Synthesis of Enantiomerically Pure (8 S, 9 S, 10 R, 6 Z

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Synthesis of Enantiomerically Pure (8S,9S,10R,6Z)-Trihydroxyoctadec-6-enoic Acid Jogula Srinivas, Yoichi Namito, Ryosuke Matsubara, and Masahiko Hayashi J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00376 • Publication Date (Web): 13 Apr 2017 Downloaded from http://pubs.acs.org on April 13, 2017

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The Journal of Organic Chemistry

Synthesis of Enantiomerically Pure (8S,9S,10R,6Z)-Trihydroxyoctadec-6enoic Acid Jogula Srinivas, Yoichi Namito, Ryosuke Matsubara and Masahiko Hayashi* Department of Chemistry, Graduate School of Science, Kobe University, Nada, Kobe 657-8501, Japan Supporting Information GRAPHICAL ABSTRACT

ABSTRACT: We have accomplished the asymmetric synthesis of (8S,9S,10R,6Z)-trihydroxyoctadec-6enoic acid in optically pure form, and determined the absolute configuration of the natural product based on stereodetermined chiral building block 7, which was prepared by the catalytic enantioselective allylic oxidation of 4,5-epoxycyclohex-1-ene using an S-configurated N,N-bidentate ligand-copper catalyst. INTRODUCTION Oxylipins is the general term used to describe oxidized fatty acids, which are widely distributed in aerobic organisms, including plants, animals, and fungi.1 Many oxylipins have physiological significance as a class of signaling molecules in plants, especially with regard to plant stress responses.2,3 In 2009, Pizza and his co-workers isolated four novel oxylypins (1__4) from Dracontium Loretense (Figure 1).4 They determined relative stereochemistry of 1 and 2 by 1D (1H, 13C, TOCSY) and 2D (DQFCOSY, HMBC, HSQC, and ROESY) NMR experiments as well as electrospray ionization multistage ion trap mass spectrometry (ESI-ITMS) analysis. However, the absolute configuration was elucidated to be 8R, 9R, 10S for compound 1 and 9S, 10R, 11R for compound 2 by comparison with the known absolute configuration for a similar compound 5.5a Recently, several groups reported the asymmetric synthesis of oxylipins and their related compounds. 5b

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Figure 1. Oxylipins family 1-4 and related compound 5 In 2011, Sharma and his co-workers reported the synthesis of (6S,9R,10S,7E)-6,9,10trihydroxyoctadeca-7-enoic acid starting from protected glyceraldehyde as a chiral template, followed by two organometallic additions to aldehyde and alkene-cross metathesis.6 In 2012, Naraiah and hisworkers reported the synthesis of (6R,9R,10R,7E)-6,9,10-trihydroxyoctadec-7-enoic acid starting from ndecanal using Sharpless asymmetric dihydroxylation and CBS reduction to build the chiral center.7 Barura et al. reported oxylipin-related compounds using L-ascorbic acid and Jacobsen’s hydrolytic kinetic resolution.8 More recently, Yadav and his co-workers reported the related compounds starting from Dribose as a chiral pool.9 On the other hand, we reported the enantioselective allylic oxidation of 4,5-epoxycyclohex-1-ene, 6 with t-butyl perbenzoate, catalytic amount of a chiral S-configurated N,N-bidentate ligand, and a copper catalyst. This reaction afford (3S,4S,5S)-3-benzoyl-4,5-epoxycyclohex-1-ene, with 84% ee, In order to get high ee, we convert benzoyl group to p-nitrobenzoyl group, followed by using the recrystallization technique, we got 710 in optically pure form (Scheme 1). The innovative feature here is, from an achiral compound 6, in a single step we generated three contiguous chiral centers. By simply reverting the chirality in chiral Schiff’s base, it is possible to get the exact enantiomer of compound 7. Therefore this method has a great explore in asymmetric synthesis of stereotriad building blocks. Using 7, we also reported the formal synthesis of (-)-oseltamivir phosphate.11 Scheme 1: Asymmetric allylic oxidation


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In this paper, we would like to report an efficient synthesis of (8S,9S,10R,6Z)-trihydroxyoctadec-6enoic acid and determination of the absolute configuration of natural compound 1. Furthermore, we will provide a new strategy to construct acyclic three contiguous stereogenic centers in an acyclic system from a chiral building block 7. RESULTS AND DISCUSSION Scheme 2 shows the retrosynthetic analysis starting from optically pure (3S,4S,5S)-3-p-nitrobenzoyl4,5-epoxycyclohex-1-ene 7. Route A includes two Wittig reactions for carbon-carbon bond formation, while route B includes a Wittig reaction and a copper-catalyzed coupling reaction between the tosylate compound and the Grignard reagent. Scheme 2. Retrosynthetic analysis of (8S,9S,10R,6Z)-Trihydroxyoctadec-6-enoic Acid

Scheme 3. Synthesis of (8S,9S,10R,6Z)-trihydroxyoctadec-6-enoic acid (ent-1) via route A

As shown in Scheme 3, treatment of optically pure olefinic epoxide 7 with aq. H2SO4 in DMSO at 60 ºC for 3 h gave diol 8 in 86% yield. Acetonization of 8 using 2,2-dimethoxypropane (2,2-DMP) provided



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compound 9 in 93% yield. Ozonolysis of 9, followed by reduction with NaBH4, afforded chiral diol 10 in 93% yield. After de-4-nitrobenzoylation (11: 91% yield), selective acetonization (12: 86% yield) and oxidation of the primary alcohol with IBX afforded di-acetonide aldehyde 13 in 84% yield. Compound 13 was used in the Wittig reaction with 14 to afford 15 in 74% yield, and subsequent hydrogenation furnished 16 in 96% yield. Deacetonization (17: 78%), followed by t-butyldimethylsilylation, afforded tetra-t-butyldimethylsiloxy compound 18. Selective desilylation of primary alcohol (19: 94%) and oxidation with IBX gave trisiloxyaldehyde 20 in 86% yield. Wittig reaction of aldehyde 20 with 21 provided trisiloxycarbozylic acid 22 in 71% yield. Finally, the action of HCl in THF on 22 accomplished the desilylation to furnish the desired product ent-1 (Scheme 3). All the absolute configurations in synthetic ent-1 were fixed based on compound 7. The []D value of the synthetic product was [α]D26 +18.1 (c 0.2, CH3OH), while that of the reported natural product 1 was [α]D25 -17.4 (c 0.2, CH3OH); therefore, the absolute configuration of the latter was established as 8R,9R,10S. Scheme 4. Synthesis of (8S,9S,10R,6Z)-trihydroxyoctadec-6-enoic acid (ent-1) via route B

As shown in Scheme 4, the alternative route B also started from compound 7. The ring-opening product, i.e., the diol, was t-butyldimethylsilylated to give 23. Ozonolysis of 23, followed by selective protection of the aldehyde with propane diol, gave cyclic acetal 25. The Wittig reaction between 21 and 25 proceeded smoothly at 30 ºC for 3 h to afford carboxylic acid 26 in 56% yield from compound 23. After esterification, the 4-nitrobenzoyl group was removed to obtain 28, and subsequent reduction with LiAlH4 afforded triol 29. t-Butyldimethylsilylation of triol and cleavage of the cyclic acetal were carried ACS Paragon Plus Environment

