General information

IR spectra were recorded on a JASCO FT/ IR -4100 spectrometer using an ATR (ZnSe) attachment. NMR spectra were recorded with TMS as an internal standard in CDCl3 by a Varian 400-MRTT spectrometer (400 MHz for ¹H and 100 MHz for ^{1 3}C) or a Varian 600TT spectrometer (600 MHz for ¹H and 150 MHz for ^{1 3}C). Optical rotation values were measured with a JASCO P -2200 polarimeter. Mass spectra were obtained with a JEOL JMS700 double-focusing magnetic sector mass spectrometer operated in the EI or FAB mode. Melting points were determined with a Yanaco MP-J3 apparatus and are uncorrected. Kanto Chemical silica gel 60N (spherical neutral, 40−50 μm or 63-210 μm) was used for column chromatography. Analytical thin-layer chromatography was performed using Merck silica gel 60 F2 5 4 plates (0.25 mm thick). Solvents for reactions were distilled prior to use: THF and Et2O from Na and benzophenone; CH2Cl2 from CaH2; MeOH from Mg(OMe)2. All airor moisture-sensitive reactions were conducted under a nitrogen atmosphere

62 3.1.1 2.3に関する実験

Ethyl 5-methyl-1H-pyrrole-2-carboxylate (37).

To a stirred solution of ethyl 3-oxobutanoate (42) (47.5 mL, 376 mmol) in THF (133 mL) was added a solution of sodium nitrite (31.2 g, 455 mmol) in water (47 mL) at 0 °C. The reaction mixture was stirred for 30 min at 0 °C and another 13 h at room temperature. 4,4-dimethoxy-2-butanone (41) (27.0 mL) and zinc powder (54.2 g) were sequentially added, and the reaction mixture was stirred for 10 min at 120 °C. After gradually cooling in room temperature, the reaction mixture was stirred for 2 h at 0 °C. The resulting solid was collected by filtration and washed with water. The collected solid was dissolved in acetone and dried using Na2SO4. The filtrate was concentrated to give 27 as a pale yellow solid (33%, 10.3 g); ¹H NMR (400 MHz, CDCl3) δ 1.35 (t, J = 7.2 Hz, 3H), 2.31 (s, 3H), 4.30 (q, J = 7.2 Hz, 2H), 5.94-5.96 (m, 1H), 6.81-6.82 (m, 1H).

Ethyl 3,4-dichloro-5-(chloromethyl)-1H-pyrrole-2-carboxylate (40).

To a stirred solution of 37 (11.7 g, 76.4 mmol) in carbon tetrachloride (58 mL) was added dropwise sulfuryl chloride (24 ml, 296 mmol) over 30 min at 0 °C. The reaction mixture was stirred for 1.5 h at 0 °C. The resulting solid was then collected by filtration, washed with cold carbon tetrachloride to give 40 as a pale brown solid (80%, 15.7 g); ¹H NMR (400 MHz, CDCl3) δ 1.41 (t, J = 7.2 Hz, 3H), 4.41 (q, J = 7.2 Hz, 2H), 4.62 (s, 2H).

Ethyl 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylate (38).

To a stirred solution of 40 (17.5 g, 68.2 mmol) in N-methylpyrrolidone (55 mL) was added sodium cyanoborohydride (5.15 g, 81.0 mol). The reaction mixture was stirred for 3 h at 20 h at room temperature. The resulting mixture was diluted with methyl tert-butyl ether, washed with satd aq NaCl dried (Na2SO4), and concentrated to give 38 as a pale yellow solid (82 %, 12.4 g); ¹H NMR (400 MHz, CDCl3) δ 1.39 (t, J = 7.2 Hz, 3H), 2.29 (s, 3H), 4.36 (q, J = 7.2 Hz, 2H).

3,4-Dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (39).

To a stirred solution of 38 (1.78 g, 8.02 mmol) in THF (13 ml) was added a solution of lithium hydroxide monohydrate (1.02g, 24.3 mmol) in H2O (4.5 ml). The reaction mixture was stirred for 20 h at 80 °C. The reaction mixture was cooled to 0 °C, acidified with 2M hydrochloric acid. The reaction mixture

63

was stirred for another 1 h at 0 °C. The resulting mixture was diluted with EtOAc and washed with brine. The organic layer was dried using MgSO4. The organic layer was dried (Na2SO4), concentrated in vacuo and washed with hexane to give 39 as a pale brown solid (82%, 1.27 g); ¹H NMR (400 MHz, CD3OD) δ 2.22 (s, 3H).

76: ¹H NMR (600 MHz, CDCl3) δ 2.25 (s, 3H), 3.81 (s, 3H), 4.60 (d, J = 6.0 Hz, 1H), 4.76 (s, 1H), 6.98 (t, J = 5.4 Hz, 1H), 6.87-6.90 (m, 2H), 7.25-7.27 (m, 2H); ¹³C{¹H} NMR (150 MHz, CDCl3) δ 11.2, 42.9, 55.3, 110.2, 111.1, 114.2, 118.3, 128.3, 128.8, 129.9, 159.1, 159.5; HRMS (FAB) m/z calcd for C14H15Cl2N2O2 ([M+H]⁺) 313.0505, found 313.0510.

3,4-dichloro-5-methyl-N-((3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1H-pyrrole-2-carboxamide (46).

The reaction mixture of 39 (51.5 mg, 0.265 mmol), D-glucosamine hydrochloride (47) (83.6 mg, 0.388 mmol), HOBt (35.3 mg, 0.261 mmol) and Na2CO3 (82.6 mg, 0.779 mmol) in THF (1 ml) was stirred for 2 h at room temperature. To a stirred solution was added EDC·HCl (89.5 mg, 0.467 mmol). After 36 h of stirring at room temperature, the mixture was filtered and washed with EtOH and THF. The filtrate was concentrated and purified by SiO2 flash column chromatography (CHCl3/CH3OH = 10:1 to 6:1) to give 46 as a white solid (𝛼-anomer/𝛽-anomer = 92:8) (53.2 mg, 56%); [α]D20

+57.9 (c 0.510, CHCl3); IR  max 3396 (s), 2930 (s), 1632 (s), 1539 (s), 1417 (m), 1296 (m), 1065 (m); ¹H NMR (400 MHz, CD3OD) (𝛼) δ 2.23 (s, 3H), 3.43 (t, J = 9.2 Hz, 1H), 3.71-3.87 (m, 4H), 4.06 (dd, J = 3.2, 10.4 Hz, 1H), 5.19 (d, J = 3.2 Hz, 1H). ¹³C NMR (100 MHz, CD3OD) (𝛼) δ 10.8, 55.5, 62.7, 72.2, 73.3, 73.8, 92.7, 110.6, 112.2, 119.7, 129.5, 161.2; HRMS (FAB) m / z calcd for C12H17Cl2N2O6 ([M+H]⁺) 355.0458 found 355.0467.

((2R,3S,4R,5R)-5-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)-3,4,6-trihydroxytetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate (48).

To a stirred solution of 46 (45.2 mg, 0.089 mmol) in pyridine (350 μL) was added dropwise 0.7 M p-toluenesulfonyl chloride in pyridine (270 μL, 0.189 mmol) over 30 min at 0 °C. The reaction mixture was stirred for 2 h at 0 °C and another 12 h at room temperature. The mixture was diluted with hexane / EtOAc (1:1).

64

The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (CHCl3/CH3OH=6/1) to give 48 as a white solid (𝛼-anomer/𝛽-anomer = 93:7) (37.9 mg, 59%);[α]D20 +55.6 (c 0.350, CHCl3) ; IR  max : 3399 (s), 2932 (s), 1736 (s), 1698 (m), 1634 (s), 1541 (s), 1457 (m), 1250 (s), 1176 (s); ¹H NMR (400 MHz, CD3OD) (𝛼) δ 2.22 (s, 3H), 2.46 (s, 3H), 3.29-3.34 (m, 1H), 3.65 (t, J = 9.6 Hz, 1H), 3.93-3.98 (m, 2H), 4.21 (dd, J = 5.2, J=10.8 Hz, 1 H), 4.29 (dd, J = 2.0, 10.8 Hz, 1H), 5.07 (d, J = 3.6 Hz, 1H), 7.43-7.45 (m, 2H), 7.79-7.81 (m, 2H). ¹³C NMR (100 MHz, CD3OD) (𝛼) δ 10.8, 21.6, 55.2, 70.8, 71.0, 71.8, 73.6, 92.7, 110.6, 112.2, 119.7, 129.1, 129.5, 131.0, 134.3, 146.4, 161.1.; HRMS (FAB) m / z calcd for C19H23Cl2N2O8S ([M+H]⁺) 509.0547, found 509.0551.

3,4-dichloro-N-((1R,2S,3R,4R,5R)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]octan-4-yl)-5-methyl-1H-pyrrole-2-carboxamide (49).

To a stirred solution of 48 (369 mg, 1.09 mmol) in EtOH (5.5 mL) was added DBU (216 μL, 1.44 mmol) at room temperature. After 16 h of stirring at room temperature, the reaction mixture was diluted with hexane / EtOAc (1:1). The organic layer was separated, washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (CHCl3/CH3OH = 10:1) to give 49 as a white solid (196 mg, 80%); [α]D20

+52.7 (c 0.520, CHCl3); IR  max 3389 (s), 2906 (m), 1627 (s), 1535 (s), 1270 (d), 1095 (m); ¹H NMR (400 MHz, CD3OD) δ 2.23 (s, 3H), 3.65-3.73 (m, 3H), 4.07 (d, J = 1.2 Hz, 1H), 4.29 (dd, J = 0.8, 7.2 Hz, 1H), 4.54 (d, J = 5.2 Hz, 1H), 5.36 (s, 1H). ¹³C NMR (100 MHz, CD3OD) δ 10.8, 52.4, 66.2, 71.6, 73.2, 77.4, 101.9, 110.7, 112.5, 119.5, 129.7, 160.1; HRMS (FAB) m / z calcd for C12H15Cl2N2O5 ([M+H]⁺) 337.0353, found 337.0356.

(1R,2S,3R,4R,5R)-4-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)-3-hydroxy-6,8-dioxabicyclo[3.2.1]octan-2-yl pivalate (50).

To a stirred solution of 49 (30.5 mg, 1.09 mmol) in pyridine (0.3 mL) was added pivaloyl chloride (44 μL, 1.44 mmol) at 0 °C. After stirring of 12 h at 0 °C, the reaction mixture was diluted with hexane/ EtOAc (1:1). The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2

flash column chromatography (CHCl3 / CH3OH = 10:1) to give 50 as a white solid (21.3 mg, 56%); [α]D20 +45.6(c 0.520, CHCl3); IR  max 3403 (s), 3226 (s), 2975 (s), 1732 (s), 1631 (s), 1531 (s), 1289 (m), 1136 (m); ¹H NMR (400 MHz, CD3OD) δ 1.14 (1H, s,

65

CH3×3), 2.23 (1H, s, CH3), 3.65 (d, J = 1.6 Hz, 1H), 3.78 (dd, J = 6.0, 7.6 Hz, 1H), 4.04 (d, J = 1.2 Hz, 1H), 4.32 (dd, J = 1.2, 7.6 Hz, 1H), 4.58-4.61 (m, 1H), 4.71 (m, 1H), 5.48 (s, 1H); ¹³C NMR (100 MHz, CD3OD) δ 10.8, 27.3, 39.7, 52.8, 66.6, 70.9, 73.7, 75.2, 102.2, 110.7, 112.1, 119.5, 130.1, 160.3, 178.7; FAB-MS m / z calcd for C17H23Cl2N2O6

([M+H]⁺) 421.0928, found 421.0932.

50a: ¹H NMR (400 MHz, CD3OD) δ 1.24 (s, 9H), 2.23 (s, 3H), 3.66 (d, J = 1.6 Hz, 1H), 3.78 (dd, J = 5.6, 7.6 Hz, 1H), 4.03 (d, J = 0.8 Hz, 1H), 4.19 (dd, J = 0.8, 7.6 Hz, 1H), 4.58 (m, 1H), 4.71 (m, 1H), 4.69 (quin, J = 1.6 Hz, 1H), 5.35 (s, 1H); ¹³C NMR (100 MHz, CD3OD) δ 10.8, 27.3, 39.7, 50.0, 66.3, 69.2, 73.5, 77.3, 101.6, 110.7, 112.6, 119.4, 130.0, 160.0, 178.3.

(1R,2R,3R,4R,5R)-3-allyl-4-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)-3-hydroxy-6,8-dioxabicyclo[3.2.1]octan-2-yl pivalate (44).

To a stirred solution of 50 (100 mg, 0.237 mmol), AZADOL (4.0 mg, 0.026 mmol) and KBr (28.3 mg, 0.238 mmol) in CH2Cl2 (3 ml) and sat.

NaHCO3 aq. (1.5 ml) was added NaClO (Nacalai Tesque, available chlorine: 8.5-13.5%, 1.5 ml) at 0 °C. After stirring of 30 min at 0 °C, the reaction mixture was quenched with Na2S2O3 aq. (30 w/v %). the reaction mixture was diluted with hexane/ EtOAc (1:1). The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo to give crude 33. To a stirred solution of crude 45 in THF (2.3 mL) was added dropwise allylmagnesium chloride (2 M in THF, 0.5 ml) over 20 min at -78 °C. After stirring of 1 h, the reaction mixture was quenched with 2 M HCl aq (1 ml). The reaction mixture was diluted with hexane / EtOAc (1:1). The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was concentrated and purified by SiO2

flash column chromatography (hexane / ether = 1:4) to give 44 as a pale yellow solid (43.1 mg, 39%, 2 steps); ¹H NMR (600 MHz, CDCl3) δ 1.28 (s, 9H), 2.18 (d, J = 3.0 Hz, 1H), 2.32-2.44 (m, 5H), 3.22 (s, 1H), 3.80 (dd, J = 5.4, 7.8 Hz, 1H), 4.33 (d, J = 10.2 Hz, 1H), 4.40 (d, J = 7.8 Hz, 1H), 4.54 (dd, J = 1.8, 5.4 Hz, 1H), 4.70 (s, 1H), 5.12 (dd, J = 1.8, 17.4 Hz, 1H), 5.20 (dd, J = 1.8, 10.2 Hz, 1H), 5.49 (d, J = 1.8 Hz, 1H), 5.68-5.75 (m, 1H), 7.13 (d, J = 10.2 Hz, 1H), 10.03 (s, 1H); ¹³C NMR (100 MHz, CDCl3) δ 11.4, 27.1, 29.3, 38.9, 40.0, 53.2, 66.1, 72.4, 72.7, 74.6, 101.8, 110.6, 111.6, 117.9, 121.0, 128.7, 130.9, 159.0, 177.3; FAB-MS m / z calcd for C20H27Cl2N2O6 ([M+H]⁺) 461.1241, found 461.1246.

66

52: ¹H NMR (600 MHz, CDCl3) δ 1.27 (s, 9H) 2.31 (s, 3H), 2.56-2.57 (m, 2H), 2.82 (s, 1H), 3.76 (dd, J = 4.8, 7.8 Hz, 1H), 4.02 (d, J = 7.8 Hz, 1H), 4.19 (dd, J = 1.2, 9.0 Hz, 1H), 4.48 (dd, J = 1.8, 4.8 Hz, 1H), 4.75 (d, J = 1.8 Hz, 1H), 5.15 (dd, J = 1.8, 17.4 Hz, 1H), 5.21 (dd, J = 1.8, 10.8 Hz, 1H), 5.48 (d, J = 1.2 Hz, 1H), 5.86-5.93 (m, 1H), 7.36 (d, J = 9.6 Hz, 1H), 10.11 (s, 1H); ¹³C NMR (100 MHz, CDCl3) δ 11.4, 27.1, 39.1, 43.0, 54.7, 66.6, 69.9, 73.4, 75.7, 102.5, 110.5, 111.7, 118.0, 120.1, 128.7, 132.4, 159.7, 177.9;

FAB-MS m / z calcd for C20H27Cl2N2O6 ([M+H]⁺) 461.1241, found 461.1247.

(3R,4R)-4-((S)-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)(1,3-dithian-2-yl)methyl)-1,2,4-trihydroxyhept-6-en-3-yl pivalate (61).

