ac PMB Ac 2, DMAP H H H H H H PMB pyridine PMB 22 0 C to rt, 71% 23 TBDPS TBDPS Acetate 23. To a solution of alcohol 22 (3.2 mg, 3.5 µmol) in pyridine (0.2 ml) at 0 C were added Ac 2 (0.010 ml, 0.11 mmol) and a catalytic amount of DMAP, and the resultant solution S17

18 was stirred at room temperature for 12 h. The reaction was quenched with saturated aqueous NH 4 Cl solution. The resultant mixture was extracted with EtAc, and the organic layer was washed with H 2 and brine, dried over Na 2 S 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 10% EtAc/hexanes) gave acetate 23 (2.4 mg, 71%) as a colorless oil: [α] 24 D 27.3 (c 0.20, CHCl 3 ); IR (film) 2929, 1732, 1513, 1247, 1036, 820 cm 1 ; 1 H NMR (600 MHz, CD 3 CN) δ (m, 4H), (m, 2H), (m, 4H), (m, 2H), (m, 2H), (m, 2H), (m, 2H), 5.02 (dq, J = 9.2, 1.3 Hz, 1H), 4.87 (dd, J = 3.0, 3.0 Hz, 1H), 4.59 (d, J = 11.0 Hz, 1H), 4.45 (d, J = 11.0 Hz, 1H), 4.32 (s, 2H), 4.20 (m, 1H), 3.95 (ddd, J = 8.7, 6.4, 6.4 Hz, 1H), 3.90 (m, 1H), 3.75 (s, 3H), 3.71 (s, 3H), 3.65 (dd, J = 10.1, 1.9 Hz, 1H), 3.52 (dd, J = 9.6, 5.5 Hz, 1H), 3.39 (dd, J = 9.6, 7.8 Hz, 1H), (m, 4H), 2.61 (m, 1H), 2.37 (dd, J = 14.2, 1.9 Hz, 1H), 2.10 (m, 1H), (m, 4H), 1.86 (s, 3H), (m, 8H), (m, 5H), (m, 2H), 0.99 (m, 12H), 0.86 (t, J = 7.3 Hz, 3H); 13 C NMR (150 MHz, CD 3 CN) δ 170.7, , , (2C), (2C), 134.8, (2C), 132.7, 132.2, 130.7, (2C), (2C), (2C), (2C), (2C), (2C), (2C), 99.8, 82.5, 81.8, 79.3, 76.2, 74.4, 73.0, 69.3, 69.0, 67.2, 55.7 (2C), 49.9, 43.3, 41.3, 36.4, 33.5, 31.4, 29.2, 28.6, 27.2 (3C), 26.4, 25.1, 23.5, 21.5, 19.7, 17.8, 17.0, 14.3; HRMS (ESI) calcd for C 58 H SiNa [(M + Na) + ] , found H PMB TBS TBSTf PMB 2,6-lutidine H H H H H H PMB CH 2 Cl 2, 78 C PMB 22 81% S5 TBDPS TBDPS TBS ether S5. To a solution of alcohol 22 (2.5 mg, 2.7 µmol) in CH 2 Cl 2 (0.4 ml) at 78 C were added 2,6-lutidine (0.040 ml, 0.35 mmol) and TBSTf (0.010 ml, mmol), and the resultant solution was stirred at 78 C for 1.5 h. The reaction was quenched with saturated aqueous NaHC 3 solution. The resultant mixture was extracted with EtAc, and the organic layer was S18