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out with TMSOTf to provide unstable aldehyde 31, which was instantly reduced with NaBH4 to give alcohol 32, which was converted into tosylate 33. The tosylate 33, coupled with Grignard reagent in the presence of a catalytic amount of CuI to provide tetra-t-butylsilylated compound 34.12 Selective deprotection of the primary siloxy group of 34 by CSA yielded 35. After oxidation of this alcohol 35 was oxidized to carboxylic acid 36 with TEMPO and PhI(OAc)2 system, t-butyldimethylsilyl group remained in 36 was deprotected with TBAF to provide ent-1 (Scheme 4). The []D value of the product obtained by route B was [α]D26 +18.0 (c 0.2, CH3OH). CONCLUSION In conclusion, we have revealed two synthetic routes to (8S,9S,10R,6Z)-trihydroxyoctadec-6-enoic acid (ent-1) and determined the absolute configuration of natural product 1. Among the two routes, route A is somewhat better than route B. Furthermore, the optically pure 7 proved to be a versatile chiral building block for cyclic compounds such as (-)-Oseltamivir Phosphate,11,13a 2-Deoxystreptamine11,13b as well as acyclic systems such as (+)-Aspicilin,13c Pironetin13d possessing three contiguous stereogenic centers, via ozonolysis. EXPERIMENTAL SECTION General. All reactions were carried out in oven-dried glassware under magnetic stirring. All starting materials were obtained from commercial sources or were synthesized using standard procedures. Melting points were measured on a Yanaco MP-500D instrument and were not corrected. 1H and 13C NMR spectra (400 and 100 MHz, respectively) were recorded on a Bruker Avance III HD 400 spectrometer; TMS (0 ppm) and CDCl3 (77.0 ppm) were used as internal standards, respectively. The following abbreviations are used to describe NMR peak multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet. HRMS was measured using JEOL JMS-T100LP. Optical rotations were measured on a HORIBA SEPA-300 polarimeter for solution in a 1 dm cell. Thin layer chromatography (TLC) was carried out on Merck 25 TLC silica gel 60 F254 aluminum sheets. (1S,5R,6S)-5,6-Dihydroxycyclohex-2-en-1-yl 4-nitrobenzoate (8). To a stirred solution of 7 (2.5 g, 9.57 mmol) in DMSO (50 mL) was added 10% aq. H2SO4 (2.55 mL, 4.78 mmol) slowly at room temperature. The reaction mixture was stirred at 60 ºC for 3 h. After completion of starting material monitored by TLC, the reaction mixture was quenched by slow addition of aq. NaHCO3 solution and extracted with ethyl acetate (120 mL x 4). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silicagel flash column chromatography using a mixture of 50% ethyl acetate and hexane as an eluent to afford 8 (2.3 g, 86%) as a white solid. Rf = 0.1 (50% ethyl acetate and hexane). mp: 127__130 ºC; [α]D29 +178.2



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(c 1.0, CHCl3); IR (neat): νmax (cm-1) 3392, 3249, 2924, 1725, 1609, 1521, 1344, 1267, 1133, 1062, 870, 784; 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 9.0 Hz, 2H), 8.24 (d, J = 9.0 Hz, 2H), 5.85 (ddd, J = 8.0, 5.0, 2.4 Hz, 1H), 5.66__5.58 (m, 2H), 3.96__3.83 (m, 2H), 3.19 (m, 1H), 2.84 (m, 1H), 2.60 (dt, J = 17.3, 5.3 Hz, 1H), 2.29__2.15 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 165.3, 150.8, 135.2, 131.0, 128.5, 124.5, 123.6, 77.7, 75.9, 69.9, 32.5; HRMS [DART+] (m/z): [M+H]+ Calcd for C13H14NO6 280.0821, Found 280.0827. (3aS,4S,7aR)-2,2-Dimethyl-3a,4,7,7a-tetrahydrobenzo[d][1,3]dioxol-4-yl 4-nitrobenzoate (9). To a stirred solution of 8 (2.2 g, 7.88 mmol) in 2,2-dimethoxy propane (15 mL) was added p-TSA.H2O (0.15 g, 0.78 mmol), the reaction mixture was stirred at room temperature for 1 h. After completion of reaction monitored by TLC, the mixture was quenched with sat. sodium bicarbonate solution, and extracted with DCM (100 mL x 2). The combined organic layers were dried over sodium sulfate, concentrated, then crude was purified by silica-gel flash column chromatography using a mixture of 12% ethyl acetate and hexane as an eluent to afford 9 (2.34 g, 93%) as a colourless oil. Rf = 0.1 (10% ethyl acetate and hexane); [α]D29 +108.6 (c 1.1, CHCl3); IR (neat): νmax (cm-1) 2983, 2931, 1723, 1605, 1526, 1347, 1266, 1228, 1101, 968, 847, 717;

1

H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 9.1 Hz, 2H), 8.25 (d, J = 9.1 Hz, 2H),

5.92__5.79 (m, 2H), 5.70__5.64 (m, 1H), 3.87 (dd, J = 9.5, 8.2 Hz, 1H), 3.81 (td, J = 9.7, 5.0 Hz, 1H), 2.67 (ddd, J = 6.3, 3.9, 1.3 Hz, 1H), 2.42__2.28 (m, 1H), 1.49 (d, J = 4.7 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 164.2, 150.6, 135.4, 131.0, 128.3, 125.8, 123.5, 110.8, 79.3, 75.1, 74.5, 30.4, 27.1, 26.9; HRMS [DART+] (m/z): [M-CH3COCH3+H] + Calcd for C13H12NO5 262.0715, Found 262.0732. (S)-2-Hydroxy-1-((4S,5R)-5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl 4-nitrobenzoate (10). To a stirred solution of 9 (2.2 g, 6.89 mmol) in 1:1 DCM:MeOH (35 mL) was added NaHCO3 (0.58 g, 6.89 mmol). The reaction mixture was cooled to -78 ºC and bubbled with O3 flow, till pale blue color persisted (about 1 h). A stream of N2 was bubbled through the solution to remove residual O3 until the solution become colorless, then was added Me2S (1.52 mL, 20.68 mmol) at the same temperature and the reaction mixture was stirred at room temperature for 1 h. Again the reaction mixture was cooled to 0 ºC, NaBH4 (0.52 g, 13.79 mmol) was added in one portion. The reaction mixture was stirred for further 1 h at the same temperature. To the reaction mixture was added 5 mL of sat. ammonium chloride solution, then concentrated under reduced pressure and the crude was purified by flash column chromatography using a mixture of 50% ethyl acetate and hexane as an eluent to give 10 (1.98 g, 93%) as a colorless oil. Rf = 0.1 (50% ethyl acetate and hexane); [α] D29 +9.3 (c 0.7, CHCl3); IR (neat): νmax (cm-1) 3388, 2987, 1722, 1605, 1525, 1347, 1272, 1102, 872, 780, 718; 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 8.9 Hz, 2H), 8.23 (d, J = 9.0 Hz, 2H), 4.55 (dd, J = 11.6, 7.1 Hz, 1H), 4.44 (dd, J = 11.6, 4.2 Hz, 1H), 4.25 (td, J = 8.0, 4.4 Hz, 1H), 4.05__3.94 (m, 1H), 3.84 (m, 3H), 2.62 (d, J = 9.1 Hz, 1H), 2.27 (s, 1H), 1.94-1.82 (m,


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2H), 1.43 (d, J = 3.5 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 164.7, 150.7, 135.2, 130.8, 123.6, 109.6, 80.6, 76.0, 67.8, 67.6, 60.4, 34.8, 27.4, 26.9; HRMS [DART+] (m/z): [M-CH3COCH3+H] + Calcd for C13H16NO7 298.0927, Found 298.0932. (S)-1-((4R,5R)-5-(2-Hydroxyethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethane-1,2-diol (11). To a stirred solution of 10 (1.8 g, 5.07 mmol) in methanol (25 mL) was added K2CO3 (0.35 g, 2.53 mmol), then reaction mixture was stirred at room temperature for 1 h. After completion of reaction monitored by TLC, solvent was removed under reduced pressure, then, the obtained crude was purified by silica-gel flash column chromatography using a mixture of 10% methanol and ethyl acetate as an eluent to afford 11 (0.95 g, 91%) as a semi solid. Rf = 0.2 (5% methanol and ethyl acetate); [α]D27 +43.1 (c 1.2, CH3OH); IR (neat): νmax (cm-1) 3281, 2931, 2832, 1369, 1216, 1041, 868; 1H NMR (400 MHz, MeOD) δ 4.86 (s, 2H), 4.14 (td, J = 8.7, 3.3 Hz, 1H), 3.78 – 3.60 (m, 4H), 1.85 (dtd, J = 10.7, 7.5, 3.3 Hz, 1H), 1.79__1.67 (m, 1H), 1.37 (d, J = 4.6 Hz, 6H); 13C NMR (100 MHz, MeOD) δ 108.4, 81.0, 73.8, 70.0, 63.3, 58.6, 35.6, 26.3, 25.7; HRMS [DART+] (m/z): [M+H] + Calcd for C9H19O5 207.1232, Found 207.1215. 2-((4S,4'S,5R)-2,2,2’,2’-Tetramethyl-[4,4'-bi(1,3-dioxolan)]-5-yl)ethanol (12). To a stirred solution of 11 (0.9 g, 4.36 mmol) in dehydrated (10 mL) were added 2,2-dimethoxy propane (1.07 mL, 8.73 mmol) and p-TSA.H2O (0.083 g, 0.43 mmol) at room temperature. The mixture was stirred for 1 h at the same temperature. After completion of reaction monitored by TLC, sat. sodium bicarbonate solution was added and then extracted with DCM (80 mL x 2). The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, then crude was purified by silica-gel flash column chromatography using a mixture of 35% ethyl acetate and hexane to afford 12 (0.92 g, 86%) as a colorless oil. Rf = 0.2 (30% ethyl acetate and hexane); [α]D29 +14.6 (c 0.9, CHCl3); IR (neat): νmax (cm-1) 3458, 2987, 2935, 1369, 1249, 1055, 874, 846; 1H NMR (400 MHz, CDCl3) δ 4.18 (td, J = 7.0, 4.4 Hz, 1H), 4.11 (td, J = 8.4, 3.5 Hz, 1H), 4.05 (dd, J = 8.2, 6.7 Hz, 1H), 3.89__3.75 (m, 4H), 2.49__2.42 (m, 1H), 1.94__1.74 (m, 2H), 1.37__1.45 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 109.7, 109.4, 80.6, 76.4, 74.9, 65.6, 60.6, 35.4, 27.3, 26.9, 26.2, 25.5; HRMS [DART+] (m/z): [M-CH3COCH3+H] + Calcd for C9H17O4 189.1127; Found 189.1108. 2-((4S,4’S,5R)-2,2,2’,2’-Tetramethyl-[4,4’-bi(1,3-dioxolan)]-5-yl)acetaldehyde (13). To a stirred solution of 12 (0.80 g, 3.20 mmol) in DMSO (15 mL) was added 2-Iodoxybenzoic acid (2.73 g, 9.75 mmol) at room temperature, and the mixture was stirred for 1 h at the same temperature. After completion of reaction monitored by TLC, sat. sodium bicarbonate solution was added and extracted with DCM (60 mL x 2). The combined organic layers were dried over sodium sulfate, and concentrated under reduced pressure, then crude was purified by silica-gel flash column chromatography using a mixture of 25% ethyl acetate and hexane to afford 13 (0.66 g, 84%) as a colourless oil. Rf = 0.2 (20% ethyl acetate and hexane); [α]D29 +15.6 (c 0.6, CHCl3); IR (neat): νmax (cm-1) 2983, 2931, 1725, 1370, 1212, 1156, 1057, 846; 1H NMR (400 MHz, CDCl3) δ 9.83 (t, J = 2.0 Hz, 1H), 4.45 (ddd, J = 8.1, 7.0, 5.1 Hz, 1H), 4.22 (td, J = 6.9, ACS Paragon Plus Environment


