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    Total Synthesis of (+)-Phorboxazole A

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    Total Synthesis of (+)-Phorboxazole A Exploiting the Petasis−Ferrier Rearrangement si

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    Total Synthesis of (+)-Phorboxazole A

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    © All Rights Reserved
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    26 views40 pages

    Total Synthesis of (+) - Phorboxazole A Exploiting The Petasis Ferrier Rearrangement Si

    Uploaded by

    Chen yu
    Total Synthesis of (+)-Phorboxazole A

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    © All Rights Reserved
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    © 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III ja0116041 Supporting Info Page 1 Materials and Methods. Reactions were carried out in oven or flame-dried glassware under an argon ‘atmosphere, unless otherwise noted. All solvents were reagent grade. Diethyl ether and tetrahydrofuran (THF) were freshly distled from sodium/benzophenone under argon. Dichloromethane, benzene and diisopropylamine were freshly distiled from calcium hydride. Triethylamine was distilled from calcium hhydride and stored over potassium hydroxide. Anhydrous pyridine, dimethylformamide and dimethyl sulfoxide were purchased from Aldrich and used without purification. r-Butylithium and #butyllithium were purchased from Aldrich. Except as indicated otherwise, reactions were magnetically stirred and ‘monitored by thin layer chromatography with 0.25-mm E, Merck pre-coated slica gel plates. Flash chromatography was performed with slica gel 60 (particle size 0.040-0.062 mm) supplied by E. Merck. Yields refer to chromatographically and spectroscopically pure compounds, unless otherwise stated. Metting points were determined on a Bristoline heated-stage microscope or Thomas-Hoover apparatus and are corrected. Infrared spectra were recorded with a Perkin-Elmer Model 283B spectrometer with Polystyrene as external standard. Proton NMR spectra were recorded on a Bruker AM-500 spectrometer. Carbon-13 NMA spectra were recorded on a Bruker AM-500. Chemical shifts are reported relative to intemal tetramethylslane (6 0.00) or chioroform (6 7.24) for Hand either chloroform (677.0), or benzene (6 128.0) for °C. Optical rotations were obtained with a Perkin-Elmer model 241 polarimeter. High resolution mass spectra were measured at the University of Pennsyvania Mass Spectrometry Service Center on either a VG Micromass 70/70H or VG ZAB-E spectrometer. Microanalyses were performed by at the University of Pennsylvania. High performance liquid chromatography (HPLC) was performed with a Waters analytical/semi-prep system, Compounds On the Linear Sequence (50 Enone (-)-5! To a solution of F(+)-Binol (780 mg, 0.2 equiv), powdered 4A molecular sieves (5.24 9), and titanium tetraisopropoxide (386 mg, 0.1 equiv) in Et,0 (40 mL) was added trifluoroacetic acid (Catalytic amount). The