Stereocontrolled First Total Syntheses of Amarouciaxanthin A and B

Transcription

1 Stereocontrolled First Total Syntheses of Amarouciaxanthin A and B Yumiko Yamano,* Mahankhali Venu Chary, and Akimori Wada Department of Organic Chemistry for Life Science, Kobe Pharmaceutical University, , Motoyamakita-machi, Higashinada-ku, Kobe , Japan y-yamano@kobepharma-u.ac.jp General UV-vis spectra were recorded on a JASCO Ubest-55 instrument. IR spectra were measured on a Perkin-Elmer FT-IR spectrometer, spectrum 100, using chloroform solution. 1 H and 13 C NMR spectra were determined on a Varian Gemini-300 superconducting FT-NMR spectrometer, using deuteriochloroform solutions (tetramethylsilane as internal reference). J values are given in Hz. Mass spectra were taken on a Thermo Fisher Scientific Exactive spectrometer. Optical rotations were measured on a JASCO DIP-181 porarometer and CD spectra on a Shimadzu-AVIN 62A DS circular dichroism spectrometer. Flash column chromatography (CC) was performed on using Kanto Silica Gel 60 N. Short-CC was conducted on silca gel (Merck Art. 7739) under reduced pressure. Preparative HPLC was carried out on a Shimadzu LC-6A with a UV-vis detector. All operations were carried out under nitrogen or argon. Evaporation of the extract or the filtrate was carried out under reduced pressure. Ether refers to diethyl ether, and hexane to n-hexane. NMR assighments are given using the carotenoid nmbering system. Experimental (4R,6R)-2,2,6-Trimethyl-4-triethylsilyloxycyclohexanone (14) TESCl (7.34 ml, 43.7 mmol) was added dropwise to a stirred solution of ( )-actinol (12) (6.50 g, 41.7 mmol), DMAP (508 mg, 4.2 mmol) and Et 3 N (6.99 ml, 50.0 mmol) in dry CH 2 Cl 2 (30 ml) at 0 C. After being stirred at rt for 30 min, the mixture was poured into saturated aq. NH 4 Cl and extracted with ether. The extracts were washed with brine, dried and evaporated to give a residue, which was purified by flash CC (ether-hexane, 7:93) to afford the TES ether 14 (10.97 g, 99%) as a colorless oil: [α] 21 D 64.5 (c 0.91, MeOH); IR ν max cm (CO); 1 H NMR (300 MHz) δ 0.63 (6H, q, J 8, SiCH 2 3), 0.99 (9H, t, J 8, SiCH 2 Me 3), 1.01 (3H, d, J 6.5, 5-Me), 1.02, 1.35 (each 3H, s, gem-me), 1.60 (1H, td, J 13.5, 3, 4-Hα), 1.68 (1H, dd, J 13.5, 3,5, 2-Hα), 1.92 (1H, dt, J 13.5, 3.5, 2-Hβ), 2.03 (1H, m, 4-Hβ), 3.20 (1H, dquint-like, 13,5, 3.5, 5-H), 4.12 (1H, quint, J 3.5, 1

2 3-H); 13 C NMR (75 MHz) δ 4.77, 6.85, 14.55, 26.37, 28.44, 35.30, 43.85, 44.89, 48.01, 66.38, ; HRMS (ESI) m/z calcd for C 15 H 31 O 2 Si (MH) , found (R)-2,6,6-Trimethyl-4-triethylsilyloxycyclohex-1-en-1-yl Trifluoromethanesulfonate (15) To a stirred solution of diisopropylamine (5.13 ml, 36.7 mmol) in dry THF (60 ml) was added dropwise n-buli (1.63 M in hexane; 22.5 ml, 36.7 mmol) at 78 C and the mixture was stirred for a further 30 min. To this LDA solution was added dropwise a solution of the ketone 14 (9.00 g, 33.3 mmol) in dry THF (45 ml) at 78 C. After being stirred for a further 1 h, a solution of Tf 2 NPh (12.50 g, 35.0 mmol) in dry THF (45 ml) was then added dropwise to this mixture. The mixture was stirred at 78 C for 1 h and then allowed to warm to rt overnight. The mixture was poured into saturated aq. NH 4 Cl and extracted with ether. The extracts were washed with brine, dried and evaporated to give a residue, which was purified by flash CC (ether-hexane, 4:96) to afford the triflate 15 (12.36 g, 92%) as a colorless oil: [α] 22 D 22.3 (c 1.01, MeOH); 1 H NMR (300 MHz) δ 0.61 (6H, q, J 8, SiCH 2 3), 0.96 (9H, t, J 8, SiCH 2 Me 3), 1.15, 1.21 (each 3H, s, gem-me), 1.69 (1H, t, J 12.5, 2-Hβ), 1.75 (3H, br s, 5-Me), 1.76 (1H, ddd, J 12.5, 4, 1.5, 2-Hα), 2.19 (1H, ddq, 17, 9, 1, 4-Hβ), 2.36 (1H, ddd, J 17, 5.5, 1.5, 4-Hα), 4.02 (1H, m, 3-H); 13 C NMR (75 MHz) δ 4.81 (C 3), 6.76 (C 3), 17.55, 26.54, 27.28, 36.72, 41.68, 49.30, 63.93, (d, J 318), , ; HRMS (ESI) m/z calcd for C 16 H 30 O 4 F 3 SSi (MH) , found (R)-Methyl 2,6,6-Trimethyl-4-triethylsilyloxycyclohex-1-enecarboxylate (16) CO gas was bubling to a stirred solution of the triflate 15 (12.27 g, 30.5 mmol), Pd(PPh 3 ) 4 (1.04 g, 0.90 mmol) and Et 3 N (13.0 ml, 92.9 mmol) in DMF (80 ml) and MeOH (35 ml) at 70 C over 4 h. After cooling, the mixture was poured into saturated aq. NH 4 Cl and extracted with AcOEt. The extract was washed with brine, dried and evaporated to give a residue, which was purified by flash CC (ether-hexane, 1:9 to 15:85) to provide the ester 16 (8.66 g, 91%) as a colorless oil: [α] 25 D 47.8 (c 1.02, MeOH); IR ν max cm (conj. CO), 1656 (C=C); 1 H NMR (300 MHz) δ 0.61 (6H, q, J 8, SiCH 2 3), 0.97 (9H, t, J 8, SiCH 2 Me 3), 1.04, 1.20 (each 3H, s, gem-me), 1.48 (1H, t, J 12, 2-Hβ), 1.65 (1H, ddd, J 12, 3.5, 1.5, 2-Hα), 1.67 (3H, br s, 5-Me), 2.04 (1H, ddq, J 17, 9, 1, 4-Hβ), 2.23 (1H, ddd, J 17, 5.5, 1.5, 4-Hα), 3.74 (3H, s, CO 2 Me), 3.99 (1H, m, 3-H); 13 C NMR (75 MHz) δ 4.79, 6.83, 21.15, 28.52, 29.15, 35.85, 41.51, 47.79, 51.26, 64.90, , , ; HRMS (ESI) m/z calcd for C 17 H 33 O 3 Si (MH) , found [(R)-2,6,6-Trimethyl-4-triethylsilyloxycyclohex-1-en-1-yl]methanol (17) DIBALH (1.0 M in hexane; 33.4 ml, 33.4 mmol) was added dropwise to a stirred solution of the ester 16 (4.76 g, 15.3 mmol) and 5 drops of Et 3 N in dry 2