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4.0 Hz, 1H), 4.06 (dd, J = 8.3, 6.8 Hz, 1H), 3.89 (dd, J = 8.3, 7.1 Hz, 1H), 3.79 (dd, J = 8.1, 4.0 Hz, 1H), 2.74__2.63 (m, 2H), 1.37__1.45 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 199.8, 109.9, 109.8, 80.0, 74.2, 72.0, 65.6, 46.9, 27.2, 26.8, 26.1, 25.3; HRMS [DART+] (m/z): [M+H] + Calcd for C12H21O5 245.1389, Found 245.1397. Bromo(hexyl)triphenylphosphorane (14). To a solution of 1-bromohexane (4 g, 24.24 mmol) in toluene (80 mL) under Ar atmosphere was added triphenyl phosphine (5.51 g, 21.81 mmol). Reaction mixture was stirred at 100 ºC for 48 h. The resulted white solid was filtered and washed with diethyl ether (50 mL x 3). The white crystalline solid was dried under vacuum for 4 h to afford 1414 (5.47 g, 61%) as a white solid; mp: 199__202 ºC; IR (neat): νmax (cm-1) 2850, 1464, 1437, 1113, 691; 1H NMR (400 MHz, CDCl3) δ 7.93__7.61 (m, 15H), 3.65__3.74 (m, 2H), 1.55__1.63 (m, 4H), 1.07__1.22 (m, 4H), 0.82 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 135.1, 135.0, 133.7, 133.6, 130.6, 130.5, 118.7, 117.9, 31.3, 30.0, 23.1, 22.6, 22.2, 13.9; HRMS [DART+] (m/z): [M+H] + Calcd for C24H29BrP 427.1190, Found 427.1205. (4R,4’S)-2,2,2’,2’-Tetramethyl-5-((Z)-oct-2-en-1-yl)-4,4’-bi(1,3-dioxolane) (15). To a stirred solution of 14 (1.20 g, 2.81 mmol) in THF (15 mL) under Ar atmosphere was added 1M NaHMDS in THF (2.52 mL, 2.52 mmol) at 0 ºC, the mixture was stirred for 1 h at the same temperature. Aldehyde 13 (0.61 g, 2.52 mmol) in THF (10 mL) was added slowly to the above reaction mixture at 0 ºC and stirred for further 1 h at the same temperature. After completion of reaction monitored by TLC, the mixture was quenched with sat. ammonium chloride solution and then extracted with ethyl acetate (60 mL x 2). The combined organic layers were dried over sodium sulfate, concentrated, then crude was purified by silica-gel flash column chromatography using a mixture of 10% ethyl acetate and hexane as an eluent to afford 15 (0.58 g, 74%) as a colorless oil. Rf = 0.1 (10% ethyl acetate and hexane); [α]D29 +13.35 (c 0.6, CHCl3); IR (neat): νmax (cm-1) 2983, 2928, 1378, 1216, 1156, 1068, 856; 1H NMR (400 MHz, CDCl3) δ 5.41-5.55 (m, 2H), 4.18__4.10 (m, 1H), 4.06__3.96 (m, 2H), 3.83 (t, J = 7.8 Hz, 1H), 3.72 (dd, J = 7.9, 4.4 Hz, 1H), 2.37 (t, J = 6.3 Hz, 2H), 2.03 (q, J = 7.1 Hz, 2H), 1.49__1.20 (m, 18H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 132.9, 123.9, 109.6, 109.1, 80.3, 76.9, 75.4, 65.8, 31.5, 30.9, 29.2, 27.5, 27.3, 26.9, 26.2, 25.6, 22.6, 14.1; HRMS [DART+] (m/z): [M+H] + Calcd for C18H33O4 313.2379, Found 313.2385. (4R,4’S)-2,2,2’,2’-Tetramethyl-5-pentyl-4,4’-bi(1,3-dioxolane) (16). To a stirred solution of 15 (0.50 g, 1.60 mmol) in methanol (20 mL) was added 10% Pd/C (0.17 g, 0.16 mmol). The reaction mixture was stirred under H2 atmosphere for 1 h. After completion of reaction monitored by TLC, the mixture was filtered through a celite pad, the filtrate was concentrated under reduced pressure, then crude was purified by silica-gel flash column chromatography using a mixture of 10% ethyl acetate and hexane as an eluent ACS Paragon Plus Environment

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to afford 16 (0.48 g, 96%) as a colourless oil. Rf = 0.1 (10% ethyl acetate and hexane); [α]D29 +18.0 (c 1.1, CHCl3); IR (neat): νmax (cm-1) 2985, 1455, 1368, 1248, 1065, 881, 851; 1H NMR (400 MHz, CDCl3) δ 4.1__4.15 (m, 1H), 4.03 (dd, J = 8.1, 6.6 Hz, 1H), 3.87__3.95 (m, 1H), 3.82 (t, J = 7.8 Hz, 1H), 3.66 (dd, J = 8.0, 4.6 Hz, 1H), 1.59__1.47 (m, 3H), 1.37__1.41 (m, 12H), 1.38__1.19 (m, 11H), 0.88 (t, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 109.6, 108.9, 80.8, 77.4, 75.5, 65.7, 33.4, 31.9, 29.7, 29.5, 29.2, 27.4, 26.9, 26.2, 26.1, 25.6, 22.7, 14.1; HRMS [DART+] (m/z): [M+H] + Calcd for C18H35O4 315.2535, Found 313.2548. (2S,3S,4R)-Dodecane-1,2,3,4-tetraol (17). To a stirred solution of 16 (0.40 g, 1.27 mmol) in methanol (15 mL) were added p-TSA.H2O (0.048 g, 0.25 mmol) and ethylene glycol (0.14 mL, 2.54 mmol), and the reaction mixture was stirred at room temperature for 16 h. After completion of reaction monitored by TLC, solvent was removed under reduced pressure, the obtained crude was purified by silica-gel flash column chromatography using a mixture of 10% methanol and ethyl acetate as an eluent to afford 17 (0.23 g, 78%) as a white solid. Rf = 0.1 (5% methanol and ethyl acetate); [α]D28 +10.6 (c 0.1, CH3OH); mp: 181__184 ºC; IR (neat): νmax (cm-1) 3403, 2950, 2848, 1469, 1113, 1066, 798, 719; 1H NMR (400 MHz, CDCl3) δ 4.2 (br s, 1H), 3.97__3.63 (m, 6H), 3.4__3.6 (m, 2H), 1.54__1.16 (m, 14H), 0.88 (t, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 77.3, 73.6, 73.4, 64.6, 33.7, 31.9, 29.7, 29.6, 29.3, 25.7, 22.7, 14.1; HRMS [DART+] (m/z): [M+H] + Calcd for C12H27O4 235.1909, Found 235.1931. (5R,6S,7S)-6,7-Bis((tert-butyldimethylsilyl)oxy)-2,2,3,3,10,10,11,11-octamethyl-5-octyl-4,9-dioxa3,10-disiladodecane (18)). To a stirred solution of 17 (0.2 g, 0.85 mmol) in dehydrated DCM (20 mL) under Ar atmosphere were added 2,6-lutidine (0.59 mL, 5.12 mmol) and TBSOTf (1.17 mL, 5.12 mmol) at 0 ºC, and the reaction mixture was stirred at the same temperature for 1 h. After completion of reaction monitored by TLC, quenched with 1M hydrochloric acid solution and extracted with DCM (50 mL x 2). The combined organic layers were dried over sodium sulfate, concentrated to give crude 18, which was purified by silica gel flash column chromatography using hexane as an eluent to afford 18 (0.54 g, 92%) as a colorless oil. Rf = 0.6 (1% ethyl acetate and hexanes); [α]D29 +0.4 (c 1, CHCl3); IR (neat): νmax (cm1

