Asymmetric Total Synthesis of Cyclocitrinol

Transcription

1 Electronic Supplementary Information Experimental Procedures and Characterization Data Asymmetric Total Synthesis of Cyclocitrinol Junyang Liu, Jianlei Wu, Jian-Hong Fan, Xin Yan, Guangjian Mei, and Chuang-Chuang Li*, Department of Chemistry, Southern University of Science and Technology, Shenzhen , China. Table of Contents 1. General Information... S2 2. Experimental Data for Compounds... S3 3. Table S1 Comparison of NMR Data for Natural and Synthetic Cyclocitrinol... S28 4. Table S2 Crystal Data and Structure Refinement for 6, CCDC S29 5. Table S3 Crystal Data and Structure Refinement for 6b, CCDC S30 6. NMR Spectra of Synthetic Compounds... S32 S1

2 1. General Information Unless otherwise mentioned, all reactions were carried out under a nitrogen atmosphere under anhydrous conditions and all reagents were purchased from commercial suppliers without further purification. Anhydrous solvents were distilled prior to use: THF (tetrahydrofuran), ether, PhMe (toluene) from Na/benzophenone; DCM (dichloromethane), MeCN (methyl cyanide), 2,6-lutidine, Py (pyridine), TMP (2,2,6,6-tetramethylpiperidine) from CaH2. Reactions were monitored by Thin Layer Chromatography on plates (GF254) supplied by Yantai Chemicals (China) using UV light as visualizing agent or an ethanolic solution of phosphomolybdic acid followed by heating. Flash column chromatography was performed using the indicated solvents on silica gel 60 ( mesh ASTM) purchased from Tsingtao Haiyang Chemicals (China). Melting points were obtained on an X-5 micro-melting point apparatus (Fukai Instrument, Beijing, China) without correction. NMR spectra were recorded on Bruker AV500, Bruker ARX400, and calibrated using residual undeuterated solvent as an internal reference. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, b = broad, m = multiplet. Infrared spectra were recorded on a Shimadzu IR Prestige 21, using thin films of the sample on KBr plates. High-resolution mass spectra (HRMS) were recorded on a Bruker Apex IV FTMS mass spectrometer using ESI (electrospray ionization). Optical rotations were recorded on a Perkin-Elmer 351 polarimeter at 589 nm, 100 mm cell at 20 o C. Data were reported as follow: optical rotation (c (g/100 ml), solvent). Compound 11, (1R,3aR,7aR)-1-[(1S)-2,2-dimethoxy-1-methylethyl]octahydro- 7a-methyl-4H-inden-4-one, CAS#: , was purchased in 500 g for 4700$ from Shanghai Huqi Pharmaceutical Science & Technology Co. Ltd. in S2

3 2. Experimental Data for Compounds Synthesis of enone 12 To a stirred solution of LDA [prepared in situ from diisopropylamine (13.4 ml, 95.6 mmol) and n BuLi (2.40 M in hexane, 39.3 ml, 94.4 mmol) in THF (50 ml) at -78 ºC] was added dropwise ketone 11 (20.0 g, 78.6 mmol) in THF (100 ml) at -78 ºC. After stirring was continued for 15 min at the same temperature, freshly distilled chlorotrimethylsilane (TMSCl, 7.5 ml, 86.5 mmol) was added. After being stirred for another 2 h at -78 ºC, the reaction was quenched with saturated NaHCO3 (aq., aqueous). The product was extracted with ether (Et2O, 3 x 150 ml). The combined organic extracts were washed with saturated NaHCO3 (aq.), brine, dried over anhydrous Na2SO4 (s, solid), filtered through a pad of silica gel, and concentrated in vacuo, the crude unstable TMS enol ether S1 was used immediately in the next reaction. To a stirred solution of the crude silylenol ether S1 obtained above in DMSO (AR, analytical reagent, 50 ml) was added 2-iodoxybenzoic acid (IBX, 28.6 g, mmol) and the reaction was stirred for 2 h at 25 o C. After being cooled to 0 ºC, the reaction was quenched with saturated Na2S2O3 (aq.). The product was extracted with ether (3 x 150 ml). The combined organic extracts were washed with H2O, brine, dried over anhydrous Na2SO4 (s), concentrated in vacuo, and the residue was chromatographed on silica gel with EtOAc-hexane (1/10 to 1/5, v/v) as eluent to give the enone 12 (15.8 g, 80%, over 2 steps) as a white powder. R f = 0.3 (EtOAc/hexane, 1/10); = +3.7 (c 0.93, CHCl3); 1 H NMR (500 MHz, CDCl3) δ 6.77 (ddd, J = 9.7, 5.8, 2.1 Hz, 1H), 6.00 (dd, J = 10.1, S3

4 3.2 Hz, 1H), 4.14 (d, J = 2.4 Hz, 1H), 3.46 (d, J = 1.1 Hz, 3H), 3.40 (d, J = 1.1 Hz, 3H), (m, 2H), (m, 1H), (m, 1H), (m, 3H), (m, 1H), (m, 1H), 0.98 (d, J = 6.5 Hz, 3H), 0.76 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 201.8, 147.7, 129.5, 108.7, 58.7, 57.0, 56.1, 52.4, 47.5, 42.8, 39.2, 26.9, 19.6, 11.9, 11.6; IR (film) ν max 2961, 1681, 1468, 1381, 1182, 1093, 974, 922 cm -1 ; HRMS (ESI) calculated for C15H25O3 + [M+H] , found Synthesis of vinyl iodide 13 To a stirred solution of enone 12 (15.0 g, 59.4 mmol) in DCM (200 ml) was added trimethylsilyl azide (TMSN3, 23.5 ml, mmol) at 0 C. The mixture was stirred for 2 h at the same temperature, after which time it was treated with a solution of iodine (37.7 g, mmol) in DCM (33 ml) and pyridine (33 ml) at 0 C. The resulting mixture was allowed to warm to 25 o C and stirred for 12 h. After being cooled to 0 ºC, the reaction was quenched with saturated Na2S2O3 (aq.). The product was extracted with ether (3 x 100 ml). The combined organic extracts were washed with saturated Na2S2O3 (aq.), brine, dried over anhydrous Na2SO4 (s), concentrated in vacuo, and the residue was chromatographed on silica gel with EtOAc-hexane (1/10 to 1/8, v/v) as eluent to give the vinyl iodide 13 (15.7 g, 70%) as a colorless powder. R f = 0.8 (EtOAc/hexane, 1/5); = (c 1.00, CHCl3); 1 H NMR (500 MHz, CDCl3) δ 7.47 (dd, J = 5.6, 3.1 Hz, 1H), 4.12 (d, J = 2.6 Hz, 1H), 3.44 (s, 3H), 3.39 (s, 3H), 2.71 (t, J = 9.6 Hz, 1H), (m, 2H), (m, 1H), (m, 3H), (m, 1H), (m, 1H), 0.95 (d, J = 6.7 Hz, 3H), 0.77 (s, 3H); S4