3 ether (90 ml) at 0 C. After being stirred for a further 20 min at 0 C, the excess of reagent was decomposed by slow addition of moist silica gel at 0 C and the mixture was stirred for 15 min at rt. The mixture was filtered through a pad of Celite, and the filtrete was evaporated to afford the residue, which was purified by purified by flash CC (acetone-hexane, 1:3) to provide the alcohol 17 (4.26 g, 98%) as a colorless solid: [α] 21 D 61.9 (c 1.14, MeOH); IR ν max cm , 3451 (OH); 1 H NMR (300 MHz) δ 0.61 (6H, q, J 8, SiCH 2 3), 0.97 (9H, t, J 8, SiCH 2 Me 3), 1.05, 1.10 (each 3H, s, gem-me), 1.49 (1H, t, J 12, 2-Hβ), 1.65 (1H, ddd, J 12, 3.5, 1.5, 2-Hα), 1.76 (3H, br s, 5-Me), 2.07 (1H, br dd, J 17, 9, 4-Hβ), 2.19 (1H, br dd, J 17, 5.5, 4-Hα), 3.91 (1H, m, 3-H), 4.08, 4.16 (each 1H, d, J 11, 7-H 2 ); 13 C NMR (75 MHz) δ 4.87 (C 3), 6.82 (C 3), 19.59, 28.51, 29.36, 36.77, 42.79, 48.62, 58.30, 65.28, , ; HRMS (ESI) m/z calcd for C 16 H 32 O 2 NaSi (M+Na) , found [(1R, 4S, 6R)-2,2,6-Trimethyl-4-triethylsilyloxy-7-oxabicyclo[4.1.0]heptan-1-yl]methanol (18) To a stirred solution of ( )-D-DET (0.72 ml, 4.21 mmol) in dry CH 2 Cl 2 (60 ml) containing powdered molecular sieves 4A (freshly dried; 2.5 g) was added Ti(O i Pr) 4 (0.83 ml, 2.81 mmol) at 20 C. After being stired at 20 C for 10 min, TBHP (5.5 M in decane; 5.1 ml, 28.1 mmol) was added to this mixture at 20 C. Then reaction mixture was cooled to 30 C and a solution of the allyl alcohol 17 (4.00 g, 14.1 mmol) in dry CH 2 Cl 2 (18 ml) was added dropwise to this mixture. After being stirred at 30 C for 1 h, the mixture was filtered through a pad of Celite and a mixed solution of FeSO 4 -citric acid-water (6:16:100; 30 ml) was added to the filtrate. After being stirred for 30 min at rt, the mixture was extracted with CH 2 Cl 2, washed with brine, dried and evaporated. The resulting residue was purified by purified by flash CC (AcOEt-hexane, 1:3) to provide the alcohol 18 (4.10 g, 97%) as a colorless solid: [α] 26 D 34.9 (c 0.96, MeOH); IR ν max cm (OH); 1 H NMR (300 MHz) δ 0.58 (6H, q, J 8, SiCH 2 3), 0.95 (9H, t, J 8, SiCH 2 Me 3), 1.07, 1.14 (each 3H, s, gem-me), 1.24 (1H, dd, J 13, 11, 2-Hβ), 1.40 (3H, s, 5-Me), 1.45 (1H, ddd, J 13, 3.5, 2, 2-Hα), 1.63 (1H, dd, J 14, 9, 4-Hβ), 1.91 (1H, br s, OH), 2.23 (1H, ddd, J 14, 5, 2, 4-Hα), 3.73, 3.84 (each 1H, br d, J 10, 7-H 2 ), 3.78 (1H, m, 3-H); 13 C NMR (75 MHz) δ 4.75 (C 3), 6.80 (C 3), 19.63, 24.77, 27.06, 34.21, 42.46, 48.40, 60.06, 64.03, 65.91, 68.19; HRMS (ESI) m/z calcd for C 16 H 32 O 3 NaSi (M+Na) , found (1R, 4S, 6R)-2,2,6-Trimethyl-4-triethylsilyloxy-7-oxabicyclo[4.1.0]heptane-1-carbaldehyde (19) To a mixture of the epoxy alcohol 18 (1.75 g, 5.83 mmol) and NaHCO 3 (588 mg, 7.0 mmol) in CH 2 Cl 2 (30 ml) was added DMP (2.97 g, 7.0 mmol) in some portions at rt and the mixture was stirred for a farther 30 min. After CH 2 Cl 2 was evaporated off, the resulting mixture was diluted with ether-hexane (1:1) and filtered through a pad of Celite. The filtrate was evaporated to afford the residue, which was purified by purified by flash CC (AcOEt-hexane, 12:88) to provide the aldehyde 19 (1.49 g, 86%) as a colorless oil: [α] 26 D 60.3 (c 3

4 0.91, MeOH); IR ν max cm (CHO); 1 H NMR (300 MHz) δ 0.58 (6H, q, J 8, SiCH 2 3), 0.95 (9H, t, J 8, SiCH 2 Me 3), 1.08, 1.28 (each 3H, s, gem-me), 1.30 (1H, dd, J 13, 9.5, 2-Hβ), 1.37 (3H, s, 5-Me), 1.49 (1H, ddd, J 13, 3.5, 1.5, 2-Hα), 1.71 (1H, dd, J 15, 8, 4-Hβ), 2.25 (1H, ddd, J 15, 5.5, 1.5, 4-Hα), 3.84 (1H, m, 3-H), 9.80 (1H, s, CHO); 13 C NMR (75 MHz) δ 4.73 (C 3), 6.80 (C 3), 20.53, 26.14, 28.07, 33.70, 41.00, 46.77, 63.95, 66.45, 77.24, ; HRMS (ESI) m/z calcd for C 16 H 31 O 3 Si (M+Na) , found Triethyl[(1R, 3S, 6R)-6-ethynyl-1,5,5-trimethyl -7-oxabicyclo[4.1.0]heptan-3-yl]oxysilane (20) To a stirred solution of diisopropylamine (1.02 ml, 7.3 mmol) in dry THF (40 ml) was added dropwise n-buli (1.63 M in hexane; 4.47 ml, 7.3 mmol) at 78 C and the mixture was stirred for a further 15 min. To this LDA solution was added dropwise TMSCHN 2 (2.0 M in ether; 3.65 ml, 7.3 mmol) at 78 C. After being stirred for a further 30 min, a solution of the aldehyde 19 (1.45 g, 4.87 mmol) in dry THF (10 ml) was then added dropwise to this mixture. The mixture was stirred at 78 C for 1 h and then allowed to warm to rt over 2 h. The mixture was poured into saturated aq. NH 4 Cl and extracted with ether. The extracts were washed with brine, dried and evaporated to give a residue, which was purified by flash CC (ether-hexane, 8:92) to afford the alkyne 20 (1.26 g, 88%) as a colorless oil: [α] 21 D 26.7 (c 1.18, MeOH); IR ν max cm ( C-H), 2117 (C C); 1 H NMR (300 MHz) δ 0.57 (6H, q, J 8, SiCH 2 3), 0.94 (9H, t, J 8, SiCH 2 Me 3), 1.11, 1.25 (each 3H, s, gem-me), 1.23 (1H, dd, J 13, 10, 2-Hβ), 1.50 (3H, s, 5-Me), 1.48 (1H, ddd, J 13, 3.5, 2, 2-Hα), 1.66 (1H, dd, J 14.5, 8, 4-Hβ), 2.23 (1H, ddd, J 14.5, 5.5, 2, 4-Hα), 2.39 (1H, s, C-H), 3.76 (1H, m, 3-H); 13 C NMR (75 MHz) δ 4.70 (C 3), 6.80 (C 3), 21.49, 25.33, 29.64, 33.92, 40.39, 46.06, 63.06, 63.90, 66.62, 73.94, 80.76; HRMS (ESI) m/z calcd for C 17 H 31 O 2 Si (MH) , found (E)-3-Methyl-5-[(1R,4S,6R)-2,2,6-trimethyl-4-triethylsilyloxy-7- oxabicyclo[4.1.0]heptan-1-yl]pent-2-en-4-yn-1-ol (22) To a stirred, degassed solution of the terminal alkyne 20 (2.41 g, 8.2 mmol) and the vinyl iodide 21 (1.98 g, 8.2 mmol) in diisopropylamine (20 ml) was added Pd(PPh 3 ) 4 (142 mg, 0.12 mmol) and CuI (23 mg, 0.12 mmol). After being stirred at rt for a further 1 h, the mixture was poured into saturated aq. NH 4 Cl and extracted with AcOEt. The extract was washed with brine, dried and evaporated to give a residue, which was purified by flash CC (AcOEt-hexane, 3:7 to 1:2) to provide the epoxyalcohol 22 (2.78 g, 93%) as a pale yellow oil: [α] 22 D 0.24 (c 1.17, MeOH); IR ν max cm , 3443 (OH), 2217 (C C), 1633, 1602 (C=C); 1 H NMR (300 MHz) δ 0.57 (6H, q, J 8, SiCH 2 3), 0.95 (9H, t, J 8, SiCH 2 Me 3), 1.11, 1.24 (each 3H, s, gem-me), 1.24 (1H, overlapped, 2-Hβ), 1.39 (1H, t, J 5, OH), 1.48 (3H, s, 5-Me), 1.49 (1H, ddd, J 13, 3.5, 1.5, 2-Hα), 1.66 (1H, dd, J 14.5, 8, 4-Hβ), 1.83 (3H, br s, 9-Me), 2.24 (1H, ddd, J 14.5, 5, 2, 4-Hα), 3.77 (1H, m, 3-H), 4.23 (2H, br t-like, J 5.5, 11-H 2 ), 6.01 (1H, tq, J 6.5, 1.5, 10-H); 13 C NMR (75 MHz) δ 4.71 (C 3), 6.77 (C 3), 17.39, 21.66, 25.52, 29.78, 4