) 2953, 2855, 1462, 1252, 1074, 1004, 831, 772; 1H NMR (400 MHz, CDCl3) δ 3.86 (td, J = 5.9, 3.2 Hz,

1H), 3.65__3.75 (m, 2H), 3.64 (t, J = 3.4 Hz, 1H), 3.44 (dd, J = 10.0, 6.2 Hz, 1H), 1.79__1.68 (m, 1H), 1.35__1.46 (m, 1H), 1.2__1.3(m, 11H), 1.05__1.13 (m, 1H), 0.87__0.84 (m, 39H), 0.04__-0.01 (m, 24H); 13C NMR (100 MHz, CDCl3) δ 73.6, 72.8, 72.3, 64.2, 32.7, 31.9, 31.6, 29.9, 29.7, 29.3, 27.1, 26.1, 26.0, 25.9, 25.8, 25.7, 22.7, 18.3, 18.1, 18.1, 18.0, 14.1, -2.9, -3.7, -3.8, -4.1, -4.4, -4.4, -4.5, -5.2, -5.3; HRMS [DART+] (m/z): [M+H] + Calcd for C36H82O4Si4 690.5290, Found 690.5298. (2S,3S,4R)-2,3,4-Tris((tert-butyldimethylsilyl)oxy)dodecan-1-ol (19). To a stirred solution of 18 (0.50 g, 0.72 mmol) in 1:1 MeOH and DCM (15 mL) was added CSA (0.05 g, 0.21 mmol) at 0 ºC, and the ACS Paragon Plus Environment


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reaction mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched with sat. sodium bicarbonate solution, extracted with DCM (40 mL x 2). The combined organic layers were dried over sodium sulfate, concentrated, crude was purified by column chromatography using hexane as an eluent afford recovered 18 (0.3 g), and 19 (0.156 g, 94% based on recovered starting material) as a colorless oil. Rf = 0.3 (2% ethyl acetate and hexanes); [α]D29 +5.3 (c 0.4, CHCl3); IR (neat): νmax (cm-1) 2953, 2927, 2855, 1471, 1251, 832, 772; 1H NMR (400 MHz, CDCl3) δ 3.75__3.66 (m, 2H), 3.60__3.49 (m, 2H), 3.48 (dd, J = 6.0, 2.8 Hz, 1H), 2.90 (dd, J=8.4, 5.1 Hz, 1H), 1.70__1.60 (m, 1H), 1.42__1.30 (m, 1H), 1.28__1.12 (m, 11H), 1.11__1.00 (m, 1H), 0.87__0.74 (m, 30H), 0.07__-0.06 (m, 18H); 13C NMR (100 MHz, CDCl3) δ 75.8, 73.6, 73.0, 64.9, 32.5, 31.9, 29.7, 29.6, 29.2, 26.7, 26.0, 26.0, 25.9, 22.7, 18.1, 18.1, 18.1, 14.1, -3.7, -3.8, -4.0, -4.2, -4.6; HRMS [DART+] (m/z): [M+H]+ Calcd for C30H69O4Si3 577.4504, Found 577.4497. (2R,3S,4R)-2,3,4-Tris((tert-butyldimethylsilyl)oxy)dodecanal (20). To a stirred solution of 19 (0.10 g, 0.17 mmol) in DMSO (8 mL) was added 2-Iodoxybenzoic acid (0.14 g, 0.52 mmol) at room temperature, and the reaction mixture was stirred for 16 h. After completion of reaction monitored by TLC, sat. sodium bicarbonate solution was added and extracted with DCM (10 mL x 2). The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, then crude was purified by silica-gel flash column chromatography using a mixture of 1% ethyl acetate and hexane as an eluent to afford 20 (0.085 g, 86%) as colorless oil. Rf = 0.4 (2% ethyl acetate and hexane); [α]D29 +2.4 (c 0.2, CHCl3); IR (neat): νmax (cm-1) 2953, 2927, 2856, 1730, 1471, 1462, 1252, 1004, 774; 1H NMR (400 MHz, CDCl3) δ 9.61 (d, J = 1.2 Hz, 1H), 3.98 (dd, J = 5.1, 1.1 Hz, 1H), 3.78 (dd, J = 5.0, 3.3 Hz, 1H), 3.67 (td, J = 6.5, 3.3 Hz, 1H), 1.77__1.67 (m, 1H), 1.43__1.32 (m, 1H), 1.15__1.25 (m, 11H), 1.10__1.0 (m, 1H), 0.90__0.78 (m, 30H), 0.05__-0.05 (m, 18H); 13C NMR (100 MHz, CDCl3) δ 201.9, 77.8, 75.6, 72.8, 32.0, 31.9, 29.7, 29.6, 29.3, 26.7, 25.9, 25.8, 25.7, 22.7, 18.2, 18.0, 18.0, 14.1, -3.9, -4.2, -4.3, -4.4, -4.6, -5.0; HRMS [DART+](m/z): [M+H]+ Calcd for C30H69O4Si3 577.4504; Found 577.4497; HRMS [DART+] (m/z): [M+H]+ calcd for C30H67O4Si3 575.4347, found 575.4360. 6-(Bromotriphenylphosphoranyl)hexanoic acid (21). To a solution of 6-bromohexanoic acid (5 g, 25.64 mmol) in dehydrated toluene (80 mL) under Ar atmosphere was added triphenylphosphine (7.38 g, 28.20 mmol). The reaction mixture was stirred at 100 ºC for 12 h. After removal of solvent under reduced pressure, white color slurry was obtained, which was dissolved in minimum amount of chloroform and recrystallized from acetone. The resulted solution was kept at 0 ºC for 2 h, filter and washed with acetone (60 mL x 2), which was dried under vacuum for 4 h to afford 2115 (10 g, 86%) as a white solid. mp: 203__206 ºC; IR (neat): νmax (cm-1) 2926, 2858, 1716, 1452, 1240, 1108, 1101, 870, 760; 1H NMR (400 MHz, CDCl3) δ 7.85__7.65 (m, 15H), 3.62 (bs, 2H), 2.37 (d, J = 6.1 Hz, 2H), 1.67 (s, 6H); 13C NMR (100 ACS Paragon Plus Environment