To a stirred solution of 44 (25.1 mg, 0.054 mmol) and 1,3-propanedithiol (108.6 mL, 1.08 mol) was added a solution of BF3·OEt2

(30.7 μL, 0.244 mmol) in CH3CN (0.55 mL) at -20 °C. The reaction mixture was stirred for 24 h at room temperature and another 24 h at 40 °C. The reaction mixture was quenched with satd aq NaHCO3 and diluted with EtOAc. The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SIO2 flash column chromatography (hexane / acetone = 2:1) to give 61 as a white solid (22.1 mg, 71%); ¹H NMR (400 MHz, CD3OD) δ 1.27 (s, 9H) 1.68-1.78 (m, 1H) 1.98-2.04 (m, 1H), 2.25 (s, 3H), 2.53-2.55 (m, 2H), 2.69-2.79 (m, 2H), 2.85-2.99 (m, 2H), 3.41 (dd, J = 6.8, 11.6 Hz), 3.52 (dd, J = 3.2, 11.6 Hz), 4.06-4.11 (m, 1H), 4.44 (d, J = 2.4 Hz, 1H), 4.58 (d, J = 2.0 Hz, 1H), 4.98(dd, J = 2.4, 10.4 Hz, 1H), 5.05 (dd, J = 2.0, 16.8 Hz, 1H), 5.25 (d, J = 8.8 Hz, 1H), 5.96-6.07 (m, 1H); ¹³C NMR (100 MHz, CD3OD) δ 10.9, 26.7, 27.7, 31.2, 32.0, 40.2, 41.8, 51.4, 56.4, 64.9, 73.3, 74.0, 79.3, 110.7, 112.3, 117.9, 119.7, 129.8, 135.0, 160.7, 179.5; FAB-MS m / z calcd for C23H35Cl2N2O6S2 ([M+H]⁺) 569.1308, found 569.1317.

(1R,2S)-2-((S)-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)(1,3-dithian-2-yl)methyl)-2-hydroxy-1-(2-thioxo-1,3-dioxolan-4-yl)pent-4-en-1-yl pivalate (65).

1H NMR (400 MHz, CD3OD) δ 1.23 (s, 9H) 1.77-1.84 (m, 1H) 2.01-2.06 (m, 1H), 2.26 (s, 3H), 2.47-2.51 (m, 1H), 2.79-2.84 (m, 2H), 2.87-3.00 (m, 3H), 4.59 (d, J = 3.6 Hz), 4.65 (d, J = 3.6 Hz), 4.81-4.89 (m, 2H), 5.13 (d, J = 10.2 Hz, 1H), 5.27 (dd, J = 0.6, 16.8 Hz, 1H), 5.69(d, J = 1.2 Hz, 1H), 5.73-5.80 (m, 2H).

67

Dimethyl (R)-(3-((4-Methoxybenzyl)oxy)-2-oxobutyl)- phosphonate (70).

To a stirred solution of dimethyl methylphosphonate (7.0 mL, 65 mmol) in THF (100 mL) was added dropwise nBuLi (1.55 M solution in hexane, 38.2 mL, 59.2 mmol) at −78 °C. After 1 h of stirring at −78 °C, a solution of 69 (2.95g, 13.2 mmol) in THF (20 mL) was added, and the mixture was gradually warmed to room temperature. After another 24 h of stirring at room temperature, the reaction mixture was quenched with satd aq NH4Cl and diluted with hexane/EtOAc (1:1). The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/EtOAc = 2:1) to give 70 as a colorless oil (4.08 g, 98%): Rf

0.33 (EtOAc), 0.03 (hexane/EtOAc = 2:1); [α]D27 +19.8 (c 1.31, CHCl3); IR  max 2957 (m), 1722 (s), 1613 (s), 1515 (s), 1252 (s), 1035 (s), 822 (s); ¹ H NMR (600 MHz, CDCl3) δ 1.34 (d, J = 6.6 Hz, 3H), 3.21−3.34 (m, 2H), 3.77 (d, J = 3.6 Hz, 3H), 3.79 (d, J = 3.6 Hz, 3H), 3.81 (s, 3H), 4.05 (q, J = 6.6 Hz, 1H), 4.48 (d, J = 11.4 Hz, 1H), 4.53 (d, J = 11.4 Hz, 1H), 6.88−6.90 (m, 2H), 7.27−7.30 (m, 2H); ¹³ C{¹ H} NMR (150 MHz, CDCl3) δ 16.6, 35.6 (d, ¹ J C,P = 132 Hz), 53.01 (d, ² J C,P = 6.5 Hz), 53.02 (d, ² J C,P = 6.0 Hz), 55.3, 71.7, 80.1 (d, ³ J C,P = 2.6 Hz), 113.9, 129.4, 129.7, 159.4, 204.2 (d, ² J C,P = 6.9 Hz);

HRMS (FAB) m/z calcd for C14H21NaO6P ([M + Na]⁺ ) 339.0968, found 339.0977.

(R,E)-2-((4-Methoxybenzyl)oxy)hex-4-en-3-one (71).

To a stirred suspension of anhydrous lithium chloride (868 mg, 20.5 mmol) in THF (100 mL) was added dropwise a solution of 70 (3.09 g, 9.77 mmol) in THF (30 mL) at room temperature. After 10 min of stirring at room temperature, i-Pr2NEt (3.55 mL, 20.3 mmol) was added, and the resulting mixture was stirred for 25 min. Acetaldehyde (5.80 mL, 104 mmol) was then added dropwise to the mixture at 0 °C, and the stirring was continued for 24 h. The reaction mixture was quenched with satd aq NH4Cl and diluted with hexane/EtOAc (1:1). The organic layer was separated, washed successively with water and brine, dried (Na2SO4), and concentrated in vacuo. The residue (E/Z = ca. 17:1, determined by ¹ H NMR) was purified by SiO2 flash column chromatography (hexane/EtOAc = 5:1) to give 71 as a colorless oil (2.04 g, 89%): Rf 0.43 (hexane/EtOAc = 5:1); [α]D27 +53.6 (c 1.29, CHCl3);

IR  max 2936 (m), 1696 (s), 1628 (s), 1515 (s), 1251 (m), 1036 (m); ¹ H NMR (600 MHz, CDCl3) δ 1.34 (d, J = 6.6 Hz, 3H), 1.93 (dd, J = 1.8, 6.6 Hz, 3H), 3.81 (s, 3H), 4.03 (q, J

= 6.6 Hz, 1H), 4.36 (d, J = 11.4 Hz, 1H), 4.49 (d, J = 11.4 Hz, 1H), 6.54 (qd, J = 1.8, 15.6 Hz, 1H), 6.87−6.90 (m, 2H), 7.07 (qd, J = 6.6, 15.6 Hz, 1H), 7.25−7.28 (m, 2H); ¹³ C{¹ H} NMR (150 MHz, CDCl3) δ 18.0, 18.6, 55.3, 71.5, 79.7, 113.8, 126.1, 129.6, 129.7,

68

144.6, 159.4, 201.3; HRMS (FAB) m/z calcd for C14H18O3Na ([M + Na]⁺ ) 257.1148, found 257.1161.

An analytical sample of the minor isomer was obtained as a colorless oil by concentrating some chromatographic fractions in vacuo.

71a: ¹ H NMR (400 MHz, CDCl3) δ 1.32 (d, J = 6.8 Hz, 3H), 2.17 (dd, J = 2.0, 7.2 Hz, 3H), 3.80 (s, 3H), 3.92 (q, J = 6.8 Hz, 1H), 4.37 (d, J = 11.2 Hz, 1H), 4.50 (d, J = 11.2 Hz, 1H), 6.39 (qd, J = 7.2, 11.6 Hz, 1H), 6.53 (qd, J = 1.6, 11.6 Hz, 1H), 6.86-6.90 (m, 2H), 7.25−7.29 (m, 2H); ¹³ C{¹ H} NMR (100 MHz, CDCl3) δ 16.4, 18.0, 55.4, 71.6, 80.9, 114.0, 123.0, 129.7, 129.9, 146.3, 159.5, 203.6.

(2R,3S,E)-2-((4-Methoxybenzyl)oxy)hex-4-en-3-ol (28).

To a stirred solution of 71 (567 mg, 2.42 mmol) in THF (16.5 mL) was added dropwise a solution of Zn(BH4)2 (0.273M in THF, 13.2 mL, 3.60 mmol) at −20 °C. After 2.5 h of stirring at −20 °C, the reaction mixture was quenched with satd aq NH4Cl and diluted with hexane/ EtOAc (1:1). The organic layer was separated, washed with water, dried (Na2SO4), and concentrated in vacuo. The residue (8/3-epi-8 = ca. 11:1, determined by ¹ H NMR) was purified by SiO2 flash column chromatography (hexane/acetone = 6:1) to give 28 as a colorless oil (440 mg, 77%): Rf

0.27 (hexane/acetone = 6:1); [α]D25 −14.8 (c 1.49, CHCl3); IR  max 3454 (s), 2935 (m), 1613 (s), 1514 (s), 1249 (s), 1080 (s), 1035 (s); ¹ H NMR (600 MHz, CDCl3) δ 1.12 (d, J

= 6.0 Hz, 3H), 1.72 (ddd, J = 0.6, 1.2, 6.6 Hz, 3H), 2.20 (brs, 1H), 3.56 (dq, J = 3.0, 6.0 Hz, 1H), 3.81 (s, 3H), 4.15 (dd, J = 3.0, 7.2 Hz, 1H), 4.46 (d, J = 11.4 Hz, 1H), 4.56 (d, J

= 11.4 Hz, 1H), 5.48 (qdd, J = 1.2, 7.2, 15.0 Hz, 1H), 5.72 (dqd, J = 1.2, 6.6, 15.0 Hz, 1H), 6.87−6.90 (m, 2H), 7.26−7.28 (m, 2H); ¹³ C{¹ H} NMR (150 MHz, CDCl3) δ 14.2, 17.9, 55.3, 70.5, 74.5, 77.3, 113.8, 128.7, 129.27, 129.33, 130.5, 159.2; HRMS (FAB) m/z calcd for C14H20O3Na ([M + Na]⁺ ) 259.1305, found 259.1314.

An analytical sample of the minor diastereomer was obtained as a colorless oil by concentrating some chromatographic fractions in vacuo.

28a: ¹ H NMR (600 MHz, CDCl3) δ 1.14 (d, J = 6.0 Hz, 3H), 1.72 (dd, J

= 1.2, 6.0 Hz, 3H), 2.81 (d, J = 2.4 Hz 1H), 3.37 (qd, J = 6.0, 7.8 Hz, 1H), 3.81 (s, 3H), 3.85 (t, J = 7.8 Hz, 1H), 4.39 (d, J = 11.4 Hz, 1H), 4.61 (d, J = 10.8 Hz, 1H), 5.41 (ddd, J = 1.8, 7.8, 15.6 Hz, 1H), 5.77 (dqd, J = 1.2, 6.6, 15.6 Hz, 1H), 5.88-6.90 (m, 2H), 7.26-7.28 (m, 2H).

69

(1R,2R)-2-((4-Methoxybenzyl)oxy)-1-((2R,3R)-3-methyloxiran-2-yl)propan-1-ol (73).

To a stirred suspension of activated 4 Å molecular sieves (powder, 806 mg) and diisopropyl D-(−)-tartrate (975 mg, 4.16 mmol) in CH2Cl2 (13 mL) was added dropwise Ti(Oi-Pr)4 (1.02 mL, 3.43 mmol) at −40 °C.

After 10 min of stirring at −20 °C, t-BuOOH (5.2 M solution in toluene, 3.96 mL, 20.6 mmol) was added dropwise, and the resulting mixture was stirred for 1 h at −20 °C. A solution of 28 (781 mg, 3.30 mmol) in CH2Cl2 (25 mL) was then added dropwise, and the stirring was continued for 36 h at −20 °C. The reaction mixture was quenched with satd aq NaHCO3 and diluted with hexane/EtOAc (1:1). The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue [dr 4.8:1, determined by ¹ H NMR) was purified by SiO2 flash column chromatography (hexane/EtOAc = 2:1; major spot: Rf 0.27, minor spot: Rf 0.25) to give 73 as a colorless oil (464 mg, 56%): Rf 0.27 (hexane/EtOAc = 2:1); [α]D26 −32.3 (c 1.02, CHCl3); IR  max

3456 (s), 2975 (m), 1613 (s), 1513 (s), 1250 (s), 1090 (s), 1036 (s); ¹ H NMR (600 MHz, CDCl3) δ 1.28 (d, J = 6.0 Hz, 3H), 1.31 (d, J = 5.4 Hz, 3H), 2.26 (d, J = 3.0 Hz, 1H), 2.85 (dd, J = 2.4, 4.8 Hz, 1H), 3.03 (dq, J = 2.4, 5.4 Hz, 1H), 3.62−3.66 (m, 2H), 3.81 (s, 3H), 4.42 (d, J = 11.4 Hz, 1H), 4.59 (d, J = 11.4 Hz, 1H), 6.87− 6.90 (m, 2H), 7.25−7.26 (m, 2H); ¹³ C{¹ H} NMR (150 MHz, CDCl3) δ 14.8, 17.2, 51.8, 55.3, 58.8, 70.4, 72.0, 75.5, 113.9, 129.4, 130.3, 159.3; HRMS (FAB) m/z calcd for C14H20O4Na ([M + Na]⁺) 275.1254, found 275.1263.

An analytical sample of the minor diastereomer [Rf 0.25 (hexane/EtOAc = 2:1)] was obtained as a colorless oil by concentrating some chromatographic fractions in vacuo.

73a: [α]D22 −43.3 (c 0.58, CHCl3); IR  max 3447 (s), 2973 (m), 1613 (s), 1514 (s), 1249 (s), 1090 (s), 1035 (s); ¹ H NMR (600 MHz, CDCl3) δ 1.27 (d, J = 6.0 Hz, 3H), 1.33 (d, J = 5.4 Hz, 3H), 2.15 (d, J = 7.2 Hz, 1H), 2.92 (dd, J = 2.4, 4.2 Hz, 1H), 3.01 (dq, J = 2.4, 5.4 Hz, 1H), 3.45 (ddd, J = 4.2, 5.4 7.2 Hz, 1H), 3.59 (quin, J = 5.4, 6.0 Hz, 1H), 3.81 (s, 3H), 4.45 (d, J = 11.4 Hz, 1H), 4.60 (d, J = 11.4 Hz, 1H), 6.87−6.90 (m, 2H), 7.26−7.28 (m, 2H); ¹³ C{¹ H}

NMR (150 MHz, CDCl3) δ 15.8, 17.2, 52.3, 55.3, 59.4, 70.8, 73.1, 76.1, 113.8, 129.3, 130.4, 159.2; HRMS (FAB) m/z calcd for C14H20O4Na ([M + Na]⁺ ) 275.1254, found 275.1261.

tert-Butyl((1R,2R)-2-((4-methoxybenzyl)oxy)-1-((2S,3R)-3-methyloxiran-2-yl)propoxy)dimethylsilane (27).

To a stirred solution of 73 (453 mg, 1.80 mmol), imidazole (733 mg, 10.8 mmol), and 4- (dimethylamino)pyridine (22 mg, 0.18 mmol) in

70

CH2Cl2 (10 mL) was added TBSCl (1.08 g, 7.17 mmol) at 0 °C. After 4 h of stirring at 0 °C, the reaction mixture was quenched with satd aq NaHCO3 and diluted with hexane/EtOAc (1:1). The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/ EtOAc = 10:1) to give 27 as a colorless oil (696 mg, quant): Rf

0.43 (hexane/EtOAc = 10:1); [α]D25 −2.62 (c 1.04, CHCl3); IR  max 2931 (m), 1614 (s), 1514 (s), 1249 (s), 1103 (s), 837 (s); ¹ H NMR (400 MHz, CDCl3) δ 0.047−0.049 (m, 6H), 0.88 (s, 9H), 1.21 (d, J = 6.4 Hz, 3H), 1.28 (d, J = 5.6 Hz, 3H), 2.75 (dd, J = 2.0, 4.0 Hz, 1H), 2.95 (dq, J = 2.0, 5.6 Hz, 1H), 3.57 (dq, J = 4.0, 6.4 Hz, 1H), 3.66 (t, J = 4.0 Hz, 1H), 3.80 (s, 3H), 4.48 (d, J = 11.6 Hz, 1H), 4.52 (d, J = 11.6 Hz, 1H), 6.85−6.89 (m, 2H), 7.25−7.27 (m, 2H); ¹³ C{¹ H} NMR (100 MHz, CDCl3) δ −4.7, −4.6, 15.3, 17.3, 18.2, 25.8, 51.6, 55.3, 59.6, 70.7, 73.6, 76.7, 113.7, 129.1, 130.9, 159.0; HRMS (FAB) m/z calcd for C20H34NaO4Si ([M + Na]⁺) 389.2119, found 389.2127.

