HETEROCYCLES

Paper | Special issue | Vol. 90, No. 2, 2015, pp. 1254-1273
Received, 13th August, 2014, Accepted, 8th September, 2014, Published online, 12th September, 2014.
DOI: 10.3987/COM-14-S(K)107

■ Synthesis of the C1-C7 and C8-C18 Segments of ent-Amphidinin A

Haruaki Ishiyama, Masahiro Hangyou, Ayumi Nakatsu, Yuta Mori, and Jun'ichi Kobayashi*

Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan

Abstract

A stereoselective synthesis of the C1-C7 and C8-C18 segments of the enantiomer of amphidinin A, a cytotoxic polyketide from the culture cells of a symbiotic marine dinoflagellate Amphidinium sp. (strain Y-5), has been achieved, utilizing sulfone-aldehyde coupling, Sharpless asymmetric dihydroxylation, Katsuki-Sharpless asymmetric epoxidation, and Julia-Kocienski olefination.

INTRODUCTION
Amphidinin A is a cytotoxic linear polyketide isolated from the culture cells of a symbiotic marine dinoflagellate Amphidinium sp. (strain Y-5) producing a number of macrolides.1 Amphidinin A exhibits moderate cytotoxicity against murine lymphoma L1210 and human epidermoid carcinoma KB cells in vitro (IC50 values, 3.6 and 3.0 µg/mL, respectively). The planar structure and partial relative configuration (THF ring moiety; C9-C12) of amphidinin A were elucidated by 2D NMR in 1994.2 In order to compare the NMR data and optical rotation of the synthetic amphidinin A with those of natural amphidinin A and to study structure-activity relationship, we started the synthesis of the C8-C18 segment of amphidinin A along with the relative configuration elucidated by NOESY data.2 More recently, we have proposed the absolute configuration of amphidinin A as 13 on the basis of J-based configuration analysis,4 modified Mosher’s method,5,6 and density functional theory (DFT) calculations.7

The proposed absolute configuration of the C8-C18 segment in amphidinin A3 was reverse to the relative configuration proposed in the previous paper,2 that is, it was the enantiomer of the proposed structure of amphidinin A.3 Therefore, in order to validate our proposed absolute configuration of amphidinin A (1),3 we decided to perform a stereoselective synthesis of the C1-C7 and C8-C18 fragments of ent-amphidinin A (2) as follows (Scheme 1), employing sufone-aldehyde coupling, Sharpless asymmetric dihydroxylation,8 Katsuki-Sharpless asymmetric epoxidation,9 and Julia-Kocienski olefination.10

RESULTS AND DISCUSSION
As outlined retrosynthetically in Scheme 1, ent-amphidinin A (2) could be obtained by olefination of ketone 3, which could be provided by dithiane coupling of the C1-C7 segment 4 with the C8-C18 segment 5. The C1-C7 segment 4, containing three stereogenic centers, could be derived via sulfone-aldehyde coupling reaction of 711 with 6.12 The C8-C18 segment 5, bearing a THF ring, could be synthesized by Julia-Kocienski reaction10 between sulfone 8 and aldehyde 9. The aldehyde 9 could be provided through THF ring formation reaction of epoxide 10, which is conceived to be obtained via Sharpless asymmetric dihydroxyration8 and Katsuki-Sharpless epoxidation9 of 11.13
The synthesis of the C1-C7 segment 4 is described in Scheme 2. Known aldehyde 6,12 derived from L-malic acid in three steps, was subjected to coupling with sulfone 711 to afford hydroxy sulfone, which was oxidized with Dess-Matin periodinane14 to give the ketone bearing a sulfone. Selective removal of the sulfone moiety of the ketone was accomplished via samarium(II) iodide-mediated reduction in THF and MeOH to provide 12 in 56% yield for the three steps. Reduction of ketone 12 with NaBH4 in MeOH

gave diols 13 and 14 (32% and 56%, respectively), which were separated by silica gel column chromatography. Protection of the secondary hydroxy group in 13 with Ac2O in pyridine provided the acetate, the TIPS group of which was removed by TBAF in THF to yield alcohol 15 in 77% yield for the two steps. Oxidation of 15 with Dess-Martin periodinane14 was followed by 1,3-dithiane ring formation catalyzed by Sc(OTf)2 to yield dithiane with 1,2-diol moiety, which was treated with 2,2-dimethoxypropane and PPTS to afford dithiane 16. The acetyl group in 16 was removed with K2CO3 in MeOH to provide alcohol, the secondary hydroxy group of which was protected as the MOM ether to furnish the (2S,4S,6R)-C1-C7 segment 4 due to the absolute configuration of the starting materials (6, 7) and a modified Mosher’s method as follows (Figure 1).

The absolute configuration at C4 in 13 was elucidated to be S by a modified Mosher’s method.5,6 Treatment of 13 with (R)- (-)- and (S)-(+)-2-methoxy-2-trifluoro-2-phenylacetyl chloride (MTPACl) provided the (S)- and (R)-MTPA esters (13a and 13b, respectively) of 13. Δδ Values ((Δδ ) δS - δR ) obtained from 1H NMR data of 13a and 13b are shown in Figure 1.
As shown in Scheme 3, the C8-C18 segment 5 was synthesized. Sharpless asymmetric dihydroxylation8 of terminal olefin 1113 with AD-mix β to introduce tertiary hydroxy group at C9 stereoselectively proceeded with concomitant cyclization to give lactones,15 which were converted into the TBDPS ethers as a separable mixture 17 and 18 (79% and 21%, respectively) by silica gel column chromatography. Treatment of lactone 17 with DIBAL at -78 °C gave lactol, which was subject to Wittig reaction with ethyl (triphenylphosphoranylidene)acetate to afford (E)-α,β-unsaturated ester 19 in 87% yield for the two steps with an E/Z ratio of greater than 20:1. The absolute configuration of (9S) for 17 was confirmed by the NOESY data16 of 17 due to the (S) configuration at C11 in 11. The tertiary hydroxy group in 19 was protected as the TES ether with TESOTf in pyridine at 50 °C and the ester moiety was reduced with DIBAL to yield allylic alcohol 20. With allylic alcohol 20 in hand, our attention was next focused on Katsuki-Sharpless asymmetric epoxidation.9 Katsuki-Sharpless asymmetric epoxidation9 using L-(+)-diethyl tartrate (DET) afforded epoxy alcohol (64%, dr 17:1), which was treated with CSA to provide diol 21 and the minor epimer was separated during these transformation. Treatment of diol 21 with NaIO4 in 60% MeCN was followed by Julia-Kocienski reaction10 of the corresponding aldehyde with sulfone 817 in DME to provide olefin with an E-selectivity (E/Z, 9:1), the TBDPS group of which was removed by TBAF in THF to furnish the (9S,11S,12R)-C8-C18 segment 5 and the Z isomer was separated at this stage. The absolute configuration of (9S, 11S, 12R) for 5 was established through the correlation of the NOESY data18 of 5 with the (S) configuration at C11 in starting material 11.

The small 1H NMR chemical shift differences between natural amphidinin A (1)2 and the C8-C18 segment 5 indicated that relative configurations at C9, C11, and C12 in 5 corresponded to those of amphidinin A (1)3 (Table 1). The 13C NMR chemical shift differences between amphidinin A (1) and 5 also showed small differences due to lack of hydrophilic moiety (C1-C7) exception at C8 and C10 (Table 2).