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MHz, CDCl3) δ 175.8, 135.2, 135.1, 133.7, 133.6, 130.7, 130.5, 118.6, 117.7, 34.2, 29.6, 24.0, 22.8, 21.9; HRMS [DART+] (m/z): [M-H]+ Calcd for C24H25O2BrP 455.0776, Found 455.0781. (8S,9S,10R,6Z)-8,9,10-Tris((tert-butyldimethylsilyl)oxy)octadec-6-enoic acid (22). To a stirred solution of 21 (0.067 g, 0.15 mmol) in THF (5 mL) under Ar atmosphere was added 1M NaHMDS in THF (0.3 mL, 0.307 mmol) at 0 ºC, and the reaction mixture was stirred for 1 h at the same temperature. The reaction mixture was cooled to -78 ºC, aldehyde 20 (0.08 g, 0.14 mmol) in THF (5 mL) was added slowly and stirred for further 1 h at the same temperature. After completion of reaction monitored by TLC, the mixture was quenched with sat. ammonium chloride solution, and sat. sodium chloride solution. The mixture was acidified with 2M hydrochloric acid solution and was extracted with ethyl acetate (10 mL x 2). The combined organic layers were dried over sodium sulfate, concentrated, then crude was purified by silica-gel flash column chromatography using a mixture of 12% ethyl acetate and hexane as an eluent to afford 22 (0.066 g, 71%) as a colorless oil. Rf = 0.4 (20% ethyl acetate and hexane); [α]D29 +14.3 (c 0.3, CHCl3); IR (neat): νmax (cm-1) 2950, 2854, 1711, 1469, 1250, 1081, 1001, 832, 772; 1H NMR (400 MHz, CDCl3) δ 5.50__5.47(m, 1H), 5.23 (dt, J = 11.2, 6.8 Hz, 1H), 4.74 (d, J = 9.1 Hz, 1H), 3.53 (ddd, J = 9.1, 5.0, 2.2 Hz, 1H), 3.34 (dd, J = 5.0, 1.7 Hz, 1H), 2.35 (t, J = 7.4 Hz, 2H), 2.19__1.95 (m, 2H), 1.89__1.77 (m, 1H), 1.7__1.6 (m, 2H), 1.54__1.36 (m, 4H), 1.31__1.21 (m, 10H), 1.08 (dd, J = 11.0, 5.4 Hz, 1H), 0.96__0.82 (m, 30H), 0.06__-0.02 (m, 18H); 13C NMR (100 MHz, CDCl3) δ 134.1, 127.4, 78.2, 75.7, 67.1, 32.1, 31.9, 29.9, 29.6, 29.3, 29.1, 27.8, 27.7, 26.0, 25.9, 25.8, 24.5, 22.7, 18.1, 18.1, 18.0, 14.1, -3.6, -3.8, -4.2, -4.3, -4.6, -4.6; HRMS [DART+] (m/z): [M-OTBS]+ Calcd for C30H61O4Si2 541.4108, Found 541.4124. (8S,9S,10R,6Z)-8,9,10-Trihydroxyoctadec-6-enoic acid (ent-1). To a stirred solution of 22 (0.05 g, 0.074 mmol) in THF (5 mL) was added 2M HCl (37μL, 0.074 mmol), then the mixture was stirred for 16 h at room temperature. After completion of reaction monitored by TLC, solvents were removed under reduced pressure, then crude was purified by silica-gel flash column chromatography using a mixture of 10% methanol and ethyl acetate as an eluent to afford (8S,9S,10R,Z)-8,9,10-trihydroxyoctadec-6-enoic acid (ent-1) (0.017 g, 73%) as semi solid. Rf = 0.3 (5% methanol and ethyl acetates); [α]D26 +18.1 (c 0.2, CH3OH); IR (neat): νmax (cm-1) 3373, 2923, 2854, 2360, 1708, 1456, 1409, 1223, 1112, 875, 668; 1H NMR (400 MHz, MeOD) δ 5.57 (dt, J = 10.6, 7.4 Hz, 1H), 5.42 (dd, J = 10.9, 9.2 Hz, 1H), 4.52__4.46 (m, 1H), 3.57__3.51 (m, 1H), 3.21 (dd, J = 6.5, 2.7 Hz, 1H), 2.28 (t, J = 7.4 Hz, 2H), 2.24__2.08 (m, 2H), 1.70__1.38 (m, 7H), 1.38__1,04 (m, 11H), 0.90 (t, J = 6.9 Hz, 3H); 13C NMR (100 MHz, MeOD) δ 132.7, 129.4, 76.1, 70.9, 68.2, 53.4, 33.8, 33.4, 31.6, 29.4, 29.3, 29.0, 28.7, 27.1, 25.4, 24.4, 22.3, 13.0; HRMS [DART+] (m/z): [M-H]+ Calcd for C18H34O5 329.2328, Found 329.2344.



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(1S,5R,6R)-5,6-Bis((tert-butyldimethylsilyl)oxy)cyclohex-2-en-1-yl 4-nitrobenzoate (23). To a stirred solution of 8 (4 g, 14.3 mmol) in DCM (80 mL) at 0 ºC and under Ar atmosphere were added 2,6-lutidine (4.97 mL, 43.01 mmol) and TBSOTf (9.87 mL, 43.01 mmol), the mixture was stirred for 1 h at room temperature. After completion of reaction, the mixture was acidified with 2M hydrochloric acid and extracted with DCM (100 mL x 2), the combined organic layers were dried over sodium sulfate, concentrated to get the crude, crude was purified by silica-gel flash column chromatography using a mixture of 10% ethyl acetate and hexane as an eluent to afford 23 (6.76 g, 93%) as a white solid. Rf = 0.2 (10% ethyl acetate and hexanes); [α]D28 +142 (c 0.34, CHCl3); mp: 75__77 ºC; IR (neat): νmax (cm-1) 2950, 2931, 2854, 1717, 1525, 1340, 1267, 1150, 1096, 958, 832, 719; 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 9.0 Hz, 2H), 8.17 (d, J = 9.1 Hz, 2H), 5.82__5.74 (m, 1H), 5.60__5.53 (m, 1H), 5.42__5.37 (m, 1H), 3.89 (dd, J = 7.1, 4.9 Hz, 1H), 3.83 (td, J = 6.6, 4.8 Hz, 1H), 2.47__2.37 (m, 1H), 2.15__2.05 (m, 1H), 0.85__0.73 (m, 18H), 0.06__-0.02 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 164.4, 150.5, 135.9, 130.9, 128.5, 123.5, 123.4, 75.7, 73.6, 69.7, 32.6, 26.1, 25.8, 18.3, 18.0, -3.9, -4.5, -4.7; HRMS [DART+] (m/z): [M+H]+ Calcd for C25H42NO6Si2 508.2551, Found 508.2560. (2R,3R,4R)-3,4-Bis((tert-butyldimethylsilyl)oxy)-1,6-dioxohexan-2-yl 4-nitrobenzoate (24). To a stirred solution of 23 (6 g, 11.83 mmol) in 5:1 DCM:MeOH (120 mL) was added NaHCO3 (0.99 g, 11.83 mmol). The reaction mixture was cooled to -78 ºC and purged with O3 flow, till blue color appeared (approximately it took 1 h). Then after the reaction mixture was purged with Ar gas till blue color disappeared (approximately it took 10 min), followed by Me2S (2.62 mL, 35.5 mmol) was added at the same temperature and the mixture was stirred at room temperature for 1 h. Then sat. sodium chloride solution was added and the mixture was extracted with ethyl acetate (150 mL x 2), the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the crude compound 24 (6.8 g), which was used directly in the next step, without further purification. Small amount of the above crude was purified by silica-gel flash column chromatography using a mixture of 30% ethyl acetate and hexane as an eluent to afford 24. Rf = 0.2 (40% ethyl acetate and hexane); [α]D29 +38 (c 0.5, CHCl3); IR (neat): νmax (cm-1) 2922, 2854, 1727, 1529, 1260, 1100, 997, 829, 717; 1H NMR (400 MHz, CDCl3) δ 9.70 (dd, J = 1.8, 1.3 Hz, 1H), 9.57 (s, 1H), 8.28 (d, J = 9.0 Hz, 2H), 8.21 (d, J = 9.1 Hz, 2H), 5.46 (d, J = 3.4 Hz, 1H), 4.39 (ddd, J=8.4, 4.9, 3.6 Hz, 1H), 4.24 (dd, J = 4.9, 3.4 Hz, 1H), 2.89 (ddd, J = 16.9, 3.5, 1.2 Hz, 1H), 2.51 (ddd, J = 16.9, 8.3, 2.1 Hz, 1H), 0.80__0.78 (m, 18H), 0.10__-0.05 (m, 12H); 13

C NMR (100 MHz, CDCl3) δ 199.9, 196.1, 163.9, 150.9, 134.6, 131.0, 123.8, 78.7, 72.8, 68.0, 46.6,

25.7, 25.6, 17.9, 17.9, -4.4, -4.5, -4.7, -4.9; HRMS [DART+] (m/z): [M+H]+ Calcd for C25H42NO8Si2 540.2449, Found 540.2451.