reaction mixture was heated at reflux for 1 h, then cooled to rt; aldehyde 49 (3.87 9, 13.6 mmo) in Et,0 (14 mL) was then added via cannula. The reaction mixture was cooled to -78 °C, followed by addition of Danishetsky’s diene (2.80 g, 1.2 equiv). The reaction was warmed to -20 °C and stimed for ca. 45 h, followed by addition of saturated NaHCOg (10 mL) and filtration through Celite. The 1 © 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III a0116041 Supporting Info Page 2 organic layer was washed with saturated NaHCO3 (25 mL), dried over MgSO4, and concentrated in vacuo, ‘The product was dissolved in methylene chloride (200 mL), and trluoroacetic acid (0.68 mL) was added at °C. The reaction mixture was stired for 1 h, quenched with saturated NaHCOg (50 mL), and extracted with methylene chloride (3 x 25 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. Flash chromatography, using hexanes-EtOAc (6:4) as eluant, gave (-)-50 (3.92 g, 64% yield, 90% ee) as a colorless oil: [af -35.8 (c 1.0, CHCl); IR (CHCl) 2980 (s) 1670 (s) 1595 (w) 1280 (6) 1100 (6) cmt, 1H NMR (600 MHz, CDCIg) 5 7.64 (m, 4H), 7.30 (m, 6H), 7.26 (d, 6.0 Hz, 1H). 5.97 (dd, J= 6.0, 1.0 He, 1H), 4.66 (m, 1 H), 3.85 (ddd, J= 13.0, 10.5, 8.2 Hz, 1 H), 3.78 (ddd, J= 10.7, 5.5, 5.3 Hz, 4 H), 2.46 (m, 2 H), 2.00 (m, 11H), 1.88 (m, 1 H), 1.02 (s, 9 H); 19¢ NMR (125 MHz, CDC) 8 192.4, 163.0, 13.5, 193.5, 129.8, 127-7, 107.1, 59.2, 41.9, 37.2, 29.8, 19. igh resolution mass spectrum (Cl, NH3) m/z 381.1888 [(M+H)*; caled for CogHagO3Si: 981.1885]. mo To a solution of copper iodide (611 mg, 3 equiv) in THF (8,7 mL) at -78 °C was added vinyl Grignard (3.1 ‘mL, 1.0 M in THF, 2.9 equiv). The reaction mixture was stirred for 10 min and DMPU (1.04 mL, 8 equiv), TMS-CI (0.407 mL, 3 equiv) and enone (-)-50 (410 mg, 1.07 mmol) in THF (2 mL) were added. The reaction mixture was stived at -78 °C (th), flowed by warming to -46 °C (90 min) then quenched with aqueous saturated NH4CI (10 mL. The reaction miure was extracted with E1OAc (2x 25mL), the organic extracts dried over MgSOq and concentrated in vacuo. Flash ‘chromatography, using EtOAc-hexanes (1:9 then 2:8) as eluant, gave the corresponding alkene (398 mg, 92% yield, 0:1 dt: [a2 -43 (c 1.0, ‘CHClg); IR (CHCig) 3080 (s), 3010 (s), 2970 (s), 2760 (s), 1720 (s),1210 (), 1115 (wy; cmt; 1H NMR, (800 MHz, CDCls) 8 7.64 (m, 4 H), 7.37 (m, 6 H), 5.84 (ddd, 7.5, 10.8, 4.6 Hz, 1H), 5.22 (m, 2H), 4.64 (m, 1H), 4.92 (m, 1H), 3.81 (ddd, J= 10.3, 8.2, 5.1 Hz, 1H), 3.71 (ddd, J= 10.3, 8.9, 6.6, 1H), 2.59 (ddd, J= 13.5, 6.0, 1.0 Hz, 1 H), 2.53 (ddd, J= 14.5, 4.6, 1.5 Hz, 1H), 2.43 (ddd, Je 14.4, 5.5, 1.5 Hz, 1 H), 2.25 (ddd, J = 14.0, 8.6, 6.1 Hz, 1H), 1.83 (ddd, J= 14.0, 6.6, 5.1 Hz,1 H), 1.72 (ddd, J= 13.9, 5.7, 2 © 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III a0116041 Supporting Info Page 3 4.9 Hz, 1H), 1.02 (5, 9H); '9C NMR (125 MHz, CDCl) 6 206.7, 137.1, 135.6, 193.7, 129.7, 127.7, 118.0, 72.8, 68.5, 59.8, 47.5, 44.7, 37.9, 26.8, 19.2; high resolution mass spectrum (Cl, NHa) m/z 409.2191 [(M+H)*; calod for CasHagOaSi: 409.2199]. Anal. Caled for CagHg2038i, C, 73.49; H, 7.90. To solution of the alkene (571 mg, 1.9 mmol) and Wikinson's catalyst (64 mg, 0.05 equiv) in Found: C, 73.43: H, 8.17, THF (14 mL) was added catecholborane (1.67 ml, 1.0 Min THF, 1.2 equiv). After 10 min, addtional atecholborane (1.0 mL, 0.7 equiv) was added. The resultant organoborane was oxidized after 10 min with sodium perborate tetrahydrate (1 g) and water (10 mL). The reaction mixture was stied 3 h and then poured into brine (20 mL) and extracted with EtOAc (3 x 25 mL); the combined organic extracts were dried over MgSOq, and concentrated in vacuo. Flash chromatography, using EtOAc-hexanes (2:8 then 6:4) as ‘eluant, gave the primary alcoho! (504 mg, 85% yield) as a yellow oll: [ol -13.6 (c 1.0, CHClg); IR (CHCla) ‘3500 (w), 2960 (s), 2860 (), 1720 (s), 1490 (s), 1110 (s) om; 1H NMR (500 MHz, CDCig) 8 7.63 (m, 4H), 7.38 (m, 6 H), 4.45 (dddd, 10.6, 9.0, §.3, 3.7 Hz, 1H), 4.19 (dddd, J= 8.5, 8.3, 4.2, 4.1 He, 11H), 3.78 (m, 1H), 3.66 (m, 1H), 2.58 (ddd, J= 14.4, 5.6, 1.2 Hz, 1H), 2.44 (ddd, J= 14.9, 4.4, 1.5 Hz, 1H), 2.28 (m, 2H), 1.82 (m, 2H), 1.66 (m, 2H), 1.03 (3, 9H); "SC NMR (125 MHz, CDCl) 5 206.9, 135.6, 133.6, 129.7, 127-7, 70.2, 69.7, 59.8, 59.8, 47.2, 46.5, 97.0, 36.4, 26.9, 19.2; high resolution mass spectrum (ES, NHg) m/z 449.2119 [(M+Na)*; calcd for CasHa404SiNa: 449.2124]. Methyltriphenylphosphonium iodide (6.7 g, 2.7 equiv) was lightly flame dried under argon and then stirred in THF (60 mL) at -10 °C, followed by addition of LDA (16.4 ml, 1.0 M THF, 2.5 equiv). After 30 min the ketone (2.615 g, 6.14 mmol) in THF (15 mL) was added via cannula. After 20 min the reaction was 3 © 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III ja0116041 Supporting Info Page 4 quenched with saturated NH4CI (75 mL) and extracted with EIOAc (3x50 mL). The organic extracts were died over MgSO4 and concentrated in vacuo, Flash chromatography, using EtOAchexanes (2:8 then 1:1) as eluant, gave the corresponding exomethylene (2.149 9, 84% yield) as a coloriess oi: fol? -24.0 (1.0, CHCig); IR (CHCig) 3500 (w), 2980 (s), 1425 (w), 1110 (6) ‘emt; 1H NMR (500 MHz, CDCig) 5 7.65 (m, 4H), 7.38 (m, 6 H), 4.75 (8, 1H), 4.71 (s, 1H), 4.14 (m, 1H), 3.76 (m, 2H), 3.66 (m, 3-H), 2.36 (dd, J= 13.3, 5.2 Hz 1H), 2.22 (dd, J = 13.1, 3.7 Hz, 1H), 2.15 (s, 1H), 1.98 (m, 2H), 1.90 (m, 1H), 1.80 (m, 1H), 1.59 (m, 2 H), 1.03 (, 9 H); 18 NMR (125 MHz, CDCig) § 141.8, 135.6, 193.9, 129.6, 127.7, 110.4, 708, 69.7, 60.7, 605, 402, 39.0, 36.4, 949, 269, 19 h resolution mass spectrum (ES, NHg) mz 447.2822 [(M+Na)*; caled for CogHag03SiNa: 447.2831], Anal. Caled for Cog HagO3Si: C, 73.54; H, 8.54. Found: C, 73.52; H, 8.90. To a solution of oxalyl chloride (820 mg, 2 equiv) in methylene chloride (50 mL) at -78 °C was added DMSO (1.0 g, 4 equiv), the exomethylene alcohol (1.97g, 3.23 mmo} in methylene chloride (15 mL), and Et,N (3.9 mL, 10 equiv). The reaction mixture was stired for 1 h, warmed to 0 °C for 30 min, quenched with saturated NaHCO (10 