On the other hand, four possible C1-C8 segment diastereomers (25, 26, 30, and 31), containing three stereogenic centers, of amphidinin A (1) were prepared as shown in Scheme 4.19 Protection of the secondary hydroxy group in 13 with MOMCl and i-PrNEt2 provided the MOM ether, the TIPS group of which was removed by TBAF in THF to yield alcohol 22 in 96% yield for the two steps. Oxidation of 22 with Dess-Martin periodinane14 was followed by Grignard reaction with MeMgBr in THF to yield the corresponding alcohol, which was oxidized with Dess-Martin periodinane14 to afford ketone 23. Wittig methylenation of 23 with [Ph3PCH3]+Br- and n-BuLi gave olefin 24, the protecting groups of which were removed by TsOH·H2O to furnish a C1-C8 segment diastereomer 25 of amphidinin A (1). The other C1-C8 segment diastereomers (26, 30, and 31) were prepared by almost the same procedure as described for synthesis of 25.
Figures 2 and 3 show the difference in 1H and 13C NMR chemical shifts between amphidinin A (1) and four synthetic C1-C8 segment diastereomeres (25, 26, 30, and 31), respectively. While 1H NMR chemical shifts differences of 1 and 25 or 31 were less than those of 1 and 26 or 30 (Figure 2), 13C NMR chemical shifts differences of 1 and 25 or 30 were less than those of 1 and 26 or 31 (Figure 3). These results indicated that relative configurations at C2, C4, and C6 in 25 corresponded to those of amphidinin A (1).3

In conclusion, the stereocontrolled synthesis of the C1-C7 segment 4 and C8-C18 segment 5 of ent-amphidinin A (2) has been achieved. As a result, it was indicated that the relative configurations at C2, C4, and C6 in 25 and at C9, C11, and C12 in 5 corresponded to those of amphidinin A (1)3 due to the smaller 1H and 13C NMR chemical shift differences between synthetic compounds (25 and 5) and natural amphidinin A (1).2 Progress toward the total synthesis of ent-amphidinin A (2) will be reported in due course.