5 34.40, 40.52, 46.21, 58.95, 63.73, 64.03, 67.16, 84.62, 87.87, , ; HRMS (ESI) m/z calcd for C 21 H 37 O 3 Si (MH) , found (1R,5S)-2-[(R,E)-5-Hydroxy-3-methylpenta-1,3-dien-1-ylidene]- 1,3,3-trimethyl-5-triethylsilyloxycyclohexanol (23) DIBALH (1.0 M in hexane; 25.2 ml, 25.2 mmol) was added dropwise to a stirred solution of the compound 22 (1.92 g, 5.27 mmol) in dry ether (50 ml) at 0 C. After being stirred at 0 C for 10 min and then rt for 20 min, the excess of reagent was decomposed by slow addition of moist silica gel at 0 C and the mixture was stirred for 15 min at rt. The mixture was filtered through a pad of Celite, and the filtrete was evaporated to afford the residue, which was purified by purified by flash CC (AcOEt-hexane, 2:3) to provide the allenic compound 23 (1.78 g, 92%) as a colorless viscous oil: [α] 26 D 25.0 (c 0.80, EtOH); IR ν max cm , 3439 (OH), 1937 (C=C=C); 1 H NMR (300 MHz) δ 0.63 (6H, q, J 8, SiCH 2 3), 0.98 (9H, t, J 8, SiCH 2 Me 3), 1.05 (3H, s, 1-Me), 1.32 (6H, s, 1-Me, 5-Me), 1.37 (1H, t, J 12.5, 2-Hβ), 1.43 (1H, dd, J 13, 11.5, 4-Hβ), 1.66 (3H, br s, 9-Me), 1.82 (1H, ddd, J 12.5, 4, 2, 2-Hα), 2.14 (1H, ddd, J 13, 4, 2, 4-Hα), 4.24 (2H, d, J 7, 11-H 2 ), 4.27 (1H, m, 3-H), 5.57 (1H, br t, J 7, 10-H), 5.92 (1H, s, 8-H); 13 C NMR (75 MHz) δ 4.82 (C 3), 6.86 (C 3), 13.47, 29.17, 31.32, 32.08, 35.55, 49.27, 49.92, 59.43, 64.56, 72.87, , , , , ; HRMS (ESI) m/z calcd for C 21 H 38 O 3 NaSi (M+Na) , found Preparation of the phosphonium salt 7 A solution of LiCl (346 mg, 8.14 mmol) in dry DMF (10 ml) was added to a stirred solution of the alcohol 23 (2.71 g, 7.40 mmol) and γ-collidine (1.79 ml, 13.3 mmol) in dry DMF (10 ml) at 0 C and the mixture was stirred at 0 C for 15 min. To this mixture was added MsCl (0.75 ml, 9.69 mmol) and the mixture was stirred at 0 C for 1 h. The mixture was poured into chilled birne and extracted with ehter. Evaporation of the dried extract provided a residue, which was purified by short-cc (ether-hexane, 3:7) to afford the allyl chloride (2.87 g, 91%). To a stirred solution of this chloride and 5 drops Et 3 N in dry CH 2 Cl 2 (15 ml) was added dropwise n Bu 3 P (1.86 ml, 7.45 mmol) at 0 C and the mixture was stirred at rt for 2 h. Evaporation of the solvent gave a residue, which was washed with ether to provide the phosphonium chloride 7 (2.87 g, 66% from 23) as a colorless solid: IR ν max cm , 3350 (OH), 1938 (C=C=C), 1630 (C=C); 1 H NMR (300 MHz) δ 0.63 (6H, q, J 8, SiCH 2 3), 0.94 (3H, s, 1-Me), 0.98 (18H, t, J 8, CH 2 Me 6), 1.31, 1.32 (each 3H, s, 1-Me, 5-Me), (2H, m, 2-Hβ, 4- Hβ), 1.53 (12H, m, CH 2 6), 1.77 (3H, d, J 3, 9-Me), 1.82 (1H, br d, J 12, 2-Hα), 2.14 (3H, br d, J 12, 4-Hα), 2.47 (6H, m, PCH 2 3), 3.63 (2H, dd, J 16 and 7.5, 11-H 2 ), 4.27 (1H, m, 3-H), 5.27 (1H, br q-like, J 6, 10-H), 5.97 (1H, s, 8-H); HRMS (ESI) m/z calcd for C 33 H 63 O 2 ClPSi (M H) , found ; HRMS (ESI) m/z calcd for C 33 H 64 O 2 PSi 5

6 (M Cl) , found (E)-Methyl 3-[(1S,4S,6R)-4-tert-Butyldimethylsilyloxy-2,2,6- trimethyl-7-oxabicyclo[4.1.0]heptan-1-yl]acrylate (27) To a stirred solution of trimethyl phosphonoacetate (2.63 ml, 16.2 mmol) in dry THF (25 ml) was added dropwise n-buli (1.59 M in hexane; 10.2 ml, 16.2 mmol) at 0 C and the mixture was stirred for a further 15 min. A solution of the aldehyde 26 (2.40 g, 8.1 mmol) in dry THF (7 ml) was then added dropwise to this solution at 0 C. After being stirred at 0 C for a further 30 min, the mixture was poured into saturated aq. NH 4 Cl and extracted with ether. The extracts were washed with brine, dried and evaporated to give a residue, which was purified by flash CC (ether-hexane, 1:4) to afford the α,β-unsaturated ester 27 (2.76 g, 97%) as a colorless oil: [α] 25 D 81.5 (c 1.00, MeOH); IR ν max cm (conj. CO), 1654 (C=C); 1 H NMR (300 MHz) δ 0.04, 0.05 (each 3H, s, SiMe 2), 0.88 (9H, s, t Bu), 0.95, 1.17, 1.18 (each 3H, s, gem-me, 5-Me), 1.26 (1H, dd, J 13, 10, 2-Hβ), 1.51 (1H, ddd, J 13, 3.5, 2, 2-Hα), 1.67 (1H, dd, J 14.5, 8, 4-Hβ), 2.24 (1H, ddd, J 14.5, 5, 1.5, 4-Hα), 3.75 (3H, s, CO 2 Me), 3.85 (1H, m, 3-H), 6.04 (1H, d, J 15.5, 8-H), 7.20 (1H, d, J 15.5, 7-H); 13 C NMR (75 MHz) δ 4.79, 4.75, 18.07, 19.96, 25.06, (C 3), 29.23, 34.84, 41.03, 46.58, 51.58, 64.47, 67.06, 69.65, , , ; HRMS (ESI) m/z calcd for C 19 H 34 O 4 NaSi (M+Na) , found Hydrogenation of the dienoate 27 A suspension of the α,β-unsaturated ester 27 (1.00 g, 2.82 mmol) and 5% palladium on carbon (100 mg) in EtOH (20 ml) was stirred under hydrogen atmosphere at rt for 2.5 h. The mixture was filtered through a pad of Celite. The filtrate was evaporated to afford the residue, which was purified by purified by flash CC (AcOEt-hexane, 15:85 to 1:3) to provide the saturated ester 27 (542 mg, 54%), accompanied by syn-hydroxy compound a (231 mg, 23 %) and anti-hydroxy compound b (84 mg, 8%) as colorless oils, respectively. Methyl 3-[(1S,4S,6R)-4-tert-Butyldimethylsilyloxy-2,2,6-trimethyl-7-oxabicyclo[4.1.0]heptan-1-yl]propanoate (28): [α] 25 D 12.6 (c 1.04, MeOH); IR ν max cm (CO); 1 H NMR (300 MHz) δ 0.02, 0.03 (each 3H, s, SiMe 2), 0.89 (9H, s, t Bu), 1.03, 1.14 (each 3H, s, gem-me), 1.18 (1H, dd, J 13, 9.5, 2-Hb), 1.31 (3H, s, 5-Me), 1.43 (1H, ddd, J 13, 3, 1.5, 2-Ha), 1.63 (1H, dd, J 14, 7.5, 4-Hb), 1.94, 2.08 (each 1H, ddd, J 15, 10, 6.5, 7-H 2 ), 2.18 (1H, ddd, J 14, 5, 1.5, 4-Ha), 2.45 (2H, m, 8-H 2 ), 3.67 (3H, s, CO 2 Me), 3.77 (1H, m, 3-H); 13 C NMR (75 MHz) δ 4.79, 4.76, 18.07, 20.93, 25.12, (C 3), 28.60, 31.21, 35.32, 41.89, 47.51, 51.64, 64.42, 65.11, 68.06, ; HRMS (ESI) m/z calcd for C 19 H 36 O 4 NaSi (M+Na) , found (E)-Methyl 3-[(1S,2R,4S)-4-tert-Butyldimethylsilyloxy-2-hydroxy- 2,6,6-trimethylcyclohexyl]acrylate (major) (a): [α] D (c 1.10, 6