mL), and extracted with methylene chloride (8 x 25 mL). The ‘organic extracts were dried over MgSOq and concentrated in vacuo. Flash chromatography, using E!OAc- hexanes (1:9) as eluant, gave (-)-51 (1.26 g, 93% yield) as a yellow oil: [a3 -26.0 (¢ 1.0, CHCl); R (CHCIg) 2950 (s), 2860 (6), 1725 (8), 1110 (6) em-1; "H NMR (500 MHz, CDCH) 5 9.65 (t, J= 2.3 Hz, 1H) 7.64 (m, 4 H), 7.98 (m, 6 H), 4.77 (s, 2H), 4.20 (m, 1 H), 4.04 (mm, 1H), 3.74 (ddd, 0.3, 7.7, 5.9 Hz, 1 H), 8.67 (ddd, J= 10.4, 6.3, 5.5 Hz, 1H), 2.64 (ddd, 6.2, 7.8, 2.6 Hz, 1H) 2.44 (ddd, J= 16.2, 5.5, 1.9 Hz, 1H), 2.36 (m, 2H), 2.01 (m, 2H), 1.88 (ddd, J= 14.0, 11.3, 8.4 Hz, 1 H), 1.65 (ddd, J= 14.0, 7.8, 6.4 Hz, 1H) 1.08 (s, 9 H); 19C NMR (125 MHz, CDCI) 6 200.7, 141.1, 135.6, 133.9, 129.6, 127.6, 111.2, © 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III ja0116041 Supporting Info Page 5 69.7, 67.2, 60.4, 47.6, 39.6, 39.2, 35.6, 26.9, 19.2; high resolution mass spectrum (Cl, NH) m/z 423.2339 [(M+H)*; caled for CagHg5OgSi: 428.2355]. ans in Toa solution of tin (I) tiflate (395 mg, 1 equiv) in methylene chloride (2 mL) at -50 °C was added ethyl piperidine (0.130 mL, 1 equiv) and thiazolidinone (-)-45 (241 mg, 1.0 mmol) in methylene Chloride (0.8 mL) via cannula. The reaction mixture was stired 4 h, cooled to -78 °C, and aldehyde (-)-51 in methylene chloride (1 mL) was added via cannula. The reaction mixture was stired 45 min, quenched with pH 7 buffer (6 mL), fitered through calite, poured into brine (25 mL), and extracted with methylene Chloride (2x25 mL). The combined extracts were dried over MgSOq and concentrated in vacuo. Flash chromatography, using EtOAc-hexanes (1:3) as eluant, gave the aldol adduct (140 mg, 85% yield, 4:1 dr): [ofB +20 (¢ 1.0, CHC); IR (CHCIa) 3480 (4), 2960 (6), 1690 (6), 1960 (6), 1185 (6, 1110 @) cmt; 1H NMA (500 MHz, CDCig) 87.67 (m, 4 H), 7.40 m, 6 H), 5.74 (4, J= 7.2 Hz, 1 H), 4.99 (dq, J= 6.9, 6.7 Hz, 1 H), 4.78 (s, 1H), 4.73 (s, 1H), 4.32 (m, 1H), 4.18 (m, 1 H), 3.95 (ddd, 2.5, 8.5, 8.0, 3.9 Hz, 1H), 8,78 (ddd, J= 13.3, 7.3, 6.0 Hz, 11H), 3.70 (ddd, J= 11.9, 6.0, 4.5 Hz, 1H), 3.52 (m, 2H), 3.43 (dd, J= 17.3, 8.2 Hz, 1H), 2.41 (dd, J= 13.3, 5.0 Hz, 1H), 2.2 (dd, 3.2, 3.8 Hz, 1 H), 2.03 (m, 2 H), 1.87 (m, 2H), 1.67 (m, 2H), 1.05 (5, 9H), 1.0 (d, J= 6.6 Hz, 3H); 19C NMR (125 MHz, CDCI) 8 184.9, 172.4, 141.4, 135.6, 199.9, 192.1, 128.5, 128.9, 128.7, 127.6, 125.8, 110.5, 83.4, 71.1, 69.9, 67.0, 60.6, 59.0, 44.8, 40.4, 40.2, 38.8, 95.2, 26.9, 19.2, 14.2; high resolution mass spectrum (Cl, NH) m/z 680.2872 [(M+Na)*; calcd for CagH47OsNSIS: 680.2842]. © 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III ja0116041 Supporting Info Page 6 (-)-52 To.a0°C solution of the aldol adduct (200 mg, 0.819 mmo)) in THF (2.4 mL) was added 1N LiOH (0.96 mL) and HOOH (30%, 0.426 mL). After § min the reaction mixture was quenched with saturated sodium thiosulfate (5 mL), acidified to pH 2 (IN HC), extracted with E1OAc (8 x 25 mL), dried over NagSO4, and concentrated in vacuo. Flash chromatography, using EtOAc-hexanes-acetic