EXPERIMENTAL
General Experimental Procedures. Optical rotations were recorded on a JASCO P-1030 polarimeter at the sodium D line (589 nm). The IR spectrum was taken on a JASCO FT/IR-5300 spectrometer and absorbance bands are reported in wavenumber (cm-1). 1H and 13C NMR spectra were recorded on a Bruker AMX-600 (600 MHz), JEOL ECA500 (500 MHz), or ECX400P (400 MHz) spectrometer. The 7.26 and 77.0 ppm resonances of residual CDCl3 and the 7.20 and 128.0 ppm resonances of residual benzene-d6 were used as internal references for 1H and 13C NMR spectra, respectively. The following abbreviations are used for spin multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. ESI mass spectra were recorded on a Thermo Fisher Scientific Exactive or JEOL JMS-T100LP spectrometer. Silica gel column chromatography was carried out on Wakogel C-200 (75~150 μm) or C-300 (45~75 μm). Analytical thin layer chromatography (TLC) was carried out on Merck Kieselgel 60 F254 plates with visualization by ultraviolet, anisaldehyde stain solution and/or phosphomolybdic acid stain solution. Reagents and solvents were purified by standard means. All reactions sensitive to oxygen or moisture were conducted under an argon atmosphere.
Kotone 12. To a solution of sulfone 7 (1.37 g, 3.70 mmol) in THF (15 mL) cooled to –78 °C was added n-BuLi (2.5 M solution in n-hexane, 2.0 mL, 5.0 mmol) dropwise. The mixture was stirred at –78 °C for 30 min, and then a solution of aldehyde 6 (279 mg, 1.52 mmol) in THF (5 mL) was added dropwise, and the resulting mixture was stirred at –78 °C for 25 min. The reaction was quenched by addition of saturated aqueous NH4Cl (15 mL) and the mixture was warmed to room temperature. The reaction mixture was extracted with EtOAc (3 × 50 mL), washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure to yield crude hydroxy sulfones. The hydroxy sulfones were employed in the next experiment without separation of the diastereomers. To a stirred solution of the diastereomeric mixture of hydroxy sulfones (1.86 g) in pyridine/ CH2Cl2 (1:9, v/v, 20 mL) was added Dess-Martin periodinane (2.09 g, 4.94 mmol) and the reaction mixture was stirred for 20 min at room temperature. To the reaction mixture was added saturated aqueous Na2S2O3 (60 mL) and extracted with Et2O (3 × 50 mL). The organic layers were washed with 3 M aqueous HCl (25 mL), saturated aqueous NaHCO3 (25 mL), and brine (25 mL), dried over Na2SO4, filtered, and concentrated to afford sulfones. The residual oil was passed through silica gel pad (n-hexane/Et2O 10:1→7:1, n-hexane/EtOAc 10:1→7:1) to remove reagents. The sulfones were employed in the next experiment without separation of the diastereomers. To a stirred solution of the sulfones (724 mg) and MeOH (0.27 mL) in THF (20 mL) was added SmI2 (0.1 M solution in THF, 65.5 mL, 6.55 mmol). After being stirred for 1.5 h, the mixture was diluted with EtOAc (35 mL). The organic layer was washed with saturated aqueous Na2S2O3 (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane/Et2O 20:1→10:1→7:1→5:1, n-hexane/EtOAc 10:1) to yield ketone 12 (350 mg, 0.849 mmol, 56% for the three steps) as a colorless oil; [α]D25 +6.1 (c 0.75, CHCl3); IR (neat) νmax 2940, 2866, 1713, 1463, 1365, 1102 cm-1; 1H NMR (500 MHz, CDCl3) δ 4.45 (1H, m), 4.17 (1H, dd, J = 8.3, 6.3 Hz), 3.58 (1H, dd, J = 9.7, 5.2 Hz), 3.51 (1H, dd, J = 8.3, 6.3 Hz), 3.44 (1H, dd, J = 9.7, 6.3 Hz), 2.91 (1H, dd, J = 16.8, 5.7 Hz), 2.69 (1H, dd, J = 16.0, 4.6 Hz), 2.56 (1H, dd, J = 16.8, 7.2 Hz), 2.21 (2H, m), 1.58 (8H, m), 1.38 (2H, m), 1.11-1.02 (21H, m), 0.90 (3H, d, J = 6.3 Hz); 13C NMR (100 MHz, CDCl3) δ 208.8, 109.4, 71.5, 69.2, 67. 7, 47.7, 47.2, 36.6, 35.0, 32.1, 25.1, 24.0, 23.8, 18.0, 16.7, 11.9; ESIMS (positive) m/z 435 (M+Na)+; HRESIMS (positive) m/z 435.2893 [(M+Na)+, calcd for C23H44O4SiNa, 435.2901].
Alcohols 13 and 14. To a solution of ketone 12 (373 mg, 0.904 mmol) in MeOH (20 mL) cooled to 0 °C was added NaBH4 (82 mg, 2.2 mmol) and the resulting mixture was stirred at room temperature for 2 h. The reaction was quenched by addition of saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (3 × 50 mL). Combined extracts were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane/Et2O 20:1→15:1→10:1→7:1→5:1, n-hexane/EtOAc 10:1→5:1) to give alcohols 13 (121 mg, 0.292 mmol, 32%) and 14 (211 mg, 0.509 mmol, 56%).
13: colorless oil; [α]D23 +1.2 (c 0.97, CHCl3); IR (neat) νmax 3523, 2940, 2866, 1463, 1101 cm-1; 1H NMR (500 MHz, CDCl3) δ 4.29 (1H, m), 4.09 (1H, dd, J = 8.0, 5.7 Hz), 3.95 (1H, m), 3.58 (3H, m), 1.86 (1H, m), 1.66 (2H, m), 1.57 (8H, m), 1.52 (1H, m), 1.45 (1H, J = 7.7, 6.0 Hz), 1.40 (2H, m), 1.14-1.04 (21H, m), 0.94 (3H, d, J = 6.9 Hz); 13C NMR (100 MHz, CDCl3) δ 109.8, 75.1, 69.4, 68.5, 68.4, 41.9, 40.7, 36.5, 35.2, 32.5, 25.1, 24.0, 23.9, 18.0, 17.7, 11.9; ESIMS (positive) m/z 437 (M+Na)+; HRESIMS (positive) m/z 437.3058 [(M+Na)+, calcd for C23H46O4SiNa, 437.3058].