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(2R,3R,4R)-3,4-Bis((tert-butyldimethylsilyl)oxy)-5-(1,3-dioxan-2-yl)-1-oxopentan-2-yl

4-

nitrobenzoate (25). To the above crude 24 setup with Dean-Stark in benzene (120 mL) under Ar atmosphere were added 1,3 propane diol (0.85 mL, 11.83 mmol) and p-TSA.H2O (0.22 g, 1.18 mmol) at room temperature. The reaction mixture was stirred at 110 º C for 4 h. After completion of reaction monitored by TLC, sat. bicarbonate solution was added and the mixture was extracted with ethyl acetate (150 mL x 2). The combined organic layers were dried over sodium sulfate, concentrated to get the crude compound 25 (7.1 g), which was used in the next step without any purification. Small amount of the above crude was purified by silica-gel flash column chromatography using a 10% ethyl acetate and hexane as an eluent to give 25. Rf = 0.2 (20% ethyl acetate and hexane); [α]D29 +47.0 (c 0.5, CHCl3); IR (neat): νmax (cm-1) 2985, 1943, 1724, 1520, 1344, 1116, 931, 832; 1H NMR (400 MHz, CDCl3) δ 9.66 (s, 1H), 8.30 (dd, J = 23.0, 9.0 Hz, 4H), 5.51 (d, J = 3.9 Hz, 1H), 4.60 (dd, J = 8.1, 3.1 Hz, 1H), 4.25__4.18 (m, 1H), 4.1__4.0 (m, 3H), 3.75__3.65 (m, 2H), 2.21 (ddd, J=13.8, 8.1, 2.5 Hz, 1H), 2.14__1.98 (m, 1H), 1.75__1.60 (m, 1H), 1.36__1.24 (m, 1H), 0.91__0.86 (m, 18H), 0.14__0.06 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 196.3, 164.1, 134.8, 131.1, 123.7, 99.5, 79.4, 73.6, 69.3, 67.0, 66.6, 37.5, 25.8, 25.7, 25.6, 17.9, 17.9, -4.1, -4.3, -4.9, -5.0; HRMS [DART+] (m/z): [M+H]+ Calcd for C28H48NO9Si2 598.2868, Found 598.2840. (8S,9R,10R,6Z)-9,10-Bis((tert-butyldimethylsilyl)oxy)-11-(1,3-dioxan-2-yl)-8-((4-nitro benzoyl)oxy)undec-6-enoic acid (26). To a stirred solution of 21 (6.26 g, 14.2 mmol) in THF (80 mL) under Ar atmosphere was added 1M NaHMDS in THF (28.4 mL, 28.4 mmol) at 0 ºC, and the mixture was stirred for 1 h at the same temperature. Reaction mixture was cooled to -20 ºC, crude aldehyde 25 in THF (30 mL) was added slowly and the mixture was stirred for further 2 h at the same temperature. After completion of reaction monitored by TLC, the mixture was quenched with sat. ammonium chloride solution. Sat. sodium chloride solution was added, then acidified with 2M hydrochloric acid solution and the mixture was extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried over sodium sulfate, and concentrated, then crude was purified by silica-gel flash column chromatography using a mixture of 20% ethyl acetate and hexane as an eluent to afford 26 (4.6 g, 56% for 3 steps from 23) as a colourless oil. Rf = 0.1 (20% ethyl acetate and hexane); [α]D29 -9.6 (c 0.62, CHCl3); IR (neat): νmax (cm-1) 2953, 2928, 2854, 2357, 1705, 1529, 1271, 1096, 937, 833, 774; 1H NMR (400 MHz, CDCl3) δ 8.17 (q, J = 9.1 Hz, 4H), 5.43 (dd, J =6.3, 2.0 Hz, 1H), 4.65 (d, J = 6.3 Hz, 1H), 4.44 (dd, J = 8.4, 2.8 Hz, 1H), 4.08__3.84 (m, 6H), 3.69__3.49 (m, 4H), 2.09__1.86 (m, 3H), 1.31 (ddd, J = 13.5, 10.4, 2.9 Hz, 1H), 1.20 (dd, J = 19.8, 13.4 Hz, 3H), 0.9__0.7 (m, 20H), 0.08__-0.02 (m, 12H);

13

C NMR (100 MHz,

CDCl3) δ 163.7, 150.4, 136.3, 131.0, 123.4, 100.0, 99.3, 71.9, 70.6, 69.4, 66.8, 66.7, 66.5, 36.8, 25.9,



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25.9, 25.8, 25.6, 18.1, 18.0, -4.0, -4.1, -5.0, -5.1; HRMS [DART+] (m/z): [M-H]+ Calcd for C34H56NO10Si2 694.3443, Found 694.3452. (2R,3R,4S,5Z)-2,3-bis((tert-butyldimethylsilyl)oxy)-1-(1,3-dioxan-2-yl)-11-methoxy-11-oxoundec5-en-4-yl 4-nitrobenzoate (27). To a stirred solution of 26 (3.0 g, 4.31 mmol) in DMF (30 mL) were added potassium carbonate (0.89 g, 6.47 mmol) and methyl iodide (0.4 mL, 6.47 mmol). The mixture was stirred for 1 h at room temperature. After completion of reaction monitored by TLC, reaction mixture was partitioned between excess of water (200 mL) and ethyl acetate (50 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the crude 27, which was purified by silica-gel flash column chromatography using a mixture of 10% ethyl acetate and hexane as an eluent to afford 27 (2.51 g, 82%) as colorless oil. Rf = 0.2 (10% ethyl acetate and hexane); [α]D29 -11.2 (c 0.66, CHCl3); IR (neat): νmax (cm-1) 2951, 2928, 2855, 1725, 1529, 1341, 1271, 1096, 938, 833, 806, 719; 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 9.0 Hz, 2H), 8.10 (d, J = 9.0 Hz, 2H), 5.98__5.90 (m, 1H), 5.50__5.41 (m, 2H), 4.47 (dd, J = 8.1, 3.1 Hz, 1H), 4.02__3.84 (m, 3H), 3.67 (dd, J = 4.5, 3.8 Hz, 1H), 3.65__3.51 (m, 5H), 2.33 (td, J = 14.3, 7.4 Hz, 1H), 2.25 (t, J = 7.5 Hz, 2H), 2.21__1.88 (m, 3H), 1.58 (ddd, J = 12.7, 8.8, 6.5 Hz, 2H), 1.50__1.42 (m, 1H), 1.35 (dq, J = 15.3, 7.6 Hz, 2H), 1.21 (d, J = 13.4 Hz, 1H), 0.88__0.80 (m, 18H), 0.05__-0.07 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 174.1, 163.4, 136.4, 133.9, 130.7, 125.9, 123.5, 99.9, 76.1, 70.8, 70.1, 66.9, 66.5, 51.4, 37.4, 34.0, 29.0, 27.8, 25.8, 25.8, 24.6, 18.0, 17.9, -3.8, -4.1, -4.8, -5.1; HRMS [DART+] (m/z): [M+H]+ Calcd for C35H60NO10Si2 710.3756, Found 710.3769. (8S,9R,10R,6Z)-Methyl

9,10-bis((tert-butyldimethylsilyl)oxy)-11-(1,3-dioxan-2-yl)-8-hydroxy

undec-6-enoate (28). To a stirred solution of 27 (2.2 g, 30.98 mmol) in methanol (30 mL) was added potassium carbonate (0.21 g, 15.49 mmol) and the mixture was stirred at room temperature for 16 h. After completion of reaction monitored by TLC, solvent was removed under reduced pressure, the obtained crude product was purified by silica-gel flash column chromatography using a mixture of 12% ethyl acetate and hexane as an eluent to afford 28 (1.21 g, 70%) as colorless oil. Rf = 0.1 (10% ethyl acetate and hexanes); [α]D29 +12.0 (c 0.3, CHCl3); IR (neat): νmax (cm-1) 2953, 2928, 2850, 2359, 1740, 1251, 1141, 1091, 835, 776; 1H NMR (400 MHz, CDCl3) δ 5.42__5.25 (m, 2H), 4.57 (t, J = 5.2 Hz, 1H), 4.49 (dd, J = 8.3, 4.0 Hz, 1H), 4.05__3.95 (m, 2H), 3.94__3.87 (m, 1H), 3.68__3.59 (m, 2H), 3.58 (s, 3H), 3.30__3.23 (m, 1H), 2.48 (d, J = 7.3 Hz, 1H), 2.23 (t, J = 7.5 Hz, 2H), 2.12__1.91 (m, 3H), 1.85 (dt, J = 14.0, 5.5 Hz, 1H), 1.66 (ddd, J = 14.0, 6.5, 4.9 Hz, 1H), 1.62__1.51 (m, 2H), 1.37__1.26 (m, 2H), 1.26__1.19 (m, 1H), 0.84__0.77 (m, 18H), -0.01 (dt, J=20.3, 7.9, 12H); 13C NMR (100 MHz, CDCl3) δ 174.0, 131.0, 130.6, 99.8, 69.0, 68.2, 66.9, 66.7, 51.5, 39.3, 34.0, 29.1, 27.7, 26.0, 25.9, 25.8, 24.7, 18.2, 18.1, -3.9, 4.0, -4.2, -4.8; HRMS [DART+] (m/z): [M-OH]+ Calcd for C28H55O6Si2 543.3537, Found 543.3559.