7 MeOH); IR ν max cm , 3472 (OH), 1709 (conj. CO), 1653, 1602 (C=C); 1 H NMR (500 MHz) δ 0.08 (6H, s, SiMe 2), 0.84 (3H, s, 1-Meβ), 0.89 (9H, s, t Bu), 1.09 (3H, s, 1-Meα), 1.12 (3H, s, 5-Me), 1.21 (1H, t-like, J 12.5, 2-Hβ), 1.35 (1H, dd, J 13, 11, 4-Hβ), 1.71 (1H, d, J 10.5, 6-H), 1.71 (1H, ddd, J 12.5, 4, 2, 2-Hα), 1.94 (1H, ddd, J 13, 4, 2, 4-Hα), 3.75 (3H, s, CO 2 Me), 4.11 (1H, tt, J 11, 4, 3-H), 5.84 (1H, d, J 15.5, 8-H), 7.05 (1H, dd, J 15.5, 10.5, 7-H) (NOE cross peaks between 6-H and 1-Meβ, 5-Me and between 5-Me and 4-Hβ were observed); 13 C NMR (75 MHz) δ 4.62, 4.56, 18.21, 22.67, (C 3), 31.76, 32.44, 33.75, 50.08, 50.78, 51.48, 57.69, 64.89, 73.61, , ; HRMS (ESI) m/z calcd for C 19 H 36 O 4 NaSi (M+Na) , found (E)-Methyl 3-[(1R,2R,4S)-4-tert-Butyldimethylsilyloxy-2-hydroxy-2,6,6-trimethylcyclohexyl]acrylate (minor) (b): [α] 25 D 5.47 (c 1.06, MeOH); IR ν max cm , 3468 (OH), 1717 (conj. CO), 1651, 1601 (C=C); 1 H NMR (500 MHz) δ 0.07 (6H, s, SiMe 2), 0.84 (3H, s, 1-Meβ), 0.89 (9H, s, t Bu), 1.15 (3H, s, 5-Me), 1.19 (3H, s, 1-Meα), 1.42 (1H, dd, J 13, 10, 2-Hβ), 1.52 (1H, br dd, J 13, 4.5, 2-Hα), 1.55 (1H, dd, J 13.5, 10, 4-Hβ), 1.78 (1H, ddt-like, J 13.5, 4.5, 1.5, 4-Hα), 1.96 (1H, d, J 11.5, 6-H), 3.75 (3H, s, CO 2 Me), 4.17 (1H, tt, J 10, 4.5, 3-H), 5.81 (1H, d, J 15.5, 8-H), 6.86 (1H, dd, J 15.5, 11.5, 7-H) (NOE cross peaks between 5-Me and 7-H were observed); 13 C NMR (75 MHz) δ 4.74, 4.70, 18.17, (C 3), 30.72, 30.88, 31.54, 34.97, 45.14, 45.51, 51.47, 59.31, 65.99, 73.99, 73.93, , , ; HRMS (ESI) m/z calcd for C 19 H 36 O 4 NaSi (M+Na) , found Methyl 3-[(1S,4S,6R)-4-tert-Butyldimethylsilyloxy-2,2,6-trimethyl-7- oxabicyclo[4.1.0]heptan-1-yl]-2-hydroxypropanoate (30) To a stirred solution of diisopropylamine (0.74 ml, 5.29 mmol) in dry THF (20 ml) was added dropwise n-buli (1.64 M in hexane; 3.21 ml, 5.26 mmol) at 78 C and the mixture was stirred for a further 20 min. To this LDA solution was added dropwise a solution of the ester 28 (620 mg, 1.74 mmol) in dry THF (10 ml) at 78 C. After being stirred at 20 C for 50 min, a solution of oxadirizine 29 (1.21 g, 5.28 mmol) in dry THF (12 ml) was added dropwise to this mixture at 78 C. After being stirred at 78 C for 50 min and then at 10 C for 20 min, the mixture was poured into saturated aq. NH 4 Cl and extracted with AcOEt. The extracts were washed with brine, dried and evaporated to give a residue, which was purified by flash CC (acetone-hexane, 17:83) to afford the α-hydroxy ester 30 (1.22 g, 93%) as a colorless oil: [α] 25 D 12.5 (c 1.25, MeOH); IR ν max cm (OH), 1736 (CO); 1 H NMR (300 MHz) δ 0.02, 0.03 (each 3H, s, SiMe 2), 0.86 (9H, s, t Bu), 1.05, 1.11 (each 3H, s, gem-me), 1.21 (1H, dd, J 13, 9, 2-Hβ), 1.33 (3H, s, 5-Me), 1.47 (1H, ddd, J 13, 3, 1.5, 2-Hα), 1.66 (1H, dd, J 14.5, 8, 4-Hβ), 2.13 (1H, dd, J 15.5, 9, 7-H), 2.19 (1H, dd, J 15.5, 3.5, 7-H), 2.24 (1H, ddd, J 14.5, 5, 1.5, 4-Hα), 2.84 (1H, d, J 4.5, OH), 3.76 (3H, s, CO 2 Me), 3.80 (1H, m, 3-H), 4.25 (1H, dt-like, J 9, 4, 8-H); 13 C NMR (75 MHz) δ 4.83, 4.77, 18.08, 20.26, 24.92, (C 3), 28.47, 32.65, 35.10, 42.05, 47.10, 7

8 52.43, 64.36, 65.31, 66.94, 68.72, ; HRMS (ESI) m/z calcd for C 19 H 36 O 5 NaSi (M+Na) , found [(1S,4S,6R)-4-tert-Butyldimethylsilyloxy-2,2,6-trimethyl-7- oxabicyclo[4.1.0]heptan-1-yl]acetaldehyde (9) A solution of α-hydroxy ester 30 (450 mg, 1.21 mmol) in dry Et 2 O (5 ml) was added dropwise to a stirred suspension of LAH (62 mg, 1.63 mmol) in dry Et 2 O (10 ml) at 0 C and the mixtre was stirred for a further 30 min. After the excess of reagent was decomposed by dropwise addition of water at 0 C, the mixture was diluted with AcOEt and filtered through a pad of Celite. The filtrete was evaporated to afford the crude 1,2-diol, which without purification was dissolved in 1,4-dioxane (10 ml) and water (3.5 ml). To this mixture was added NaIO 4 (517 mg, 2.37 mmol) in several portions at rt and the mixture was stirred for a further 40 min. The mixture was diluted with AcOEt and washed with water and then brine. The organic layer was dried and evaporated to give a residue, which was purified by purified by flash CC (AcOEt-hexane, 15:85) to provide the aldehyde 9 (318 mg, 84% from 30) as a colorless oil: [α] 25 D 49.9 (c 0.88, MeOH); IR ν max cm (CHO); 1 H NMR (300 MHz) δ 0.03, 0.12 (each 3H, s, SiMe 2), 0.84 (9H, s, t Bu), 0.99, 1.00 (each 3H, s, gem-me), 1.23 (1H, dd, J 13, 10, 2-Hβ), 1.28 (3H, s, 5-Me), 1.42 (1H, ddd, J 13, 3, 2, 2-Hα), 1.70 (1H, dd, J 14.5, 8, 4-Hβ), 2.19 (1H, dddd, J 14.5, 5, 1.5, 0.5, 4-Hα), 2.47 (1H, dd, J 18, 1.5, 7-H), 3.00 (1H, ddd, J 18, 2.5, 0.5, 7-H), 3.76 (1H, m, 3-H), 9.72 (1H, dd, J 2.5, 1.5, CHO); 13 C NMR (75 MHz) δ 4.80 (C 2), 18.01, 20.90, 24.93, (C 3), 28.44, 34.78, 41.58, 46.05, 46.89, 64.22, 64.94, 65.68, ; HRMS (ESI) m/z calcd for C 17 H 33 O 3 Si (MH) , found Preparation of C 11 -epoxyaldehyde 9 from epoxyacetate 25a A solution of the epoxyacetate 25a (2.33 mg, 6.54 mmol) in dry Et 2 O (35 ml) was added dropwise to a stirred suspension of LAH (186 mg, 4.89 mmol) in dry Et 2 O (10 ml) at 0 C and the mixtre was stirred for a further 15 min. After the excess of reagent was decomposed by dropwise addition of water at 0 C, the mixture was filtered through a pad of Celite. The filtrete was dried and evaporated to afford the crude alcohol. To a mixture of this alcohol and NaHCO 3 (275 mg, 3.27 mmol) in CH 2 Cl 2 (20 ml) was added DMP (4.17 g, 9.83 mmol) in some portions at rt and the mixture was stirred for a farther 1 h. After CH 2 Cl 2 was evaporated off, the resulting mixture was diluted with ether-hexane (1:1) and filtered through a pad of Celite. The filtrate was evaporated to afford the residue, which was purified by purified by flash CC (AcOEt-hexane, 1:4) to provide the aldehyde 9 (1.86 g, 91% from 25a) as a colorless oil. (E)-5-tert-Butyldimethylsilyloxy-1-[(1S,4S,6R)-4-tert-butyldimethylsilyloxy-2,2,6-trimethyl-7-oxabicyclo[4.1.0]heptan-1-yl]- 3-methylpent-3-en-2-ol (32) 8