14: colorless oil; [α]D23 +4.0 (c 0.88, CHCl3); IR (neat) νmax 3442, 2940, 2866, 1463, 1102 cm-1; 1H NMR (500 MHz, CDCl3) δ 4.31 (1H, m), 4.08 (1H, dd, J = 8.0, 6.3 Hz), 3.88 (1H, m), 3.61 (1H, dd, J = 9.8, 4.6 Hz), 3.56 (1H, m), 3.50 (1H, dd, J = 9.8, 8.0 Hz), 1.86 (1H, m), 1.75 (1H, ddd, J = 13.9, 7.3, 3.3 Hz), 1.67 (1H, m), 1.58 (8H, m), 1.44 (2H, m), 1.39 (2H, m), 1.15-1.06 (21H, m), 0.91 (3H, d, J = 7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 109.0, 73.6, 69.6, 69.5, 67.8, 43.8, 41.4, 36.6, 35.3, 34.4, 25.2, 24.1, 23.9, 18.0, 17.8, 11.9; ESIMS (positive) m/z 437 (M+Na)+; HRESIMS (positive) m/z 437.3052 [(M+Na)+, calcd for C23H46O4SiNa, 437.3058].
Alcohol 15. To a solution of alcohol 13 (78 mg, 0.19 mmol) in pyridine (2 mL) was added Ac2O (2 mL). After being stirred for 5 h, the mixture was concentrated under reduced pressure. Purification by silica gel column chromatography (n-hexane/EtOAc 20:1→15:1→10:1) afforded the acetate (86 mg, 0.19, quantitative) as a colorless oil; [α]D20 -0.52 (c 1.01, CHCl3); IR (neat) νmax 2940, 2866, 1463, 1366, 1237, 1101 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.06 (1H, m), 4.13 (1H, m), 4.06 (1H, dd, J = 7.8, 6.3 Hz), 3.51 (3H, m), 2.03 (3H, s), 1.94 (1H, ddd, J = 14.4, 8.0, 6.2 Hz), 1.73 (2H, m), 1.66 (1H, dd, J = 13.3, 6.9 Hz), 1.57 (8H, m), 1.42 (1H, dd, J = 8.2, 6.9 Hz), 1.38 (2H, m), 1.06 (21H, m), 0.94 (3H, d, J = 6.9 Hz); 13C NMR (100 MHz, CDCl3) δ 170.6, 109.3, 72.6, 70.3, 69.2, 67.6, 38.3, 37.6, 36.6, 35.1, 32.7, 25.1, 24.0, 23.8, 21.3, 18.0, 17.3, 11.9; ESIMS (positive) m/z 479 (M+Na)+; HRESIMS (positive) m/z 479.3161 [(M+Na)+, calcd for C21H43O4SiNa, 479.3161]. To a solution of the above acetate protected with TIPS group (443 mg, 0.971 mmol) in THF (15 mL) at 0 °C was added TBAF (1.0 M solution in THF, 1.5 mL, 1.5 mmol). The reaction mixture was stirred at room temperature for 2 h, added saturated aqueous NH4Cl (15 mL), and extracted with EtOAc (3 × 30 mL). Combined extracts were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated. Purification by column chromatography on silica gel (n-hexane/EtOAc 5:1→3:1→1:1→1:3) gave alcohol 15 (223 mg, 0.742 mmol, 77% for the two steps) as a colorless oil; [α]D19 -4.2 (c 0.96, CHCl3); IR (neat) νmax 3442, 2935, 2865, 1448, 1366, 1241, 1101, 1035 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.10 (1H, ddd, J = 11.9, 7.8, 4.3 Hz), 4.14 (1H, dt, J = 13.3, 6.5 Hz), 4.04 (1H, dd, J = 8.2, 6.0 Hz), 3.49 (3H, m), 2.03 (3H, s), 1.92 (1H, dt, J = 22.0, 7.3 Hz), 1.72 (4H, m), 1.57 (8H, m), 1.47 (1H, dd, J = 16.7, 8.5 Hz), 1.38 (2H, m), 0.94 (3H, d, J = 6.0 Hz); 13C NMR (100 MHz, CDCl3) δ 170.8, 109.5, 72.5, 70.2, 69.1, 67.5, 38.1, 37.7, 36.5, 35.1, 32.3, 25.1, 24.0, 23.8, 21.3, 17.3; ESIMS (positive) m/z 323 (M+Na)+; HRESIMS (positive) m/z 323.1839 [(M+Na)+, calcd for C16H28O5Na, 323.1834].
Dithiane 16. To a stirred solution of alcohol 15 (46 mg, 0.15 mmol) in pyridine/CH2Cl2 (1:9, v/v, 2 mL) was added Dess-Martin periodinane (163 mg, 0.385 mmol). After the solution was stirred at room temperature for 15 min, saturated aqueous Na2S2O3 (5 mL) was added, and extracted with Et2O (3 × 10 mL). The combined organic layers were washed with 3 M aqueous HCl (5 mL), saturated aqueous NaHCO3 (5 mL), and brine (5 mL), dried over Na2SO4, filtered, and concentrated. The residual oil was passed through silica gel pad (n-hexane/EtOAc 7:1→5:1→3:1) to remove reagents. To a solution of the crude aldehyde (36 mg) in CH2Cl2 (3 mL) was added 1,3-propanedithiol (24 µL, 0.24 mmol) and Sc(OTf)3 (18 mg, 36 µmol). After being stirred for 2.5 h, the reaction mixture was concentrated in vacuo to yield crude dihiane with dihydroxy group. To a solution of the crude dithiane in CH2Cl2 (3 mL) was added 2,2-dimethoxypropane (0.43 mL, 3.5 mmol) and PPTS (6.0 mg, 24 µmol). After being stirred for 10 min, the reaction mixture was concentrated under reduced pressure. Purification by silica gel column chromatography (n-hexane/EtOAc 10:1→7:1→5:1→3:1) afforded dithiane 16 protected with acetonide (20 mg, 56 µmol, 38% for the three steps) as a colorless oil: [α]D20 +9.6 (c 0.86, CHCl3); IR (neat) νmax 2933, 1735, 1371, 1238, 1063 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.06 (1H, m), 4.19 (1H, d, J = 3.2 Hz), 4.14 (1H, m), 4.06 (1H, dd, J = 7.7, 6.0 Hz), 3.52 (1H, t, J = 7.7 Hz), 2.88 (4H, m), 2.10 (2H, m), 2.04 (3H, s), 1.93 (3H, m), 1.74 (1H, ddd, J = 14.5, 6.5, 4.2 Hz), 1.60 (1H, m), 1.39 (3H, s), 1.33 (3H, s), 1.10 (3H, d, J = 6.4 Hz); 13C NMR (100 MHz, CDCl3) δ 170.7, 108.8, 72.9, 69.7, 69.4, 54.5, 38.4, 37.9, 35.1, 31.1, 30.7, 26.9, 26.3, 25.7, 21.3, 17.4; ESIMS (positive) m/z 371 (M+Na)+; HRESIMS (positive) m/z 371.1321 [(M+Na)+, calcd for C16H28O4S2Na, 371.1321].