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(8S,9R,10R,6Z)-10-((tert-Butyldimethylsilyl)oxy)-11-(1,3-dioxan-2-yl)undec-6-ene-1,8,9-triol (29). To a stirred solution of 28 (1.1 g, 1.96 mmol) in THF (30 mL) at 0 ºC, under Ar atmosphere was added lithium aluminium hydride (0.074 g, 1.96 mmol) and the mixture was stirred for 1 h at the same temperature. After completion of reaction monitored by TLC, reaction mixture was slowly quenched at 0 º

C with aq. 1M sodium hydroxide solution. Filtered through small pad of celite and concentrated to get

the crude which was purified by silica-gel flash column chromatography using a mixture of 50% ethyl acetate and hexane as an eluent to afford 29 (0.74 g, 91%) as colorless oil. Rf = 0.1 (50% ethyl acetate and hexanes); [α]31D +15.3 (c 0.6, CHCl3); IR (neat): νmax (cm-1) 3395, 2924, 2853, 2357, 1462, 1377, 1250, 1073, 1002, 836, 777; 1H NMR (400 MHz, CDCl3) δ 5.53 (dt, J = 11.3, 7.3 Hz, 1H), 5.33 (d, J = 9.4 Hz, 1H), 4.79 (dd, J = 6.1, 4.0 Hz, 1H), 4.55 (dd, J = 9.1, 6.9 Hz, 1H), 4.10 (dd, J = 11.2, 4.8 Hz, 2H), 3.79 (t, J = 11.2 Hz, 3H), 3.64 (t, J = 6.4 Hz, 2H), 3.25__3.18 (m, 1H), 2.84 (d, J = 3.8 Hz, 1H), 2.81__2.72 (m, 1H), 2.24__1.92 (m, 4H), 1.75 (ddd, J = 14.4, 6.2, 3.0 Hz, 1H), 1.66__1.51 (m, 2H), 1.48__1.31 (m, 5H), 0.96__0.86 (m, 9H), 0.15__0.03 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 174.1, 163.4, 136.4, 133.9, 130.7, 125.9, 123.5, 99.9, 76.1, 70.8, 70.1, 66.9, 66.5, 51.4, 37.4, 33.9, 29.0, 27.8, 25.8, 25.8, 24.6, 18.0, 17.9, -3.8, -4.1, -4.8, -5.1; HRMS [DART+] (m/z): [M+H]+ Calcd for C21H43O6Si1 419.2829, Found 419.2807. (5R,6S,7S,6Z)-5-((1,3-Dioxan-2-yl)methyl)-6,7-bis((tert-butyldimethylsilyl)oxy)2,2,3,3,16,16,17,17-octamethyl-4,15-dioxa-3,16-disilaoctadec-8-ene (30). To a stirred solution of 29 (0.5 g, 1.19 mmol) in DCM (30 mL) at 0 ºC and under Ar atmosphere were added 2,6-lutidine (0.62 mL, 5.38 mmol) and TBSOTf (1.23 mL, 5.38 mmol), and the mixture was stirred for 1 h at room temperature. After completion of reaction, the mixture was acidified with 2M hydrochloric acid and extracted with DCM (40 mL x 2), the combined organic layers were dried over sodium sulfate, concentrated to give the crude 30, which was purified by silica-gel flash column chromatography using a mixture of 2% ethyl acetate and hexane as an eluent to afford 30 (0.81 g, 89%) as a colorless oil. Rf = 0.4 (5% ethyl acetate and hexanes); [α]D29 +18.1 (c 0.61, CHCl3); IR (neat): νmax (cm-1) 2952, 2927, 2886, 1471, 1251, 1088, 938, 832, 772; 1H NMR (400 MHz, CDCl3) δ 5.48__5.40 (m, 1H), 5.20 (dt, J = 11.9, 7.2 Hz, 1H), 4.74 (d, J = 9.0 Hz, 1H), 4.52 (dd, J = 7.9, 3.5 Hz, 1H), 4.00 (td, J = 11.5, 4.9 Hz, 2H), 3.81 (ddd, J = 9.3, 5.2, 2.8 Hz, 1H), 3.74__3.57 (m, 2H), 3.55 (t, J = 6.6 Hz, 2H), 3.32 (dd, J = 5.2, 1.7 Hz, 1H), 2.17__1.89 (m, 4H), 1.88__1.78 (m, 1H), 1.47 (dt, J = 13.2, 6.6 Hz, 2H), 1.38__1.18 (m, 5H), 0.88__0.82 (m, 36H), 0.05__-0.06 (m, 24H); 13C NMR (100 MHz, CDCl3) δ 133.7, 128.1, 100.7, 77.7, 70.5, 67.1, 66.9, 66.4, 63.2, 37.9, 32.9, 29.6, 28.2, 26.1, 26.0, 26.0, 25.9, 25.8, 18.4, 18.2, 18.1, 17.9, -3.8, -3.9, -4.1, -4.7, -5.1, -5.3; HRMS [DART+] (m/z): [M-OTBS]+ Calcd for C33H69O5Si3 629.4453, Found 629.4456.



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Page 16 of 19

(3R,4S,5S,6Z)-3,4,5,12-Tetrakis((tert-butyldimethylsilyl)oxy)dodec-6-en-1-ol (32). To a stirred solution of 30 (0.7 g, 0.92 mmol) in DCM (20 mL) at 0 ºC and under Ar atmosphere were added 2,6lutidine (0.32 mL, 2.76 mmol) and TMSOTf (0.5 mL, 2.76 mmol),16 the mixture was stirred for 16 h at 0 º

C. Then water (6 mL) was added and the mixture was stirred for further 2 h at room temperature. After

completion of reaction monitored by TLC, the mixture was acidified with 1M hydrochloric acid solution, and the mixture was extracted with DCM (50 mL x 2). The combined organic layers were dried over sodium sulfate, concentrated to give crude 31, which was used in the next step without further purification. Rf = 0.45 (5% ethyl acetate and hexanes). To the above crude 31 in THF (40 mL) was added sodium borohydride (0.034 g, 0.92 mmol) at 0 ºC, and the mixture was stirred for 1 h at the same temperature. After completion of reaction monitored by TLC, the reaction mixture was quenched with sat. ammonium chloride solution followed by sat. sodium chloride solution. The mixture was extracted with ethyl acetate (40 mL x 2). The combined organic layers were dried over sodium sulfate, concentrated, then crude was purified by silica- gel flash column chromatography using a mixture of 4% ethyl acetate and hexane as an eluent to afford 32 (0.47 g, 73%) as a colorless oil. Rf = 0.2 (5% ethyl acetate and hexane); [α]D29 +11.0 (c 0.4, CHCl3); IR (neat): νmax (cm-1) 2953, 2928, 2887, 1473, 1388, 1251, 1083, 1004, 919, 832, 772; 1H NMR (400 MHz, CDCl3) δ 5.49__5.39 (m, 1H), 5.23 (dt, J = 11.2, 6.7 Hz, 1H), 4.79 (d, J = 9.0 Hz, 1H), 3.76__3.58 (m, 3H), 3.55 (t, J = 6.5 Hz, 2H), 3.38 (dd, J = 5.1, 1.7 Hz, 1H), 2.20__1.92 (m, 3H), 1.90 (t, J = 5.7 Hz, 1H), 1.84__1.74 (m, 1H), 1.52__1.42 (m, 2H), 1.37__1.24 (m, 4H), 0.91__0.80 (m, 36H), 0.04__0.05 (m, 24H); 13C NMR (100 MHz, CDCl3) δ 133.4, 128.6, 78.2, 73.3, 63.2, 60.9, 35.9, 32.9, 29.5, 28.2, 26.0, 26.0, 25.9, 25.9, 25.8, 18.1, 18.1, 17.9, -3.7, -4.0, -4.1, -4.1, -4.6, -5.0, -5.3; HRMS [DART+] (m/z): [M-OTBS]+ Calcd for C30H65O4Si3 573.4191, Found 573.4205. (3R,4S,5S,6Z)-3,4,5,12-Tetrakis((tert-butyldimethylsilyl)oxy)dodec-6-en-1-yl