5 13 C NMR (125 MHz, CDCl3) δ 194.6, 155.9, 108.5, 102.7, 58.2, 56.9, 56.1, 52.1, 47.7, 46.2, 39.0, 27.1, 20.6, 12.2, 11.6; IR (film) ν max 2961, 2831, 1692, 1465, 1381, 1144, 1067, 974 cm -1 ; HRMS (ESI) calculated for C15H24IO3 + [M+H] , found Synthesis of enone 14 OMe O SnBu 3 OMe H OMe TBSO 9 H OMe I CuTC, Pd(PPh 3 ) 4 O LiOAc, NMP H H O 83% O TBSO To a stirred solution of vinyl iodide 13 (8.40 g, 22.2 mmol) in N-methyl pyrrolidone [NMP, AR, 50 ml] were sequentially added copper (I) thiophene-2- carboxylate (CuTC, 4.23 g, 22.2 mmol), LiOAc (4.39 g, 66.6 mmol), Pd(PPh3)4 (763.0 mg, 0.66 mmol) and stannane 9 [1] (16.7 g, 33.3 mmol) at 25 o C. The reaction mixture was stirred at that temperature for 8 h, after which time it was quenched with saturated NaHCO3 (aq.). The product was extracted with ether (3 x 100 ml). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 (s), concentrated in vacuo, and the residue was chromatographed on silica gel with EtOAchexane (1/10 to 1/5, v/v) as eluent to give 14 (8.53 g, 83%) as a yellow oil. R f = 0.6 (EtOAc/hexane, 1/5); = (c 1.55, CHCl3); 1 H NMR (500 MHz, CDCl3) δ 7.96 (s, 1H), 6.83 (d, J = 3.6 Hz, 1H), 6.35 (s, 1H), 4.60 (s, 2H), 4.14 (s, 1H), 3.45 (s, 3H), 3.40 (s, 3H), (m, 2H), (m, 1H), (m, 1H), (m, 3H), (m, 1H), (m, 1H), 0.99 (d, J = 6.7 Hz, 3H), 0.90 (s, 9H), 0.79 (s, 3H), 0.08 (s, 6H). 13 C NMR (125 MHz, CDCl3) δ 200.1, 154.1, 141.0, 140.8, 131.4, 120.1, 108.7, 105.4, 59.1, 58.2, 57.0, 56.1, 52.5, 47.7, 42.9, 39.1, 27.2, 25.9, 19.8, 18.4, 12.1, 11.6, -5.2; IR (film) ν max 2955, 1686, 1473, 1381, 1254, 1132, 837 cm -1 ; S5

6 HRMS (ESI) calculated for C26H43O5Si + [M+H] , found Synthesis of ketone 15 To a stirred solution of enone 14 (8.48 g, 18.3 mmol) in MeOH (AR, 200 ml) was added NiCl2 6H2O (21.7 g, 91.5 mmol) at 25 o C. The mixture was cooled to -78 ºC, NaBH4 (6.92 g, mmol) was added over 30 min. After stirring was continued for 30 min at the same temperature, the reaction mixture was slowly warmed to 25 o C over 1 h. The reaction mixture was diluted with EtOAc (500 ml) and celite (30.0 g) was added. After being stirred for another 30 min, the mixture was then filtered through celite -pad and the filtrate was concentrated in vacuo. The crude product, thus obtained, was purified by column chromatography on silica gel with EtOAc-hexane (1/10 to 1/5, v/v) as eluent to give 15 (5.70 g, 67%) as a yellow powder. R f = 0.5 (EtOAc/hexane, 1/5); = +4.4 (c 0.90, MeOH); 1 H NMR (500 MHz, CDCl3) δ 7.33 (s, 1H), 6.18 (s, 1H), 4.62 (s, 2H), 4.16 (d, J = 2.4 Hz, 1H), (m,1h), 3.47 (s, 3H), 3.42 (s, 3H), 2.62 (dd, J = 11.5, 7.8 Hz, 1H), 2.31 (dddd, J = 13.7, 6.8, 4.5, 2.3 Hz, 1H), 2.18 (ddd, J = 13.2, 4.4, 2.2 Hz, 1H), (m, 1H), (m, 4H), (m, 1H), (m, 1H), (m, 1H), 1.02 (d, J = 6.5 Hz, 3H), 0.92 (s, 9H), 0.71 (s, 3H), 0.10 (s, 6H); 13 C NMR (125 MHz, CDCl3) δ 208.6, 154.0, 139.1, 122.8, 108.8, 108.6, 61.5, 58.3, 57.0, 56.1, 52.6, 50.9, 47.6, 39.2, 39.1, 32.7, 27.3, 25.9, 19.3, 18.5, 12.5, 11.8, IR (film) ν max 2953, 1716, 1464, 1381, 1254, 1072, 837 cm -1 ; HRMS (ESI) calculated for C26H45O5Si + [M+H] , found S6

7 Synthesis of diol S3 To a round-bottom flask containing CuI (4.30 g, 22.6 mmol) in ether (30 ml) was slowly added vinylmagnesium bromide (260 ml, mmol, 1.0 M in THF) at -78 ºC. After 30 min, the known epoxide S2 [2] (16.5 g, 75.6 mmol) was added slowly at the same temperature. The reaction mixture was allowed to reach 25 o C over 4 h. At this point, the reaction mixture was quenched carefully with saturated NH4Cl (aq.) (20 ml) and diluted with EtOAc (500 ml). The layers were separated, and the aqueous phase was extracted with EtOAc (3 x 100 ml). The combined organic extracts were washed with saturated NH4Cl (aq.), brine, dried over anhydrous Na2SO4 (s), concentrated in vacuo, and the residue was chromatographed on silica gel with EtOAc-hexane (1/5 to 1/3, v/v) as eluent to give S3 (16.4 g, 88%) as a colorless oil. R f = 0.4 (EtOAc/hexane, 1/4); = (c 1.20, CHCl3); 1 H NMR (500 MHz, CDCl3) δ 5.61 (ddd, J = 17.0, 10.6, 9.1 Hz, 1H), (m, 2H), 3.84 (dd, J = 10.9, 6.8 Hz, 1H), (m, 3H), (m, 1H), 2.85 (brs, 2H), (m, 1H), 0.90 (s, 9H), 0.07 (s, 6H). 13 C NMR (125 MHz, CDCl3) δ 135.4, 118.4, 74.0, 65.4, 65.2, 48.7, 25.9, 18.2, -5.4, - 5.4; IR (film) ν max 3437, 2930, 2859, 1464, 1256, 1103, 669 cm -1 ; HRMS (ESI) calculated for C12H27O3Si + [M+H] , found Synthesis of compound S4 To a stirred solution of S3 (15.8 g, 64.1 mmol) in DCM (100 ml) were sequentially S7