9 To a stirred solution of the bromide 31 (4.98 g, 18.8 mmol) in dry Et 2 O (35 ml) was added t-buli (1.59 M in pentane; 13.0 ml, 20.4 mmol) at 78 C and the mixture was stirred for a further 20 min. A solution of the aldehyde 9 (2.93 g, 9.39 mmol) in dry Et 2 O (15 ml) was added dropwise to this mixture at 78 C. After being stirred at 78 C for 1 h, the reaction mixture was quenched with saturated aq. NH 4 Cl and extracted with Et 2 O. The extracts were washed with brine, dried and evaporated to give a residue, which was purified by flash CC (EtOAc-hexane, 12:88) to provide the diastereomeric mixture (ca. 2:1) of the adducts 32 (4.52 g, 97%) as a colorless oil. A part of this mixture was further purified by flash CC (Et 2 O-hexane, 12:88) to give each pure sample. Major diastereomer (polar): [α] 22 D 0.52 (c 0.85, MeOH); IR ν max cm (OH); 1 H NMR (300 MHz) δ 0.04, 0.06 (each 6H, s, SiMe 4), 0.87, 0.90 (each 9H, s, t Bu 2), 1.06, 1.11 (each 3H, s, gem-me), 1.22 (1H, dd, J 13.5, 9, 2-Hβ), 1.33 (3H, s, 5-Me), 1.48 (1H, ddd, J 13.5, 3.5, 1.5, 2-Hα), 1.65 (3H, d, J 1,9 -Me), 1.72 (1H, dd, J 15, 7.5, 4-Hβ), 1.81 (1H, dd, J 15, 2.5, 7-H), 2.05 (1H, dd, J 15, 10.5, 7-H), 2.25 (1H, ddd, J 15, 5, 1.5, 4-Hα), 2.38 (1H, d, J 2.5, OH), 3.74 (1H, m, 3-H), 4.03 (1H, br d, J 10.5, 8-H), 4.23 (2H, d, J 6, 11-H 2 ), 5.56 (1H, br t, J 6, 10-H); 13 C NMR (75 MHz) δ 5.09 (C 2), 4.80, 4.74, 12.66, 18.10, 18.39, 20.16, 25.06, (C 3), (C 3), 28.40, 33.30, 35.24, 42.23, 46.88, 60.05, 62.91, 64.42, 65.12, 67.84, 73.79, , ; HRMS (ESI) m/z calcd for C 27 H 54 O 4 NaSi 2 (M+Na) , found Minor diastereomer (less polar): [α] 22 D 9.90 (c 0.99, MeOH); IR ν max cm (OH); 1 H NMR (300 MHz) δ 0.03, 0.07 (each 6H, s, SiMe 4), 0.87, 0.90 (each 9H, s, t Bu 2), 1.16 (6H, s, gem-me), 1.21 (1H, dd, J 13, 8.5, 2-Hβ), 1.39 (3H, s, 5-Me), 1.50 (1H, ddd, J 13, 3.5, 1.5, 2-Hα), 1.63 (3H, d, J 1, 9-Me), (2H, m, 4-Hβ, 7-H), 2.05 (1H, dd, J 15, 1.5, 7-H), 2.28 (1H, ddd, J 15, 6, 1.5, 4-Hα), 3,80 (1H, s, OH), 3.80 (1H, m, 3-H), 4.24 (2H, d, J 6, 11-H 2 ), 4.50 (1H, br d, J 10.5, 8-H), 5.62 (1H, br t, J 6, 10-H); 13 C NMR (75 MHz) δ 5.07 (C 2), 4.80, 4.74, 12.39, 18.06, 18.37, 21.37, (C 3), (C 3), 26.40, 28.82, 32.26, 35.58, 41.35, 47.13, 60.09, 64.21, 65.04, 69.84, 75.92, , ; HRMS (ESI) m/z calcd for C 27 H 54 O 4 NaSi 2 (M+Na) , found (E)-5-Hydroxy-1-[(1S,4S,6R)-4-hydroxy-2,2,6-trimethyl-7- oxabicyclo[4.1.0]heptan-1-yl]-3-methylpent-3-en-2-yl Acetate (33) Acetic anhydride (4.55 ml, 47.8 mmol) was added to a stirred solution of compound 32 (diastereomeric mixture; 7.99 g, 16.0 mmol), DMAP (0.39 g, 3.2 mmol) and Et 3 N (11.2 ml, 80.5 mmol) in dry CH 2 Cl 2 (40 ml) at rt. After being stirred at rt for 1h, the mixture was diluted with Et 2 O and successively washed with aq. 5% HCl, saturated aq. NaHCO 3 and brine. Evaporation of the dried solution gave a residue, which without purification, was dissolved in dry THF and TBAF (1.0 M in THF; 47.2 ml, 47.2 mmol) was added to it. After being stirred at 40 C for 4.5 h, the mixture was concentrated and the resulted residue was purified by flash CC (CH 2 Cl 2 -acetone-meoh, 7:2:0.5) to afford 9

10 the diol 33 (4.57 g, 91%) as pale brown syrup. For analytical purpose, isomerically pure samples were separately prepared from each diastereomer of compound 32 following the above procedure. Major diastereomer: [α] 22 D (c 0.97, MeOH); IR ν max cm , 3464 (OH), 1730 (OAc); 1 H NMR (300 MHz) δ (each 3H, s, gem-me), 1.14 (1H, dd, J 13, 10, 2-Hβ), 1.26 (3H, s, 5-Me), 1.49 (1H, br d, J 13, 2-Hα), 1.54 (1H, dd, J 14.5, 8, 4-Hβ), 1.60 (3H, br s, 9-Me), 1.83 (1H, dd, J 15, 3, 7-H), 1.99 (3H, s, OAc), 2.12 (1H, dd, J 15, 10, 7-H), 2.26 (1H, br dd, J 14.5, 4.5, 4-Hα), 3.00 (2H, br s, OH 2), 3.73 (1H, m, 3-H), 4.08 (2H, d, J 6.5, 11-H 2 ), 5.12 (1H, dd, J 10, 3, 8-H), 5.67 (1H, br t, J 6.5, 10-H); 13 C NMR (75 MHz) δ 12.47, 20.28, 21.13, 25.15, 28.61, 31.69, 35.19, 41.08, 47.07, 58.50, 63.51, 64.25, 66.07, 75.71, , , ; HRMS (ESI) m/z calcd for C 17 H 29 O 5 (MH) , found Minor diastereomer: [α] 22 D 7.73 (c 0.97, MeOH); IR ν max cm , 3469 (OH),1731 (OAc); 1 H NMR (300 MHz) δ (each 3H, s, gem-me), 1.16 (1H, dd, J 13, 8.5, 2-Hβ), 1.34 (3H, s, 5-Me), 1.53 (1H, ddd, J 13, 4, 1.5, 2-Hα), 1.61 (1H, dd, J 14.5, 7.5, 4-Hβ), 1.65 (3H, d, J 1, 9-Me), 1.95 (1H, dd, J 15.5, 7.5, 7-H), 2.00 (3H, s, OAc), 2.05 (1H, dd, J 15.5, 4.5, 7-H), 2.14 (2H, br s, OH 2), 2.29 (1H, ddd, J 14.5, 6, 1.5, 4-Hα), 3.78 (1H, m, 3-H), 4.13 (2H, d, J 6.5, 11-H 2 ), 5.36 (1H, dd, J 7.5, 4.5, 8-H), 5.66 (1H, br t, J 6.5, 10-H); 13 C NMR (75 MHz) δ 12.26, 20.88, 21.25, 25.78, 28.65, 31.66, 35.40, 40.82, 46.96, 58.77, 63.71, 63.99, 66.93, 76.30, , , ; HRMS (ESI) m/z calcd for C 17 H 29 O 5 (MH) , found (E)-3-Methyl-5-oxo-1-[(1S,4S,6R)-2,2,6-trimethyl-4-triethylsilyloxy-7-oxabicyclo[4.1.0]heptan-1-yl]pent-3- en-2-yl Acetate (34) MnO 2 (20 g) was added to a stirred solution of the diol 33 (diastereomeric mixture; 2.08 g, 6.67 mmol) in Et 2 O-hexane (1:5; 60 ml) at rt. After being stirred at rt for 3 h, the mixture was filtered through a pad of Celite and the filtrate was evaporated. To a stirred solution of the resulting crude aldehyde, DMAP (73 mg, 0.60 mmol) and Et 3 N (2.48 ml, 17.8 mmol) in dry CH 2 Cl 2 (15 ml) was added dropwise TESCl (1.49 ml, 8.88 mmol) 0 C. After being stirred at 0 C for 20 min, the mixture was poured into chilled aq. NH 4 Cl and extracted with AcOEt. The extracts were washed with brine, dried and evaporated to give a residue, which was purified by flash CC (AcOEt-hexane, 1:2) to provide the diastereomeric mixture of the aldehydes 34 (2.47 g, 87% from 33). This mixture was further purified by preparative HPLC [LiChrosorb Si 60 (7 µm) 2 25 cm; ether-hexane, 2:3, 7.0 ml/min] to afford each pure diastereomer as colorless oils, respectively. Major diastereomer (polar): [α] 22 D (c 1.34, MeOH); IR ν max cm (OAc), 1672 (conj. CHO), 1639 (C=C); 1 H NMR (300 MHz) δ 0.56 (6H, q, J 8, SiCH 2 3), 0.93 (9H, t, J 8, SiCH 2 Me 3), 1.05, 1.14 (each 3H, s, gem-me), 1.23 (1H, dd, J 13, 10, 2-Hβ), 1.31 (3H, s, 5-Me), 1.47 (1H, ddd, J 13, 3.5, 1.5, 2-Hα), 1.65 (1H, dd, J 15, 7.5, 4-Hβ), 1.96 (1H, dd, J 15, 2.5, 7-H), 2.09 (3H, s, OAc), 2.17 (3H, d, J 1.5, 9-Me), 2.19 (1H, dd, J 15, 11, 7-H), 2.24 (1H, ddd, J 15, 6, 1.5, 4-Hα), 3.77 (1H, m, 3-H), 5.13 (1H, dd, J 11, 2.5, 8-H), 5.99 (1H, dquint, J 7.5, 1.5, 10-H), (1H, d, J 7.5, CHO); 13 C NMR (75 MHz) δ 4.75 (C 3), 6.83 (C 3), 14.57, 20.47, 20.93, 10