acid (33:66:1 then 50:50:1) as eluant, gave (-)-52 (0.153 g, 99% yield) as a colorless oil: [aJ% -25.7 (¢ 1.0, CHCig); IR (CHCl) 3450 (Ww), 2950 (6), 1740 (6), 1110 (s) emt; 1H NMR (600 MHz, CDCIg) 8 7.65 (m, 4 H), 7.37 (m, 6 H), 4.77 (6, 1 H), 4.71 (6, 1H), 4.21 (m, 1 H), 4.05 (m, 1 H), 8.80 (m, 1 H), 3.73 (ddd, J= 13.6, 10.5, 4.6 Hz, 1H), 9.65 (ddd, = 12.0, 10.6, 6.2 Hz, 1 H), 2.48 (m, 2H), 2.41 (dd, 13.3, 5.4 Hz, 1H), 2.22 (dd, J= 19.2, 3.4 Hz, 1H), 1.89 (m, 1H), 1.76 (at, J= 14.4, 9.8 Hz, 1H), 1.87 (m, 11H), 1.54 (at, J=14.4, 2.9 Hz, 1 H) 1.04 (s, 9H); 18 NMR (125 MHz, CDC) 8 174.9, 140.8, 195.6, 133.8, 133.6, 129.7, 127.7, 111.0, 71.7, 705, 67.8, 60.5, 41.3, 40.5, 95.5, 34.5, 26.9, 19, igh resolution mass spectrum (ES, NHs) m/z 605.2401 [(MsNa)*; caled for CogHggOsSiNa: 505.2386]. 8% 0 (-)-53 Dioxanone (-)-83: To a solution of (-)-52. (260 mg, 0.54 mmol) in methylene chloride (0.622 mL) was added HMDS (0.182 mL, 1.2 equiv) and the reaction mixture was stired for 12h. Solvent and excess reagent were removed on high vacuum and the flask charged with aldehyde 25 (375 mg, 2.8 equiv) and © 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III a0116041 Supporting Info Page 7 ‘methylene chloride (7.65 mL) and then cooled to -78 °C. TMS-OTt (0.020 mL, 0.2 equiv) was added and the reaction mixture was warmed to -25 °C for 65 h followed by addition of EtsN (0.30 mL). The reaction mixture was poured into saturated NaHCOg (20 mL), and extracted with methylene chloride (8 x 25 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. Flash chromatography (6:4 Et,O-hexanes then E1,O then 50:50:1 EIOAc-hexanes-acetic acid) gave recovered aldehyde 25 (190 'mg), recovered acid (-}-82 (75 mg, 28.5 %) and dioxanone (-)-53 (271 mg, 71% yield, 99% BORSM, 15:1 dr) as a coloriess oil; (a]% -27.0 (c 1.0, THF); IR (CCU) 2910 (8), 1760 (8), 1110 (s) cmt; 1H NMR. (600 MHz, CgD6) 8 7.78 (m, 4H), 7.40 (s, 1 H), 7.29 (m, 6 H), 7.17 (m, 2H), 6.75 (dd, 6.6, 2.0 Hz, 2H), 5.90 (s, 1H), 4.68 (s, 2H), 4.33 (6, 2H), 4.28 (5, 2H), 3.92 (m, 1 H), 3.77 (m, 2H), 3.69 (m, 1 H), 3.55 (m, 1 H) 3.31 (s, 3H), 2.94 (dd, J= 17.6, 4.8 Hz, 1 H), 2.22 (dd, 7.6, 10.4 Hz, 1H), 2.16 (dd, 3.1, 4.3 Hz, 1H), 2.02 (dd, J= 13.2, 4.2 Hz, 1 H), 1.95 (ddd, J=14.3, 9.0, 5.4 Hz, 1H), 1.8 (m, 2H), 1.71 (dd, J= 18.2, 6.6 Hz, 1H), 1.59 (m, 1H), 1.17 (s, 9 H); 19C NMR (125 MHz, CeDe) 8 165.4, 161.9, 159.9, 142.0, 198.4, 197.5, 136.9, 194.2, 194.1, 130.1, 129.8, 129.8, 1285, 128.5, 114.2, 110.6, 97.0, 72.4, 72.1, 69.2, 67.5, 63.3, 61.0, 54.8, 39.7, 39.6, 39.1, 96.3, 36.2, 27.1, 19.4; high resolution mass spectrum (Cl, NH) m/z 712.3302 [(M+H)*; caled for C4yHgoOeNSi: 712.9306}, 4, ers or (-)-43 Enol Ether (-)-43: To a solution of dioxanone (-)-53 (27 mg, 0.038 mmol) was added freshly Prepared dimethyl itanocene (0.98 mL, 0.5 M THF, 5 equiv) and the reaction mixture heated at 65 °C for 16h. The reaction mixture was placed directly onto basic alumina (activated with 10% water wiw). Flash chromatography, using Et,0-hexanes (1:3 with 1% Et,N) as eluant, gave (-)-48 (22.5 