8 added imidazole (6.55 g, 96.2 mmol) and TIPSCl (14.4 ml, 67.3 mmol) at 0 C. The mixture was allowed to stir for 2 h at 25 o C, after which time it was quenched with sat. NH4Cl (aq.) (30 ml). The layers were separated, and the aqueous layer was extracted with ether (3 x 50 ml). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 (s), concentrated in vacuo, and the residue was chromatographed on silica gel with EtOAc-hexane (1/20, v/v) as eluent to give S4 (23.0 g, 89%) as a colorless oil. R f = 0.8 (EtOAc/hexane, 1/8); = (c 3.40, CHCl3); 1 H NMR (500 MHz, CDCl3) δ 5.81 (ddd, J = 17.2, 10.3, 9.1 Hz, 1H), (m, 2H), 3.98 (dd, J = 9.7, 4.5 Hz, 1H), 3.87 (dd, J = 9.7, 5.5 Hz, 1H), 3.78 (ddd, J = 7.9, 6.2, 3.8 Hz, 1H), 3.70 (dd, J = 10.2, 3.8 Hz, 1H), 3.58 (dd, J = 10.2, 6.2 Hz, 1H), (m, 1H), (m, 21H), 0.92 (s, 9H), 0.08 (s, 3H), 0.08 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 136.6, 117.1, 72.7, 65.6, 65.1, 48.7, 25.9, 18.3, 18.0, 11.9, -5.3, -5.4; IR (film) ν max 2943, 2866, 1464, 1256, 1099 cm -1 ; HRMS (ESI) calculated for C21H47O3Si2 + [M+H] , found Synthesis of primary alcohol S7 To a stirred solution of S4 (21.5 g, 53.4 mmol) in MeOH (AR, 100 ml) was added p-toluenesulfonic acid (PTSA, 0.46 g, 2.67 mmol) at 0 C. The reaction mixture was stirred for 30 min at the same temperature, after which time it was quenched with TEA (0.74 ml, 5.34 mmol), filtered through celite -pad, rinsed with DCM (3 x 50 ml). The S8

9 filtrate was concentrated in vacuo and the crude diol S5 was used directly in the next step without further purification. To a vigorously stirred solution of the diol S5 obtained above in DCM (AR, 300 ml) was added silica gel-supported NaIO4 reagent [3] (163.2 g, ca. 14wt%, mmol). The reaction was monitored by TLC. After completion, the reaction mixture was filtered and the silica gel was thoroughly washed with DCM (3 x 100 ml). The filtrate was concentrated in vacuo to afford the aldehyde S6 that was pure enough for the next step. To a stirred solution of the aldehyde S6 above in THF-H2O (100 ml, 4/1, v/v), NaBH4 (2.02 g, 53.4 mmol) was added at 0 C. The reaction was monitored by TLC. After completion, the reaction mixture was quenched with saturated NH4Cl (aq.) (3.0 ml) and diluted with EtOAc (300 ml). The layers were separated, and the aqueous phase was extracted with EtOAc (3 x 50 ml). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 (s), concentrated in vacuo, and the residue was chromatographed on silica gel with EtOAc-hexane, (1/8 to 1/5, v/v) as eluent to give S7 (11.2 g, 81%, over 3 steps) as a colorless oil. R f = 0.6 (EtOAc/hexane, 1/8); = (c 1.40, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 5.70 (ddd, J = 17.2, 10.7, 8.0 Hz, 1H), (m, 2H), 3.90 (dd, J = 9.8, 4.4 Hz, 1H), (m, 2H), 3.73 (dd, J = 10.7, 5.0 Hz, 1H), (m, 1H), 2.56 (brs, 1H), (m, 21H); 13 C NMR (100 MHz, CDCl3) δ 135.7, 117.4, 66.9, 65.9, 47.4, 18.0, 11.8; IR (film) ν max 3419, 2943, 2866, 1464, 1368, 1248, 1105, 683 cm -1 ; HRMS (ESI) calculated for C14H31O2Si + [M+H] , found Synthesis of bromide 10 To a stirred solution of primary alcohol S7 (10.6 g, 41.0 mmol) in DCM (50 ml) were successively added CBr4 (15.0 g, 45.1 mmol) and PPh3 (10.8 g, 41.0 mmol) at S9

10 0 C. After stirring at 25 o C for an additional 2 h, the reaction mixture was diluted with diethyl ether and filtered. The organic solvent was removed under reduced pressure, and the residue was purified by flash chromatography (eluent: hexane) to give 10 (10.4 g, 79%) as a colorless oil. R f = 0.8 (hexane); = (c 0.80, CHCl3); 1 H NMR (500 MHz, CDCl3) δ 5.80 (ddd, J = 17.9, 10.1, 7.9 Hz, 1H), (m, 2H), 3.85 (dd, J = 9.8, 4.6 Hz, 1H), 3.74 (dd, J = 9.8, 6.6 Hz, 1H), 3.64 (dd, J = 9.7, 5.9 Hz, 1H), 3.54 (dd, J = 9.7, 5.8 Hz, 1H), (m, 1H), (m, 21H); 13 C NMR (125 MHz, CDCl3) δ 136.8, 117.5, 64.3, 47.9, 35.0, 18.0, IR (film) ν max 2943, 2866, 1464, 1368, 1107, 659 cm -1 ; HRMS (ESI) calculated for C14H30BrOSi + [M+H] , found Synthesis of compound 8 To a stirred solution of bromide 10 (3.20 g, 10.0 mmol) in ether (50 ml) was added t-buli (11.5 ml, 1.3 M in pentane, 15.0 mmol) at -78 C. The reaction mixture was stirred for 30 min at the same temperature, after which time it was treated with a solution of ketone 15 (2.30 g, 4.95 mmol) in ether (20 ml). The mixture was stirred for 1 h at -78 C before it was quenched with saturated NH4Cl (aq.) (20 ml) and diluted with ether (100 ml). The layers were separated, and the aqueous phase was extracted with ether (3 x 20 ml). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 (s), concentrated in vacuo, and the residue was chromatographed on silica gel with EtOAc-hexane (1/50 to 1/20, v/v) as eluent to give 8 (2.90 g, 83%) as a colorless oil. S10