Dithiane 4. To a stirred solution of dithiane 16 protected as the acetate (51 mg, 0.15 mmol) in MeOH (8 mL) was added K2CO3 (154 mg, 1.11 mmol). After the solution was stirred for 4 h, reaction mixture was diluted with EtOAc (50 mL), washed with saturated aqueous NH4Cl (25 mL), and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated. The mixture was passed through a silica gel pad (n-hexane/EtOAc 10:1→7:1→5:1→4:1→3:1→1:1) to remove reagents. To a stirred solution of the crude alcohol (31 mg) and i-Pr2NEt (0.27 mL, 1.5 mmol) in CH2Cl2 (2 mL) cooled to 0 °C was added MOMCl (77 µL, 1.0 mmol), and the resulting solution was stirred at room temperature for 16 h. The reaction was quenched by addition of saturated aqueous NH4Cl (2 mL) and extracted with Et2O (3 × 10 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (n-hexane/Et2O 12:1→10:1→8:1→6:1→4:1) to furnish dihiane 4 (32 mg, 91 µmol, 61% for the two steps) as a colorless oil; [α]D20 +10.8 (c 0.80, CHCl3); IR (neat) νmax 2932, 1379, 1214, 1153, 1098, 1035 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.65 (1H, J = 7.4 Hz), 4.61 (1H, J = 7.4 Hz), 4.24 (1H, d, J = 3.7 Hz), 4.23 (1H, m), 4.07 (1H, dd, J = 8.0, 5.7 Hz), 3.74 (1H, m), 3.49 (1H, t, J = 8.0 Hz), 3.39 (3H, s), 2.89 (4H, m), 2.09 (2H, m), 1.93 (1H, dt, J = 14.2, 6.0 Hz), 1.84 (1H, m), 1.70 (1H, m), 1.55 (2H, m), 1.40 (3H, s), 1.35 (3H, s), 1.11 (3H, d, J = 6.9 Hz); 13C NMR (100 MHz, CDCl3) δ 108.5, 95.0, 72.9, 69.7, 55.9, 54.8, 38.6, 37.8, 35.0, 31.2, 30.7, 27.0, 26.4, 25.8, 21.0, 17.6; ESIMS (positive) m/z 373 (M+Na)+; HRESIMS (positive) m/z 373.1489 [(M+Na)+, calcd for C16H30O4S2Na, 373.1483].
(S)-MTPA ester 13a. To a solution of alcohol 13 (1.1 mg, 2.7 µmol) in CH2Cl2 (0.2 mL) at room temperature were added Et3N (3.0 µL, 22 µmol), DMAP (0.30 mg, 2.5 µmol), and (R)-MTPACl (3.0 µL, 17 µmol). After 18 h at room temperature, the reaction was quenched with N,N-dimethyl-1,3-propanediamine (3.0 µL, 23 µmol) and the resultant mixture was stirred for 10 min. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (n-hexane/EtOAc 20:1→15:1→10:1) to yield (S)-MTPA ester 13a (1.6 mg, 2.5 µmol, 96%) as a colorless oil; 1H NMR (500 MHz, CDCl3) δ 7.53 (2H, m; Ph), 7.39 (3H, m; Ph), 5.26 (1H, m; H-4), 4.10 (1H, m; H-2) 4.01 (1H, dd, J = 8.0, 5.7 Hz; H-1a), 3.54 (3H, s; OMe), 3.52 (1H, dd, J = 9.9, 5.2 Hz; H-7a), 3.47 (1H, dd, J = 8.0, 6.9 Hz; H-1b), 3.45 (1H, dd, J = 9.9, 4.9 Hz; H-7b), 2.06 (1H, dt, J = 14.3, 6.6 Hz; H-3a), 1.78 (2H, m; H-3b, H-5a), 1.57 (8H, m; cyclohexylidene), 1.53 (1H, m; H-6), 1.44 (1H, m: H-5b). 1.38 (2H, m; cyclohexylidene), 1.08-1.02 (21H, m; TIPS), 0.86 (3H, d, J = 6.9 Hz; H-22); ESIMS (positive) m/z 653 (M+Na)+; HRESIMS (positive) m/z 653.3465 [(M+Na)+, calcd for C33H53O6F3SiNa, 653.3456].
(R)-MTPA ester 13b. To a solution of alcohol 13 (0.65 mg, 1.6 µmol) was treated with (S)-MTPACl by the same prodedure as described above to afford (R)-MTPA ester 13b (0.28 mg, 0.45 µmol, 29%) as a colorless oil; 1H NMR (500 MHz, CDCl3) δ 7.54 (2H, m; Ph), 7.40 (3H, m; Ph), 5.23 (1H, m; H-4), 3.95 (1H, m; H-2), 3.91 (1H, dd, J = 7.5, 5.7 Hz; H-1a), 3.55 (3H, s; OMe), 3.57 (1H, dd, J = 9.8, 5.2 Hz; H-7a), 3.35 (1H, dd, J = 7.5, 6.9 Hz; H-1b), 3.50 (1H, dd, J = 9.8, 5.7 Hz; H-7b), 1.99 (1H, dt, J = 14.1, 6.4 Hz; H-3a), 1.86 (1H, dt, J = 13.5, 6.6 Hz; H-5a), 1.73 (1H, ddd, J = 14.1, 6.6, 4.6 Hz; H-3b), 1.66 (1H, m; H-6), 1.53 (8H, m; cyclohexylidene), 1.47 (1H, m; H-5b), 1.37 (2H, m; cyclohexylidene), 1.09-1.01 (21H, m; TIPS), 0.94 (3H, d, J = 6.9 Hz; H-22); ESIMS (positive) m/z 653 (M+Na)+; HRESIMS (positive) m/z 653.3458 [(M+Na)+, calcd for C33H53O6F3SiNa, 653.3456].
Lactones 17 and 18. AD-mix β (48.7 g) and MeSO2NH2 were stirred in t-BuOH/H2O (1:1, v/v, 200 mL) at 0 °C for 30 min. To this mixture was added a solution of olefin 11 (9.98 g, 34.7 mmol) in t-BuOH/H2O (1:1, v/v, 100 mL), and the mixture was stirred at 4 °C for 34 h. The reaction was quenched by the addition of saturated aqueous Na2SO3 (150 mL), and the whole was stirred at 0 °C for another 30 min then extracted with EtOAc (4 × 40 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO4, and concentrated in vacuo to afford crude lactones. To a stirred solution of the crude lactones (14.47 g), Et3N (9.0 mL, 64.7 mmol), and DMAP (852 mg, 6.97 mmol) in CH2Cl2 (2 mL) cooled to 0 °C was added TBDPSCl (13.5 mL, 51.9 mmol), and the resulting solution was stirred at room temperature for 22 h. The reaction was quenched by addition of saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with H2O (100 mL) and brine (100 mL), drided with Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (n-hexane/Et2O 15:1 n-hexane/EtOAc 15:1→10:1→5:1) to afford lacones 17 (10.5 g, 27.4 mmol, 79% for the two steps) and 18 (2.73 g, 7.15 mmol, 21% for the two steps).
Lactone 17: colorless oil; [α]D20 +7.0 (c 1.76, CHCl3); IR (neat) νmax 2931, 2858, 1771, 1113 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.68-7.65 (4H, m), 7.43-7.38 (6H, m), 3.68 (1H, d, J = 10.9 Hz), 3.54 (1H, d, J = 10.9 Hz), 2.83 (1H, m), 2.08 (2H, m), 1.33 (3H, s), 1.29 (3H, d, J = 6.8 Hz), 1.06 (9H, s); 13C NMR (100 MHz, CDCl3) δ 179.2, 135.7, 135.6, 133.1, 132.6, 129.8, 127.8, 83.7, 68.6, 37.2, 34.8, 26.7, 22.8, 19.3, 15.7; ESIMS (positive) m/z 405 (M+Na)+; HRESIMS (positive) m/z 405.1861 [(M+Na)+, calcd for C23H30O3SiNa, 405.1856].