(2S,3S,4S,5R)-2-Azido-4-((tert-butyldimethylsilyl)oxy)-5-((4-methoxybenzyl)oxy) hexan-3-ol (81).

To a solution of 27 (629 mg, 1.72 mmol) in EtOH/H2O (8:1, 13.5 mL) in a pressure bottle (Biotage, microwave reaction vial 354833) were added sodium azide (1.12 g, 17.2 mmol) and trimethylamine hydrochloride (495 mg, 5.18 mmol) at room temperature. The bottle was sealed with a septum, and the mixture was stirred at 100 °C (oil both) for 7 days before being concentrated in vacuo and then diluted with CH2Cl2. The resulting mixture was washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2

flash column chromatography (hexane/EtOAc = 12:1) to give 81 as a colorless oil (402 mg, 57%): Rf 0.23 (hexane/EtOAc = 12:1); [α]D26+13.1 (c 1.40, CHCl3); IR  max 3477 (s), 2933 (m), 2098 (s), 1613 (s), 1250 (s), 1038 (s); ¹ H NMR (600 MHz, CDCl3) δ 0.07 (s, 3H), 0.10 (s, 3H), 0.88 (s, 9H), 1.19 (d, J = 6.6 Hz, 3H), 1.30 (d, J = 6.6 Hz, 3H), 2.31 (d, J = 3.6 Hz, 1H), 3.60 (ddd, J = 3.6, 4.8, 6.6 Hz, 1H), 3.67−3.75 (m, 2H), 3.78 (dd, J = 3.6, 6.6 Hz, 1H), 3.81 (s, 3H), 4.43 (d, J = 11.4 Hz, 1H), 4.52 (d, J = 11.4 Hz, 1H), 6.86−6.89 (m, 2H), 7.25−7.26 (m, 2H); ¹³ C{¹ H} NMR (150 MHz, CDCl3) δ −5.0, −3.9, 13.6, 15.0, 18.2, 26.0, 55.3, 58.2, 70.5, 74.6, 75.4, 75.5, 113.7, 129.3, 130.5, 159.1;

HRMS (FAB) m/z calcd for C20H35N3NaO4Si ([M + Na]⁺) 432.2289, found 432.2295.

An analytical sample of the minor regioisomer was obtained as a colorless oil by concentrating some chromatographic fractions in vacuo.

81a: ¹ H NMR (400 MHz, CDCl3) δ 0.06 (s, 3H), 0.15 (s, 3H), 0.87 (s, 9H), 1.19 (d, J = 6.0 Hz, 3H), 1.24 (d, J = 6.8 Hz, 3H), 2.20 (d, J =

71

1.8 Hz, 1H), 3.65-3.72 (m, 3H), 3.81-3.87 (m, 4H), 4.42 (d, J = 11.2 Hz, 1H), 4.53 (d, J

= 11.2 Hz, 1H), 6.87−6.90 (m, 2H), 7.24−7.26 (m, 2H).

2S,4R,5R)-2-Azido-4-((tert-butyldimethylsilyl)oxy)-5-((4-methoxybenzyl)oxy)hexan-3-one (26).

To a stirred solution of 81 (377 mg, 0.920 mmol) in CH2Cl2 (10 mL) were added pyridine (0.30 mL, 3.72 mmol) and Dess−Martin periodinane (780 mg, 1.84 mmol) at room temperature. After 1 h of stirring at room temperature, the reaction mixture was quenched with satd aq NaHCO3, concentrated in vacuo, and diluted with hexane/EtOAc (1:1). The resulting mixture was washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/EtOAc = 10:1) to give 26 as a colorless oil (371 mg, 99%): Rf 0.50 (hexane/EtOAc = 10:1); [α]D26 +86.4 (c 1.28, CHCl3); IR  max

2933 (m), 2103 (s), 1729 (s), 1614 (s), 1515 (s), 1253 (s), 1107 (s); ¹ H NMR (400 MHz, CDCl3) δ 0.05 (s, 3H), 0.09 (s, 3H), 0.92 (s, 9H), 1.20 (d, J = 6.4 Hz, 3H), 1.36 (d, J = 6.8 Hz, 3H), 3.73 (dq, J = 4.8, 6.4 Hz, 1H), 3.80 (s, 3H), 4.26−4.31 (m, 2H), 4.38 (d, J = 11.2 Hz, 1H), 4.52 (d, J = 11.2 Hz, 1H), 6.85−6.88 (m, 2H), 7.20−7.23 (m, 2H); ¹³ C{¹ H} NMR (100 MHz, CDCl3) δ −5.0, −4.6, 15.6, 15.7, 18.1, 25.8, 55.3, 58.6, 70.8, 77.4, 79.7, 113.7, 129.3, 130.0, 159.2, 208.6; HRMS (FAB) m/z calcd for C20H33N3O4NaSi ([M + Na]⁺) 430.2133, found 430.2137.

(Z)-1-(((2-Bromovinyl)oxy)methyl)-4-methoxybenzene (82).

To a stirred solution of 4-methoxybenzyl vinyl ether (84) (17.00 g, 103.5 mmol) in CH2Cl2 (85 mL) was added dropwise bromine (5.35 mL, 103.8 mmol) over a period of 2 h at −78 °C, and the resulting mixture was stirred for 30 min at −78 °C. Triethylamine (21.7 mL, 155.7 mmol) was then added dropwise to the mixture over a period of 1 h at −78 °C. The reaction mixture was warmed to 0 °C over a period of 2 h. After 2 h of stirring at 0 °C, the reaction mixture was quenched with water at 0 °C, concentrated in vacuo, and diluted with hexane/EtOAc (1:1). The resulting mixture was washed with sat aq NaCl, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 column chromatography (hexane/ EtOAc = 4:1) to give 82 as a pale yellow oil (13.53 g, 54%): Rf 0.52 (hexane/EtOAc = 4:1); IR  max 2934 (m), 1640 (m), 1514 (m), 1249 (m); ¹ H NMR (600 MHz, CDCl3) δ 3.81 (s, 3H), 4.89 (s, 2H), 5.13 (td, J = 1.2, 4.2 Hz, 1H), 6.65 (td, J = 1.2, 4.2 Hz, 1H), 6.89−6.92 (m, 2H), 7.28−7.29 (m, 2H); ¹³ C{¹ H} NMR (150 MHz, CDCl3) δ 55.3, 74.2, 83.1, 114.0, 128.4, 129.3, 146.8, 159.7; HRMS (EI) m/z calcd for C10H11BrO2 (M⁺) 241.9937, found 241.9940.

72

(3S,4R,5R,E)-3-((S)-1-Azidoethyl)-4-((tert-butyldimethylsilyl)oxy)-1,5-bis((4-methoxybenzyl)oxy)hex-1-en-3-ol (25).

To a stirred solution of 82 (104 mg, 0.428 mmol) in Et2O (3 mL) was added dropwise t-BuLi (1.62 M in hexane, 0.565 mL, 0.915 mmol) at −78 °C. After 30 min of stirring, a solution of 26 (110 mg, 0.270 mmol) in Et2O (2 mL) was added dropwise over a period of 15 min at −78 °C. After 30 min of stirring at −78 °C, the reaction mixture was quenched with satd aq NH4Cl and diluted with hexane/EtOAc (1:1). The organic layer was separated, washed with water, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/EtOAc = 7:1) to give 25 as a colorless oil (129 mg, 84%): Rf 0.38 (hexane/EtOAc = 7:1); [α]D25 −8.33 (c 1.21, CHCl3); IR  max

2934 (m), 2116 (s), 1613 (s), 1515 (s), 1251 (s), 1037 (s); ¹ H NMR (600 MHz, CDCl3) δ 0.06 (s, 3H), 0.12 (s, 3H), 0.90 (s, 9H), 1.19 (d, J = 6.6 Hz, 3H), 1.23 (d, J = 6.6 Hz, 3H), 3.64 (q, J = 6.6 Hz, 1H), 3.68 (dq, J = 2.4, 6.6 Hz, 1H), 3.80 (m, 6H), 4.00 (s, 1H), 4.11 (d, J = 2.4 Hz, 1H), 4.26 (d, J = 7.2 Hz, 1H), 4.31 (d, J = 11.4 Hz, 1H), 4.40 (d, J = 11.4 Hz, 1H), 4.70 (d, J = 11.4 Hz, 1H), 4.73 (d, J = 11.4 Hz, 1H), 6.12 (d, J = 7.2 Hz, 1H), 6.83−6.88 (m, 4H), 7.18−7.20 (m, 2H), 7.22−7.24 (m, 2H); ¹³ C{¹ H} NMR (150 MHz, CDCl3) δ −5.1, −3.5, 14.5, 15.3, 18.6, 26.2, 55.2, 55.3, 62.6, 69.8, 74.4, 75.5, 77.9, 80.7, 106.2, 113.5, 114.0, 128.3, 129.0, 129.4, 131.0, 145.5, 158.8, 159.7; HRMS (FAB) m/z calcd for C30H45N3NaO6Si ([M + Na]⁺) 594.2970, found 594.2972.

N-((2S,3S,4R,5R)-4-((tert-Butyldimethylsilyl)oxy)-3-hydroxy-5-((4- methoxybenzyl)oxy)-3-((E)-2-((4-methoxybenzyl)oxy)vinyl)hexan2-yl)-3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamide (66).

To a stirred solution of 25 (44.8 mg, 78.4 μmol) in MeOH (0.78 mL) was added tributylphosphine (46.5 μL, 18.8 μmol) at room temperature. After 12 h of stirring, the mixture was concentrated in vacuo and the residue (containing 85) was dissolved in CH2Cl2 (0.80 mL). To the solution were successively added 39 (16.7 mg, 86.1μmol), triethylamine (13.1 μL, 94.0 μmol), 1-hydroxybenzotriazole monohydrate (12.7 mg, 93.9 μmol), and EDC·HCl (22.6 mg, 11.8 μmol) at 0 °C. The mixture was stirred at 0 °C for 1 h and then at room temperature for an additional 1 h before being quenched with methanol. The mixture was diluted with hexane/EtOAc (1:1), washed with water, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/EtOAc = 5:2) to give 66 as a colorless oil (54.5 mg, 96% from 75): Rf 0.34 (hexane/EtOAc = 5:2); [α]D25 −2.15 (c 0.825, CHCl3); IR  max

73

3204 (s) 2933 (m), 1624(s), 1528 (s), 1251 (s), 1076 (s); ¹ H NMR (600 MHz, CDCl3) δ 0.06 (s, 3H), 0.08 (s, 3H), 0.91 (s, 9H), 1.15 (d, J = 6.0 Hz, 3H), 1.22 (d, J = 6.6 Hz, 3H), 2.21 (s, 3H), 3.66 (qd, J = 6.0, 7.2 Hz, 1H), 3.76 (s, 3H), 3.80 (s, 3H), 4.11 (d, J = 1.2 Hz, 1H), 4.14 (s, 1H), 4.23−4.30 (m, 3H), 4.44 (dq, J = 6.6, 8.4 Hz, 1H), 4.70 (d, J = 12.0 Hz, 1H), 4.74 (d, J = 12.0 Hz, 1H), 6.16 (d, J = 7.2 Hz, 1H), 6.74−6.75 (m, 2H), 6.85−6.86 (m, 2H), 7.09−7.12 (m, 3H), 7.21− 7.23 (m, 2H), 9.71 (s, 1H); ¹³ C{¹ H} NMR (150 MHz, CDCl3) δ −4.9, −3.8, 11.2, 15.3, 16.7, 18.5, 26.1, 49.7, 55.2, 55.3, 69.7, 74.3, 75.3, 78.8, 79.4, 106.4, 110.0, 110.7, 113.3, 113.9, 118.9, 127.3, 128.3, 128.7, 129.4, 131.2, 145.7, 158.6, 158.7, 159.6; HRMS (FAB) m/z calcd for C36H50Cl2NaN2O7Si ([M + Na]⁺) 743.2657, found 743.2665.

An analytical sample of by product was obtained as a colorless oil by concentrating some chromatographic fractions in vacuo.

86: ¹ H NMR (400 MHz, CDCl3) δ 0.03 (s, 6H), 0.88 (s, 9H), 1.18 (d, J = 6.4 Hz, 3H), 1.28 (d, J = 6.8 Hz, 3H), 2.26 (s, 3H), 3.37 (d, J = 7.2 Hz, 1H), 3.55 (d, J = 5.2 Hz, 1H), 3.78-3.84 (m, 4H), 4.30 (d, J = 0.8 Hz, 1H), 4.40 (d, J = 7.6 Hz, 1H), 4.61 (dqd, J = 1.2, 6.8, 9.6 Hz, 1H), 4.70 (d, J = 12.0 Hz, 1H), 4.77 (d, J = 12.0 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 6.86−6.90 (m, 2H), 7.08 (d, J = 9.6 Hz, 1H), 7.24−7.26 (m, 2H), 9.88 (s, 1H)

N-((S)-1-((2R,3R,4R)-3-((tert-Butyldimethylsilyl)oxy)-4,6-dihydroxy-2- methyltetrahydro-2H-pyran-4-yl)ethyl)-3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamide (87).

To a stirred solution of 66 (20.2 mg, 28.0 μmol) in CH2Cl2

(0.45 mL) was added dropwise trifluoroacetic acid (0.05 mL) at −20 °C. After 2 h of stirring at −20 °C, the mixture was gradually warmed to 0 °C over a period of 1 h. The reaction mixture was quenched with satd aq NaHCO3 and diluted with hexane/EtOAc (1:1). The organic layer was separated, washed with water, dried (Na2SO4), and concentrated in vacuo. The residue was purified by repeated SiO2 flash column chromatography (hexane/acetone = 3:1 and then hexane/Et2O = 1:3) to give 87 as a white solid (α-anomer/β-anomer = ca. 1:3) (11.2 mg, 83%): Rf 0.38 (hexane/Et2O = 1:3); [α]D21+60 (c 0.485, CHCl3); IR  max 3231 (s), 2930 (m), 1631 (s), 1536 (s), 1260 (s), 1092 (s); ¹ H NMR (600 MHz, CDCl3) δ 0.17−0.21 (m, 6H), 0.96−0.97 (m, 9H), 1.20−1.22 (m, 3H), 1.29−1.31 (m, 3H), 1.55 (ddd, J = 2.4, 9.0, 13.2 Hz, 1H × 0.75), 1.77 (ddd, J = 2.4, 3.6,

74

13.8 Hz, 1H × 0.25), 1.95 (dd, J = 1.2, 13.8 Hz, 1H × 0.25), 2.01 (dd, J = 1.8, 13.2 Hz, 1H × 0.75), 2.23 (s, 3H × 0.75), 2.25 (s, 3H × 0.25), 2.77 (d, J = 2.4 Hz, OH, 1H × 0.75), 3.41−3.44 (m, 1H + 1H × 0.75), 3.62 (d, J = 2.4 Hz, OH, 1H × 0.25), 3.80 (dq, J = 6.6, 8.4 Hz, 1H × 0.75), 4.05 (dq, J = 6.0, 8.4 Hz, 1H × 0.25), 4.47−4.55 (m, 1H), 5.16−5.20 (m, 1H), 5.50 (d, J = 10.2 Hz, OH, 1H × 0.25), 6.62−6.65 (m, NH, 1H), 9.52 (brs, NH, 1H); ¹³ C{¹ H} NMR (150 MHz, CDCl3) δ −3.42, −3.37, −3.27, −3.26, 11.31, 11.35, 16.3, 18.4, 18.5, 19.1, 19.2, 26.1, 32.1, 35.6, 48.8, 48.9, 64.4, 70.6, 74.1, 74.4, 76.1, 77.5, 91.5, 92.6, 110.4, 110.6, 111.1, 111.3, 118.2, 118.5, 127.5, 127.9, 160.2, 160.4; HRMS (FAB) m/z calcd for C20H34NaCl2N2O5Si ([M + Na]⁺) 503.1506, found 503.1514.