11 R f = 0.2 (EtOAc/hexane, 1/20); = -7.9 (c 0.66, CHCl3); 1 H NMR (500 MHz, CDCl3) δ 7.23 (s, 1H), 6.25 (s, 1H), (m, 1H), (m, 2H), 4.59 (s, 2H), 4.15 (d, J = 2.4 Hz, 1H), (m, 1H), 3.46 (s, 3H), 3.39 (s, 3H), 3.34 (dd, J = 9.4, 7.9 Hz, 1H), 2.61 (dd, J = 12.8, 4.2 Hz, 1H), 2.33 (dt, J = 8.6, 4.1 Hz, 1H), (m, 2H), (m, 1H), (m, 2H), 1.65 (dd, J = 14.0, 3.1 Hz, 1H), 1.58 (d, J = 12.7 Hz, 1H), (m, 5H), (m, 1H), (m, 24H), 0.95 (d, J = 6.7 Hz, 3H), 0.90 (s, 9H), 0.07 (s, 3H), 0.07 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 153.4, 141.5, 139.8, 126.7, 116.1, 109.9, 109.0, 75.0, 68.3, 58.4, 56.9, 56.0, 54.6, 52.6, 43.8, 43.2, 42.5, 41.3, 40.2, 38.8, 28.3, 27.0, 25.9, 20.6, 18.5, 18.0, 13.2, 11.9, 11.5, -5.2; IR (film) ν max 3481, 2943, 2866, 1464, 1368, 1076, 837, 683 cm -1 ; HRMS (ESI) calculated for C40H75O6Si2 + [M+H] , found S11

12 Synthesis of enone 6 To a stirred solution of 8 (1.93 g, 2.73 mmol) in THF (60 ml) was added tetrabutylammonium fluoride (TBAF, 6.90 ml, 1.0 M in THF, 6.90 mmol) at 25 o C. The reaction was monitored by TLC. After completion, the reaction mixture was cooled to 0 o C. H2O (20 ml), NaHCO3 (0.33 g, 3.93 mmol), NaOAc (0.49 g, 6.03 mmol) and N-bromosuccinimide (NBS, 0.56 g, 3.14 mmol) were sequentially added to the reaction mixture. Stirring was continued for 0.5 h. The reaction was quenched with saturated Na2S2O3 (aq.) (10 ml) and diluted with ether (100 ml). The layers were separated, and the aqueous phase was extracted with ether (2 x 20 ml). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 (s), concentrated in vacuo, and the crude product 16 was directly used in the next step without further purification. To a stirred solution of 16 obtained above in DCM (50 ml) were successively added TMP (1.84 ml, 10.9 mmol), DMAP (0.16 g, 1.36 mmol) and Ac2O (0.77 ml, 8.19 mmol) at 25 o C. Stirring was continued for 0.5 h. The mixture was then filtered through silica gel-pad and the filtrate was concentrated in vacuo. The crude acetylation product 7, thus obtained, was directly used in the next step. To a stirred solution of the crude acetylation product 7 obtained above in MeCN S12

13 (750 ml) was added TMP (1.84 ml, 10.9 mmol) at 25 o C. The resulting mixture was transferred to a sealed tube, heated to 155 ºC and stirred for 10 hours. After cooling to 25 o C, the solvent was evaporated in vacuo. The residue was chromatographed on silica gel with EtOAc-hexane (1/3 to 2/1, v/v) as eluent to give 6 (0.88 g, 68%, over 3 steps) as a solid. Note: Using the described route, 3.5 g of 6 was prepared readily after four parallel operations. R f = 0.6 (EtOAc/hexane, 1/1); m.p. (DCM/hexane): o C; = (c 1.30, CHCl3); 1 H NMR (500 MHz, CDCl3) δ 6.23 (d, J = 7.2 Hz, 1H), 5.96 (s, 1H), 4.43 (d, J = 8.3 Hz, 1H), 4.11 (d, J = 2.5 Hz, 1H), 3.98 (dd, J = 11.2, 3.9 Hz, 1H), 3.91 (dd, J = 11.2, 6.1 Hz, 1H), 3.43 (s, 3H), 3.39 (s, 3H), 2.55 (dt, J = 12.7, 8.9 Hz, 1H), (m, 1H), 2.32 (dd, J = 13.0, 3.4 Hz, 1H), (m, 1H), (m, 1H), 2.06 (s, 3H), (m, 1H), 1.85 (dd, J = 14.7, 4.2 Hz, 1H), (m, 4H), 1.52 (dd, J = 14.6, 12.3 Hz, 1H), (m, 5H), 1.30 (dd, J = 12.3, 7.0 Hz, 1H), 0.98 (s, 3H), 0.94 (d, J = 6.6 Hz, 3H); 13 C NMR (125 MHz, CDCl3) δ 196.2, 170.9, 170.0, 124.0, 108.8, 80.3, 75.8, 74.2, 68.2, 59.1, 56.9, 56.0, 52.1, 49.7, 45.0, 43.2, 41.3, 40.7, 40.2, 38.8, 33.1, 26.6, 26.4, 20.9, 18.9, 13.3, 11.5; IR (film) ν max 3481, 2943, 1736, 1676, 1603, 1449, 1238, 1072 cm -1 ; HRMS (ESI) calculated for C27H41O7 + [M+H] , found S13

14 Synthetic route to 6b: Synthesis of compound S8: OMe OMe H MgBr OH H OMe OMe O H O H THF, 0 o C 87% TBSO O H H OTBS 15 S8 To a stirred solution of ketone 15 (0.65 g, 1.40 mmol) in THF was slowly added 3-butenylmagnesium bromide (8.4 ml, 0.5 M in THF, 4.20 mmol) at 0 ºC. Stirring was continued for 30 min. The reaction was quenched with saturated NH4Cl (aq.) (5 ml) and diluted with ether (100 ml). The layers were separated, and the aqueous phase was extracted with ether (2 x 20 ml). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 (s), concentrated in vacuo. The residue was chromatographed on silica gel with EtOAc-hexane (1/20 to 1/10, v/v) as eluent to give S8 (0.63 g, 87%) as a colorless oil. S14

15 R f = 0.5 (EtOAc/hexane, 1/10); = +8.1 (c 1.60, CHCl3); 1 H NMR (500 MHz, CDCl3) δ 7.24 (d, J = 0.9 Hz, 1H), 6.20 (d, J = 0.9 Hz, 1H), 5.75 (ddt, J = 16.7, 10.2, 6.5 Hz, 1H), 5.01 (dd, J = 17.1, 1.7 Hz, 1H), 4.94 (dd, J = 10.1, 1.6 Hz, 1H), 4.62 (s, 2H), 4.16 (d, J = 2.5 Hz, 1H), 3.47 (s, 3H), 3.41 (s, 3H), 2.56 (dd, J = 12.9, 4.1 Hz, 1H), (m, 4H), (m, 1H), (m, 1H), (m, 2H), (m, 4H), (m, 3H), 1.04 (s, 3H), 0.97 (d, J = 6.8 Hz, 3H), 0.92 (s, 9H), 0.09 (s, 3H), 0.09 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 154.2, 139.2, 138.1, 125.7, 114.4, 109.1, 109.0, 74.7, 58.4, 56.9, 56.0, 52.8, 43.0, 40.8, 40.2, 38.9, 29.2, 27.0, 26.5, 25.9, 20.3, 18.5, 13.3, 11.5, IR (film) ν max 3474, 2857, 1462, 1381, 1258, 1078 cm -1 ; HRMS (ESI) calculated for C30H53O5Si + [M+H] , found Synthesis of compound 6a: S15