Lactone 18: colorless oil; [α]D18 -26 (c 1.99, CHCl3); IR (neat) νmax 2933, 2858, 1772, 1113 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.67-7.65 (4H, m), 7.46-7.38 (6H, m), 3.66 (1H, d, J = 10.9 Hz), 3.50 (1H, d, J = 10.9 Hz), 2.95 (1H, m), 2.61 (1H, dd, J = 12.7, 9.5 Hz), 1.34 (3H, s), 1.29 (1H, dd, J = 12.7, 10.4 Hz), 1.28 (3H, d, J = 7.2 Hz), 1.06 (9H, s); 13C NMR (100 MHz, CDCl3) δ 179.9, 135.6, 135.5, 134.8, 132.8, 132.3, 129.9, 127.8, 83.6, 77.2, 69.5, 39.6, 36.2, 26.7, 24.3, 19.1, 16.7; ESIMS (positive) m/z 405 (M+Na)+; HRESIMS (positive) m/z 405.1860 [(M+Na)+, calcd for C23H30O3SiNa, 405.1856].
(E)-α,β-Unsaturated ester 19. To a solution of lactone 17 (586 mg, 1.53 mmol) in CH2Cl2 (20 mL) cooled to –78 °C was added DIBAL (1.0 M solution in n-hexane, 1.6 mL, 1.6 mmol) dropwise. After the solution was stirred for 30 min at -78 °C, the reaction was quenched with MeOH (3 mL) and saturated aqueous Rochelle solution (25 mL) and the resultant mixture was stirred for 30 min at room temperature. The reaction mixture was extracted with EtOAc (3 × 40 mL), washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure to yield crude lactols. The lactols were employed to the next step without further purification. To a solution of crude lactols in toluene (20 mL) was added ethyl (triphenylphosphoranylidene)acetate (801 mg, 2.30 mmol) and the reaction mixture was stirred for 12 h at 100 °C. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (n-hexane/EtOAc 10:1→7:1→5:1→3:1) to afford ester 19 (606 mg, 1.33 mmol, 87% for the two steps) as a colorless oil; [α]D19 +18.4 (c 0.36, CHCl3); IR (neat) νmax 3479, 2960, 2931, 2858, 1717 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.67-7.63 (4H, m), 7.45-7.38 (6H, m), 6.94 (1H, dd, J = 15.5, 8.4 Hz), 5.69 (1H, J = 15.5, 0.9 Hz), 4.16 (2H, q, J = 7.0 Hz), 3.46 (1H, d, J = 9.6 Hz), 3.40 (1H, d, J = 9.6 Hz), 2.52 (1H, m), 2.33 (1H, brs), 1.68 (1H, dd, J = 14.2, 8.6 Hz), 1.51 (1H, dd, J = 14.2, 4.3 Hz), 1.28 (3H, t, J = 7.0 Hz), 1.14 (3H, s), 1.08 (9H, s), 1.06 (3H, d, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 166.9, 155.5, 135.6, 132.9, 129.9, 129.8, 127.8, 119.0, 72.7, 70.9, 60.1, 44.7, 32.6, 26.9, 23.9, 21.9, 19.3, 14.2; ESIMS (positive) m/z 477 (M+Na)+; HRESIMS (positive) m/z 477.2440 [(M+Na)+, calcd for C27H38O4SiNa, 477.2432].
Allylic alcohol 20. To a stirred solution of (E)-α,β-unsaturated ester 19 (379 mg, 0.834 mmol) and DMAP (20 mg, 0.16 mmol) in pyridine (2.5 mL) cooled to 0 °C was added TESOTf (145 µL, 0.642 mmol), and the resulting solution was stirred at 50 °C for 4 h. The reaction was quenched by addition of saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with H2O (20 mL) and brine (3 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (n-hexane/Et2O 150:1→100:1→50:1→10:1) to afford TES ether (419 mg, 0.736 mmol, 88%) as a colorless oil; [α]D20 +39.9 (c 2.03, CHCl3); IR (neat) νmax 2956, 2875, 1719, 1110 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.66-7.63 (4H, m), 7.45-7.36 (6H, m), 6.97 (1H, dd, J = 15.8, 8.4 Hz), 5.72 (1H, dd, J = 15.8, 0.9 Hz), 4.17 (2H, q, J = 7.2 Hz), 3.47 (1H, d, J = 9.5 Hz), 3.32 (1H, d, J = 9.5 Hz), 2.56 (1H, m), 1.74 (1H, dd, J = 14.0, 7.2 Hz), 1.59 (1H, dd, J = 14.0, 5.0 Hz), 1.27 (3H, t, J = 7.2 Hz), 1.16 (3H, s), 1.07 (9H, s), 1.07 (3H, d, J = 6.8 Hz), 0.84 (9H, t, J = 7.7 Hz) , 0.47 (6H, q, J = 7.7 Hz); 13C NMR (100 MHz, CDCl3) δ 167.7, 156.4, 135.7, 133.4, 129.6, 127.6, 118.6, 76.0, 70.4, 60.0, 45.8, 32.5, 26.9, 26.0, 21.9, 19.2, 14.3, 7.0, 6.7; ESIMS (positive) m/z 591 (M+Na)+; HRESIMS (positive) m/z 591.3290 [(M+Na)+, calcd for C33H52O4Si2Na, 591.3296]. The ethyl ester (419 mg, 0.736 mmol) was dissolved in CH2Cl2 (15 mL), and DIBAL (1.0 M solution in n-hexane, 2.2 mL, 2.2 mmol) was slowly added to the solution at -45 °C. After the solution was stirred for 30 min at -78 °C, the reaction was quenched with MeOH (2 mL) and saturated aqueous Rochelle solution (20 mL), and the resultant mixture was stirred for 30 min at room temperature. The reaction mixture was extracted with EtOAc (3 × 40 mL), washed with brine (15 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/Et2O 50:1→30:1→10:1, n-hexane/EtOAc 10:1) to yield allylic alcohol 20 (332 mg, 0.631 mmol, 86%) as a colorless oil; [α]D20 +25.5 (c 0.87, CHCl3); IR (neat) νmax 3347, 2956, 2875, 1459, 1428, 1113, 1011 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.67-7.64 (4H, m), 7.45-7.36 (6H, m), 5.62 (1H, ddt, J = 15.8, 8.4, 1.2 Hz), 5.48 (1H, dt, J = 15.6, 5.7 Hz), 3.96 (2H, dd, J = 5.7, 1.2 Hz), 3.50 (1H, d, J = 9.5 Hz), 3.36 (1H, d, J = 9.5 Hz), 2.42 (1H, m), 1.67 (1H, dd, J = 14.0, 7.2 Hz), 1.52 (1H, dd, J = 14.0, 4.5 Hz), 1.20 (3H, s), 1.07 (9H, s), 1.02 (3H, d, J = 6.8 Hz), 0.88 (9H, t, J = 8.0 Hz), 0.50 (6H, q, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 140.8, 135.7, 133.7, 133.6, 129.6, 126.1, 76.2, 70.2, 63.9, 46.3, 32.2, 26.9, 26.6, 22.9, 19.2, 7.1, 6.8; ESIMS (positive) m/z 549 (M+Na)+; HRESIMS (positive) m/z 549.3191 [(M+Na)+, calcd for C31H50O3Si2Na, 549.3191].