11 25.21, 28.60, 31.41, 35.22, 42.01, 47.35, 63.95, 64.44, 65.78, 74.33, , , , ; HRMS (ESI) m/z calcd for C 23 H 41 O 5 Si (MH) , found Minor diastereomer (less polar): [α] 22 D (c 1.02, MeOH); IR ν max cm (OAc), 1674 (conj. CHO), 1638 (C=C); 1 H NMR (300 MHz) δ 0.56 (6H, q, J 8, SiCH 2 3), 0.94 (9H, t, J 8, SiCH 2 Me 3), 1.01, 1.16 (each 3H, s, gem-me), 1.23 (1H, dd, J 13, 8.5, 2-Hβ), 1.35 (3H, s, 5-Me), 1.47 (1H, ddd, J 13, 3.5, 1.5, 2-Hα), 1.67 (1H, dd, J 14.5, 7.5, 4-Hβ), 1.99 (1H, dd, J 15.5, 8.5, 7-H), 2.07 (3H, s, OAc), 2.18 (1H, dd, J 15.5, 4, 7-H), 2.27 (3H, d, J 1.5, 9-Me), 2.24 (1H, ddd, J 14.5, 5.5, 1.5, 4-Hα), 3.76 (1H, m, 3-H), 5.39 (1H, dd, J 8.5, 4.0, 8-H), 6.05 (1H, br d, J 8, 10-H), (1H, d, J 8, CHO); 13 C NMR (75 MHz) δ 4.72 (C 3), 6.79 (C 3), 14.32, 20.83, 20.98, 25.86, 28.60, 31.66, 35.38, 41.68, 47.24, 63.90, 64.09, 66.56, 75.00, , , , ; HRMS (ESI) m/z calcd for C 23 H 41 O 5 Si (MH) , found (2E,4E,6E,8E,10E)-12-Hydroxy-2,7,11-trimethyl-13- [(1S,4S,6R)-4-hydroxy-2,2,6-trimethyl- 7-oxabicyclo[4.1.0]heptan-1-yl]trideca-2,4,6,8,10-pentaenal (6) To a solution of C 10 -phosphonate 11 (2.62 g, 7.94 mmol) and DMPU (1.91 ml, 15.8 mmol) in dry THF (25 ml) was added n-buli (1.60 M in hexane; 5.0 ml, 8.0 mmol) at 0 C. After being stirred at 0 C for 20 min, a solution of the major diastereomer of epoxy aldehyde 34 (1.68 g, 3.96 mmol) in dry THF (10 ml) was added to the reaction mixture and stirring was continued at 0 C for 30 min. After being quenched with saturated aq. NH 4 Cl, the mixture was extracted with ether. The extracts were washed with brine, dried and evaporated to give the residue, which was purified by flash CC (EtOAc-hexane, 2:8) to provide the isomeric mixture of (all-e: ~ 70% from 1 H NMR) conjugated ester (1.90 g, 80%) as an yellow foam: IR ν max cm (OAc), 1693 (conj. CO), 1614, 1568 (C=C); 1 H NMR (300 MHz) δ 0.56 (6H, q, J 8, SiCH 2 3), 0.93 (9H, t, J 8, SiCH 2 Me 3), 1.05, 1.16 (each 3H, s, gem-me), 1.23 (1H, dd, J 13, 10, 2-Hβ), 1.31 (3H, s, 5-Me), 1.32 (3H, t, J 7, OCH 2 Me), 1.46 (1H, br d, J 13, 2-Hα), 1.63 (1H, dd, J 14.5, 8, 4-Hβ), 1.82, 1.96, 1.98 (each 3H, br s, 9-Me, 13-Me, 13 -Me), 1.88 (1H, dd, J 15, 3, 7-H), 2.05 (3H, s, OAc), (2H, m,, 4-Hα, 7-H), 3.76 (1H, m, 3-H), 4.22 (2H, q, J 7, OCH 2 Me), 5.27 (1H, br d, J 10, 8-H), 6.17, 6.23 (each 1H, d, J 12, 10-H, 14-H), 6.32 (1H, d, J 15, 12-H), (2H, m, 11-H, 15 -H), 6.87 (1H, dd, J 15, 12, 15-H), 7.29 (1H, br d, J 11, 14 -H); HRMS (ESI) m/z calcd for C 35 H 56 O 6 NaSi (M+Na) , found for major diastereomer. A solution of the isomeric mixture of this ester (1.90 g, 3.17 mmol) in dry ether (20 ml) was added dropwise to a stirred suspension of LAH (240 mg, 6.32 mmol) in dry ether (50 ml) at 0 C. After being stirred at 0 C for 15 min, the excess of LAH was decomposed by dropwise addition of moist ether and the mixture was filtered through a pad of Celite. The filtrate was dried and evaporated to give the crude diol (1.78 g), which without purification, was dissolved in THF (5 ml) and ether (30 ml) and stirred with MnO 2 (18 g) at rt for 40 min. After MnO 2 was filtered off, the filtrate was concentrated. To a solution of the resulting crude aldehyde (1.77 g) in 11

12 THF (20 ml) was added AcOH (1.0 M in THF; 0.63 ml, 0.63 mmol) followed by TBAF (1.0 M in THF; 4.75 ml, 4.75 mmol) at rt and the mixture was stirred at rt for 30 min. The mixture was concentrated to give the residue, which was purified by falsh CC (acetone-ch 2 Cl 2, 18:82) to provide the isomeric mixture of the apocarotenal 6 (1.14 g, 72% from 34). Purification of this isomeric mixture by preparative HPLC [LiChrosorb Si 60 (7 µm) 2 25 cm; acetone-ch 2 Cl 2 -hexane, 15:56:28] afforded all-e-apocarotenal 6 (794 mg, 50% from 34) and its 13Z-isomer (295 mg, 19% from 34) as an yellow foam, respectively. Similarly, the minor diastereomer of epoxy aldehyde 32 was also converted into the minor diastereomer of 6. All-E-Isomer (major diastereomer): UV λ max (EtOH) nm: 397; IR ν max cm , 3481 (OH), 1661 (conj. CHO), 1610, 1562 (C=C); 1 H NMR (500 MHz) δ 1.10, 1.14 (each 3H, s, gem-me), 1.23 (1H, dd, J 13, 10, 2-Hβ), 1.39 (3H, s, 5-Me), 1.60 (1H,br s, OH), 1.61 (1H, ddd, J 13, 3.5, 1.5, 2-Hα), 1.67 (1H, dd, J 14.5, 8, 4-Hβ), 1.85 (3H, d, J 1, 9-Me), 1.88 (3H, d, J 1, 13 -Me), 1.89 (1H, dd, J 15, 2.5, 7-H), 2.02 (3H, br s, 13-Me), 2.08 (1H, dd, J 15, 10, 7-H), 2.39 (1H, ddd, J 14.5, 5.5, 1.5, 4-Hα), 2.57 (1H, br s, OH), 3.87 (1H, m, 3-H), 4.12 (1H, br d, J 10, 8-H), 6.24 (1H, br d, J 11.5, 10-H), 6.27 (1H, br d, J 12, 14-H), 6.35 (1H, d, J 15, 12-H), 6.64 (1H, dd, J 15, 11.5, 11-H), 6.68 (1H, dd, J 14.5, 11.5, 15 -H), 6.93 (1H, br d, J 11.5, 14 -H), 7.02 (1H, dd, J 14.5, 12, 15-H), 9.45 (1H, s, CHO); 13 C NMR (125 MHz) δ 9.58, 13.65, 20.06, 25.01, 28.47, 33.64, 35.37, 41.57, 46.94, 63.89, 65.24, 67.70, 73.87, , , , , , , , , , , ; HRMS (ESI) m/z calcd for C 25 H 36 O 4 Na (M+Na) , found All-E-Isomer (minor diastereomer): UV λ max (EtOH) nm: 398; IR ν max cm , 3479 (OH), 1661 (conj. CHO), 1610, 1562 (C=C); 1 H NMR (500 MHz) δ 1.21 (6H, s, gem-me), 1.24 (1H, dd, J 13, 9, 2-Hβ), 1.43 (3H, s, 5-Me), 1.62 (1H, ddd, J 13, 3.5, 1.5, 2-Hα), 1.68 (1H, dd, J 15, 11, 7-H), 1.71 (1H, dd, J 14.5, 7, 4-Hβ), 1.76 (1H, br s, OH), 1.85 (3H, d, J 1, 9-Me), 1.88 (3H, br s, 13 -Me), 2.02 (3H, br s, 13-Me), 2.13 (1H, dd, J 15, 2, 7-H), 2.41 (1H, ddd, J 14.5, 6, 1.5, 4-Hα), 3.87 (1H, m, 3-H), 3.93 (1H, br s, OH), 4.60 (1H, br d, J 11, 8-H), 6.28 (1H, br d, J 12, 14-H), 6.29 (1H, br d, J 11, 10-H), 6.36 (1H, d, J 15, 12-H), 6.65 (1H, dd, J 15, 11, 11-H), 6.68 (1H, dd, J 15, 12, 15 -H), 6.96 (1H, br d, J 12, 14 -H), 7.02 (1H, dd, J 15, 12, 15-H), 9.45 (1H, s, CHO); 13 C NMR (125 MHz) δ 9.52, 13.40, 20.87, 21.21, 26.42, 28.86, 32.66, 35.68, 40.66, 47.13, 63.67, 65.08, 69.58, 75.93, , , , , , , , , , , ; HRMS (ESI) m/z calcd for C 25 H 36 O 4 Na (M+Na) , found Z-Isomer (major diastereomer): UV λ max (EtOH) nm: 275, 383; IR ν max cm , 3490 (OH), 1662 (conj. CHO), 1612, 1577 (C=C); 1 H NMR (500 MHz) δ 1.10, 1.14 (each 3H, s, gem-me), 1.23 (1H, dd, J 13, 9, 2-Hβ), 1.39 (3H, s, 5-Me), 1.60 (1H, br s, OH), 1.62 (1H, ddd, J 13, 3.5, 1.5, 2-Hα), 1.68 (1H, dd, J 14.5, 8, 4-Hβ), 1.86 (3H, d, J 1, 9-Me), 1.87 (3H, br s, 13 -Me), 1.89 (1H, dd, J 15, 2.5, 7-H), 2.03 (3H, br s, 13-Me), 2.09 (1H, dd, J 15, 10, 7-H), 2.39 (1H, ddd, J 14.5, 5.5, 1.5, 4-Hα), 2.59 (1H, br s, OH), 3.87 (1H, m, 3-H), 4.12 (1H, br d, J 10, 8-H), 6.15 (1H, br d, J 12, 14-H), 6.29 (1H, br d, J 11.5, 10-H), 6.60 (1H, dd, J 14.5, 11.5, 15 -H), 6.63 (1H, dd, J 15, 11.5, 11-H), 6.88 (1H, d, J 15, 12-H), 6.93 (1H, br d, J 11.5, 14 -H), 7.16 (1H, dd, J 14.5, 12, 15-H), 9.45 (1H, s, CHO); 13 C NMR (125 MHz) δ 9.57, 13.72, 20.06, 20.92, 25.02, 28.45, 33.67, 35.37, 41.57, 46.90, 63.95, 12