3,4-Dichloro-5-methyl-N-((S)-1-((2R,3R,4R)-3,4,6-trihydroxy-2-methyltetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrrole-2-carboxamide (21).

To a stirred solution of 87 (11.0 mg, 22.8 μmol) in THF (0.2 mL) was added dropwise TBAF (1 M solution in THF, 0.039 mL, 39.0 μmol) at room temperature. After 12 h of stirring, THF (1 mL) and SiO2 (ca. 5 mg) were added to the reaction mixture at 0 °C. The resulting slurry was stirred at room temperature for 1 h and then filtered through a ppad of Celite. The filtrate was concentrated in vacuo, and the residue was purified by SiO2 flash column chromatography (EtOAc/CH3OH = 20:1) to give 21 as a white solid (α-anomer/βanomer = ca. 1:1) (7.9 mg, 94%): Rf 0.56 (EtOAc/MeOH = 20:1) [α]D27 +19 (c 0.225, CHCl3); IR  max 3410 (m), 2926 (m), 1631 (s), 1539 (s), 1081 (s); ¹ H NMR (600 MHz, CDCl3) δ 1.32−1.36 (m, 6H), 1.44 (dd, J = 9.0, 13.2 Hz, 1H × 0.5), 1.69 (dd, J = 3.6, 13.8 Hz, 1H × 0.5), 1.95 (dd, J = 1.2, 13.8 Hz, 1H × 0.5), 1.99 (dd, J = 2.4, 13.2 Hz, 1H × 0.5), 2.27 (d, J = 10.8 Hz, OH, 1H × 0.5), 2.29 (s, 3H × 0.5), 2.31 (s, 3H × 0.5), 2.34 (d, J = 10.8 Hz, OH, 1H × 0.5), 2.84 (d, J = 6.0 Hz, OH, 1H × 0.5), 3.14−3.19 (m, 1H), 3.70 (qd, J = 6.0, 9.0 Hz, 1H × 0.5), 3.99 (qd, J = 6.0, 9.0 Hz, 1H × 0.5), 4.37−4.41 (m, 1H), 5.15 (ddd, J = 2.4, 6.0, 9.0 Hz, 1H × 0.5), 5.22 (dd, J = 3.6, 10.2 Hz, 1H × 0.5), 5.26 (s, OH, 1H × 0.5), 5.58 (d, J = 10.2 Hz, OH, 1H × 0.5), 6.33 (s, OH, 1H × 0.5), 6.59−6.61 (m, NH, 1H), 9.09−9.11 (m, NH, 1H); ¹³ C{¹ H} NMR (150 MHz, CDCl3) δ 11.47, 11.52, 16.3 (2C), 18.1, 18.2, 33.6, 37.5, 52.3, 52.6, 64.7, 70.8, 74.0, 74.1, 76.3, 77.4, 92.2, 93.0, 111.06, 111.11, 112.5, 112.6, 117.3, 117.5, 129.0, 129.2, 161.5, 161.7; HRMS (FAB) m/z calcd for C14H21Cl2N2O5 ([M + H]⁺) 367.0822, found 367.0831.

75

3,4-Dichloro-N-((S)-1-((2R,3R,4R,6S)-3,4-dihydroxy-6-methoxy-2-methyltetrahydro-2H-pyran-4-yl)ethyl)-5-methyl-1H-pyrrole-2-carboxamide (31) and Its β-Anomer (30).

To a stirred solution of 87 (14.0 mg, 29.1 μmol) in MeOH (0.7 mL) was added dropwise TMSCl (3.7 μL, 29.3 μmol) at room temperature. After 62 h of stirring, the mixture was concentrated in vacuo and diluted with CH2Cl2. The resulting solution was washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/EtOAc = 1:3) to give 31 (α-anomer) as a white solid (2.1 mg, 19%) and 30 (β-anomer) as a white solid (5.5 mg, 50%).

31: Rf 0.14 (hexane/EtOAc = 1:3); mp 72 °C; [α]D25 +134 (c 0.02, CHCl3); IR  max 3415 (m), 3217 (m), 2931 (m), 1634 (s), 1538 (s), 1054 (s); ¹ H NMR (600 MHz, CDCl3) δ 1.27 (d, J = 7.2 Hz, 3H), 1.34 (d, J = 6.6 Hz, 3H), 1.82 (dd, J = 3.0, 13.8 Hz, 1H), 1.99 (dd, J = 1.2, 13.8 Hz, 1H), 2.27−2.29 (m, 4H), 3.25 (t, J = 10.2 Hz, 1H), 3.38 (s, 3H), 3.68 (qd, J

= 6.6, 9.6 Hz, 1H), 4.17 (s, OH, 1H), 4.41 (qd, J = 7.2, 7.8 Hz, 1H), 4.84 (d, J = 3.0 Hz, 1H), 6.81 (d, J = 7.8 Hz, NH, 1H), 9.25 (brs, NH, 1H); ¹³ C{¹ H} NMR (150 MHz, CDCl3) δ 11.3, 16.3, 17.9, 34.9, 50.5, 55.2, 65.2, 73.5, 74.2, 98.2, 110.3 110.8, 118.7, 127.5, 159.2;

HRMS (FAB) m/z calcd for C15H23Cl2N2O5 ([M + H]⁺ ) 381.0979, found 381.0983.

30: Rf 0.30 (hexane/EtOAc = 1:3); mp 204 °C; [α]D27

−2.1 (c 0.250, CHCl3); IR  max 3410 (m), 3225 (m), 2933 (m), 1627 (s), 1540 (s), 1081 (s); ¹ H NMR (600 MHz, CDCl3) δ 1.30 (d, J = 7.2 Hz, 3H), 1.35 (d, J = 6.0 Hz, 3H), 1.50 (dd, J = 9.0, 13.2 Hz, 1H), 1.92 (dd, J = 2.4, 13.2 Hz, 1H), 2.28 (s, 3H), 2.54 (d, J = 10.2 Hz, OH, 1H), 3.17 (dd, J = 9.6, 10.2 Hz, 1H), 3.49 (s, 3H), 3.64 (qd, J = 6.0, 9.6 Hz, 1H), 4.43 (dq, J = 6.6, 7.2 Hz, 1H), 4.69 (dd, J = 2.4, 9.0 Hz, 1H), 5.07 (s, OH, 1H), 6.64 (d, J = 6.6 Hz, NH, 1H), 9.62 (brs, NH, 1H); ¹³ C{¹ H} NMR (150 MHz, CDCl3) δ 11.4, 16.1, 18.0, 36.2, 52.5, 56.6, 70.4, 74.1, 76.3, 99.7, 111.0 112.4, 117.3, 128.7, 161.3; HRMS (FAB) m/z calcd for C15H23Cl2N2O5 ([M + H]⁺ ) 381.0979, found 381.0986.

76 3.1.2 2.4に関する実験

2-(((tert-butyldimethylsilyl)oxy)methyl)acrylaldehyde (114).

To a stirred solution of 1,3-dihydroxyacetone dimer (113) (15.0 g, 83.3 mmol) and imidazole (5.72 g, 84.0 mmol) in DMF (80 mL) was added dropwise a solution of TBSCl (8.38 g, 55.6 mmol) in Et2O (20 ml) at

−20 °C. After 12 h of stirring at −20 °C, the reaction mixture was gradually warmed to room temperature. After 6 h of stirring at room temperature, the reaction mixture was quenched with satd aq NaHCO3 and diluted with hexane/EtOAc (1:1). The organic layer was separated, washed with brine. The aqueous layer was extracted with hexane/EtOAc (1:1) (×2), dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2

flash column chromatography (hexane/Et2O = 1:1) to give crude 114 as pale yellow syrup.

To a stirred solution of methyltriphenylphosphonium bromide (20.1 g, 56.3 mmol) of THF (400 mL) was added NaHMDS (1.9 M solution in THF, 25.0 mL, 47.5 mmol) at 0 °C. After 1 h of stirring at 0 °C, to the reaction mixture was added a solution of crude 114in THF (100mL). After 1 h of stirring at 0 °C, the mixture was gradually warmed to room temperature. After 36 h of stirring at room temperature, the reaction mixture was quenched with satd aq NH4Cl and diluted with hexane/Et2O (1:1). The organic layer was separated, washed with brine. The aqueous layer was extracted with hexane/Et2O (1:1) (×2), dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/Et2O = 1:1) to give crude 115 as a pale yellow syrup.

To stirred solution of crude 115 in CH2Cl2 (20 mL) was added MnO2

(11.5 g, 132.3 mmol) at room temperature. After 48 h of stirring at room temperature, the reaction mixture was concentrated in vacuo and passed through a short pad of silica gel (hexane/Et2O = 2:1). The filtrate was concentrated in vacuo and purified by SiO2 flash column chromatography (hexane/Et2O = 2:1) to give 116 as a pale yellow syrup (1.80 g, 16% from TBSCl): Rf 0.83 (hexane/Et2O = 1/1); ¹ H NMR (600 MHz, CDCl3) δ 0.087 (s, 6H), 0.93 (s, 9H), 4.40 (t, J = 1.8 Hz, 2H), 6.11 (dt, J = 1.2, 1.8 Hz, 1H), 6.53 (dt, J = 1.2, 2.4 Hz, 1H), 9.62 (s, 1H).

tert-butyl (E)-4-(((tert-butyldimethylsilyl)oxy)methyl)penta-2,4-dienoate (118).

To a stirred solution of 116 (973 mg, 4.86 mmol) in CH2Cl2 (10 mL) was added 117 (2.38 g, 6.32 mmol) at room temperature.

77

After 12 h of stirring at room temperature, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/Et2O = 8:1) to give 118 as colorless oil (1.04 g, 72%): Rf 0.57 (hexane/Et2O = 8/1); IR  max 2931 (m), 1712 (s), 1635 (s), 1472 (s), 1271 (s), 1154 (s), 839 (s);¹ H NMR (600 MHz, CDCl3) δ 0.086 (s, 6H), 0.92 (s, 9H), 1.50 (s, 9H), 4.32 (t, J = 1.8 Hz, 2H), 5.45 (s, 1H), 5.64 (q, J = 1.8 Hz, 1H), 5.77 (d, J = 16.2 Hz, 1H), 7.23 (d, J = 16.2 Hz, 1H); ¹³ C{¹ H} NMR (150 MHz, CDCl3) δ -5.43, 18.4, 25.9, 28.1, 62.1, 80.4, 119.4, 121.4, 142.8, 143.3, 166.3.

tert-butyl (E)-4-(hydroxymethyl)penta-2,4-dienoate (119).

To a stirred solution of 118 (1.03 g, 3.45 mmol) in CH3OH (3 mL) was added PPTS (173 mg, 0.688 mmol) at room temperature. After 36 h of stirring at room temperature, the reaction mixture was diluted with hexane/Et2O (1:1), filtered and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/Et2O = 1:1) to give crude 119 as pale yellow oil (617 mg, 97%):

Rf 0.37 (hexane/Et2O = 1/1); IR  max 3422 (s), 2978 (m), 1708 (s), 1633 (s), 1315 (s), 1275 (s), 1151 (s), 981 (s); ¹ H NMR (600 MHz, CDCl3) δ 1.49 (s, 9H), 4.35 (s, 2H), 5.49 (s, 1H), 5.61 (d, J = 1.2 Hz, 1H), 5.90 (d, J = 16.2 Hz, 1H), 7.24 (d, J = 16.2 Hz, 1H); ¹³ C{¹ H} NMR (150 MHz, CDCl3) δ 28.1, 62.5, 80.6, 120.6, 122.3, 142.5, 143.5, 166.2.

HRMS (FAB) m/z calcd for C10H17O3 ([M + H]⁺) 185.1172, found 185.1182.

1-(tert-butyl) 7-methyl (E)-4-methylenehept-2-enedioate (120).

To a stirred solution of 119 (166 mg, 0.901 mmol) in trimethyl orthoacetate (2.26 mL, 18.0 mmol) was added propionic acid (27.0 μl, 0.360 mmol) at room temperature. After 24 h of stirring at 100 °C, the reaction mixture was concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/Et2O = 2:1) to give crude 120 as pale yellow syrup (58.7 mg, 27%): Rf 0.60 (hexane/Et2O = 2/1); IR  max 2978 (m), 1739 (s), 1707 (s), 1631 (s), 1438 (s), 1279 (s), 1149 (s), 983 (s); ¹ H NMR (600 MHz, CDCl3) δ 1.50 (s, 9H), 2.51−2.58 (m, 4H), 3.69 (s, 3H), 5.32 (s, 1H), 5.39 (s, 1H), 5.87 (d, J = 16.2 Hz, 1H), 7.21 (d, J = 16.2 Hz, 1H); ¹³ C{¹ H} NMR (150 MHz, CDCl3) δ 26.7, 28.1, 32.5, 51.7, 80.5, 120.3, 123.0, 143.0, 144.8, 166.3, 173.2; HRMS (FAB) m/z calcd for C13H20O4Na ([M + Na]⁺) 263.1254, found 263.1262.

78 Synthesis of 121 from 2,3-dibromopropene (24).

To a stirred suspension of CuI (7.78 g, 40.9 mmol) in THF (60 mL) were added MeOAc (1.62 mL, 20.2 mmol) and NaHMDS (1.9 M in THF, 11.8 mL, 22.4 mmol) at －78 °C. After 30 min of stirring at －78 °C, to the reaction mixture was added a solution of 2,3-dibromopropane (24) (1.0 mL, 9.82 mmol) in THF (20 mL) at －78 °C. After 1 h of stirring at －78 °C, the reaction mixture was gradually warmed to －20 °C over a period for 30 min. After 16 h of stirring at －20 °C, the reaction mixture was quenched with satd aq NaHCO3 and diluted with hexane/Et2O (1:1). The organic layer was separated, washed with brine. The aqueous layer was extracted with hexane/Et2O (1:1) (×2), dried (Na2SO4), and concentrated in vacuo to give crude 121.

To a stirred suspension of crude 121, tri(o-tolyl)phosphine (709 mg, 2.33 mmol) and K2CO3 (1.61 g, 11.6 mmol) in DMF (3.0 mL) in a pressure bottle (Biotage, microwave reaction vial 354833) was added t-Bu acrylate (3.3 mL, 22.8 mmol). After the mixture was deaerated by N2, to the suspension was added Pd(OAc)2 (260 mg, 1.16 mmol) at room temperature. The bottle was sealed with a septum, and the mixture was stirred for 1 h at 80 °C. The reaction mixture was diluted with hexane/Et2O (1:1) and washed with brine. The aqueous layer was extracted with hexane/Et2O (1:1) (×2), dried (Na2SO4), and concentrated in vacuo.

The residue was purified by SiO2 flash column chromatography (hexane/Et2O = 4:1) to give 120 as a yellow syrup (1.54 g, 63%).

tert-butyl (E)-8-(dimethoxyphosphoryl)-4-methylene-7-oxooct-2-enoate (122).