16 To a stirred solution of S8 (568.0 mg, 1.09 mmol) in THF (21 ml) was added tetrabutylammonium fluoride (TBAF, 1.50 ml, 1.0 M in THF, 1.50 mmol) at 25 o C. The reaction was monitored by TLC. After completion, the reaction mixture was cooled to 0 o C. H2O (7 ml), NaHCO3 (121.0 mg, 1.44 mmol), NaOAc (197.0 mg, 2.40 mmol) and N-bromosuccinimide (NBS, mg, 1.25 mmol) were sequentially added to the reaction mixture. Stirring was continued for 0.5 h. The reaction was quenched with saturated Na2S2O3 (aq.) (10 ml) and diluted with ether (100 ml). The layers were separated, and the aqueous phase was extracted with ether (2 x 20 ml). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 (s), concentrated in vacuo, and the crude product S9 was directly used in the next step without further purification. To a stirred solution of S9 obtained above in DCM (50 ml) were successively added TMP (0.73 ml, 4.36 mmol), DMAP (67.0 mg, 0.55 mmol) and Ac2O (0.20 ml, 2.18 mmol) at 25 o C. Stirring was continued for 0.5 h. The mixture was then filtered through silica gel-pad and the filtrate was concentrated in vacuo. The crude acetylation product 7a, thus obtained, was directly used in the next step. To a stirred solution of the crude acetylation product 7a obtained above in MeCN (200 ml) was added TMP (0.73 ml, 4.36 mmol) at 25 o C. The resulting mixture was transferred to a sealed tube, heated to 155 ºC and stirred for 10 hours. After cooling to 25 o C, the solvent was evaporated in vacuo. The residue was chromatographed on silica gel with EtOAc-hexane (1/3 to 2/1, v/v) as eluent to give 6a and 6a as an inseparable mixture (289.0 mg, 65%, over 3 steps, 6a:6a = 5:1). Analysis data for 6a (major): R f = 0.5 (EtOAc/hexane, 1/1); 1 H NMR (500 MHz, CDCl3) δ 5.93 (s, 1H), 4.58 (d, J = 7.4 Hz, 1H), 4.51 (d, J = 8.3 Hz, 1H), 4.13 (d, J = 2.4 Hz, 1H), 3.46 (s, 3H), 3.41 (s, 3H), (m, 1H), 2.56 (dt, J = 12.9, 9.1 Hz, 1H), (m, 1H), (m, 2H), 1.94 (dt, J = 15.6, 8.0 Hz, 1H), (m, 1H), 1.82 (dd, J = 14.3, 8.2 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 8H), 1.00 (s, 3H), 0.97 (d, J S16

17 = 6.7 Hz, 3H); 13 C NMR (125 MHz, CDCl3) δ 196.8, 166.7, 121.8, 108.8, 82.6, 81.7, 71.3, 57.4, 56.9, 56.0, 54.0, 52.5, 43.4, 39.6, 38.8, 38.4, 36.9, 34.2, 26.9, 24.8, 21.8, 20.4, 13.7, 11.5; IR (film) ν max 2943, 1672, 1449, 1603, 1265, 1068 cm -1 ; HRMS (ESI) calculated for C24H37O5 + [M+H] , found To a stirred solution of 6a and 6a (200.0 mg, 6a:6a = 5:1, 0.49 mmol) in THF (10 ml) was added diisobutylaluminium hydride (DIBAL, 0.62 ml, 1.2 M solution in toluene, 0.74 mmol) dropwise at -78 ºC. Stirring was continued for 30 min at the same temperature. The reaction was quenched with saturated potassium sodium tartrate (aq.) (10 ml) at -78 ºC, stirred for 1 h at 25 ºC and diluted with ether (100 ml). The layers were separated, and the aqueous phase was extracted with ether (2 x 20 ml). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 (s), concentrated in vacuo. The residue was chromatographed on silica gel with EtOAchexane (1/2 to 1/1, v/v) as eluent to give 6b (141.0 mg, 71%) as a solid. R f = 0.4 (EtOAc/hexane, 1/1); m.p. (DCM/hexane): o C; = (c 0.54, CHCl3); 1 H NMR (500 MHz, CDCl3) δ 5.30 (d, J = 1.8 Hz, 1H), (m, 1H), (m, 1H), (m, 2H), 3.43 (s, 3H), 3.38 (s, 3H), 2.51 (dtd, J = 15.7, 9.5, 6.1 Hz, 1H), 2.24 (ddd, J = 13.0, 10.3, 7.8 Hz, 1H), 1.99 (dt, J = 12.7, 3.2 Hz, 1H), (m, 2H), (m, 5H), (m, 9H), 0.97 (s, 3H), 0.94 (d, J = 6.8 Hz, 3H); 13 C NMR (125 MHz, CDCl3) δ 144.1, 121.0, 108.9, 81.5, 78.1, 71.3, 68.6, 57.2, 57.0, S17

18 55.9, 52.5, 43.4, 40.9, 40.1, 38.9, 36.4, 33.1, 27.1, 24.1, 22.5, 20.5, 13.8, IR (film) ν max 3448, 2987, 2937, 1460, 1379, 1263, 1095 cm -1 ; HRMS (ESI) calculated for C24H39O5 + [M+H] , found Synthesis of compound 17 To a stirred solution of enone 6 (0.88 g, 1.85 mmol) in THF-H2O (40 ml, 4/1, v/v) was added NaBH4 (0.21 g, 5.54 mmol) at 0 C. The reaction was monitored by TLC. After completion, the reaction mixture was quenched with saturated NH4Cl (aq.) (10 ml) and diluted with EtOAc (100 ml). The layers were separated, and the aqueous phase was extracted with EtOAc (3 x 20 ml). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 (s), concentrated in vacuo. The crude product S10, thus obtained, was directly used in the next step. To a stirred solution of secondary alcohol S10 in THF (30 ml) was added potassium bis(trimethylsilyl)amide (KHMDS, 1.94 ml, 1.0 M in THF, 1.94 mmol) at - 78 C. The reaction mixture was stirred for 10 min at the same temperature, followed by dropwise addition of CS2 (0.42 ml, 6.98 mmol) and MeI (0.43 ml, 6.98 mmol). S18