13 65.22, 67.71, 73.85, , , , , , , , , , , ; HRMS (ESI) m/z calcd for C 25 H 36 O 4 Na (M+Na) , found Z-Isomer (minor diastereomer): UV λ max (EtOH) nm: 275, 387; IR ν max cm , (OH), 1661 (conj. CHO), 1613, 1577 (C=C); 1 H NMR (500 MHz) δ 1.20 (6H, s, gem-me), 1.23 (1H, dd, J 13, 9, 2-Hβ), 1.43 (3H, s, 5-Me), 1.61 (1H, ddd, J 13, 3.5, 1.5, 2-Hα), 1.67 (1H, dd, J 15, 11, 7-H), 1.70 (1H, dd, J 14.5, 7.5, 4-Hβ), 1.71 (1H, br s, OH), 1.85 (3H, br s, 9-Me), 1.86 (3H, br s, 13 -Me), 2.02 (3H, br s, 13-Me), 2.13 (1H, dd, J 15, 2, 7-H), 2.40 (1H, ddd, J 14.5, 6, 1.5, 4-Hα), 3.86 (1H, m, 3-H), 3.94 (1H, br s, OH), 4.60 (1H, br d, J 11, 8-H), 6.14 (1H, br d, J 12, 14-H), 6.32 (1H, br d, J 11.5, 10-H), 6.60 (1H, dd, J 14.5, 11.5, 15 -H), 6.63 (1H, dd, J 15, 11.5, 11-H), 6.88 (1H, d, J 15, 12-H), 6.92 (1H, br d, J 11.5, 14 -H), 7.16 (1H, dd, J 14.5, 12, 15-H); 13 C NMR (125 MHz) δ 9.52, 13.40, 20.87, 21.21, 26.42, 28.86, 32.66, 35.68, 40.66, 47.13, 63.67, 65.08, 69.58, 75.93, , , , , , , , , , , ; HRMS (ESI) m/z calcd for C 25 H 36 O 4 Na (M+Na) , found Isomerization of 13Z-izomer of apocarotenal 6 A solution (1 ml) prepared from PdCl 2 (MeCN) 2 (13 mg), Et 3 N (7 µl) and water (1.2 ml) in MeCN (8.8 ml) was added to a solution of 13Z-isomer of apocarotenal 6 (major diastereomer; 30 mg) in MeCN (5 ml) and the mixture was stirred at rt for 4.5 h. The solvent was evaporated off to give a residue, which was purified by short-cc (acetone-hexane, 1:2) to provide an isomeric mixture of apocarotenal 6 (29 mg, all-e: 73% from HPLC analysis). Purification of this isomeric mixture by preparative HPLC [LiChrosorb Si 60 (7 µm) 2 25 cm; acetone-ch 2 Cl 2 -hexane, 15:56:28] afforded all-e-apocarotenal 6 (major diastereomer). (S)-4-Hydroxy-3,5,5-trimethyl-4-[(3E,5E,7E,9E,11E,13E,15E)-3,7,12,16-tetramethyl-2-oxo-18-((R)-2,6,6- trimethyl-4-triethylsilyloxycyclohex-1-en-1-yl)octadeca-3,5,7,9,11,13,15-heptaen-17-yn-1-yl]cyclohex-2- enone (36) To a solution of the C 15 -phosphonium salt 8 (426 mg, 0.75 mmol) and the all-e apocarotenal 6 (major diastereomer; 200 mg, 0.50 mmol) in CH 2 Cl 2 (15 ml) was added NaOMe (1 M in MeOH; 1.0 ml, 1.0 mmol) at rt. After being stirred at rt for 15 min, the mixture was diluted with AcOEt and washed with brine. Evaporation of the dried solution gave a residue, which was purified by flash CC (acetone-hexane, 3:7) to afford the compound 35 (272 mg, 76%; all-e >90% from 1 H NMR) [UV λ max (EtOH) nm: 405, 428, 455, HRMS (ESI) m/z calcd for C 46 H 70 O 4 NaSi (M+Na) , found ]. To a solution of 35 (272 mg, 0.38 mmol) in DMSO (6 ml) and THF (1 ml) were added 3 drops Et 3 N and then IBX (430 mg, 1.54 mmol) at rt. After being stirred at rt for 15 min, the mixture was diluted with AcOEt and washed with 5% aq. Na 2 S 2 O 3 and brine. After evaporation of the dried solution gave a residue, which was purified by flash CC (AcOEt-hexane, 3:7) to afford 13

14 the crude 5,6-epoxy-3,8-diketone (186 mg), which was dissolved in AcOEt (50 ml) and silica gel ( mesh Merck ; 10 g) was added to it. After being stirred at rt for 19 h, the mixture was filtered through sintered glass funnel and the filtrate was evaporated to provide 36 (164 mg, 61% from 35), a part of which was purified by preparative HPLC [LiChrosorb Si 60 (7 µm) 2 25 cm; AcOEt-hexane, 15:85] to provide isomeric pure sample of 36 as a red solid: UV λ max (EtOH) nm: 465; IR ν max cm (OH), 2170 (C C), 1658 (conj. CO), 1620, 1601, 1571, 1529, 1522 (C=C); 1 H-NMR (500 MHz, CDCl 3 ) δ 0.61 (6H, q, J 8, SiCH 2 3), 0.97 (9H, t, J 8, SiCH 2 Me 3), 1.05, 1.09 (each 3H, s, 1-gem-Me), 1.14, 1.18 (each 3H, s, 1 -gem-me), 1.48 (1H, t, J 12, 2 -Hβ), 1.74 (1H, ddd, J 12.5, 3.5, 2, 2 -Hα), 1.90 (3H, d, J 1.5, 5-Me), 1.91 (3H, br s, 5 -Me), 1.95 (3H, br s, 9-Me), 1.99 (6H, br s, 13-Me, 13 -Me), 2.02 (3H, d, J 1, 9 -Me), 2.11 (1H, br dd, J 18, 10, 4 -Hβ), 2.29 (1H, br dd, J 18, 5, 4 -Hα), 2.33, 2.47 (each 1H, d, J 18, 2-H 2 ), 2.93, 3.05 (each 1H, d, J 15, 7-H 2 ), 3.93 (1H, m, 3 -H), 5.84 (1H, t, J 1, 4-H), 5.85 (1H, s, OH), 6.29 (1H, br d, J 11.5, 14 -H), 6.36 (1H, d, J 15, 12 -H), 6.46 (2H, br d, J 11.5, 14-H, 10 -H), 6.57 (1H, dd, J 15, 11, 11-H), 6.58 (1H, dd, J 15, 11.5, 11 -H), 6.64 (1H, dd, J 14.5, 11.5, 15-H), 6.71 (1H, d, J 15, 12-H), 6.77 (1H, dd, J 14.5, 11.5, 15 -H), 7.10 (1H, br d, J 11 Hz, 10-H); 13 C-NMR (125 MHz, CDCl 3 ) δ: 4.88, , 12.71, 12.89, , 20.77, 22.56, 23.25, 24.87, 28.66, 30.50, 36.60, 38.58, 42.03, 42.17, 47.12, 49.72, 65.10, 78.55, 89.71, 98.39, , , , , , , , , , , , , , , , , , , , ; HRMS (ESI) m/z calcd for C 46 H 67 O 4 Si (MH) , found Amarouciaxanthin B (2) A methanolic solution of PPTS (0.01M; 1.6 ml, mmol) was added to a stirred solution of the TES ether 36 (116 mg, 0.16 mmol) in MeOH (10 ml) at 0 C. After being stirred at 0 C for 30 min, the mixture was poured into saturated aq. NaHCO 3 and extracted with AcOEt. The extracts were washed with brine, dried and evaporated to give a residue, which was purified by flash CC (acetone-hexane-ch 2 Cl 2, 18:42:60) to afford amarouciaxanthin B (2) (87 mg, 89%) as a red solid: UV λ max (EtOH) nm: 464; UV λ max (Et 2 O) nm: 452; IR ν max cm , 3403 (OH), 2171 (C C), 1657 (conj. CO), 1620, 1602, 1571, 1530, 1523 (C=C); 1 H-NMR (500 MHz, CDCl 3 ) δ 1.05, 1.09 (each 3H, s, 1-gem-Me), 1.15, 1.20 (each 3H, s, 1 -gem-me), 1.46 (1H, t, J 12, 2 -Hβ), 1.83 (1H, ddd, J 12, 4, 1.5, 2 -Hα), 1.90 (3H, d, J 1.5, 5-Me), 1.93 (3H, br s, 5 -Me), 1.95 (3H, br s, 9-Me), 1.99 (6H, br s, 13-Me, 13 -Me), 2.02 (3H, d, J 1, 9 -Me), 2.07 (1H, br dd, J 17, 9, 4 -Hβ), 2.33, 2.47 (each 1H, br d, J 17.5, 2-H 2 ), 2.43 (1H, br dd, J 17, 5, 4 -Hα), 2.93, 3.05 (each 1H, d, J 15, 7-H 2 ), 4.00 (1H, m, 3 -H), 5.84 (1H, br s, 4-H), 5.85 (1H, s, OH), 6.29 (1H, br d, J 11.5, 14 -H), 6.36 (1H, d, J 15, 12 -H), 6.45, 6.46 (each 1H, br d, J 11.5, 10 -H, 14-H), 6.57 (1H, dd, J 15, 11.5, 11-H), 6.58 (1H, dd, J 15, 11.5, 11 -H), 6.64 (1H, dd, J 14.5, 11.5, 15-H), 6.71 (1H, d, J 15, 12-H), 6.77 (1H, dd, J 14.5, 11.5, 15 -H), 7.10 (1H, br d, J 11.5, 10-H); 13 C-NMR (125 MHz, CDCl 3 ) δ: (9-Me), 12.69, (13-Me, 13 -Me), (9 -Me), (5-Me), (5 -Me), 23.23, 14