To a stirred solution of dimethyl methylphosphonate (153 μL, 1.43 mmol) in THF (6 mL) was added dropwise n-BuLi (2.67 M solution in hexane, 530 μL, 1.41 mmol) at −78 °C. After 1 h of stirring at －78 °C, to the reaction mixture was added a solution of 120 (201 mg, 0.836 mmol) in THF (6 mL) at －78 °C. After 2 h of stirring at －78 °C, the reaction mixture was gradually warmed to room temperature over a period for 1 h. After 20 h of stirring at room temperature, the reaction mixture was quenched with satd aq NH4Cl and diluted with EtOAc. The organic layer was separated, washed with brine. The aqueous layer was extracted with EtOAc (×2), dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (EtOAc) to give 122 as colorless syrup (255 mg, 92%): Rf 0.30

79

(EtOAc); IR  max 2978 (m), 1710 (s), 1632 (s), 1313 (s), 1259 (s), 1155 (s), 1034 (s), 773 (s); ¹ H NMR (400 MHz, CDCl3) δ 2.52 (t, J = 7.2 Hz, 2H), 2.84 (t, J = 7.6 Hz, 2H), 3.11 (d, J = 22.8 Hz, 2H), 3.78 (s, 3H), 3.81 (s, 3H), 5.32 (s, 1H), 5.38 (s, 1H), 5.84 (d, J = 16.0 Hz, 1H), 7.21 (d, J = 16.0 Hz, 1H); ¹³ C{¹ H} NMR (100 MHz, CDCl3) δ 25.1, 28.1, 40.8, 42.1, 42.3 (d, ¹ J C,P = 7.2 Hz), 53.1 (d, ² J C,P = 25.2 Hz), 80.5, 120.3, 123.2, 142.9, 144.9, 166.3, 200.6 (d, ² J C,P = 25.2 Hz); HRMS (FAB) m/z calcd for C15H26O6P ([M + H]⁺) 333.1462, found 333.1468.

tert-butyl (2E,8E,10E)-4-methylene-7-oxododeca-2,8,10-trienoate (124).

To a stirred solution of dry LiBr (927 mg, 10.7 mmol) in THF (30 mL) was added dropwise a solution of 122 (1.46 g, 4.39 mmol) at room temperature. After 10 min of stirring at room temperature, Et3N (1.23 mL, 8.82 mmol) was added, and the resulting mixture was stirred for 15 min. Acetaldehyde (3.64 mL, 65.1 mmol) was then added dropwise to the mixture at 0 °C, and the stirring was continued for 12 h. The reaction mixture was quenched with satd aq NH4Cl and diluted with hexane/Et2O (1:1). The organic layer was separated, washed with brine. The aqueous layer was extracted with hexane/Et2O (1:1) (×2), dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/Et2O = 2:1, 0.1% Et3N) to give 124 as a yellow syrup (E/Z = 9.8:1) (957 mg, 79%): Rf 0.38 (hexane/EtOAc = 5:1); ¹ H NMR (400 MHz, CDCl3) δ 1.50 (s, 9H), 1.88 (d, J = 5.2 Hz, 3H), 2.56 (t, J = 8.0 Hz, 2H), 2.75 (t, J = 8.0 Hz, 2H), 5.31 (s, 1H), 5.37 (s, 1H), 5.87 (d, J = 16.0 Hz, 1H), 6.08 (d, J = 14.8 Hz, 1H), 6.16−6.26 (m, 2H), 7.11−7.18 (m, 1H), 7.22 (d, J = 16.0 Hz, 1H); ¹³ C{¹ H} NMR (100 MHz, CDCl3) δ 18.4, 25.9, 28.2, 38.7, 80.5, 120.3, 123.0, 127.4, 130.2, 140.7, 143.2, 143.6, 145.0, 166.4, 199.3.

tert-butyl (R,2E,8E,10E)-7-hydroxy-4-methylenedodeca-2,8,10-trienoate (112)

To a stirred solution of (S)-CBS (204 mg, 0.736 mmol) in THF (2 ml) was added dropwise BH3·THF (1.0 M solution in THF, 0.543 mL, 0.543 mmol) at 0 °C. After 15 min of stirring at 0 °C, a solution of 124 (102 mg, 0.369 mmol) (azeotropically dried with toluene) in THF (2 ml) was added dropwise to the reaction mixture at －78 °C, and the mixture was stirred for 1 h at －78 °C. To the mixture was added dropwise BH3·THF (1.0 M solution in THF, 0.543 ml, 0.543 mmol) over a period for 45 min at －78 °C. The mixture was gradually warmed to － 40 °C over a period for 30 min. The mixture was stirred for 8 h at －40 °C. The reaction

80

mixture was quenched with satd aq NH4Cl and diluted with hexane/Et2O (1:1) and washed with brine. The aqueous layer was extracted with hexane/Et2O (1:1) (×2), dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/Et2O = 2:1, 0.1% Et3N) to give 112 as a pale yellow syrup (E/Z

= 6.7:1.0, 88% ee) (101.1 mg, 99 %): ¹ H NMR (600 MHz, CDCl3) δ 1.50 (s, 9H), 1.67−1.77 (m, 5H), 2.24-2.36 (m, 2H), 4.15 (quin, J = 4.8, 7.2 Hz, 1H), 5.32 (s, 1H), 5.36 (s, 1H), 5.57 (dd, J = 7.2, 15.6 Hz, 1H), 5.73 (qd, J = 7.2, 15.0 Hz, 1H), 5.86 (d, J = 16.2 Hz, 1H) 6.05 (dd, J = 10.8, 15.0 Hz, 1H), 6.19 (dd, J = 10.8, 15.6 Hz, 1H), 7.21 (d, J = 16.2 Hz, 1H).

tert-butyl (R,2E,8E,10E)-7-acetoxy-4-methylenedodeca-2,8,10-trienoate (112a).

To a stirred solution of 112 (31.5 mg, 0.113 mmol, 88% ee) and DMAP (1.5 mg, 0.012 mmol) in CH2Cl2 (0.50 ml) were added pyridine (54.7 μL, 0.679 mmol) and acetic anhydride (42.8 μL, 0.453 mmol) at room temperature. After 12 h of stirring at room temperature, the reaction mixture was quenched with satd aq NaHCO3 and diluted with CHCl3 and washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2

flash column chromatography (hexane/EtOAc = 2:1, 0.1% Et3N) to give 112a as a pale yellow syrup (E/Z = 9.3:1.0) (32.5 mg, 90%): ¹ H NMR (400 MHz) δ 1.50 (s, 9H), 1.75−1.91 (m, 5H), 2.06 (s, 3H), 2.17-2.30 (m, 2H), 5.24−5.29 (m, 2H), 5.36 (s, 1H), 5.47 (dd, J = 7.6, 15.2 Hz, 1H), 5.71−5.84 (m, 1H), 6.02 (ddd, J = 1.6, 10.4, 14.8 Hz, 1H), 6.23 (dd, J = 10.4, 15.2 Hz, 1H), 7.20 (d, J = 16.0 Hz, 1H).

tert-butyl (R,2E,8E,10E)-7-((tert-butyldiphenylsilyl)oxy)-4-methylenedodeca-2,8,10-trienoate (112b).

To a stirred solution of 112 (20.0 mg, 0.072 mmol, 88% ee), imidazole (19.6 mg, 0.288 mmol) and DMAP (1.5 mg, 0.012 mmol) in CH2Cl2 (2 ml) was added TBDPCl (36.7 μL, 0.141 mmol) at 0 °C.

After 12 h of stirring at room temperature, the reaction mixture was quenched with satd aq NaHCO3 and diluted with CHCl3 and washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/EtOAc = 3:1, 0.1% Et3N) to give 112b as a colorless syrup (E/Z

= 7.9:1.0) (23.9 mg, 64%):¹ H NMR (600 MHz) δ 1.07 (s, 9H), 1.50 (s, 9H), 1.57−1.68

81

(m, 2H), 1.73 (d, J = 5.4 Hz, 3H), 2.12 (t, J = 7.8 Hz, 2H), 4.18 (q, J = 6.0 Hz, 1H), 5.11 (s, 1H), 5.23 (s, 1H), 5.49 (dd, J = 6.6, 15.0 Hz, 1H), 5.55 (qd, J = 6.6, 13.8 Hz, 1H), 5.73 (d, J = 15.6 Hz, 1H), 5.85 (dd, J = 10.2, 15.0 Hz, 1H), 5.95 (ddd, J = 1.2, 10.2, 15.0 Hz, 1H), 7.13 (d, J = 16.2 Hz, 1H), 7.34−7.43 (m, 6H), 7.63-7.68 (m, 4H).

To a stirred solution of 112 (100 mg, 0.359 mmol) in CH2Cl2 (3 mL) was added dropwise DIBAL-H (1.0 M solution in hexane, 1.08 mL, 1.08 mmol) at －78 °C. After 7 h of stirring at －78 °C, the reaction mixture was quenched with satd aq Rochelle salt and diluted with CH2Cl2 and washed with brine, dried (Na2SO4), and concentrated in vacuo.

The residue was purified by SiO2 flash column chromatography (hexane/EtOAc = 1:1) to give 126 as a pale yellow syrup (40.5 mg, 54%) and 127 as a colorless syrup (25.9 mg, 35%).

To a stirred solution of 127 (25.9 mg, 0.124 mmmol) in CH2Cl2 (2 mL) were added a mixed solution of 0.5 M NaHCO3 and 0.05 M K2CO3 (2.0 mL), TBACl (6.9 mg, 0.025 mmol) and TEMPO (3.9 mg, 0.025 mmol) 0 °C. NCS was then added to the reaction mixture at 0 °C, and the stirring was continued for 5 h at room temperature. The reaction mixture was diluted with CH2Cl2 and washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/EtOAc = 1:1) to give 126 as a pale yellow syrup (E/Z = 11.5:1.0) (21.3 mg, 83%):

Rf 0.37 (hexane/EtOAc = 1:1); ¹ H NMR (600 MHz) δ 1.53 (d, J = 3.6 Hz, 1H), 1.68−1.80 (m, 2H), 2.29−2.42 (m, 2H), 4.15−4.17 (m, 1H), 5.49 (s, 1H), 5.52 (s, 1H), 5.56 (dd, J = 6.6, 15.0 Hz, 1H), 5.74 (dq, J = 6.6, 15.0 Hz, 1H), 6.05 (dd, J = 10.2, 15.0 Hz, 1H), 6.17−6.24 (m, 2H), 7.13 (d, J = 16.2 Hz, 1H), 9.60 (d, J = 7.8 Hz, 1H); ¹³ C{¹ H} NMR (150 MHz) δ 18.2, 27.4, 35.3, 72.3, 125.3, 128.8, 130.5, 130.7, 131.6, 132.4, 144.6, 154.5, 194.3.

DIBAL-H THF, －78 ^ΟC, 7 h

+

TEMPO, NCS, nBu₄NCl CH₂Cl₂, NaHCO₃aq/K₂CO₃aq

82 (6E,8E)-2-bromodeca-1,6,8-trien-5-one (132).

To a stirred suspension of NaH (60%, dispersion in Paraffin Liquid, 3.17 g, 79.3 mmol), (washed with n-hexane to remove mineral oil ×2) in THF (165 ml) was added dropwise a solution of dimethyl (2-oxopropyl) phosphonate (128) (12.8 g, 77.1 mmol) at 0 °C. After 1.5 h of stirring at 0 °C, n-BuLi (1.6 M in hexane, 82.5 ml, 132 mmol) was added dropwise, and the mixture was stirred for 1 h at the same temperature. 2,3-dibromopropene (124) was then added dropwise at －40 °C, and stirred for 1 h at the same temperature. The reaction mixture was quenched with satd aq NH4Cl, and diluted with EtOAc, washed with brine. The aqueous layer was extracted with EtOAc (×4), dried (Na2SO4), and concentrated in vacuo.

The residue was purified by SiO2 flash column chromatography (hexane/EtOAc = 1:4) to give crude 129 as a pale yellow syrup (12.6 g, 44.2 mmol): Rf = 0.24 (hexane/EtOAc = 1:4). To a solution of dry LiBr (4.59 g, 52.9 mmol) in THF (100 mL) was added a solution of crude 129 (12.6 g, 44.2 mmol) in THF (100 mL) via the cannula at room temperature.

After 10 min of stirring at the same temperature, Et3N (10.4 ml, 74.6 mmol) was added.

After 1 h of stirring at the same temperature, the mixture was cooled to 0 °C and then crotonaldehyde (10.8 ml, 131 mmol) was added dropwise. The mixture was stirred for 6 h at room temperature. The mixture was quenched with satd aq NH4Cl, and diluted with hexane/Et2O (1:1), washed with brine. The aqueous layer was extracted with hexane/Et2O (1:1) (×2), dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2

flash column chromatography (hexane/Et2O = 3:1) to give 132 as a pale yellow syrup (E/Z = 14:1) (9.02 g, 39.4 mmol, 51%): Rf = 0.39: (hexane/Et2O = 3:1). IR  max 2977 (m), 1687 (s), 1660 (s), 1634 (s), 1595 (s), 1146 (s), 994 (s); ¹H NMR (400 MHz, CDCl3): δ 1.88 (d, J = 5.2 Hz, 3H), 2.74−2.78 (m, 2H), 2.82−2.88 (m, 2H), 5.41 (d, J = 1.6 Hz, 1H), 5.63 (td, J = 1.2, 1.6 Hz, 1H), 6.08 (d, J = 15.6 Hz, 1H), 6.16−6.28 (m, 2H), 7.14−7.20 (m, 1H); ¹³C{¹H} NMR (150 MHz, CDCl3) δ 18.9, 35.9, 38.7, 117.5, 127.4, 130.2, 133.1, 140.9, 143.4, 198.6; HRMS (FAB) m/z calcd for C10H14BrO ([M+H]⁺) 229.0223, found 229.0232.

(2E,4E,10E)-12,12-diethoxy-9-methylenedodeca-2,4,10-trien-6-one (133).

To a stirred solution of 132 (1.60 g, 6.98 mmol) in DMF (2.33 ml) in a pressure bottle (Biotage, microwave reaction vial 354833) were added potassium carbonate (1.45 g, 10.5 mmol) and acrolein diethyl acetal (5.32 ml, 34.8 mmol) at room temperature. After the mixture was deaerated by N2, to the suspension was added Pd(OAc)2 (47.0 mg, 0.209 mmol) at room temperature. The bottle was sealed with a septum, and the mixture was stirred for 72 h at

83

40 °C. The reaction mixture was diluted with hexane/Et2O (1:1) and washed with brine.

The aqueous layer was extracted with hexane/Et2O (1:1) (×2), dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/Et2O = 3:1, 0.1% Et3N) to give 133 as a pale yellow oil (E/Z = 16:1) (1.47 g, 5.28 mmol, 76%): Rf = 0.25 (hexane/Et2O = 3:1). IR  max 2976 (m), 1687 (s), 1667 (s), 1639 (s), 1597 (s), 1143 (s), 1054 (s), 999 (s); ¹H NMR (600 MHz, CDCl3) δ 1.23 (t, J = 7.2 Hz, 6H), 1.88 (d, J = 4.8 Hz, 3H), 2.54 (t, J = 7.2 Hz, 2H), 2.75 (t, J = 7.2 Hz, 2H), 3.52 (qd, J = 7.2, 9.6 Hz, 2H), 3.65 (qd, J = 7.2, 9.6 Hz, 2H), 4.97 (d, J = 4.8 Hz, 1H), 5.04 (s, 1H), 5.09 (s, 1H), 5.72 (dd, J = 4.8, 16.2 Hz, 1H), 6.08 (d, J = 15.0 Hz, 1H), 6.19−6.20 (m, 2H), 6.37 (d, J = 16.2 Hz, 1H), 7.12−7.16 (m, 1H); ¹³C{¹H} NMR (150 MHz, CDCl3) δ 15.3, 18.8, 26.2, 38.9, 61.0, 101.4, 117.3, 126.3, 127.5, 130.3, 134.7, 140.5, 143.0, 144.1, 199.9; HRMS (FAB) m/z calcd for C17H26NaO3 ([M+Na]⁺) 301.1774, found 301.1785.

An analytical sample of the minor product [Rf 0.17 (hexane/Et2O = 3:1)] was obtained as a pale yellow oil by concentrating some chromatographic fractions in vacuo.

134: IR  max 2923 (m), 1697 (s), 1636 (s), 1576 (s), 1436 (s) 1385 (s), 1007 (s), 913 (s); ¹H NMR (600 MHz, CDCl3) δ 2.16 (s, 3H), 2.42−2.44 (m, 2H), 2.56−2.58 (m, 2H), 5.18 (d, J = 10.2 Hz, 1H), 5.37 (d, J = 16.8 Hz, 1H), 6.25 (d, J = 16.2 Hz, 1H), 6.39 (td, J = 10.2, 16.8 Hz, 1H), 7.34 (dd, J = 10.8, 15.6 Hz, 1H); ¹³C{¹H} NMR (150 MHz, CDCl3) δ 17.6, 31.7, 34.9, 118.8, 121.4, 133.4, 134.9, 137.9, 171.5, 208.0; HRMS (EI) m/z calcd for C10H12O ([M]⁺) 148.0883, found 148.0891.