19 washed with H 2 and brine, dried over Na 2 S 4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 5 to 7% EtAc/hexanes) gave TBS ether S5 (2.3 mg, 81%) as a colorless oil: [α] 22 D 24.5 (c, CHCl 3 ); IR (film) 2954, 1513, 1457, 1247, 1112, 1039 cm 1 ; 1 H NMR (600 MHz, C 6 D 6 ) δ (m, 4H), (m, 4H), (m, 6H), (m, 2H), (m, 2H), 5.26 (d, J = 9.2 Hz, 1H), (m, 3H), 4.60 (d, J = 11.5 Hz, 1H), 4.45 (m, 1H), 4.32 (m, 1H), 4.12 (m, 1H), 4.07 (ddd, J = 8.8, 6.4, 6.4 Hz, 1H), 4.02 (m, 1H), 3.74 (dd, J = 9.7, 5.0 Hz, 1H), 3.57 (s, 3H), 3.51 (dd, J = 8.8, 6.9 Hz, 1H), (m, 7H), 2.93 (d, J = 14.2 Hz, 1H), 2.79 (m, 1H), 2.55 (dd, J = 14.2, 10.1 Hz, 1H), 2.22 (m, 1H), (m, 5H), (m, 8H), (m, 5H), (m, 12H), 0.99 (s, 9H), 0.90 (t, J = 7.3 Hz, 3H), 0.06 (s, 3H), 0.03 (s, 3H); 13 C NMR (150 MHz, C 6 D 6 ) δ 159.5, 159.3, (2C), (2C), 135.3, 134.4, 134.3, 132.4, 132.2, 129.9, (2C), 129.2, 128.9, (2C), (2C), (2C), (2C), (2C), 100.3, 81.9, 81.3, 78.2, 75.9, 72.7, 71.8, 68.9, 68.3, 67.5, 54.7 (2C), 50.1, 43.5, 40.6, 36.1, 33.0, 31.2, 28.8, 28.4, 27.4, 27.2 (3C), 26.3 (3C), 25.8, 23.3, 19.5, 18.4, 18.0, 17.1, 14.3, 3.9, 4.5; HRMS (ESI) calcd for C 62 H 92 9 Si 2 Na [(M + Na) + ] , found TBS PMB TBS PMB TBAF/AcH H H H H H H PMB THF, 0 C to rt PMB S5 87% 24 TBDPS H Primary alcohol 24. A stock solution of TBAF/AcH was freshly prepared by mixing TBAF (1.0 M solution in THF, 2.0 ml, 2.0 mmol), AcH (0.12 ml, 2.1 mmol), and THF (2.0 ml). To a solution of TBS ether S5 (4.9 mg, 4.7 µmol) in THF (0.5 ml) at 0 C was added the above stock solution of TBAF/AcH (0.23 ml), and the resultant solution was stirred at room temperature for 37 h. The reaction was quenched with saturated aqueous NaHC 3 solution. The reaction mixture was extracted with EtAc, and the organic layer was washed with saturated aqueous NaHC 3 solution and brine, dried over Na 2 S 4, filtered, and concentrated under reduced pressure. S19

20 Purification of the residue by flash column chromatography (silica gel, 10 to 15% EtAc/hexanes) gave primary alcohol 24 (3.3 mg, 87%) as a colorless oil: [α] 22 D 21.3 (c 0.21, CHCl 3 ); IR (film) 3485, 2928, 1726, 1513, 1462, 1111, 1037 cm 1 ; 1 H NMR (600 MHz, C 6 D 6 ) δ (m, 2H), (m, 2H), (m, 2H), (m, 2H), 5.18 (d, J = 9.7 Hz, 1H), 4.81 (s, 2H), 4.76 (d, J = 11.5 Hz, 1H), 4.60 (d, J = 11.5 Hz, 1H), 4.47 (m, 1H), 4.35 (d, J = 9.2 Hz, 1H), 4.13 (m, 1H), 4.07 (ddd, J = 8.3, 6.0, 6.0 Hz, 1H), 4.02 (m, 1H), 3.59 (s, 3H), 3.36 (dd, J = 10.1, 5.9 Hz, 1H), (m, 7H), 3.25 (dd, J = 10.1, 7.3 Hz, 1H), 2.90 (d, J = 13.3 Hz, 1H), (m, 2H), 2.35 (m, 1H), 2.22 (m, 1H), (m, 5H), (m, 3H), (m, 5H), (m, 4H), 1.21 (m, 1H), 1.01 (s, 9H), (m, 6H), 0.09 (s, 3H), 0.04 (s, 3H); 13 C NMR (150 MHz, C 6 D 6 ) δ 159.6, 159.5, 136.2, 132.3, 132.2, 130.0, 129.3, 129.1, (2C), (2C), (2C), 100.4, 82.0, 81.3, 77.8, 75.9, 72.7, 68.4, 67.9, 67.7, (2C), 54.71, 50.1, 43.5, 40.7, 36.1, 33.0, 31.2, 28.8, 28.4, 27.5, 26.3 (3C), 25.8, 23.3, 18.4, 17.2, 17.0, 14.3, 3.9, 4.5; HRMS (ESI) calcd for C 46 H 74 9 SiNa [(M + Na) + ] , found TBS PMB 1. DMP, NaHC 3 TBS CH 2 Cl 2, 0 C to rt Li, CeCl 3 PMB H H H THF, 78 C H H H PMB 3. DMP, NaHC PMB 3 24 CH 2 Cl 2, 0 C to rt 4 73% (3 steps) H 8 The C8 C29 fragment 4. To a solution of 24 (3.1 mg, 3.9 µmol) in CH 2 Cl 2 (0.5 ml) at 0 C were added NaHC 3 (10.2 mg, mmol) and Dess Martin periodinane (16.6 mg, 39.1 µmol), and the resultant mixture was stirred at room temperature for 1 h 40 min. The reaction was quenched with a 1:1 mixture of saturated aqueous Na 2 S 3 solution and saturated aqueous NaHC 3 solution. The resultant mixture was extracted with t-bu. 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, 4 to 7% EtAc/hexanes) gave an aldehyde (3.4 mg), which was directly used in the next reaction without further purification. To a suspension of CeCl 3 (19.6 mg, mmol) in THF (0.4 ml) at 78 C was added Li S20