19 Stirring was continued for 30 min. The reaction was quenched with saturated NH4Cl (aq.) (20 ml) and diluted with ether (100 ml). The layers were separated, and the aqueous phase was extracted with ether (2 x 20 ml). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 (s), concentrated in vacuo, and the crude xanthate S11 was directly used in the next step without further purification. To a stirred solution of the crude xanthate S11 obtained above in PhMe (30 ml) were sequentially added 2,2'-azobis(2-methylpropionitrile (AIBN, 68.0 mg, 0.41 mmol) and n-bu3snh (4.98 ml, 18.5 mmol) at 25 o C. The mixture was degassed under Ar for 15 min, heated to 80 C and stirred for 1 h. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel with EtOAc-hexane (1/50 to 1/2, v/v) as eluent to give 17 (0.35 g, 41%, over 3 steps) as a foam. R f = 0.4 (EtOAc/hexane, 1/2); = (c 1.10, MeOH); 1 H NMR (500 MHz, CDCl3) δ 5.67 (d, J = 6.5 Hz, 1H), 5.36 (d, J = 5.1 Hz, 1H), 4.42 (dd, J = 7.5, 5.1 Hz, 1H), 4.11 (s, 1H), 4.04 (dd, J = 10.9, 4.0 Hz, 1H), 3.89 (dd, J = 10.9, 7.0 Hz, 1H), 3.43 (s, 3H), 3.38 (s, 3H), 2.68 (dd, J = 17.0, 4.7 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), 2.06 (s, 3H), (m, 3H), (m, 2H), 1.70 (dd, J = 17.4, 5.5 Hz, 1H), (m, 2H), (m, 1H), (m, 7H), 0.93 (s, 3H), 0.92 (d, J = 5.6 Hz, 3H); 13 C NMR (125 MHz, CDCl3) δ 171.2, 144.1, 117.6, 108.9, 74.8, 74.5, 73.3, 69.0, 59.8, 56.9, 56.0, 52.2, 48.8, 48.1, 44.9, 43.2, 40.6, 40.2, 39.1, 38.8, 34.1, 27.6, 26.7, 21.1, 19.0, 13.4, 11.4; IR (film) ν max 3482, 2940, 2831, 2369, 1736, 1375, 1066 cm -1 ; HRMS (ESI) calcula1ted for C27H43O6 + [M+H] , found S19

20 Synthesis of triol 19 To a stirred solution of 17 (250.0 mg, 0.54 mmol) in DCM (10 ml) were sequentially added 2,4,6-trimethylpyridine (360 μl, 2.70 mmol), SOCl2 (120 μl, 1.62 mmol), pyridine (220 μl, 2.70 mmol) at 0 C. The reaction mixture was stirred for 10 min at the same temperature before it was quenched with saturated NaHCO3 (aq.) (20 ml) and diluted with ether (100 ml). The layers were separated, and the aqueous phase was extracted with ether (3 x 20 ml). The combined organic extracts were washed with 1M HCl (aq.), brine, dried over anhydrous Na2SO4 (s), concentrated in vacuo, and the residue, thus obtained, was used directly in the next step. The 1 H NMR data of the crude product shows that the desired compound 18 is the major product, and the ratio of inseparable 18:18a:18b is 9:1:1. R f = 0.6 (EtOAc/hexane, 2/3); NMR data of 18 (major): 1 H NMR (500 MHz, CDCl3) δ 5.38 (s, 1H), (m, 1H), 4.52 (t, J = 6.3 Hz, 1H), 4.37 (d, J = 6.9 Hz, 1H), 4.14 (d, J = 2.5 Hz, 1H), (m, 2H), 3.45 (s, 3H), 3.39 (s, 3H), (m, 2H), 2.66 (dd, J = 17.4, 5.3 Hz, 1H), (m, 1H), (m, 1H), 2.06 (s, 3H), (m, 1H), (m, 2H), (m, 3H), (m, 7H), 0.97 (d, J = 6.9 Hz, 3H), 0.62 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 171.3, 144.0, 140.8, 122.0, 115.4, 109.0, 75.0, 74.9, S20

21 68.3, 57.0, 55.9, 54.7, 52.1, 50.6, 46.7, 44.0, 40.6, 39.8, 39.4, 38.8, 34.2, 30.1, 27.0, 23.4, 21.1, 12.0, Freshly cut lithium slices (80.0 mg, 11.4 mmol) were added rapidly to a solution of the crude product obtained above in ethylamine (5 ml) at 25 o C. The mixture turned blue and was vigorously stirred for further 45 min. The reaction was quenched with cyclopentadiene (1 ml) and saturated NH4Cl (aq.) (3 ml). Water (1 ml) is added and the mixture is extracted with EtOAc (100 ml). The combined organic extracts were washed with 1M HCl (aq.), brine, dried over anhydrous Na2SO4 (s), concentrated in vacuo, and the residue was chromatographed on silica gel with EtOAc as eluent to give 19 (99.0 mg, 51%, over 2 steps) as a foam. R f = 0.3 (EtOAc); = (c 1.00, MeOH); 1 H NMR (500 MHz, MeOD -d4) δ 5.50 (t, J = 7.5 Hz, 1H), (m, 1H), (m, 1H), 3.62 (dd, J = 10.7, 3.4 Hz, 1H), 3.57 (dd, J = 10.7, 3.2 Hz, 1H), 3.49 (dd, J = 10.7, 6.9 Hz, 1H), 3.26 (dd, J = 10.6, 7.1 Hz, 1H), (m, 1H), (m, 1H), 2.49 (ddd, J = 13.3, 11.4, 6.0 Hz, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 1H), (m, 2H), (m, 2H), (m, 4H), (m, 4H), 1.04 (d, J = 6.6 Hz, 3H), 0.67 (s, 3H); 13 C NMR (125 MHz, MeOD -d4) δ 147.3, 140.4, 122.8, 117.6, 66.4, 64.5, 63.8, 55.2, 52.7, 51.2, 43.8, 43.4, 39.5, 39.4, 39.2, 35.8, 35.7, 31.7, 28.4, 26.8, 23.0, 16.1, 11.3; IR (film) ν max 3348, 2926, 2868, 1458, 1375, 1261, 1026 cm -1 ; HRMS (ESI) calcula1ted for C23H37O3 + [M+H] , found S21

22 Synthesis of aldehyde S12 To a stirred solution of the triol 19 (70.0 mg, 194 μmol) in dichloromethane (20 ml) and sodium bicarbonate-potassium carbonate buffer (ph 8.6, 20 ml) were added tetrabutyl ammonium chloride (TBACl, mg, 776 µmol), N-chlorosuccinimide (NCS, mg, 776 µmol) and 2,2,6,6-tetramethylpiperidinooxy (TEMPO, 15.1 mg, 0.97 mmol) at 25 o C. After consumption of the starting material, the mixture was quenched with saturated Na2S2O3 (aq.) and diluted with EtOAc (50 ml). The aqueous phase was extracted with EtOAc (3 x 20 ml). The combined organic phases were washed with brine, and dried over Na2SO4 (s), concentrated in vacuo, and the residue was chromatographed on silica gel with EtOAc-hexane (1/4 to 1/1, v/v) as eluent to give S12 (48.0 mg, 70%) as a colorless oil. R f = 0.5 (EtOAc/hexane, 1/1); = (c 0.40, CHCl3); 1 H NMR (500 MHz, CDCl3) δ 9.77 (d, J = 2.1 Hz, 1H), 9.61 (d, J = 3.1 Hz, 1H), 5.58 (t, J = 7.3 Hz, 1H), (m, 1H), 3.86 (t, J = 10.7 Hz, 1H), 3.49 (ddd, J = 11.0, 4.1, 2.2 Hz, 1H), (m, 1H), 2.58 (ddd, J = 13.4, 11.4, 6.1 Hz, 1H), 2.50 (d, J = 12.7 Hz, 1H), (m, 5H), (m, 3H), (m, 1H), (m, 4H), (m, 3H), 1.16 (d, J = 6.9 Hz, 3H), 0.68 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 204.8, 203.2, 145.9, 142.6, 119.0, 114.5, 64.3, 55.0, 51.2, 51.2, 50.1, 49.7, 44.7, 43.9, 39.0, 36.2, 35.3, 31.4, 28.4, 26.4, 23.5, 13.6, 12.7; IR (film) ν max 3439, 2928, 2852, 1722, 1482, 1265, 1026 cm -1 ; HRMS (ESI) calcula1ted for C23H33O3 + [M+H] , found S22