An analytical sample of the minor product [Rf 0.19 (hexane/Et2O = 3:1)] was obtained as colorless oil by concentrating some chromatographic fractions in vacuo.

135: IR  max 2916 (m), 1733 (s), 1638 (s), 1595 (s), 1371 (s), 1181 (s), 999 (s); ¹H NMR (600 MHz, CDCl3) δ 1.26 (t, J = 7.2 Hz, 3H), 1.88 (d, J

= 4.8 Hz, 3H), 2.36 (q, J = 7.2 Hz, 4H), 2.47 (dd, J = 6.6, 9.0 Hz, 2H), 2.71 (dd, J = 7.8, 9.6 Hz, 2H), 4.13 (q, J = 7.2 Hz, 2H), 4.76 (s, 2H), 6.08 (d, J = 15.0 Hz, 1H), 6.20−6.22 (m, 2H), 7.13−7.17 (m, 1H); ¹³C{¹H} NMR (150 MHz, CDCl3) δ 14.2, 18.9, 30.3, 31.1, 32.6, 38.6, 60.4, 109.6, 127.5, 130.2, 140.5, 143.0, 146.9, 173.2, 200.0; HRMS (FAB) m/z calcd for C15H23O3 ([M+H]⁺) 251.1642, found 251.1648.

(R,2E,4E,10E)-12,12-diethoxy-9-methylenedodeca-2,4,10-trien-6-ol (141).

To a stirred solution of (S)-CBS (2.93 g, 10.6 mmol) in THF (14 ml) was added dropwise BH3·THF (1.0 M solution in THF, 7.94 ml, 7.94 mmol) at 0 °C. After 15 min of stirring at 0 °C, a solution of 133 (1.47 g, 5.28 mmol) (azeotropically dried with toluene) in THF (29 ml) was added

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dropwise to the reaction mixture at －78 °C, and the mixture was stirred for 1 h at － 78 °C. To the mixture was added dropwise BH3·THF (1.0 M solution in THF, 7.94 ml, 7.94 mmol) over a period for 1 h at －78 °C. The mixture was gradually warmed to － 40 °C over a period for 30 min. The reaction mixture was stirred for 30 min at the same temperature. The mixture was quenched with satd aq NH4Cl and diluted with CHCl3, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/Et2O = 1:1, 0.1% Et3N) to give 141 as a pale yellow oil (E/Z = 16.1:1, 96% ee) (1.41 g, 95 %): Rf = 0.41 (hexane/Et2O = 1:1).

[α]D27 0.089 (c 0.795, CHCl3); IR  max 3421 (s), 2976 (m), 1339 (m), 1139 (s), 1054 (s), 989 (s); ¹H NMR (600 MHz, CDCl3) δ 1.23 (t, J = 7.2 Hz, 6H), 1.49 (d, J =3.6 Hz, 1H), 1.67−1.79 (m, 5H), 2.22−2.34 (m, 2H), 3.51 (qd, J = 7.2, 9.6 Hz, 2H), 3.65 (qd, J = 7.2, 9.6 Hz, 2H), 4.15 (six, J = 3.6, 6.6 Hz, 1H), 4.95 (d, J =5.4 Hz, 1H), 5.06 (s, 1H), 5.08 (s, 1H), 5.57 (dd, J =7.2, 15.0 Hz, 1H), 5.68−5.75 (m, 2H), 6.05 (ddd, J = 1.2, 10.8, 15.0 Hz, 1H), 6.18 (dd, J =10.8, 15.0 Hz, 1H), 6.36 (d, J = 16.2 Hz, 1H); ¹³C{¹H} NMR (150 MHz, CDCl3) δ 15.3, 18.1, 27.6, 35.5, 61.0, 72.5, 101.6, 117.0, 126.1, 130.2, 130.7, 131.2, 132.9, 135.0, 144.7; HRMS (FAB) m/z calcd for C17H28NaO3 ([M+Na]⁺) 303.1931, found 3031939.

(1S,2S,4aR,5R,8aS)-5-hydroxy-2-methyl-8-methylene-1,2,4a,5,6,7,8,8a-octahydronaphthalene-1-carbaldehyde (22).

To a stirred solution of 141 (1.10 g, 3.92 mmol) in THF (20 mL) was added 0.25 M HCl aq (2 ml) at 0 °C. After 30 min of stirring at the same temperature, the mixture was quenched with satd aq NaHCO3 and diluted with CH2Cl2. The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo to give crude 23 as a pale yellow syrup. To a stirred solution of crude 23 (azeotropically dried with toluene) in CH2Cl2 (78 mL) was added Et2AlCl (0.87 M solution in toluene, 9.0 ml, 7.83 mmol) over a period for 10 min at － 20 °C. The mixture was gradually warmed to 0 °C over a period for 30 min. After 8.5 h of stirring at 0 °C, the mixture was quenched with satd aq NaHCO3 and satd aq Rochelle salt. After 1 h of stirring at 0 °C, the mixture was stirred for 1 h at room temperature. The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/EtOAc = 1:1 and then hexane/Et2O = 1:2) to give 22 as a colorless oil (91% ee) (575 mg, 71%): Rf

0.47 (hexane/EtOAc = 1:1) [α]D27 200.7 (c 1.225, CHCl3); IR  max 3419 (s), 2935 (m), 1716 (s), 1454 (s), 1052 (s), 1032 (s); ¹H NMR (600 MHz, CDCl3) δ 1.02 (d, J = 7.2 Hz, 3H), 1.44−1.51 (m, 2H), 1.82 (dt, J = 2.4, 10.2 Hz, 1H), 2.20−2.25 (m, 2H), 2.32 (t, J =

85

11.4 Hz, 1H), 2.38−2.42 (m, 1H), 2.67−2.74 (m, 2H), 3.51 (ddt, J = 4.8, 5.4, 10.2 Hz, 1H), 4.40 (s, 1H), 4.84 (s, 1H), 5.72 (ddd, J = 2.4, 4.2, 10.2 Hz, 1H), 5.97 (td, J = 1.2, 10.2 Hz, 1H), 9.65 (d, J = 4.2 Hz, 1H); ¹³C{¹H} NMR (150 MHz, CDCl3) δ 16.7, 32.3, 34.7, 36.9, 37.8, 50.0, 50.1, 73.5, 107.5, 125.5, 132.1, 148.6, 207.4; HRMS (FAB) m/z calcd for C13H19O2 ([M+H]⁺) 207.1380, found 207.1386.

(1S,2S,4aR,5R,8aS)-5-hydroxy-2-methyl-8-methylene-1,2,4a,5,6,7,8,8a-octahydronaphthalene-1-carboxylic acid (22a).

To a stirred solution of 22 (20.1 mg, 0.097 mmol) in t-BuOH (0.2 mL) were added 2-methyl-2-butene (0.10 ml, 0.95 mmol) and a pre-mixed solution of NaH2PO4 (58.3 mg, 0.49 mmol) and NaClO2 (26.3 mg, 0.29 mmol) in H2O (0.2 ml) at room temperature. After 12 h of stirring at the same temperature, the mixture was diluted with CHCl3. The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/EtOAc = 1:3) to give 22a as a white solid (21.0 mg, 97%): Rf 0.41 (hexane/EtOAc = 1:3); mp 193.2 °C; [α]D26 169.6 (c 0.520, MeOH); IR  max 3334 (s), 2941 (m), 1708 (s), 1451 (s), 1413 (s), 1024 (s); ¹H NMR (400 MHz, acetone-d6) δ 0.94 (d, J = 7.2 Hz, 3H), 1.35−1.46 (m, 1H), 1.70 (qt, J = 2.0, 10.4 Hz, 1H), 2.04−2.20 (m, 7H), 2.28−2.33 (m, 1H), 2.59−2.64 (m, 1H), 2.82−2.87 (m, 1H), 3.39 (dt, J = 4.4, 10.0 Hz, 1H), 3.89 (s, 1H), 4.50 (s, 1H), 4.69 (d, J = 0.8 Hz, 1H), 5.71 (ddd, J = 2.8, 4.4, 10.0 Hz, 1H), 6.02 (td, J = 1.6, 10.0 Hz, 1H), 10.63 (s, 1H); ¹³C{¹H}

NMR (100 MHz, acetone-d6) δ 18.6, 32.1, 35.6, 39.0, 39.0, 45.8, 51.2, 73.4, 104.4, 126.9, 131.8, 152.0, 174.8; HRMS (FAB) m/z calcd for C13H19O3 ([M+H]⁺) 223.1329, found 223.1330.

(1R,2R,4aS,5R,8aR)-2-methyl-8-methylene-5-((triisopropylsilyl)oxy)-1,2,4a,5,6,7,8,8a-octahydronaphthalene-1-carbaldehyde (144a).

To a stirred solution of 141 (50.1 mg, 0.179 mmol), imidazole (73.6 mg, 1.08 mmol), and 4-(dimethylamino)pyridine (2.0 mg, 0.016 mmol) in CH2Cl2 (0.89 mL) was added TIPSCl (0.15 ml, 0.710 mmol) at 0 °C.

After 20 h of stirring at room temperature, the reaction mixture was quenched with satd aq NaHCO3 and diluted with hexane/EtOAc (1:1). The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/ Et2O = 5:1) to give 144a as a colorless oil (65.1 mg, 83%): ¹H NMR (600 MHz, CDCl3): δ 1.05 (a, 21H), 1.21−1.26 (m, 7H),

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1.68−1.76 (m, 5H), 2.17−2.24 (m, 1H), 3.51 (quin, J = 7.2 Hz, 2H), 3.64 (quin, J = 7.2 Hz, 2H), 4.29 (dt, J = 5.4, 7.2 Hz, 1H), 4.95 (d, J = 4.8 Hz, 1H), 5.02 (s, 1H), 5.04 (s, 1H), 5.53 (dd, J = 6.6, 14.4 Hz, 1H), 5.64−5.70 (m,1H), 6.06 (qd, J = 10.2, 14.4 Hz, 1H), 6.34 (d, J = 16.2 Hz, 1H).

(1R,2R,4aS,5R,8aR)-2-methyl-8-methylene-5-((triisopropylsilyl)oxy)-1,2,4a,5,6,7,8,8a-octahydronaphthalene-1-carbaldehyde (152).

To a stirred solution of 144a (147 mg, 0.337 mmol) in THF (1.7 mL) was added 0.25 M HCl aq. (0.17 ml) at 0 °C. After 30 min of stirring at the same temperature, the mixture was quenched with satd aq NaHCO3 and diluted with CH2Cl2. The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo to give crude 149 as a pale yellow syrup. To a stirred solution of 149 (azeotropically dried with toluene) in CH2Cl2 (6.8 mL) was added Et2AlCl (0.87 M solution in toluene, 0.78 ml, 0.679 mmol) over a period for 10 min at

－20 °C. The mixture was gradually warmed to 0 °C over a period for 30 min. After 7.5 h of stirring at 0 °C, the mixture was quenched with satd aq NaHCO3 and satd aq Rochelle salt. After 1 h of stirring at 0 °C, the mixture was stirred for 1 h at room temperature. The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/EtOAc = 8:1 and then hexane/Et2O = 15:1) to give 152 as a colorless oil (12.1 mg, 8%): Rf 0.35 (hexane/Et2O = 15:1) [α]D27 －162.3 (c 0.285, CHCl3); IR  max 2942 (s), 2867 (m), 1722 (s), 1649 (s), 1461 (s), 1107 (s); ¹H NMR (400 MHz, CDCl3) δ 1.03 (d, J = 6.8 Hz, 3H), 1.09 (s, 18H), 1.56−1.65 (m, 1H), 1.96−2.05 (m, 2H), 2.18 (ddd, J = 2.0, 4.8, 12.8 Hz, 1H), 2.57−2.67 (m, 3H), 3.08 (t, J = 11.2 Hz, 1H), 4.25 (q, J = 2.4 Hz, 1H), 4.32 (s, 1H), 4.77 (s, 1H), 5.50 (d, J = 10.0 Hz, 1H), 5.65 (ddd, J = 2.4, 4.0, 10.0 Hz, 1H), 9.67 (d, J = 4.4 Hz, 1H); ¹³C{¹H} NMR (150 MHz, CDCl3) δ 12.8, 16.4, 18.3, 18.3, 32.1, 32.5, 32.6, 36.5, 49.6, 50.3, 70.5, 105.7, 129.1, 132.0, 151.1, 208.7; HRMS (FAB) m/z calcd for C22H38NaO2Si ([M+Na]⁺) 385.2533, found 385.2538.

An analytical sample of by product was obtained as a colorless oil by concentrating some chromatographic fractions in vacuo.

144: ¹H NMR (600 MHz, CDCl3) δ 1.18 (t, J = 7.2 Hz, 3H), 1.63−1.69 (m, 1H), 1.76−1.83 (m, 4H), 2.26−2.38 (m, 2H), 3.28 (qd, J = 7.2, 9.6 Hz, 1H), 3.55 (qd, J = 7.2, 9.6 Hz, 1H), 3.65 (q, J = 7.2 Hz, 1H), 5.40 (dd, J

= 7.8, 15.0 Hz, 1H), 5.46 (s, 1H), 5.51 (s, 1H), 5.72 (qd, J = 6.6, 15.0 Hz, 1H), 6.06 (ddd, J = 1.2, 10.2, 15.0 Hz, 1H), 6.22 (dd, J = 7.8, 16.2 Hz, 1H), 7.13 (d, J =

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15.6 Hz, 1H), 9.60 (d, J = 7.8 Hz, 1H).

145: ¹H NMR (600 MHz, CDCl3) δ 1.19 (t, J = 7.2 Hz, 3H), 1.25 (d, J = 6.6 Hz, 3H), 2.28−2.32 (m, 2H), 2.35−2.38 (m, 2H), 3.35 (qd, J = 7.2, 9.6 Hz, 1H), 3.50 (qd, J = 7.2, 9.6 Hz, 1H), 3.85 (quin, J = 6.6 Hz, 1H), 5.47 (s, 1H), 5.51 (dd, J = 7.8, 15.0 Hz, 1H), 5.54 (s, 1H), 5.66 (td, J = 6.6, 15.0 Hz, 1H), 6.04−6.14 (m, 1H), 6.20 (dd, J = 7.8, 15.6 Hz, 1H), 7.13 (d, J = 16.2 Hz, 1H), 9.61 (d, J = 7.8 Hz, 1H).

3.1.3 2.5に関する実験

158: ¹H NMR (400 MHz, CDCl3) δ 1.18−1.23 (m, 3H), 1.31−1.34 (m, 3H), 1.54 (s, 3H×0.20), 1.64 (s, 3H×0.80), 2.62−2.64 (m, 1H), 3.46 (s, 3H), 2.62−2.64 (m, 1H) 3.57 (q, J = 7.2 Hz, 2H×0.80), 2.66−3.80 (m, 2H×0.20), 3.83 (dt, J = 4.0, 5.6 Hz, 1H×0.80), 4.04 (dd, J = 2.0, 6.4 Hz, 1H×0.20), 4.07−4.15 (m, 1H×0.80, 2H×0.20), 4.24−4.27 (m, 1H), 4.39 (t, J = 6.4 Hz, 1H×0.80), 4.71 (d, J = 4.0 Hz, 1H×0.80), 4.74 (d, J = 4.4 Hz, 1H×0.20); ¹³C{¹H} NMR (150 MHz, CDCl3) δ 15.4, 15.5, 16.1, 16.2, 22.4, 23.3, 55.4, 55.4, 58.1, 58.5, 63.8, 64.0, 67.9, 68.4, 75.4, 75.6, 75.9, 76.3, 97.9, 98.2, 121.3, 121.9

(2S,3aR,4S,6R,7aR)-2-ethoxy-6-methoxy-2,4-dimethyldihydro-4H-[1,3]dioxolo[4,5-c]pyran-7(6H)-one (160).