21 (1.08 M solution in Et 2, ml, mmol), and the resultant mixture was stirred at 78 C for 30 min. To this mixture was added a solution of the above aldehyde (3.4 mg) in THF (0.2 ml, 0.2 ml ml rinse), and the resultant mixture was stirred at 78 C for 1 h. The reaction was quenched with saturated aqueous NH 4 Cl solution. The resultant mixture was extracted with t-bu. 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, 7 to 10% EtAc/hexanes) gave an alcohol (2.3 mg), which was directly used in the next reaction without further purification. To a solution of the above alcohol (2.3 mg) in CH 2 Cl 2 (0.5 ml) at 0 C were added NaHC 3 (10.0 mg, mmol) and Dess Martin periodinane (16.7 mg, 39.4 µmol), and the resultant mixture was stirred at room temperature for 1.5 h. The reaction was quenched with a 1:1 mixture of saturated aqueous Na 2 S 3 solution and saturated aqueous NaHC 3 solution. The resultant mixture was extracted with t-bu. 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, 5 to 10% EtAc/hexanes) gave the C8 C29 fragment 4 (2.3 mg, 73% for the three steps) as a colorless oil: [α] 23 D 75.8 (c 0.20, CHCl 3 ); IR (film) 2928, 1715, 1513, 1463, 1247, 1038 cm 1 ; 1 H NMR (600 MHz, C 6 D 6 ) δ (m, 2H), (m, 2H), (m, 2H), (m, 2H), 5.29 (d, J = 9.7 Hz, 1H), (m, 3H), 4.59 (d, J = 11.0 Hz, 1H), 4.46 (m, 1H), 4.31 (d, J = 8.8 Hz, 1H), 4.12 (m, 1H), 4.07 (ddd, J = 8.2, 5.9, 5.9 Hz, 1H), 4.00 (m, 1H), 3.56 (s, 3H), (m, 7H), 3.20 (dq, J = 6.9, 6.9 Hz, 1H), 2.91 (m, 1H), 2.56 (dd, J = 14.2, 9.6 Hz, 1H), 2.21 (m, 1H), (m, 5H), 1.76 (s, 3H), (m, 7H), (m, 5H), 1.21 (m, 1H), 1.12 (d, J = 6.9 Hz, 3H), (s, 9H), 0.90 (t, J = 7.3 Hz, 3H), 0.06 (s, 3H), 0.03 (s, 3H); 13 C NMR (150 MHz, C 6 D 6 ) δ 207.4, 159.6, 159.5, 141.5, 137.5, 132.1, (2C), (2C), 126.7, 114,0 (2C), (2C), 100.3, 81.9, 81.2, 77.9, 75.9, 72.7, 68.4, 67.7, 54.7 (2C), 50.1, 47.4, 43.5, 40.6, 33.0, 31.2, 30.2, 28.8, 28.4, 27.51, 27.46, 26.2 (3C), 25.7, 23.3, 18.4, 16.9, 16.5, 14.3, 3.9, 4.6; HRMS (ESI) calcd for C 47 H 74 9 SiNa [(M + Na) + ] S21

22 , found S22

23 Modified Mosher analysis of compound 17 H 19 H 17 H PMB (R)- or (S)-MTPAH DCC, DMAP (CH 2 Cl) 2, rt (R)-MTPA ester: 80% MTPA 0.06 H H 0.04 (S)-MTPA ester: 96% PMB (R)-A/(S)-A Δδ = δ [(S)-A] δ [(R)-A] (600 MHz, CDCl 3 ) S23

24 (600 MHz, CDCl 3 ) = AT-IV-124_proton-4-3.jdf Experiment = proton.jxp Sample_Id = AT-IV-124 = CHLRFRM-D Creation_Time = 28-JAN :19:57 Revision_Time = 11-MAR :27:33 Current_Time = 11-MAR :28:04 = single_pulse Data_Format = 1D CMPLEX Dim_Title = Proton X_Acq_Duration = [s] = 1H = 5[ppm] X_Prescans = 1 X_Resolution = [Hz] = [kHz] _ = [kHz] Tri_Domain = Proton Tri_Freq Tri_ffset = 5[ppm] = FALSE Scans = 8 Total_Scans = 8 Recvr_Gain = 30 = 20.6[dC] X_90_Width = 7.215[us] X_Acq_Time = [s] = 45[deg] = 4[dB] = [us] Irr_Mode Tri_Mode Dante_Presat = FALSE Repetition_Time = [s] X : parts per Million : Proton S24