15 24.84 (1-gem-Me), 28.75, (1 -gem-me), (C1 ), (C7), (C4 ), (C1), (C2 ), (C2), (C3 ), (C6), (C7 ), (C8 ), (C9 ), (C11), (C6 ), (C11 ), (C4), (C15), (C14 ), (C15 ), , (C9, C10 ), (C13), (C5 ), (C12 ), (C14), (C13 ), (C10), (C12), (C5), (C3), (C8); HRMS (ESI) m/z calcd for C 40 H 53 O 4 (MH) , found Treatment of compound 36 with TBAF in the presence of AcOH A mixed solution of TBAF-AcOH (1:1) [each 0.5 M in THF; 3.4 ml, each 1.7 mmol] was added to a stirred solution of TES ether 36 (161 mg, 0.23mmol) in dry THF (6 ml) at rt. After being stirred at rt for 1 h, the mixture was poured into saturated aq. NaHCO 3 and extracted with AcOEt. The extracts were washed with brine, dried and evaporated to give a residue, which was purified by flash CC (acetone-hexane, 3:7) and then preparative HPLC [LiChrosorb Si 60 (7 µm) 2 25 cm; THF-hexane-MeOH, 25:75:0.5] to provide amarouciaxanthin B (2) (42 mg, 31%) and the rearranged product 37 (66 mg, 49%) as a red solid, respectively. Compound 37: UV λ max (EtOH) nm: 455, 474sh; IR ν max cm , 3476 (OH), 2172 (C C), 1707 (CO), 1649 (conj. CO), 1608, 1574, 1530 (C=C); 1 H-NMR (500 MHz, CDCl 3 ) δ 1.15, 1.20 (each 3H, s, 1 -gem-me), 1.23, 1.37 (each 3H, s, 1-gem-Me), 1.24 (3H, s, 5-Me), 1.46 (1H, t, J 12, 2 -Hβ), 1.84 (1H, ddd, J 12, 3.5, 2, 2 -Hα), 1.89 (3H, br s, 9-Me), 1.92 (3H, br s, 5 -Me), 1.99 (6H, br s, 13-Me, 13 -Me), 2.02 (3H, br s, 9 -Me), 2.07 (1H, br dd, J 17.5, 10, 4 -Hβ), 2.40 (1H, d, J 17, 4-H), 2.43 (1H, br dd, J 17.5, 5.5, 4 -Hα), 2.59 (1H, d, J 17, 2-H), 2.72 (1H, d, J 18, 7-H), 2.95 (1H, d, J 17, 2-H), 3.14 (1H, d, J 17, 4-H), 3.62 (1H, d, J 18, 7-H), 3.99 (1H, m, 3 -H), 6.29 (1H, br d, J 11.5, 14 -H), 6.36 (1H, d, J 15, 12 -H), 6.39 (1H, br d, J 11.5, 14-H), 6.46 (1H, br d, J 11.5, 10 -H), 6.56 (2H, dd, J 15, 11.5, 11-H, 11 -H), 6.64 (1H, dd, J 14.5, 11.5, 15-H), 6.67 (1H, d, J 15, 12-H), 6.74 (1H, dd, J 14.5, 11.5, 15 -H), 7.15 (1H, br d, J 11, 10-H); 13 C-NMR (125 MHz, CDCl 3 ) δ: (9-Me), 12.76, (13-Me, 13 -Me), (9 -Me), (5 -Me), 27.29, (1-gem-Me), (5-Me), 28.78, (1 -gem-me), (C1 ), (C4 ), (C1), (C5), (C2 ), (C7), (C4), (C2 ), (C3 ), (C7 ), (C8 ), (C9 ), (C11), (C6 ), (C11 ), (C15), (C15 ), (C14 ), (C9), (C10 ), (C13), (C14), (C5 ), (C12 ), (C13 ), (C10), (C12), (C8), (C3), (C6); HRMS (ESI) m/z calcd for C 40 H 53 O 4 (MH) , found Amarouciaxanthin A (1) To a solution of the C 15 -phosphonium salt 7 (813 mg, 1.39 mmol) and the all-e 15

16 apocarotenal 6 (major diastereomer: 370 mg, 0.93 mmol) in CH 2 Cl 2 (25 ml) was added NaOMe (1 M in MeOH; 1.9 ml, 1.9 mmol) at rt. After being stirred at rt for 40 min, the mixture was diluted with AcOEt and washed with brine. Evaporation of the dried solution gave a residue, which was purified by flash CC (acetone-hexane-meoh, 35:75:2) to afford the condensed product (411 mg, 61%; all-e >90% from 1 H NMR). This was dissolved in DMSO (10 ml) and THF (4 ml), and 4 drops Et 3 N and then IBX (786 mg, 1.07 mmol) were added to it. After being stirred at rt for 30 min, the mixture was diluted with AcOEt and washed with 5% aq. Na 2 S 2 O 3 and brine. After evaporation of the dried solution gave a residue, which was purified by flash CC (acetone-hexane, 3:7 to 1:2) to afford the crude 5,6-epoxy-3,8-diketone (381 mg), which was dissolved in AcOEt (120 ml) and silica gel ( mesh Merck ; 35 g) was added to it. After being stirred at rt for 16 h, the mixture was filtered through sintered glass funnel and the filtrate was evaporated to provide 37 (380 mg, 56% from 6) as a red solid. A methanolic solution of PPTS (0.01M; 5.2 ml, mmol) was added to a stirred solution of the TES ether 37 (380 mg, 0.52 mmol) in MeOH (20 ml) and THF (10 ml) at 0 C. After being stirred at 0 C for 30 min, the mixture was poured into saturated aq. NaHCO 3 and extracted with AcOEt. The extracts were washed with brine, dried and evaporated to give a residue, which was purified by flash CC (acetone-ch 2 Cl 2 -MeOH, 20:80:2) to afford amarouciaxanthin A (1) (275 mg, 86% from 38; 48% form 6; all-e >80% from 1 H NMR) as a red solid. This was then purified by preparative HPLC [LiChrosorb Si 60 (7 µm) 2 25 cm; THF-hexane-MeOH, 30:7:2] to provide isomeric pure sample: UV λ max (EtOH) nm: 468; UV λ max (Et 2 O) nm: 468; IR ν max cm , 3403 (OH), 1928 (C=C=C), 1658 (conj. CO), 1622, 1602, 1573, 1530 (C=C); 1 H-NMR (500 MHz, CDCl 3 ) δ 1.05, 1.09 (each 3H, s, 1-gem-Me), 1.07, 1.34 (each 3H, s, 1 -gem-me), 1.34 (1H, overlapped, 2 -Hβ), 1.35 (3H, s, 5 -Me), 1.41 (1H, br t, J 12.5, 4 -Hβ), 1.82 (3H, br s, 9 -Me), 1.90 (3H, d, J 1, 5-Me), 1.95 (1H, overlapped, 2 -Hα), 1.95 (3H, br s, 9-Me), 1.99 (3H, br s, 13-Me), 2.00 (3H, br s, 13 -Me), 2.27 (1H, ddd, J 12.5, 4, 2, 4 -Hα), 2.33, 2.47 (each 1H, br d, J 18, 2-H 2 ), 2.93, 3.05 (each 1H, d, J 15, 7-H 2 ), 4.32 (1H, m, 3 -H), 5.84 (1H, br s, 4-H), 5.85 (1H, s, OH), 6.04 (1H, s, 8 -H), 6.12 (1H, br d, J 11, 10 -H), 6.27 (1H, br d, J 11.5, 14 -H), 6.34 (1H, d, J 15, 12 -H), 6.46 (1H, br d, J 11.5, 14-H), 6.56 (1H, dd, J 15, 11.5, 11-H), 6.62 (1H, dd, J 15, 11, 11 -H), 6.63 (1H, dd, J 14, 11.5, 15-H), 6.71 (1H, d, J 15, 12-H), 6.78 (1H, dd, J 14.5, 11.5, 15 -H), 7.10 (1H, br d, J 11, 10-H); 13 C-NMR (125 MHz, CDCl 3 ) δ: (9-Me), 12.69, (13-Me, 13 -Me), (9 -Me), (5-Me), 23.27, (1-gem-Me), 29.36, (1 -gem-me), (5 -Me), (C1 ), (C7), (C1), (C4 ), (C2 ), (C2), (C3 ), (C5 ), (C6), (C8 ), (C6 ), (C11), , (C4, C11 ), (C10 ), (C15), (C14 ), (C9 ), (C15 ), (C9), (C13), (C12 ), (C14), (C13 ), (C10), (C12), (C5), (C3), (C 7), (C8); HRMS (ESI) m/z calcd for C 40 H 55 O 5 (MH) , found