To a stirred solution of 159 (2.05 g, 8.26 mmol) in CH2Cl2 (12 mL) and satd aq NaHCO3 (12 ml) were added AZADOL (126 mg, 0.822 mmol) and KBr (985 mg, 8.28 mmol) at room temperature. The mixture was cooled to 0 °C and added dropwise NaClO aq. (Nacalai Tesque, available chlorine: 8.5–

13.5%, 12 ml). After 1 h of stirring at the same temperature, the mixture was quenched with satd aq Na2S2O3 and diluted with CH2Cl2. The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo to give crude 160 as a pale yellow syrup Rf 0.38 (hexane/EtOAc = 1:1).

(2R,3aR,4S,6R,7R,7aS)-2-ethoxy-6-methoxy-2,4-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-ol (157).

To a stirred solution of crude 160 (2.04 g) in CH2Cl2 (30 mL) was added dropwise DIBAL-H (1M in hexane, 12.4 ml, 12.4 mmol) at －78 °C. After 3 h of stirring at the same temperature, the mixture was quenched with satd aq NaHCO3 and satd aq Rochelle salt. The mixture was stirred for 1 h at

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room temperature. The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo to give crude 157 as a pale yellow syrup Rf 0.37 (hexane/EtOAc

= 1:1).

(2S,3aR,4S,6R,7R,7aR)-2-ethoxy-6,7-dimethoxy-2,4-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran (162).

To a stirred solution of crude 157 (2.36 g) in CH3CN (40 mL) were added Ag2O (5.74 g, 24.8 mmol) and MeI (3.09 ml, 49.6 mmol) at room temperature. The mixture was heated to 75 °C. After 14 h of stirring at the same temperature, the mixture was filtrated and concentrated in vacuo. The residue was purified by SiO2 short flash column chromatography (hexane/EtOAc = 1:1) to give crude 162 as a pale yellow syrup Rf 0.45 (hexane/EtOAc = 1:1).

An analytical sample of the minor product [Rf 0.41 (hexane/Et2O = 1:1)] was obtained as white solid by concentrating some chromatographic fractions in vacuo.

161: mp 57.6 °C; [α]D24 －83.4 (c 0.750, CHCl3); IR  max 2937 (m), 1787 (s), 1699 (s), 1422 (s), 1080 (s); ¹H NMR (600 MHz, CDCl3) δ 1.37 (d, J = 6.6 Hz, 3H), 1.81 (s, 3H), 3.43 (s, 3H), 3.88−3.92 (m, 3H), 4.79 (s, 1H), 4.95 (s, 1H); ¹³C{¹H} NMR (150 MHz, CDCl3) δ 16.0, 17.9, 55.5, 62.1, 71.9, 73.5, 75.4, 97.3, 121.6; HRMS (FAB) m/z calcd for C9H15O5 ([M+H]⁺) 203.0914, found 203.0924.

(2R,3R,4R,5R,6S)-3,5-dihydroxy-2-methoxy-6-methyltetrahydro-2H-pyran-4-yl acetate (164).

To a stirred solution of crude 162 (1.45 g) in CHCl3 (30 mL) was added TsOH·H2O (1.05 g, 5.52 mmol) at room temperature. After 1 h of stirring at the same temperature, the mixture was quenched with satd aq NaHCO3 and diluted with CHCl3. The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/EtOAc = 1:2) to give 164 as a white solid (1.10 g, 57%, 4 steps): Rf 0.41 (hexane/EtOAc = 1:2) mp 94.8 °C; [α]D26 －113.8 (c 1.035, CHCl3); IR

 max 3505 (s), 2936 (m), 1740 (s), 1377 (s), 1235 (s), 1112.7 (s), 1055 (s); ¹H NMR (400 MHz, CDCl3) δ 1.30 (d, J = 6.4 Hz, 3H), 2.17 (s, 3H), 3.38−3.41 (m, 4H), 3.52−3.54 (m, 4H), 3.68 (tdd, J = 1.2, 3.2, 11.2 Hz, 1H), 3.90 (q, J = 6.4 Hz, 1H), 4.82 (d, J = 1.6 Hz, 1H), 5.03 (t, J = 3.2 Hz, 1H); ¹³C{¹H} NMR (150 MHz, CDCl3) δ 16.3, 21.2, 55.1, 59.7, 67.2, 69.6, 70.9, 78.5, 98.4, 170.4; HRMS (FAB) m/z calcd for C10H19O6 ([M+H]⁺) 235.1176, found 235.1181.

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An analytical sample of the minor product [Rf 0.19 (hexane/EtOAc = 1:2)] was obtained as white solid by concentrating some chromatographic fractions in vacuo.

165: mp 66.3 °C; [α]D26 －58.8 (c 0.510, CHCl3); IR  max 3481 (s), 2938 (m), 1736 (s), 1383 (s), 1241 (s), 1116 (s); ¹H NMR (400 MHz, CDCl3) δ 1.20 (d, J = 6.4 Hz, 3H), 2.20 (s, 3H), 2.76 (d, J = 10.8 Hz, 1H), 3.31−3.33 (m, 1H), 3.38 (s, 3H), 3.51 (s, 3H), 3.93−3.99 (m, 2H), 4.88 (s, 1H), 5.12 (dd, J = 1.2, 4.4 Hz, 1H); ¹³C{¹H} NMR (150 MHz, CDCl3) δ 16.4, 21.0, 55.1, 59.8, 64.2, 65.1, 71.8, 77.9, 98.0, 171.4; HRMS (FAB) m/z calcd for C10H19O6 ([M+H]⁺) 235.1176, found 235.1179.

(2S,3R,4R,5R,6R)-3-(carbamoyloxy)-5,6-dimethoxy-2-methyltetrahydro-2H-pyran-4-yl acetate (170)

To a stirred solution of 164 (572 mg, 2.44 mmol) in CH2Cl2 (15 mL) was added trichloroacetyl isocyanate (0.430 ml, 3.64 mmol) at room temperature. After 30 min of stirring at the room temperature, to the mixture was added enough of alumina to just absorb all the solvent (The activity of neutral alumina (ICN BIOMEDICALS, gradeⅠ) was adjusted by adding 3 ml of water to 30 g of the alumina and mixing thoroughly). After 30 min of standing at the room temperature, the mixture was diluted with EtOAc, filtrated and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (CHCl3/CH3OH

= 20:1) to give 170 as a white solid (664 mg, 98%): Rf 0.29 (CHCl3/CH3OH = 20:1); mp 110.6 °C; [α]D24 －58.7 (c 1.025, CH3OH); IR  max 3345 (s), 2938 (m), 1714 (s), 1330 (s), 1238 (s), 1124 (s), 1056 (s); ¹H NMR (600 MHz, CDCl3) δ 1.26 (d, J = 6.6 Hz, 3H), 2.11 (s, 3H), 3.39 (s, 3H), 3.42 (d, J = 3.6 Hz, 1H), 3.51 (s, 3H), 4.07 (dq, J = 0.6, 6.6 Hz, 1H), 4.83 (s, 1H), 5.03 (d, J = 3.6 Hz, 1H), 5.18 (t, J = 3.6 Hz, 1H); ¹³C{¹H} NMR (150 MHz, CDCl3) δ 16.0, 21.0, 55.1, 60.0, 64.8, 68.5, 70.4, 76.6, 99.4, 156.7, 170.2; HRMS (FAB) m/z calcd for C11H20NO7 ([M+H]⁺) 278.1234, found 278.1246.

An analytical sample of by product was obtained as a colorless oil by concentrating some chromatographic fractions in vacuo.

169: Rf 0.39 (hexane/EtOAc = 1:2); ¹H NMR (600 MHz, CDCl3) δ 1.34 (d, J = 6.6 Hz, 3H), 3.41 (t, J = 3.6 Hz, 1H), 3.44 (s, 3H), 3.52 (s, 3H), 3.95 (q, J = 6.6 Hz, 1H), 4.58 (dd, J = 1.8, 7.8 Hz, 1H), 4.73 (d, J = 4.8 Hz, 1H), 5.00 (dd, J = 3.0, 7.8 Hz, 1H); ¹³C{¹H} NMR (150 MHz, CDCl3) δ 15.3, 55.3, 59.2, 63.5, 73.2, 76.0, 76.4, 100.2, 154.2.

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168: Rf 0.22 (CHCl3/CH3OH = 25:1); ¹H NMR (600 MHz, CDCl3) δ 1.23 (d, J = 6.6 Hz, 3H), 2.19 (s, 1H), 3.40 (s, 3H), 3.47-3.48 (m, 1H), 3.50 (s, 3H), 4.07 (dq, J = 1.2, 6.6 Hz, 1H), 4.87 (d, J = 1.2 Hz, 1H), 5.13 (t, J = 3.6 Hz, 1H), 5.22 (d, J = 3.0 Hz, 1H), 5.32 (s, 1H), 7.52-7.57 (m, 2H);

13C{¹H} NMR (150 MHz, CDCl3) δ 16.0, 20.9, 55.2, 60.0, 64.5, 69.2, 70.7, 76.4, 99.2, 152.9, 153.3, 171.2.

(2S,3R,4R,5R)-3-(carbamoyloxy)-6-hydroxy-5-methoxy-2-methyltetrahydro-2H-pyran-4-yl acetate (18)

To a stirred solution of 170 (100 mg, 0.361 mmol) in CH2Cl2 (6.6 mL) and EtOAc (0.7 ml) was added TiBr4 (385 mg, 1.05 mmol) at room temperature. After 21 h of stirring at the room temperature, the mixture was quenched with NaHCO3 (powder) and satd aq NaHCO3

(ca. 0.2 ml). The mixture was filtrated and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (CHCl3/CH3OH = 15:1) to give 18 as a white solid (60.5 mg, 64%, ca. 𝛼 anomer/𝛽 anomer = 7:3): Rf 0.20 (CHCl3/CH3OH = 15:1); mp 167.7 °C; [α]D24 －83.0 (c 1.025, CH3OH); IR  max 3414 (s), 2939 (m), 1689 (s), 1324 (s), 1227 (s), 1034 (s); ¹H NMR (600 MHz, CDCl3) δ 1.26 (d, J = 6.6 Hz, 3H × 0.7), 1.31 (d, J = 6.6 Hz, 3H × 0.3), 2.12−2.13 (m, 3H), 3.48−3.49

(m, 1H × 0.7), 3.53 (s, 3H × 0.7), 3.55 (quin, J = 1.2, 3.0 Hz, 1H × 0.3), 3.66 (s, 3H × 0.3), 3.75 (dq, J = 1.2, 6.6 Hz, 1H × 0.3), 4.38 (dq, J = 1.2, 6.6 Hz, 1H × 0.7), 4.73 (s, 1H

× 0.3), 4.98−5.01 (m, 2H × 0.3), 5.06 (s, 1H × 0.7), 5.27 (t, J = 3.6 Hz, 1H × 0.7), 5.39 (s, 1H × 0.7); ¹³C{¹H} NMR (150 MHz, CDCl3) δ 16.0, 16.1, 20.8, 21.0, 60.0, 61.7, 65.2, 68.1, 69.2, 69.9, 70.5, 71.6, 76.7, 77.5, 93.3, 93.8, 156.5, 156.7, 170.0, 170.2; HRMS (FAB) m/z calcd for C10H18NO7 ([M+H]⁺) 264.1078, found 264.1079.

3.1.4 2.6に関する実験

Ethyl-3-((1S,2S,4aR,5R,8aS)-5-hydroxy-2-methyl-8-methylene-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)-3-oxopropanoate (178).

To a stirred solution of ethyl diazoacetate (ca. 15.5 v/v%, 45.8 μl, 0.068 mmol) and BF3·OEt2 (18.3 μl, 0.146 mmol) in CH2Cl2 (0.050 mL) was added a solution of 22 (10.3 mg, 0.050 mmol) in CH2Cl2 (0.3 ml) at 0 °C.

After 3 h of stirring at 0 °C, the reaction mixture was quenched with satd aq NaHCO3 and diluted with CHCl3. The organic layer was separated,

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washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/EtOAc = 1:1) to give 178 as a pale yellow solid (11.6 mg, 79%).

One-pot synthesis of 178

To a stirred solution of 141 (119.7 mg, 0.427 mmol) in THF (2.2 mL) was added 0.25 M HCl aq (0.22 ml) at 0 °C. After 30 min of stirring at the same temperature, the mixture was quenched with satd aq NaHCO3 and diluted with CH2Cl2. The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo to give crude 23 as a pale yellow syrup. To a stirred solution of 23 (azeotropically dried with toluene) in CH2Cl2 (8.4 mL) was added Et2AlCl (0.87 M solution in toluene, 0.97 ml, 0.84 mmol) over a period for 10 min at －20 °C. The mixture was gradually warmed to 0 °C over a period for 30 min. After 6 h of stirring at 0 °C, to a stirred mixture were added ethyl diazoacetate (ca. 15.5 v/v%, 0.40 ml, 0.590 mmol) and BF3·OEt2 (0.16 ml, 1.27 mmol) at 0 °C. After 1 h of stirring at the same temperature, the mixture was quenched with satd aq NaHCO3 and satd aq Rochelle salt. The mixture was stirred for 1 h at room temperature.

The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/EtOAc = 1:1) to give 178 as a white solid (58.7 mg, 47%, 91% ee).

Rf 0.46 (hexane/EtOAc = 1:1) [α]D26 105.4 (c 0.515, CHCl3); IR  max 3363 (s), 2936 (m), 1739 (s), 1705 (s), 1331 (s), 1252 (s), 1063 (s), 1027 (s); ¹H NMR (400 MHz, CDCl3) δ 0.87 (d, J = 6.8 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H), 1.38−1.49 (m, 2H), 1.80 (tq, J = 2.4, 10.8 Hz, 1H), 2.16−2.26 (m, 3H), 2.33−2.38 (m, 1H), 2.67−2.72 (m, 1H), 3.20 (dd, J = 6.0, 11.6 Hz, 1H), 3.43−3.58 (m, 3H), 4.17−4.25 (m, 2H), 4.26 (s, 1H), 4.76 (s, 1H), 5.74 (ddd, J = 2.8, 4.8, 10.0 Hz, 1H), 5.95 (td, J = 1.6, 10.0 Hz, 1H); ¹³C{¹H} NMR (150 MHz, CDCl3) δ 14.1, 17.7, 31.0, 34.6, 37.9, 37.9, 49.5, 50.2, 51.5, 61.4, 73.6, 105.8, 125.3, 131.5, 149.2, 167.1, 203.4; HRMS (FAB) m/z calcd for C17H25O4 ([M+H]⁺) 293.1747, found 293.1750.

Methyl-((2S,3R,4R,5R,6S)-4-acetoxy-5-(carbamoyloxy)-3-methoxy-6-methyltetrahydro-2H-pyran-2-yl)-L-valinate (180)

To a stirred solution of 18 (145 mg, 0.551 mmol) and PPTS (27.6 mg, 0.110 mmol) in CH2Cl2 (2.0 mL) was added L-valine methyl ester (134 μl, 0.989 mmol) at room temperature. After 15 h of stirring at the same temperature, the mixture was concentrated in vacuo. The residue was purified by SiO2 flash column chromatography

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(CHCl3/CH3OH = 15:1) to give 180 as a white solid (70.9 mg, 99%, ca. 𝛼 anomer/𝛽 anomer = 1:9): Rf 0.37 (CHCl3/CH3OH = 15:1); mp 61.5 °C; [α]D20 －17.9 (c 1.020, CHCl3); IR  max 3382 (s), 2960 (m), 1732 (s), 1235 (s), 1092 (s); ¹H NMR (600 MHz, CDCl3) δ 0.89−0.90 (m, 3H), 0.96−0.99 (m, 3H), 1.15 (d, J = 6.0 Hz, 3H × 0.9), 1.21 (d, J = 6.6 Hz, 3H × 0.1), 1.79 (six, J = 6.6 Hz, 1H × 0.9), 2.01 (dq, J = 4.8, 6.6 Hz, 1H × 0.1), 2.11 (s, 3H), 2.87 (t, J = 12.6 Hz, 1H × 0.9), 2.98 (dd, J = 7.2, 10.8 Hz, 1H × 0.9), 3.31−3.33 (m, 2H × 0.1), 3.46 (s, 3H × 0.1), 3.53−3.58 (m, 2H × 0.9), 3.60 (s, 3H × 0.9), 3.69 (s, 3H × 0.9), 3.74 (s, 3H × 0.1), 3.94 (d, J = 12.6 Hz, 1H × 0.9), 4.35 (dq, J = 1.2, 6.6 Hz, 1H × 0.1), 4.50 (s, 1H × 0.1), 4.91 (t, J = 3.6 Hz, 1H × 0.9), 4.99−5.00 (m, 1H), 5.20 (t, J = 3.6 Hz, 1H × 0.1), 5.68 (brs, 1H × 0.9); ¹³C{¹H} NMR (150 MHz, CDCl3) δ 15.9 (2C), 17.9, 19.0, 19.0, 19.8, 21.0, 21.1, 31.3, 31.8, 51.6, 51.8, 59.4, 61.2, 62.7, 64.5, 65.5, 68.9, 69.2, 70.5, 70.8, 72.3, 77.4, 77.8, 84.9, 88.7, 156.8, 157.0, 170.1, 170.4, 175.5, 176.3; HRMS (FAB) m/z calcd for C16H29N2O8 ([M+H]⁺) 377.1918, found 377.1923.