mg, 88% yield) as a yellow oi [e} -11.4 (¢ 1.0, THF); IR (CCy) 2820 (s)1665 (w), 1610 (w), 1190 (s) cmt; 1H NMR (500 7 © 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III a0116041 Supporting Info Page 8 MHz, CgDg) 8 7.81 (m, 4 H), 7.58 (5, 1 H), 7.28 (m, 6 H), 7.17 (m, 2H), 6.75 (dd, J= 6.6, 2.0 Hz, 2H), 5.76 (8,1 H), 4.72 (4, d= 1.7 Hz, 1H), 4.7 (5, 1H), 4.7 (6, 1 H), 4.94 (6, 2H), 4.31 (6, 2H), 3.95 (m, 1H), 3.81 (m, 4H), 3.31 (s, 3H), 2.20 (m, 4H), 2.06 (dd, = 18.8, 2.7 Hz, 1H), 1.85 (mn, 3H), 1.60 (m, 1H), 1.42 (m, 1 H),1.19 (6, 9H); 8c NMR (125 MHz, CeDe) 6 161.4, 159.8, 156.6, 142.4, 139.8, 197.4, 196.0, 194.2, 130.0, 129.0, 128.2, 114.1, 110.4, 97.5, 94.1, 74.2, 72.2, 69.0, 67.9, 63.4, 61.1, 54.7, 40.0, 39.7, 39.2, 36.9, 34.9, 30.5, 27.1, 19.4; high resolution mass spectrum (CI, NHg) m/z 710.3508 [(M+H)*; calod for CggHs207NSi: 710.9513} m3 ars A (-)-42 Ketone (-)-42: To asolution of enol ether (-)-43 (200 mg, 0.26 mmol in methylene chloride (5.35 mL) was added dimethylaluminum chloride (1.0 M in hexanes, 0.28 mL, 1.2 equiv). After 2 min the reaction mixture was quenched with saturated NaHCOs (50 mL), and extracted with methylene chloride (3 x 100 mil). The organic extracts were dried over MgSO and concentrated in vacuo. Flash chromatography, using EtOAcchexanes (1:2) as eluant, gave (-)-42 (178 mg, 89% yield) as an oil: [a}%9 - 15.0 (¢0.23, CHClg); IR (CHClg) 2940 (s), 1720 (s), 1105 (6) cmt; 1H NMR (500 MHz, CDCI) 5 7.65 (m, 4H), 7.49 (6, 1 H), 7.8 (mn, 6H), 7.25 (m, 2H), 6.87 (dd, J = 6.6, 2.1 Hz, 2H), 4.72 (6, 2H), 4.52 (6, 2H), 4351 (6, 2H), 4.5 (m, 1 H), 4.00 (m, 1 H), 3.92 (m, 1 H), 3.82 (m, 1 H), 3.79 (8, 9H), 3.74 (m, 1 H), 3.67 (rm, 1 H), 2.69 (dd, J=14.4, 11.8 Hz, 1 H) 2.58 (at, J= 14.3, 26 Hz, 1H), 2.49 (ddd, J= 14.5, 2.3, 2.1 Hz, 1H), 2.39 (m, 3H), 2.16 (mn, 1 H), 2.02 (m, 2H), 1.78 (m, 1 H), 1.65 (m, 2 H), 1.04 (8, 9H); 18¢ NMR (125 MHz, CDCI § 205.6, 161.3, 159.5, 141.7, 140.4, 195.9, 195.5, 193.9, 129.7, 129.6, 129.2, 127.7, 118.9, 110.5, 74.3, 72.3, 72.8, 71.7, 69.0, 68.2, 63.5, 60.5, 55.3, 47.2, 46.3, 99.6, 99.5, 99.4, 36.4, 26 EI SEOD'S?T=~~ © 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III ja0116041 Supporting Info Page 9 192; high resolution mass spectrum (ES, NHa) vz 732.9356[(MsNa)*; calcd for CagHe1O7NSiNa: Pe a 732.3333}, ‘To asolution of ketone (-)-42 (44 mg, 0.062 mmol) in THF (1.25 ml) at -78 °C was added Ke Selectde (0.074 mL, 1.0 Min THF, 1.2 equiv). After 1 h the reaction was quenched with NaOH (0.305 mL, 1 N solution), HOOH (0.175 mL, 30% solution) and reaction warmed to 0 °C for 2h. The reaction imture was poured into brine (20 ml) and extracted with methylene chloride (8x 20 ml). The organic crtacts wore dried over MgSOs and concentrated in vacuo. Flash chromatography, using EIOAc- hexanes (1) as eluant, gave the minor equatorial alcohol (3.0 mg, 7% yleld) and the major anal alochol (89 mg, 89%) as an oil: [alf -9.6 (c 1.0, CHCl); IR (CHCig) 3400 (w), 2940 (8), 1610 (Ww), 1100 (s) emrt; 1H [NMR (600 MHz, CDCig) 8 7.65 (m, 4 H), 7.48 (s,1H), 7.97 (m, 6H), 7.27 (, = 8.7 Hz, 2H), 6.85 (dd, J: 07,24 Ha, 2H), 4.79 (dd, J=11.6, 1.7 Hz, 1 H) 4.71 (6,2 H), 451 (6, 4H), 4.22 (m, 1H), 3.98 (m, 24), $91 (1H), 8.78 (6, 9H), 3.72 (m,2H), 2:31 (m, 2H), 1.95 (m, 41H), 1.89 (m, 2H), 1.63 (m, 2 H), 1.50 (m, 2H), 1.96 (bs, 1H), 1.02 (, 9 Hy; 190 NMR (125 Miz, COCK) 8160.8, 169.5, 142.3, 142.2, 198. 