4-methyl

benzenesulfonate (33). To a stirred solution of 32 (0.4 g, 0.56 mmol) in DCM (30 mL) under Ar atmosphere were added tosyl chloride (0.16 g, 0.85 mmol), triethylamine (0.23 mL, 1.70 mmol), 4(dimethylamino)pyridine (0.007 g, 0.056 mmol) at room temperature, and the mixture was stirred for 3 h at the same temperature. After completion of reaction monitored by TLC, sat. sodium bicarbonate solution was added and mixture was extracted with DCM (30 mL x 2). The combined organic layers were dried over sodium sulfate, concentrated, then crude was purified by silica-gel flash column chromatography using a mixture of 2% ethyl acetate and hexane as an eluent to afford 33 (0.39 g, 81%) as a colorless oil. Rf = 0.3 (5% ethyl acetate and hexanes); [α]D29 +17.2 (c 0.2, CHCl3); IR (neat): νmax (cm-1) 2952, 2927, 2894, 2855, 1471, 1361, 1251, 1188, 1098, 1004, 921, 832, 773; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 5.42 (dd, J = 11.0, 9.2 Hz, 1H), 5.22 (dt, J = 11.4, 7.3 Hz, 1H), 4.75 (d, J = 9.0 Hz, 1H), 4.13 – 3.96 (m, 2H), 3.64 (ddd, J = 8.8, 5.2, 3.2 Hz, 1H), 3.55 (t, J = 6.5 Hz, ACS Paragon Plus Environment

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2H), 3.30 (dd, J = 5.3, 1.0 Hz, 1H), 2.40 (s, 3H), 2.32__2.19 (m, 1H), 2.07__1.81 (m, 3H), 1.51__1.41 (m, 2H), 1.35__1.25 (m, 4H), 0.92__0.72 (m, 36H), 0.07__-0.11 (m, 24H); 13C NMR (100 MHz, CDCl3) δ 144.4, 133.5, 133.3, 129.7, 128.5, 127.9, 77.6, 70.9, 68.5, 66.9, 63.1, 32.8, 32.2, 29.5, 28.2, 26.0, 26.0, 25.8, 25.8, 25.8, 21.6, 18.4, 18.0, 17.8, -3.7, -4.0, -4.1, -4.2, -4.8, -5.1, -5.3; HRMS [DART+] (m/z): [MOTBS]+ Calcd for C37H71O6S1Si3 727.4279, Found 727.4296. (5R,6S,7S,8Z)-6,7-Bis((tert-butyldimethylsilyl)oxy)-2,2,3,3,16,16,17,17-octamethyl-5-octyl-4,15dioxa-3,16-disilaoctadec-8-ene (34). To a stirred solution of 33 (0.3 g, 0.35 mmol) in THF (25 mL) under Ar atmosphere at 0 ºC was added copper iodide (0.006 g, 0.035 mmol), hexylmagnesium bromide (2M in diethyl ether, 0.70 mmol) and the reaction mixture was stirred for 1 h at the same temperature. After completion of reaction monitored by TLC, sat. ammonium chloride and sat. sodium chloride solutions were added and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over sodium sulfate, and concentrated, then crude was purified by silica-gel flash column chromatography using a mixture of 0.5% ethyl acetate and hexane as an eluent to afford 34 (0.186 g, 69%) as a colorless oil. Rf = 0.5 (2% ethyl acetate and hexane); [α]30D +12.0 (c 0.25, CHCl3); IR (neat): νmax (cm-1) 2953, 2927, 2891, 2854, 1469, 1384, 1252, 1101, 1005, 936, 832, 772; 1H NMR (400 MHz, CDCl3) δ 5.43 (dd, J = 11.1, 9.3 Hz, 1H), 5.19 (dt, J = 11.2, 7.1 Hz, 1H), 4.71 (d, J = 9.0 Hz, 1H), 3.55 (t, J = 6.6 Hz, 2H), 3.48 (ddd, J = 9.2, 4.9, 2.1 Hz, 1H), 3.29 (dd, J = 5.1, 1.7 Hz, 1H), 2.08__1.89 (m, 2H), 1.84__1.72 (m, 1H), 1.49__1.42 (m, 3H), 1.32__1.16 (m, 15H), 1.11__1.02 (m, 1H), 0.87__0.81 (m, 39H), 0.03__-0.05 (m, 24H); 13C NMR (100 MHz, CDCl3) δ 133.7, 128.1, 78.2, 77.2, 75.7, 67.1, 63.2, 32.9, 32.1, 31.9, 29.9, 29.6, 29.6, 29.3, 28.2, 27.7, 26.1, 26.0, 26.0, 25.9, 25.9, 25.8, 22.7, 18.4, 18.1, 18.1, 18.0, 14.1, 1.0, -0.0, -3.6, -3.8, -4.2, -4.3, -4.6, -4.6, -5.3; HRMS [DART+] (m/z): [M-OTBS]+ Calcd for C36H77O3Si3 641.5181, Found 641.5189. (8S,9S,10R,6Z)-8,9,10-Tris((tert-butyldimethylsilyl)oxy)octadec-6-en-1-ol (35). To a stirred solution of 34 (0.15 g, 0.19 mmol) in 1:1 MeOH and DCM (8 mL) was added CSA (0.013 g, 0.058 mmol) at 0

º

C, the mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched with sat. sodium bicarbonate solution, then extracted with DCM (15 mL x 2). The combined organic layers were dried over sodium sulfate, concentrated, then crude was purified by column chromatography using 0.5% ethyl acetate and hexane as an eluent gave recovered 34 (0.064g), and 35 (0.061 g, 83% based on recovered starting material) as a colorless oil. Rf = 0.3 (2% ethyl acetate and hexane); [α] D28 +16.0 (c 0.3, CHCl3); IR (neat): νmax (cm-1) 2954, 2927, 2855, 1471, 1254, 1080, 834, 805, 773; 1H NMR (400 MHz, CDCl3) δ 5.46__5.38 (m, 1H), 5.18 (dt, J = 11.1, 7.2 Hz, 1H), 4.69 (d, J = 9.1 Hz, 1H), 3.64__3.54 (m, 2H), 3.50__3.43 (m, 1H), 3.28 (d, J = 5.0 Hz, 1H), 2.09__1.88 (m, 2H), 1.82__1.71 (m, 1H), 1.54__1.50 (m, 2H), 1.47__1.28 (m, 6H), 1.27__1.09 (m, 12H), 1.05__0.92 (m, 1H), 0.89__0.76 (m, 29H), -0.02__-0.08 (m, 18H); 13

C NMR (100 MHz, CDCl3) δ 132.8, 126.9, 77.2, 76.2, 74.7, 66.0, 62.0, 31.7, 31.1, 30.9, 28.9, 28.6,



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Page 18 of 19

28.5, 28.3, 27.1, 26.6, 25.0, 24.9, 24.8, 24.6, 21.7, 17.1, 17.0, 17.0, 13.1, -0.0, -1.0, -4.6, -4.8, -5.2, -5.3, -5.6, -5.6; HRMS [DART+] (m/z): [M-OTBS]+ Calcd for C30H63O3Si2 527.4316, Found 527.4302. (8S,9S,10R,6Z)-8,9,10-Trihydroxyoctadec-6-enoic acid (ent-1). To a stirred solution of 35 (30 mg, 45 μmol) in MeCN/H2O 4:1 (5 ml) were added (diacetoxyiodo)benzene (1.5 mg, 4 μmol) and TEMPO (0.7 mg, 4 μmol) at 0 ºC and the mixture was stirred 4 h at room temperature. After completion of the reaction monitored by TLC, the solvents were removed under reduced pressure, and the crude mixture was dissolved in ethyl acetate, and sat. sodium thiosulfate solution (3 ml) was added. The combined organic layer was dried over sodium sulfate, and concentrated in vacuo to give the crude 36, which was used in the next step without further purification. To the above crude in THF (4 mL) was added tetrabutylammonium fluoride 1M in THF (204 μL, 204 μmol) and the mixture was stirred at 35 ºC for 4 h. After completion of reaction monitored by TLC, sat. sodium chloride solution (2 mL) was added and the mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulfate, concentrated, crude was purified by silica-gel flash column chromatography using a mixture of 10% methanol and ethyl acetate as an eluent to afford ent-1 (7.2 mg, 48% 2 steps) as semi solid. [α]D26 +18.0 (c 0.1, CH3OH). ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publication website at DOI: Copies of all 1H and 13C spectra (PDF). AUTHOR INFORMATOION Corresponding Author *E-mail: [email protected] ORCID Masahiko Hayashi: 0000-0002-1716-6686 Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS

The work was supported by Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan and by Special Coordination Funds for Promoting Science and Technology, Creation of Innovation Centers for Advanced Interdisciplinary Research Areas (Innovative Bioproduction Kobe), MEXT, Japan.


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Synthesis of Enantiomerically Pure (8 S, 9 S, 10 R, 6 Z

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