Diol 21. Titanium (IV) isopropoxide (110 µL, 0.372 mmol) was added to a stirred suspension of crushed molecular sieves 4A (100 mg) in CH2Cl2 (3 mL) containing diethyl (+)-tartrate (88 mg, 0.427 mmol) at -30 °C. After 10 min, a solution of allylic alcohol 20 (162 mg, 0.308 mmol) in CH2Cl2 (1.0 mL) was added dropwise, and the mixture was stirred for 30 min. Then a 3.8 M toluene solution of tert-butyl hydroperoxide (TBHP, 250 µL, 0.950 mmol) was added and the whole was stirred for 4 h at -30 °C. The reaction was quenched by addition of 10% aqueous tartric acid (1.0 mL) and the mixture was filtered with Celite pad. The filtrate was diluted with Et2O and washed with H2O, and the organic layer was concentrated. The residue in Et2O (5 mL) was treated with 1 M aqueous NaOH (2 mL) at 0 °C for 1 h. The reaction mixture was diluted with Et2O (20 mL), washed with H2O (3 × 4 mL) and brine (3 mL), dried over Na2SO4, and concentrated under reduced pressure. Purification by silica gel column chromatography (n-hexane/EtOAc 20:1→15:1→10:1→5:1) afforded epoxide (107 mg, 0.197 mmol, 64%, dr 17:1) as a colorless oil; [α]D20 +4.7 (c 2. 71, CHCl3); IR (neat) νmax 3412, 2956, 2875, 1459, 1428, 1112, 1011 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.69-7.65 (4H, m), 7.45-7.36 (6H, m), 3.89 (1H, dd, J = 12.5, 2.5 Hz), 3.57 (1H, dd, J = 12.5, 4.8 Hz), 3.51 (1H, d, J = 9.5 Hz), 3.37 (1H, d, J = 9.5 Hz), 2.96 (1H, m), 2.85 (1H, dd, J = 5.9, 2.3 Hz), 1.82 (1H, dd, J = 13.7, 4.8 Hz), 1.76 (1H, m), 1.48 (1H, dd, J = 13.7, 6.3 Hz), 1.25 (3H, s), 1.08 (9H, s), 0.97 (3H, d, J = 6.8 Hz), 0.86 (9H, t, J = 7.9 Hz), 0.48 (6H, q, 7.9 Hz); 13C NMR (100 MHz, CDCl3) δ 135.7, 133.5, 129.6, 127.6, 76.1, 70.3, 62.1, 60.7, 56.8, 43.5, 30.5, 26.9, 26.2, 19.2, 17.6, 7.0, 6.8; ESIMS (positive) m/z 565 (M+Na)+; HRESIMS (positive) m/z 565.3136 [(M+Na)+, calcd for C31H50O4Si2Na, 565.3140]. A solution of the epoxide (53 mg, 98 µmol) in MeOH/THF (5:1, v/v, 1.2 mL) was treated with CSA (5.6 mg, 24 µmol) at 0 °C for 2.5 h. After addition of saturated aqueous NaHCO3 (3 mL), the whole was extracted with EtOAc (3 × 25 mL), washed with brine (3 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/EtOAc 8:1→6:1→4:1→2:1→1:1) to separate the minor isomer and diol 21 (36 mg, 84 µmol, 86%). 21: colorless oil; [α]D20 -4.6 (c 1.55, CHCl3); IR (neat) νmax 3390, 2967, 2930, 2858, 1112 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.69-7.67 (4H, m), 7.45-7.36 (6H, m), 3.73 (2H, m), 3.67 (1H, m), 3.53 (1H, d, J = 10.4 Hz), 3.48 (1H, d, J = 10.4 Hz), 2.55 (1H, m), 2.38 (1H, brs), 1.80 (1H, dd, J = 12.7, 7.7 Hz), 1.73 (1H, dd, J = 12.7, 6.8 Hz), 1.19 (3H, s), 1.07 (9H, s), 1.03 (3H, d, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 135.7, 135.6, 133.4, 133.3, 129.7, 127.7, 127.6, 83.0, 81.5, 70.7, 70.3, 65.4, 41.5, 35.1, 26.8, 24.2, 19.3, 15.0; ESIMS (positive) m/z 451 (M+Na)+; HRESIMS (positive) m/z 451.2283 [(M+Na)+, calcd for C25H36O4SiNa, 451.2275].
Olefin 5. To a solution of diol 21 (21 mg, 49 µmol) in MeCN/H2O (3:2, v/v, 0.6 mL) cooled to 0 °C was added NaIO4 (21 mg, 98 µmol), and the resulting solution was stirred at 0 °C for 30 min. The reaction was diluted with H2O (3 mL), extracted with EtOAc (3 × 8 mL), washed with brine (3 mL), dried over Na2SO4, filtered, and concentrated to afford crude aldehyde. To a solution of sulfone 8 (20 mg, 72 µmol) in 1,2-demthoxyethane (0.45 mL) was added KHMDS (0.7 M in toluene, 0.1 mL, 70 µmol) dropwise at -78 °C. After the solution was stirred for 15 min at -78 °C, a solution of crude aldehyde (19 mg) in 1,2-demthoxyethane (0.4 mL) was added dropwise, and the mixture was stirred for 30 min at -78 °C. The reaction was quenched by addition of saturated aqueous NH4Cl (3 mL) and extracted with EtOAc (3 × 8 mL). Combined organic extracts were washed with brine (3 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (n-hexane/Et2O 150:1→100:1→50:1→30:1→20:1) afforded olefin (13 mg, 29 µmol, 59% for the two steps, E/Z 9:1) as a colorless oil; [α]D20 -4.2 (c 0.80, CHCl3); IR (neat) νmax 2963, 2929, 2858, 1459, 1428, 1112 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.71-7.69 (4H, m), 7.42-7.38 (6H, m), 5.58 (1H, dt, J = 14.9, 6.9 Hz), 5.46 (ddt, J = 14.8, 8.0, 1.1 Hz), 4.70 (1H, s), 4.67 (1H, s), 4.43 (1H, dd, J = 7.8, 7.4 Hz), 3.56 (2H, s), 2.66 (2H, dd, J = 6.6, 6.6 Hz), 2.50 (1H, m), 1.82 (1H, m), 1.77 (1H, m), 1.67 (3H, brs), 1.23 (3H, s), 1.07 (9H, s), 0.89 (3H, d, J = 7.2 Hz); 13C NMR (125 MHz, CDCl3) δ 144.5, 135.7, 133.7, 133.5, 130.5, 130.2, 129.5, 127.6, 110.7, 82.9, 82.8, 70.9, 41.6, 40.8, 36.6, 26.9, 24.6, 22.4, 19.3, 15.2; ESIMS (positive) m/z 471 (M+Na)+; HRESIMS (positive) m/z 471.2701 [(M+Na)+, calcd for C29H40O2SiNa, 471.2690]. To a solution of the above olefin with TBDPS group (5.0 mg, 11 µmol) in THF (0.5 mL) at 0 °C was added TBAF (1.0 M solution in THF, 15 µL, 15 µmol). The reaction mixture was stirred at room temperature for 28 h, treated with saturated aqueous NH4Cl (2 mL), and extracted with EtOAc (3 × 8 mL). Combined organic extracts were washed with brine (3 mL), dried over Na2SO4, filtered, and concentrated.
The residue was purified by silica gel column chromatography (n-hexane/EtOAc 10:1→8:1→6:1→4:1) to separate Z isomer and olefin 5 (2.0 mg, 9.5 µmol, 77%). 5: colorless oil; [α]D25 –3.6 (c 0.8, MeOH); IR (neat) νmax 3440, 2938, 2868, 1465, 1103 cm-1; 1H NMR (Table 1); 13C NMR (Table 2); ESIMS (positive) m/z 233 (M+Na)+; HRESIMS (positive) m/z 233.1519 [(M+Na)+, calcd for C13H22O2Na, 233.1517].
Alcohol 22. To a solution of alcohol 13 (121 mg, 0.292 mmol) and i-Pr2NEt (0.76 mL, 4.4 mmol) in CH2Cl2 (5 mL) cooled to 0 °C was added MOMCl (0.22 mL, 2.92 mmol), and the resulting solution was stirred at room temperature for 17 h. The reaction was quenched by addition of saturated aqueous NH4Cl (8 mL), and the resulting mixture was extracted with Et2O (3 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (n-hexane/Et2O 15:1→10:1→7:1) to afford MOM ether (129 mg, 0.281 mmol, 96%) as a colorless oil; [α]D25 +7.5 (c 1.04, CHCl3) IR (neat) νmax 2939, 2866, 1463, 1099, 1039 cm-1; 1H NMR (500 MHz, CDCl3) δ 4.63 (2H, s), 4.24 (1H, m), 4.07 (1H, dd, J = 8.0, 5.8 Hz), 3.73 (1H, m), 3.52 (3H, m), 3.37 (3H, s), 1.93 (1H, ddd, J = 13.9, 6.2, 6.2 Hz), 1.72 (4H, m), 1.58 (8H, m), 1.38 (2H, m), 1.10-0.98 (21H, m), 0.93 (3H, d, J = 6.3 Hz); 13C NMR (100 MHz, CDCl3) δ 109.0, 95.2, 73.6, 72.5, 69.4, 68.2, 55.6, 38.2, 38.0, 36.7, 35.3, 32.7, 25.2, 24.0, 23.9, 18.0, 17.3, 12.0; ESIMS (positive) m/z 481 (M+Na)+; HRESIMS (positive) m/z 481.3313 [(M+Na)+, calcd for C25H50O5SiNa, 481.3320]. To a solution of MOM ether with TIPS group (125 mg, 0.274 mmol) in THF (3.5 m) at 0 °C was added TBAF (1.0 M solution in THF, 0.41 mL, 0.41 mmol). The reaction mixture was stirred at room temperature for 3 h, treated with saturated aqueous NH4Cl (3 mL), and extracted with EtOAc (3 × 15 mL). Combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification by column chromatography on silica gel (n-hexane/EtOAc 5:1→4:1→3:1→2:1→1:1) gave alcohol 22 (86.0 mg, 0.274 mmol, quantitative) as a colorless oil; [α]D22 -2.6 (c 0.91, CHCl3) IR (neat) νmax 3445, 2935, 2865, 1448, 1098, 1037 cm-1; 1H NMR (500 MHz, CDCl3) δ 4.65 (2H, s), 4.21 (1H, m), 4.06 (1H, dd, J = 7.7, 6.0 Hz), 3.84 (1H, m), 3.51 (2H, m), 3.45 (1H, dd, J = 17.2, 6.3 Hz), 3.38 (3H, s), 2.35 (1H, brs), 1.94 (1H, ddd, J = 14.3, 7.5, 5.8 Hz), 1.84 (1H, m), 1.73 (1H, dt, J = 14.2, 5.9 Hz), 1.67 (1H, ddd, J = 14.3, 7.5, 5.7 Hz), 1.58 (8H, m), 1.51 (1H, dt, J = 14.2, 5.9 Hz), 1.39 (2H, m), 0.93 (3H, d, J = 6.9 Hz); 13C NMR (100 MHz, CDCl3) 109.4, 95.4, 73.7, 72.4, 69.3, 68.1, 55.7, 38.3, 37.8, 36.6, 35.3, 32.1, 25.1, 24.0, 23.9, 17.8; ESIMS (positive) m/z 325 (M+Na)+; HRESIMS (positive) m/z 325.1985 [(M+Na)+, calcd for C16H30O5Na, 325.1986].