6, 1940, 193.8, 129.7, 1296, 129.8, 127.6, 118.9, 110.3, 726, 69.0, 68.9, 68.5, 67.9, 642, 63.6, 60.8, 55:3, 99.8, 39.4, 39.4, 98.0, 37.7, 96.5, 26.9, 19.2; high resolution mass spectrum (ES, NH) mz 734.3809 [(M+Na)*; caled for C4aHsg07NSiNa: 734.3489], = EEE S'’ZS rr © 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III ja0116041 Supporting Info Page 10 To a solution of the alcoho! (26 mg, 0.037 mmo) in methylene chloride (2.99 mL) at -78 °C was added 2,6-utidne (0.081 mL, 12 equiv) and TBS-OTT (0.034 ml, 4 equiv) and the reaction was stimed for Sh. The reaction mixture wes poured into saturated NaHCO, (15 mL) and extracted with methylene chloride (820 mL}. The combined extracts were cried over MgSOg and concentrated in vacuo, Flash Chromatography, using EtOAc hexanes (1:8) as eluant, gave (-)-54 (29.5 mg, 98% yield) as an lor? - 11.3 (61.0, CHC): IR (CHCIg) 2040 (8), 1500 (w), 1100 (6) om; 1H NMR (500 Miz, CDCI) 5 7.65 (rm, 4 H), 7.48 (8, 1 H), 7.97 (m, 6 H), 7.26 (4, J= 8.6 Hz, 2H), 6.86 (dd, 7, 2.1 Hz, 2H), 4.84 (dd, J= 11.5, 18H2, 1H) 4.70(s, 2H), 4.52 (5, 2H), 4.51 (6,24), 424 (m, 1 H), 3.99 (m, 3H), 3.78 (6, 9H), 871 (ddd, Y=129, 9.3, 6.4 He, 1H), 3.67 (ded, J= 12.0, 10.3, 6.1 He, 1H), 2.34 (dd, J= 19.2, 45 He, 4 H), 2.20 (94, d= 19.2, 4.1 He, 11H), 2.02 (dd, J= 13.2, 5.8 Hz, 11H), 1.95 (dd, J=18.2, 6.9 He, 1H), 1.88 (m, 2H), 1.78 (m, 2 H), 1.65 (m, 2H), 1.02 (s, 9H), 0.90 (s, 9H), 0.05 (s, 6 H); "36 NMR (125 MHz, CDOig) 8 160.7, 1895, 142.7, 1429, 195.6, 134.0, 198.9, 129.7, 129.5, 1292, 127.6, 113.9, 110.1, 72.6, 69:1, 68.8, 875, 64.7, 63:7, 60.7, 55:3, 39.7, 39.6, 39.3, 39.2, 39.0, 38.3, 96.6, 26.9, 25.8, 19.2, 18.1, 4, 8, -4 high resolution mass spectrum (ES, NHs) m/z 848.4963 [(M+Na)*; caled for ‘C4gHe7O7NSigNa: On BPS 0, 848.4354) Toa solution of PMB ether (-)4 (52 mg, 0.068 mmol) in methylene chioride (6.20 mL) and water (0.42 ml) was added DQ (90 mg, 2.1 equiv). Ater 8h the reaction miure was quenched with saturated NaHOOs (10 mL) and extracted wit methylene chloride (8x 10 mL), The combined extracts were dried over M@S06 and concentrated in vacuo. Fash chromatography, using ElOAchexanes (1:4) as eluant, S2Ve Ihe primary alcoho (43 mg, 96% yield) as an ot: [olf -16.0 (€0.5, CHC) IR (CHC) 3400 (w), 2950 (9) 1425 (w), 100 (8) emt; HMA (500 Me, CDCI) 87.65 (m, 4 H), 7.44 (6, 1H), 7.96 (m6 H), 4.82 (06, d= 11.4 241 Ha, 1H), 470 (6, 2H), 4.66 (6,2 H), 4.25 (m, 1 H), 3.99 (m, 3H), 3.74 (ed, 10 © 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III ja0116041 Supporting Info Page 11 10.3, 7.0 Hz, 1 H), 3.67 (ddd, 2.2, 10.4, 6.1 Hz, 1 H), 2.99 (s, 1 H), 2.38 (dd, = 13.2, 4.5 Hz, 1H), 2.29 (dd, 13.2, 4.8 Hz, 1H), 1.96 (m, 2H), 1.83 (m, 3H), 1.64 (m, 3H), 