25 (150 MHz, CDCl 3 ) = AT-IV-124_Carbon-1-3.jdf Experiment = carbon.jxp Sample_Id = AT-IV-124 = CHLRFRM-D Creation_Time = 28-JAN :18:10 Revision_Time = 11-MAR :23:41 Current_Time = 11-MAR :24:07 = single pulse decoupled gat Data_Format = 1D CMPLEX Dim_Title = Carbon13 X_Acq_Duration = [s] = 13C = [MHz] = 100[ppm] X_Prescans = 4 X_Resolution = [Hz] = [kHz] _ = [kHz] = FALSE Scans = 72 Total_Scans = 72 Recvr_Gain = 54 = 20.8[dC] X_90_Width = 10.5[us] X_Acq_Time = [s] = 30[deg] = 7.4[dB] = 3.5[us] Irr_Atn_Dec = [dB] Irr_Atn_Noe = [dB] Irr_Noise = WALTZ Irr_Pwidth = 76[us] Decoupling Noe Noe_Time = 2[s] Repetition_Time = [s] X : parts per Million : Carbon S25

26 (600 MHz, CDCl 3 ) = AT-IV-125_proton-2-7.jdf Experiment = proton.jxp Sample_Id = AT-IV-125 = CHLRFRM-D Creation_Time = 5-FEB :41:12 Revision_Time = 11-MAR :35:22 Current_Time = 11-MAR :37:10 = single_pulse Data_Format = 1D CMPLEX Dim_Title = Proton X_Acq_Duration = [s] = 1H = 5[ppm] X_Prescans = 1 X_Resolution = [Hz] = [kHz] _ = [kHz] Tri_Domain = Proton Tri_Freq Tri_ffset = 5[ppm] = FALSE Scans = 8 Total_Scans = 8 Recvr_Gain = 40 = 20.9[dC] X_90_Width = 7.215[us] X_Acq_Time = [s] = 45[deg] = 4[dB] = [us] Irr_Mode Tri_Mode Dante_Presat = FALSE Repetition_Time = [s] X : parts per Million : Proton S26

27 (150 MHz, CDCl 3 ) = AT-IV-125_Carbon-1-6.jdf Experiment = carbon.jxp Sample_Id = AT-IV-125 = CHLRFRM-D Creation_Time = 5-FEB :45:00 Revision_Time = 11-MAR :30:07 Current_Time = 11-MAR :30:40 = single pulse decoupled gat Data_Format = 1D REAL Dim_Title = Carbon13 X_Acq_Duration = [s] = 13C = [MHz] = 100[ppm] X_Prescans = 4 X_Resolution = [Hz] = [kHz] _ = [kHz] Scans = 468 Total_Scans = 468 Recvr_Gain = 54 = 21[dC] X_90_Width = 10.5[us] X_Acq_Time = [s] = 30[deg] = 7.4[dB] = 3.5[us] Irr_Atn_Dec = [dB] Irr_Atn_Noe = [dB] Irr_Noise = WALTZ Irr_Pwidth = 76[us] Decoupling Noe Noe_Time = 2[s] Repetition_Time = [s] X : parts per Million : Carbon S27

28 S1 (600 MHz, C 6 D 6 ) = AT-IV-127_proton-1-4.jdf Experiment = proton.jxp Sample_Id = AT-IV-127 = BENZENE-D6 Creation_Time = 6-FEB :28:22 Revision_Time = 11-MAR :54:12 Current_Time = 11-MAR :54:51 = single_pulse Data_Format = 1D CMPLEX Dim_Title = Proton X_Acq_Duration = [s] = 1H = 5[ppm] X_Prescans = 1 X_Resolution = [Hz] = [kHz] _ = [kHz] Tri_Domain = Proton Tri_Freq Tri_ffset = 5[ppm] = FALSE Scans = 8 Total_Scans = 8 Recvr_Gain = 32 = 20.7[dC] X_90_Width = 7.215[us] X_Acq_Time = [s] = 45[deg] = 4[dB] = [us] Irr_Mode Tri_Mode Dante_Presat = FALSE Repetition_Time = [s] X : parts per Million : Proton S28