Ketone 23. To a solution of alcohol 22 (43.0 mg, 0.141 mmol) in pyridine/CH2Cl2 (1:9, v/v, 2 mL) was added Dess-Martin periodinane (150 mg, 0.353 mmol). After being stirred at room temperature for 25 min, the reaction mixture was treated with saturated aqueous Na2S2O3 (4 mL) and extracted with Et2O (3 × 20 mL). The combined organic layers were washed with 3 M aqueous HCl (10 mL), saturated aqueous NaHCO3 (10 mL), and brine (10 mL), dried over Na2SO4, filtered, and concentrated to afford crude aldehyde. To a stirred solution of the crude aldehyde (51 mg) in THF (1 mL) cooled to 0 °C was added a solution of MeMgBr (3.0 M solution in THF, 0.11 mL, 0.33 mmol). After 1 h at 0 °C, the reaction mixture was quenched with saturated aqueous NH4Cl (4 mL) and the resulting mixture was extracted with EtOAc (3 × 10 mL). Combined organic extracts were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated. The residual oil was passed through silica gel pad (n-hexane/EtOAc 5:1→4:1→3:1→2:1→1:1) to remove reagents. To a solution of the diastereomeric mixture of alcohols (40 mg) in pyridine/CH2Cl2 (1:9, v/v, 1.8 mL) was added Dess-Martin periodinane (134 mg, 0.316 mmol). After being stirred at room temperature for 30 min, the reaction mixture was treated with saturated aqueous Na2S2O3 (4 mL) and extracted with Et2O (3 × 10 mL). The combined organic layers were washed with 3 M aqueous HCl (10 mL), saturated aqueous NaHCO3 (10 mL), and brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification by silica gel column chromatography (n-hexane/EtOAc 10:1→7:1→5:1→3:1→1:1) afforded ketone 23 (36.0 mg, 0.113 mmol, 80% for the three steps) as a colorless oil; [α]D23 -1.0 (c 0.99, CHCl3) IR (neat) νmax 2936, 2855, 1714, 1448, 1363, 1101, 1036 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.65 (2H, s), 4.21 (1H, m), 4.06 (1H, dd, J = 7.8, 5.9 Hz), 3.64 (1H, m), 3.50 (1H, t, J = 7.8 Hz), 3.36 (3H, s), 2.77 (1H, m), 2.17 (3H, s), 2.01 (1H, ddd, J = 14.3, 8.8, 4.5 Hz), 1.93 (1H, ddd, J = 14.3, 7.0, 5.4 Hz), 1.68 (1H, dt, J = 14.4, 5.7 Hz), 1.59 (8H, m), 1.52 (1H, dt, J = 7.2, 4.7 Hz), 1.39 (2H, m), 1.11 (3H, d, J = 7.3 Hz); 13C NMR (100 MHz, CDCl3) δ 212.3, 109.3, 95.8, 73.7, 72.2, 69.3, 55.8, 43.1, 38.4, 37.4, 36.7, 35.3, 28.4, 27.5, 25.1, 24.0, 17.2; ESIMS (positive) m/z 337 (M+Na)+; HRESIMS (positive) m/z 337.1984 [(M+Na)+, calcd for C17H30O5Na, 337.1996].
Olefin 24. To a cooled mixture of methyltriphenylphosphonium bromide (297 mg, 0.833 mmol) in THF (3.5 mL) was added n-BuLi (2.5 M solution in n-hexane, 0.33 mL, 0.83 mmol), and the reaction mixture was stirred at 0 °C for 30 min. To the reaction mixture was added a solution of ketone 23 (36.0 mg, 113 µmol) in THF (3 mL) dropwise at 0 °C. After the reaction mixture was stirred for 3.5 h at room temperature, the reaction was quenched by addition of saturated aqueous NH4Cl (5 mL) and the resulting mixture was extracted with Et2O (3 × 15 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated. Purification by silica gel column chromatography (n-hexane/Et2O 10:1→7:1→5:1, n-hexane/EtOAc 7:1→5:1→3:1) afforded olefin 24 (30 mg, 96 µmol, 85%) as a colorless oil; [α]D23 +19 (c 0.79, CHCl3) IR (neat) νmax 2935, 2865, 1448, 1365, 1103, 1039 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.73 (2H, m), 4.62 (2H, s), 4.21 (1H, ddd, J = 13.3, 7.3, 6.0 Hz), 4.06 (1H, dd, J = 7.8, 6.0 Hz), 3.61 (1H, m), 3.49 (1H, t, J = 7.8 Hz), 3.37 (3H, s), 2.41 (1H, m), 1.92 (1H, ddd, J = 14.2, 7.2, 5.3 Hz), 1.69 (1H, m), 1.66 (3H, s), 1.63 (1H, m), 1.58 (8H, m), 1.49 (1H, ddd, J = 14.2, 8.7, 5.3 Hz), 1.38 (2H, m), 1.02 (3H, d, J = 6.9 Hz); 13C NMR (100 MHz, CDCl3) δ 149.3, 110.3, 109.1, 96.2, 74.3, 72.4, 69.5, 55.7, 39.9, 38.8, 37.6, 36.6, 35.3, 25.2, 24.0, 23.9, 20.4, 18.5; ESIMS (positive) m/z 335 (M+Na)+; HRESIMS (positive) m/z 335.2193 [(M+Na)+, calcd for C18H32O4Na, 335.2193].
Triol 25. To a solution of 24 (10.0 mg, 32.3 µmol) in MeOH (1 mL) was added TsOH·H2O (32.0 mg, 0.168 mmol) and the mixture was stirred at room temperature for 22 h. The reaction mixture was diluted with CHCl3 (4 mL) and passed through silica gel pad to remove reagents. The resultant mixture was concentrated, and the residue was purified by column chromatography on silica gel (n-hexane/acetone 1:1→1:3→1:5, MeOH) to afford 25 (0.58 mg, 3.1 µmol, 10 %) as a colorless oil; [α]D20 -16.8 (c 0.11, MeOH) IR (neat) νmax 3334, 2924, 1651, 1467 cm-1; 1H NMR (600 MHz, C6D6) δ 4.96 (1H, s), 4.88 (1H, s), 3.96 (1H, m), 3.90 (1H, m), 3.64 (1H, dd, J = 11.3, 3.3 Hz), 3.52 (1H, dd, J = 11.3, 6.6 Hz), 2.62 (1H, dt, J = 21.6, 6.9 Hz), 1.68 (3H, s), 1.66 (1H, m), 1.51 (2H, m), 1.44 (1H, dt, J = 14.4, 3.0 Hz), 1.10 (3H, d, J = 7.2 Hz); 13C NMR (150 MHz, C6D6) δ 149.5, 110.7, 72.7, 69.9, 67.0, 43.6, 40.3, 37.8, 20.6, 18.8; ESIMS (positive) m/z 211 (M+Na)+; HRESIMS (positive) m/z 211.1308 [(M+Na)+, calcd for C10H20O3Na, 211.1305].
Triol 26: colorless oil; [α]D20 -25.6 (c 0.08, MeOH) IR (neat) νmax 3353, 2923, 1732, 1467 cm-1; 1H NMR (600 MHz, C6D6) δ 4.86 (1H, s), 4.78 (1H, s), 4.40 (1H, m), 3.97 (1H, m), 3.57 (1H, dd, J = 10.8, 3.0 Hz), 3.50 (1H, dd, J = 10.8, 7.2 Hz), 2.40 (1H, dt, J = 21.0, 6.9 Hz), 1.69 (3H, s), 1.57 (1H, ddd, J = 14.1, 8.7, 2.7 Hz), 1.42 (2H, ddd, J = 14.3, 9.2, 3.2 Hz), 1.29 (1H, ddd, J = 14.1, 7.2, 4.8 Hz), 1.04 (3H, d, J = 7.2 Hz); 13C NMR (150 MHz, C6D6) δ 150.8, 109.9, 69.8, 67.5, 67.2, 43.3, 40.0, 38.4, 19.6, 19.1; ESIMS (positive) m/z 211 (M+Na)+; HRESIMS (positive) m/z 211.1311 [(M+Na)+, calcd for C10H20O3Na, 211.1305].
Triol 30: colorless oil; [α]D22 -23.4 (c 0.11, MeOH); IR (neat) 3396, 2923, 1641, 1445, 1085 cm-1; 1H NMR (600 MHz, C6D6) δ 4.88 (1H, br s), 4.81 (1H, br s), 4.04 (1H, m), 3.91 (1H, m), 3.70 (1H, m), 3.57 (1H, m), 2.50 (1H, m), 1.70 (3H, brs), 1.64 (1H, m), 1.60 (1H, m), 1.35 (1H, m), 1.25 (1H, m), 1.03 (3H m); 13C NMR (150 MHz, C6D6) δ 150.8, 109.8, 72.9, 70.4, 67.0, 43.7, 39.9, 38.0, 19.5, 19.1; ESIMS (positive) m/z 211 (M+Na)+; HRESIMS (positive) m/z 211.1309 [(M+Na)+, calcd for C10H20O3Na, 211.1305].
Triol 31: colorless oil; [α]D23 -99.4 (c 0.15, MeOH); IR (neat) 3400, 2925, 1645, 1455, 1085 cm-1; 1H NMR (600 MHz, C6D6) δ 4.98 (1H, br s), 4.90 (1H, br s), 4.17 (1H, m), 4.05 (1H, m), 3.72 (1H, dd, J = 11.1, 2.9 Hz), 3.63 (1H, dd, J = 11.1, 7.6 Hz), 2.64 (1H, m), 1.71 (3H, brs), 1.63 (1H, m), 1.55 (2H, m), 1.39 (1H, m), 1.14 (3H, d, J = 6.9 Hz); 13C NMR (150 MHz, C6D6) δ 149.6, 110.7, 69.8, 67.4, 66.9, 43.2, 40.6, 38.2, 20.6, 18.8; ESIMS (positive) m/z 211 (M+Na)+; HRESIMS (positive) m/z 211.1307 [(M+Na)+, calcd for C10H20O3Na, 211.1305].

ACKNOWLEDGEMENTS
The authors thank Ms. S. Oka and Ms. A. Tokumitsu, Center of Instrumental Analysis, Hokkaido University, for measurements of MS data.

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