Methyl-N-((2R,3R,4R,5R,6S)-4-acetoxy-5-(carbamoyloxy)-3-methoxy-6-methyltetrahydro-2H-pyran-2-yl)-N-((2-nitrophenyl)sulfonyl)-L-valinate (187)

To a stirred solution of 180 (28.0 mg, 0.106 mmol), 179 (83.6 mg, 0.264 mmol) and PPh3 (36.1 mg, 0.138 mmol) in THF (1.2 mL) was added DIAD (26.7 μl, 0.136 mmol) at 0 °C. After 20 min of stirring at room temperature, the reaction mixture was concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/EtOAc

= 1:2) to give 187 as a white solid (46.1 mg, 77%): Rf 0.34 (hexane/EtOAc = 1:2); ¹H NMR (600 MHz, CDCl3) δ 0.92 (d, J = 6.6 Hz, 3H), 1.11 (d, J = 6.0 Hz, 3H), 1.30 (d, J

= 7.2 Hz, 3H), 2.01−2.07 (m, 1H), 2.16 (s, 3H), 3.34 (s, 3H), 3.40 (s, 3H), 4.18 (d, J = 10.8 Hz, 1H), 4.29−4.33 (m, 2H), 4.69 (s, 1H), 5.01 (dd, J = 3.0, 6.6 Hz, 1H), 5.10 (d, J

= 9.6 Hz, 1H), 5.84 (t, J = 3.0 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.66 (t, J = 6.6 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H); ¹³C{¹H} NMR (150 MHz, CDCl3) δ 13.4, 19.0, 19.2, 21.2, 29.4, 51.5, 57.2, 65.3, 68.4, 68.4, 70.8, 75.8, 78.5, 123.0, 130.4, 131.5, 133.4, 133.6, 149.1, 155.0, 169.6, 170.0; HRMS (FAB) m/z calcd for C21H31NaN3O12 ([M+Na]⁺) 584.1521, found 584.1527.

tert-butyl(((2R,3S,E)-2-((4-methoxybenzyl)oxy)hex-4-en-3-yl)oxy)dimethylsilane (172).

To a stirred solution of 28 (9.33 g, 39.5 mmol) in CH2Cl2 (200 mL) were added imidazole (10.8 g, 159 mmol), and 4- (dimethylamino)pyridine (482 mg, 3.95 mmol) and TBSCl (11.9 g, 79.0

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mmol) at 0 °C. After 2 h of stirring at 0 °C, the ice bath was removed, and the stirring was continued for 12 h at room temperature. The reaction mixture was quenched with satd aq NaHCO3 and diluted with CHCl3, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/ EtOAc

= 5:1) to give 172 as a colorless syrup (13.2 g, 96%): Rf 0.58 (hexane/EtOAc = 5:1); [α]D24

13.1 (c 1.18, CHCl3); IR  max 2930 (m), 1613 (s), 1513 (s), 1248 (s), 1090 (s), 835 (s); ¹ H NMR (600 MHz, CDCl3) δ 0.016 (s, 3H), 0.044 (s, 3H), 0.89 (s, 9H), 1.11 (d, J = 6.0 Hz, 3H), 1.70 (dd, J = 1.2, 6.0 Hz, 3H), 3.41 (dq, J = 4.8, 6.0 Hz, 1H), 3.80 (s, 3H), 4.00 (t, J = 6.0 Hz, 1H), 4.51 (d, J = 11.4 Hz, 1H), 4.54 (d, J = 11.4 Hz, 1H), 5.48 (ddd, J = 1.8, 6.6, 15.6 Hz, 1H), 5.61 (dqd, J = 1.2, 6.0, 15.6 Hz, 1H), 6.85−6.87 (m, 2H), 7.25−7.26 (m, 2H); ¹³ C{¹ H} NMR (150 MHz, CDCl3) δ −4.73, −4.20, 16.1, 17.8, 18.2, 25.9, 55.3, 71.1, 76.9, 78.5, 113.6, 126.9, 129.2, 131.3, 131.8, 158.9; HRMS (FAB) m/z calcd for C20H34NaO3Si ([M + Na]⁺ ) 373.2169, found 373.2182.

(2R,3S,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-((4-methoxybenzyl)oxy)hexane-2,3-diol (173).

To a stirred suspension of AD-mix-β (20.54 g, 1.40 g / 1 mmol of olefin) and MeSO2NH2 (1.41 g, 14.8 mmol) in H2O (70 mL) and t-BuOH (70 mL) was stirred until the reaction mixture became clear at room temperature. After the reaction mixture was cooled to 0 °C, a solution of 172 (5.15 g, 14.7 mmol) in t-BuOH (10 mL, rinse) was added to the reaction mixture, and the stirring was continued for 48 h at 0 °C. The reaction mixture was quenched with sodium sulfite (21.5 g, 171 mmol). The reaction mixture was gradually warmed to room temperature over a period for 1 h. The resulting mixture was diluted with EtOAC, washed with brine. The aqueous layer was extracted with EtOAc (×2), and concentrated in vacuo.

The residue was purified by SiO2 flash column chromatography (hexane/ EtOAc = 2:1) to give 173 as a colorless syrup (5.31 g, 94%): Rf 0.28 (hexane/EtOAc = 2:1); [α]D24 −25.1 (c 1.04, CHCl3); IR  max 3444 (s), 2930 (m), 1613 (s), 1513 (s), 1247 (s), 1036 (s), 835 (s); ¹ H NMR (400 MHz, CDCl3) δ 0.11 (s, 3H), 0.13 (s, 3H), 0.90 (s, 9H), 1.17 (d, J = 6.0 Hz, 3H), 1.23 (d, J = 6.4 Hz, 3H), 2.60 (d, J = 7.6 Hz, 1H), 2.72 (d, J = 3.2 Hz, 1H), 3.49 (ddd, J = 2.0, 4.0, 7.6 Hz, 1H), 3.66 (quin, J = 6.0 Hz, 1H), 3.78 (dd, J = 4.0, 5.6 Hz, 1H), 3.81 (s, 3H), 4.06 (ddq, J = 2.0, 3.2, 6.4 Hz, 1H), 4.38 (d, J = 11.2 Hz, 1H), 4.54 (d, J = 11.2 Hz, 1H), 6.86−6.89 (m, 2H), 7.21−7.25 (m, 2H); ¹³ C{¹ H} NMR (100 MHz, CDCl3) δ -4.45, -4.32, 16.1, 18.1, 19.5, 26.0, 55.3, 66.7, 70.5, 74.8, 75.8, 78.1, 113.8, 129.3, 130.2, 159.2; HRMS (FAB) m/z calcd for C20H37O5Si ([M + H]⁺) 385.2405, found 385.2413.

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(2R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-((4-methoxybenzyl)oxy)-3-oxohexan-2-yl 4-methylbenzenesulfonate (176).

To a stirred solution of 173 (3.80 g, 9.88 mmol), Me3N∙HCl (94.4 mg, 0.988mmol) and Et3N (3.44 ml, 24.7 mmol) in CH2Cl2 (9.9 mL) was added a solution of TsCl (2.82 g, 14.8 mmol) in CH2Cl2 (9.9 mL) at 0 °C. After 40 min of stirring at 0 °C, Dess-Martin periodinane was added to the reaction mixture at 0 °C. After 1 h of stirring at 0 °C, the resulting mixture was quenched with NaHCO3 and diluted with (hexane/Et2O = 5:1). The mixture was filtered, extracted with (hexane/Et2O = 1:1) (×3), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/ Et2O = 2:1) to give 176 as a pale yellow syrup (4.30 g, 81%): Rf 0.31 (hexane/Et2O = 2:1); [α]D25 6.10 (c 1.36, CHCl3); IR  max

2931 (m), 1737 (s), 1613 (s), 1513 (s), 1368 (s), 1249 (s), 1176 (s), 834 (s); ¹ H NMR (600 MHz, CDCl3) δ 0.075 (s, 6H), 0.91 (s, 9H), 1.09 (d, J = 6.6 Hz, 3H), 1.38 (d, J = 7.2 Hz, 3H), 2.44 (s, 3H), 3.81 (s, 3H), 3.86 (dq, J = 3.6, 6.6 Hz, 1H), 4.40−4.47 (m, 3H), 5.43 (q, J = 7.2 Hz, 1H), 6.86−6.87 (m, 2H), 7.22−7.24 (m, 2H), 7.32−7.33 (m, 2H), 7.78−7.79 (m, 2H); ¹³ C{¹ H} NMR (150 MHz, CDCl3) δ -5.31, -4.48, 14.9, 17.1, 18.2, 21.7, 25.8, 55.3, 70.6, 76.2, 78.4, 79.6, 113.7, 127.9, 129.3, 129.8, 130.2, 133.7, 144.9, 159.1, 206.1; HRMS (FAB) m/z calcd for C27H40NaO7SSi ([M + Na]⁺ ) 559.2156, found 559.2161.

An analytical sample of by product was obtained as a colorless syrup by concentrating some chromatographic fractions in vacuo.

175: Rf 0.34 (hexane/Et2O = 2:1); [α]D24 1.94 (c 0.510, CHCl3); IR  max

3537 (s), 2930 (m), 1472 (s), 1376 (s), 1255 (s), 1116 (s), 838 (s); ¹ H NMR (600 MHz, CDCl3) δ 0.127 (s, 6H), 0.93 (s, 9H), 1.26−1.30 (m, 6H), 2.67 (d, J = 6.6 Hz, 1H), 3.54 (q, J = 6.0 Hz, 1H), 3.70 (t, J = 5.4 Hz, 1H), 3.73−3.77 (m, 2H);

13 C{¹ H} NMR (150 MHz, CDCl3) δ -4.85, -4.47, 18.0, 18.9, 19.0, 25.7, 76.2, 77.3, 79.4, 79.8; HRMS (FAB) m/z calcd for C12H27O3Si ([M + H]⁺ ) 247.1724, found 247.1733.

(2S,4R,5R)-2-azido-4-((tert-butyldimethylsilyl)oxy)-5-((4-methoxybenzyl)oxy)hexan-3-one (26).

To a stirred solution of 176 (2.59 g, 4.83 mmol) in DMF (10 mL) was added NaN3 (629 mg, 9.68 mmol) at room temperature. After 30 min of stirring at room temperature, the resulting mixture was diluted with (hexane/Et2O = 1:1), washed with brine. The aqueous layer was

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extracted with (hexane/Et2O = 1:1) (×2), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/ EtOAc = 12:1) to give 26 as a pale yellow syrup (1.92 g, 98%).

((1R,4R,5S,6S)-4-((tert-butyldimethylsilyl)oxy)-5-hydroxy-3,6-dimethyl-2-oxa-7-azabicyclo[3.2.1]octan-7-yl)(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)methanone (191).

To a stirred solution of 87 (10.0 mg, 0.021 mmol) in CH2Cl2

(0.2 mL) were added DBU (3.1 μl, 0.021 mmol) and CCl3Cl (3.1 μl, 0.208 mmol) at 0 °C. After 24 h of stirring at room temperature, the reaction mixture was concentrated in vacuo.

The residue was purified by SiO2 flash column chromatography (hexane/EtOAc = 2:1) to give 191 as a white solid (8.1 mg, 84%): Rf 0.28 (hexane/EtOAc = 2:1); mp 188.4 °C;

[α]D20 －69.7 (c 0.370, CHCl3); IR  max 3420 (s), 3323 (s), 2929 (m), 1633 (s), 1492 (s), 1390 (s), 1089 (s); ¹H NMR (600 MHz, CDCl3) δ 0.18−0.19 (m, 6H), 0.96 (s, 9H), 1.42 (d, J = 6.6 Hz, 3H), 1.45 (d, J = 6.6 Hz, 3H), 1.75 (dd, J = 3.0, 11.4 Hz, 1H), 2.25 (s, 3H), 2.35 (d, J = 11.4 Hz, 1H), 2.98 (s, 1H), 3.89−3.99 (m, 3H), 5.37 (d, J = 3.6 Hz, 1H) 9.86 (s, 1H); ¹³C{¹H} NMR (150 MHz, CDCl3) δ -4.4, -4.1, 11.6, 12.6, 18.1, 21.4, 25.7, 36.6, 57.9, 74.3, 75.1, 75.4, 84.9, 111.6, 117.9, 118.4, 126.7, 160.1; HRMS (FAB) m/z calcd for C20H33Cl2N2O4Si ([M+H]⁺) 463.1581, found 463.1586.

N-((S)-1-((2R,3R,4R,6R)-3-((tert-butyldimethylsilyl)oxy)-6-(((1R,4aS,5S,6S,8aR)-5- formyl-6-methyl-4-methylene-1,2,3,4,4a,5,6,8a-octahydronaphthalen-1-yl)oxy)-4- hydroxy-2-methyltetrahydro-2H-pyran-4-yl)ethyl)-3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamide (192).

A stirred solution of 191 (6.0 mg, 0.0129 mmol), 22 (5.4 mg, 0.0262 mmol) and MS4A (12.1 mg) in CH2Cl2 (0.2 mL) was stirred for 1 h at room temperature. To reaction mixture was added TBSOTf (5.9 μl, 0.0257 mmol) at 0 °C.

After 3 h of stirring at 0 °C, the reaction mixture was stirred for 21 h at room temperature. The mixture was quenched with satd aq NaHCO3, diluted with CHCl3, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 flash column chromatography (hexane/EtOAc = 2:1) to give 192 as a white solid (5.1 mg, 59%): Rf 0.32 (hexane/EtOAc

= 3:1);¹H NMR (400 MHz, CDCl3) δ 0.18 (s, 3H), 0.21 (s, 3H), 0.98 (s, 9H), 1.01 (d, J = 7.2 Hz, 1H), 2.41 (d, J = 6.8 Hz, 1H), 1.29-1.39 (m, 4H), 1.56-1.63 (m, 1H), 1.84-1.92 (m, 2H), 2.13(dt, J = 4.8, 14.4 Hz, 1H), 2.24-2.41 (m, 6H), 2.64-2.75 (m, 2H), 2.80 (d, J

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= 2.4 Hz, 1H), 3.43 (d, J = 8.8 Hz, 1H), 3.60 (dt, J = 4.4, 10.8 Hz, 1H), 3.72 (qd, J = 6.4, 8.8 Hz, 1H), 4.38 (s, 1H), 4.51 (qd, J = 6.8, 8.4 Hz, 1H), 4.83 (s, 1H), 4.93 (dd, J = 2.0, 9.2 Hz, 1H), 5.63 (ddd, J = 2.4, 4.0, 10.0 Hz, 1H), 6.03 (td, J = 1.6, 10.0 Hz, 1H), 6.57 (d, J = 8.8 Hz, 1H), 9.08 (s, 1H), 9.64 (d, J = 4.4 Hz, 1H); HRMS (FAB) m/z calcd for C33H50Cl2N2O6Si ([M+Na]⁺) 691.2707, found 691.2720.

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