23 Synthesis of aldehyde 20 To a stirred solution of the aldehyde S12 (40.0 mg, 0.11 mmol) in DCM (5 ml) were subsequently added 2,6-lutidine (77.0 μl, 0.66 mmol) and triethylsilyl trifluoromethanesulfonate (TESOTf, 75.0 μl, 0.33 mmol) at -78 C. The reaction mixture was stirred at the same temperature for 30 min. After consumption of the starting material, the mixture was quenched with saturated NaHCO3 (aq.) (10 ml) and diluted with EtOAc (50 ml). The aqueous phase was extracted with EtOAc (3 x 20 ml). The combined organic phases were washed with brine, dried over Na2SO4 (s), concentrated in vacuo, and the residue was chromatographed on silica gel with EtOAchexane (1/20 to 1/10, v/v) as eluent to give 20 (45.0 mg, 86%) as a colorless oil. R f = 0.8 (EtOAc/hexane, 1/4); = (c 0.31, CHCl3); 1 H NMR (500 MHz, CDCl3) δ 9.75 (s, 1H), 9.59 (s, 1H), 5.54 (t, J = 7.3 Hz, 1H), 5.23 (s, 1H), 3.80 (t, J = 11.3 Hz, 1H), 3.48 (d, J = 11.1 Hz, 1H), (m, 1H), 2.61 (td, J = 12.4, 6.1 Hz, 1H), 2.49 (d, J = 12.6 Hz, 1H), (m, 5H), (m, 4H), (m, 4H), (m, 3H), 1.14 (d, J = 6.8 Hz, 3H), 0.94 (t, J = 7.9 Hz, 9H), 0.66 (s, 3H), 0.58 (q, J = 8.0 Hz, 6H); 13 C NMR (125 MHz, CDCl3) δ 204.8, 203.2, 145.8, 142.5, 119.4, 114.5, 64.5, 55.0, 51.2, 51.2, 50.3, 49.8, 44.7, 44.4, 39.1, 36.9, 35.9, 31.5, 28.4, 26.4, 23.5, 13.6, 12.7, 6.9, 4.7; IR (film) ν max 2951, 2873, 1724, 1460, 1238, 1069, 742 cm -1 ; HRMS (ESI) calculated for C29H47O3Si + [M+H] , found S23

24 Synthesis of ketone 21 To a stirred solution of the aldehyde 20 (80.0 mg, μmol) in t-buoh (5 ml, degassed with Ar) was added t-buok (330.0 μl, 1.8 M in THF, 0.59 mmol) at 25 o C. O2 was bubbled for 10 min. The reaction mixture was quenched with saturated NH4Cl (aq.) (5 ml) and diluted with EtOAc (50 ml). The aqueous phase was extracted with EtOAc (3 x 20 ml). The combined organic phases were washed with brine, and dried over Na2SO4 (s), concentrated in vacuo, and the residue was chromatographed on silica gel with EtOAc-hexane (1/6 to 1/4, v/v) as eluent to give ketone 21 (42.0 mg, 56%) as a white powder. R f = 0.6 (EtOAc/hexane, 1/4); = (c 0.60, CHCl3); 1 H NMR (500 MHz, CDCl3) δ 5.62 (s, 1H), 5.60 (t, J = 7.4 Hz, 1H), 3.47 (t, J = 11.0 Hz, 1H), 2.83 (dd, J = 12.3, 5.6 Hz, 2H), (m, 2H), (m, 3H), (m, 2H), (m, 2H), 2.18 (s, 3H), (m, 2H), (m, 5H), 0.99 (t, J = 7.9 Hz, 9H), 0.66 (s, 3H), 0.63 (q, J = 8.0 Hz, 6H); 13 C NMR (125 MHz, CDCl3) δ 208.7, 205.1, 155.8, 145.4, 125.6, 122.8, 65.0, 63.5, 55.8, 53.8, 49.0, 46.6, 42.0, 38.1, 36.8, 31.5, 27.6, 27.6, 23.2, 22.5, 13.8, 6.9, 4.7; IR (film) ν max 2953, 2872, 1699, 1660, 1458, 1357, 1259, 1016 cm -1 ; HRMS (ESI) calculated for C27H43O3Si + [M+H] , found S24

25 Synthesis of compound 4a To a stirred solution of the known alcohol S13 [4] (0.39 g, 1.08 mmol) in DCM (5 ml) were subsequently added 2,6-lutidine (0.25 ml, 2.16 mmol) and triethylsilyl trifluoromethanesulfonate (TESOTf, 0.25 ml, 1.08 mmol) at -78 C. The reaction mixture was stirred at the temperature for 30 min. After consumption of the starting material, the mixture was quenched with saturated NaHCO3 (aq.) (5 ml) and diluted with EtOAc (50 ml). The aqueous phase was extracted with EtOAc (3 x 10 ml). The combined organic phases were washed with brine, dried over Na2SO4 (s), concentrated in vacuo, and the residue was chromatographed on silica gel with hexane as eluent to give 4a (0.47 g, 92%) as a colorless oil. R f = 0.9 (hexane); = (c 2.40, CHCl3); 1 H NMR (500 MHz, CDCl3) δ (m, 2H), 4.25 (tdd, J = 6.6, 5.1, 3.5 Hz, 1H), (m, 6H), (m, 6H), 1.24 (d, J = 6.4 Hz, 3H), 0.98 (t, J = 7.9 Hz, 9H), 0.90 (t, J = 7.3 Hz, 15H), 0.62 (q, J = 7.9 Hz, 6H); 13 C NMR (125 MHz, CDCl3) δ 152.7, 125.3, 72.0, 29.1, 27.3, 24.4, 13.7, 9.4, 6.9, 4.8; IR (film) ν max 2957, 1458, 1128, 1092, 1003 cm -1 ; S25

26 Synthesis of cyclocitrinol (3) To a stirred solution of stannane 4a (109.0 mg, 0.23 mmol) in THF (50 ml) was added n-buli (110.0 μl, 1.6 M in hexane, 0.18 mmol) at -78 C. The reaction mixture was stirred for 30 min at the same temperature, after which time it was treated with a solution of ketone 21 (20.0 mg, 45.2 μmol) in THF (3 ml) and stirred for 1 h until it was quenched with MeOH (100 μl). The mixture was allowed to warm to 25 o C and tetrabutylammonium fluoride (TBAF, μl, 1.0 M in THF, 0.54 mmol) was added. After stirring was continued for 1 h at the same temperature, the reaction mixture was quenched with saturated NH4Cl (aq.) (2 ml) and diluted with EtOAc (50 ml). The layers were separated, and the aqueous phase was extracted with EtOAc (3 x 20 ml). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 (s), concentrated in vacuo, and the residue was chromatographed on silica gel with EtOAc as eluent to give 3 (15.0 mg, 84%) as a white powder. R f = 0.4 (EtOAc); = (c 0.45, MeOH); 1 H NMR (500 MHz, DMSO-d6) δ 5.64 (dd, J = 15.6, 1.3 Hz, 1H), 5.54 (dd, J = 8.1, 6.4 Hz, 1H), 5.50 (dd, J = 15.6, 5.4 Hz, 1H), 5.38 (s, 1H), 4.60 (d, J = 4.4 Hz, 1H), 4.55 (d, J = 4.6 Hz, 1H), 4.21 (s, 1H), (m, 1H), (m, 1H), 2.79 (dd, J = 12.0, 5.4 Hz, 1H), (m, 1H), 2.62 (brd, J = 12.7 Hz, 1H), 2.47 (brs, 2H), (ddd, J = 13.2, 11.1, 6.2, 1H), (m, 3H), (m, 1H), (m, 8H), 1.20 (s, 3H), 1.09 (d, J = 6.4 Hz, 3H), 0.71 (s, 3H); 13 C NMR (500 MHz, DMSO-d6) δ 204.1, 157.1, 145.7, 136.0, 130.7, 124.5, 121.9, 73.3, 66.2, 63.1, 60.0, 55.2, 53.2, 48.1, 45.9, 41.3, 38.8, 35.9, 28.9, 27.5, 27.1, 24.0, S26

27 22.3, 22.1, 14.3; IR (film) ν max 3374, 2928, 2855, 1647, 1458, 1364, 854 cm -1 ; HRMS (ESI) calculated for C25H37O4 + [M+H] , found S27

28 3. Table S1 Comparison of NMR Data for Natural and Synthetic Cyclocitrinol 1 H &ppm (J in Hz), DMSO-d6 13 C &ppm, DMSO-d6 position isolated [5] (600M) synthetic (500M) ΔδH (i-s) isolated [5] (150M) synthetic (125M) ΔδC (i-s) , dd (6.8, 8.7) 5.54, dd (6.4, 8.1) , ddt (2.1, 8.2, 13.3) 2.07, m , ddd (6.4, 11.0, 13.3) 2.34, ddd (6.2, 11.1, 13.2) , m 3.11, m , brd (13.2) 2.62, brd (12.7) , dd (4.0, 13.2) 1.51, m , m 2.67, m , s 5.38, s , dd (5.5, 12.4) 2.79, dd (5.4, 12.0) , m 1.49, m , m 1.76, m , m 1.43, m , m 2.13, m , m 2.10, m , m 1.39, m , m 1.46, m , m 1.57, m , m 1.66, m , m 1.66, m , brs 2.47, brs , m 2.47, brs , s 0.71, s , s 1.20, s , dd (1.3, 15.6) 5.64, dd (1.3, 15.6) , dd (5.5, 15.6) 5.50, dd (5.4, 15.6) , m 4.09, m S28

29 , d (6.4) 1.09, d, (6.4) OH 4.61, d (4.5) 4.60, d (4.4) OH 4.22, s 4.21, s OH 4.57, d (4.5) 4.55, d (4.6) Table S2 Crystal Data and Structure Refinement for 6, CCDC Identification code 6 Empirical formula C27H40O7 Formula weight Temperature/K 100 Crystal system hexagonal Space group P61 a/å (2) b/å (2) c/å (8) α/ 90 β/ 90 γ/ 120 Volume/Å (16) Z 6 ρcalcg/cm μ/mm F(000) Crystal size/mm Radiation CuKα (λ = ) 2Θ range for data collection/ to Index ranges -13 h 13, -13 k 13, -41 l 41 Reflections collected Independent reflections 4673 [Rint = , Rsigma = ] S29

30 Data/restraints/parameters 4673/1/315 Goodness-of-fit on F Final R indexes [I>=2σ (I)] R1 = , wr2 = Final R indexes [all data] R1 = , wr2 = Largest diff. peak/hole / e Å /-0.19 Flack parameter 0.03(11) 5. Table S3 Crystal Data and Structure Refinement for 6b, CCDC Identification code 6b Empirical formula C24H38O5 Formula weight Temperature 296(2) K Wavelength Å Crystal system Monoclinic Space group P2 1 Unit cell dimensions a = (2) Å = 90. b = (6) Å = (12). c = (2) Å = 90. Volume (5) Å 3 Z 2 Density (calculated) Mg/m 3 Absorption coefficient mm -1 F(000) 444 Crystal size x x mm 3 Theta range for data collection to Index ranges -7<=h<=5, -30<=k<=30, -8<=l<=8 Reflections collected Independent reflections 3958 [R(int) = ] S30

31 Completeness to theta = % Absorption correction multi-scan Max. and min. transmission and Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 3958 / 1 / 262 Goodness-of-fit on F Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Absolute structure parameter -0.1(3) Extinction coefficient n/a Largest diff. peak and hole and e.å -3 References (1) For the preparation of 9 see: Liu, X.; Liu, J.; Zhao, J.; Li, S.; Li, C.-C. Org. Lett. 2017, 19, (2) Known epoxide S2 was easily prepared by Sharpless asymmetric epoxidation of the corresponding olefin: Eppley, A. W.; Totah, N. I. Tetrahedron 1997, 53, (3) Zhong, Y.-L.; Shing, T. K. M. J. Org. Chem. 1997, 62, (4) Weber, F.; Brückner, R. Org. Lett. 2014, 16, (5) Du, L.; Zhu, T.; Fang, Y.; Gu, Q.; Zhu, W. J. Nat. Prod. 2008, 71, S31

32 6. NMR Spectra of Synthetic Compounds S32

33 S33

34 S34

35 S35

36 S36

37 S37

38 S38

39 S39

40 S40

41 S41

42 S42

43 S43

44 S44

45 S45

46 S46

47 S47

48 S48

49 S49

50 S50

51 S51

52 S52

53 S53

54 S54

55 Natural 600M DMSO-d6 Synthetic 500M DMSO-d6 Natural 150M DMSO-d6 Synthetic 125M DMSO-d6 S55