1.51 (m, 2H), 1.02 (s, 9 H), 0.90 (5, 9H), 0.08 (6, 6H); 190 NMR (125 M2, COCK) 6 163.1, 142.4, 142.9, 195.4, 135.2, 1940, 193.9, 129.5, 127.6, 110.1, 69.1, 69.1, 68.8, 67.3, 64,7, 60.7, 57.5, 39.6, 39.3, 39.3, 39.0, 38.3, 36.6, 26.9, 25.8, 19.2, 18.1, -4.8, 9; high resolution mass spectrum (ES, NH) m/z 728.3786 [(M+Na)*; caled for CagHsg0eNSigNa: 728.3779}, Toa solution ofthe alcohol (82 mg, 0.116 mmol) in methylene chloride (5.0 mL) and CCl, (1.0 mL) was added triphenylphosphine (300 mg, 10 equiv) and the reaction mixture stired 1 h. The reaction mixture was poured into saturated aqueous sodium bicarbonate (25 ml) and extracted wih methylene chloride (3 x 25 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. Flash ‘chromatography, using EtOAc-hexanes (1:10) as eluant, gave the primary chloride (83 mg, 100% yield) [oS -14. (¢ 1.0, CHO'); IR (CHC) 9040 (5), 2400 (w), 1220 (3), 750 (6) om; 1H NM (500 Miz, CDCig) 5 7.66 (m, 4 H), 7.50, 1H), 7.37 (m, 6H), 4.85 (0, J= 10.3 Hz, 1H), 4.74 (6, 2H), 4.87 (6, 2H), 4.25 (m, 1 H), 3.99 (m, 3 H), 3.75 (ddd, J= 13.1, 10.3, 6.7 Hz, 1 H), 3.68 (ddd, 12.0, 10.4, 6.1 Hz, 1H), 2.95 (0d, J= 19.2, 4.4 Hz, 1H), 2.91 (dd, J= 13.2, 4.1 Hz, 1H), 2.02 (dd, J= 19.2, 5.7 Hz, 1 H), 1.92 (dd, J= 18-1, 69 Hz, 1H), 1.89 (m, 4 H), 1.68 (rm, 2H), 1.54 (m, 2H), 1.02 (6, 9 H), 0.89 (6, 9 H), 0.05 (6, 6 H); 18C NMR (125 MHz, COCK) 6 158.8, 149.3, 142.3, 196.3, 195.6, 193.9, 129, 5, 127.6, 110.10, 69.1, 69.1, 68.8, 67.4, 64.7, 60.65, 39.64, 89.3, 39.3, 99.0, 98.3, 36.6, 35.9, 26.9, 19.2, 18.1, -4.8, 4.9; high resolution mass spectrum (Ci, NHg) m/z 746.2462 [(M+Na)*; caled for CagHsgOsNSisCINa: 746.3440}. "1 CC IIEIIISSOSOSOO'SS © 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III ja0116041 Supporting Info Page 12 (-)-12 Phosphonium Salt (-}-12, To a solution of the primary chloride (89 mg, 0.116 mmo) in OMF (4 mL) was added trbuiyiphosphine (0.06 mL, 2 equiv). The reaction mixture was sted for 16 h and Concentrated in vacuo, Flash chromatography, using methylene chiride-methanol (1:20 then 1:10) as. eluant, gave (-)-12 (106 mg, 100% yield) : [a?9 -8.8 (0.50, CHCl); IR (CHCi) 2910 (s), 1460 (w), 1100 (©), 820 (8) cm; 1HINMR (500 Mz, CDCis) 87.65 (, 4H), 7.48 (, 1 H), 7.99 (m, 6 H), 4.78 (4, d= 11.2 He 1H), 4:72 (8,2 H), 448 (dd, J= 16:7, 15.0 Ha, 1 H), 440 (46, J= 16.7, 14.8 He, 1 H), 4.24 (m, 1H), 4.00 (m, 2 H),3.95 (m, 1H), 8.75 (ddd, J= 10.3, 7.1, 6.0 Hz, 1 H), 3.67 (ddd, J 2.0, 10.8, 6.0 Hz, 1 H), 2.60 (m, 6H), 299 (dd, J= 13.9, 45 Hz, 11H), 2.90 (ld, J= 18.0, 4.1 He, 1H), 2.02 (m, 2H), 1.82 (m, 8H, 1.64 (m, 2 H), 1.48 (m, 15 H), 1.01 (6, 9H), 0.9 (m, 18 H), 0.05 (6, 6H), ; 190 NMA (125 MHz, CDCig) 51589, 1498, 1422, 196.1, 195.5, 1339, 129.6, 127.6, 110.1, 692, 69.1, 68,7, 676, 646, 60.6, 400, 99.8, 98.2, 39.0, 38.6, 36.5, 28.8, 25.9, 25.8, 29.9, 28.8, 23.7, 209, 205, 19.5, 192, 19.1, 18.0, 188, -48, ~4.9; high resolution mass spectrum (Cl, NHg) m/z 890.6705 [(M-C)*; calod tor Lh ef C5gHesOsNSigP: 890.5704]. To 2 solution of trethylborane (14.1 mL, 1.1 equiv) in methylene chloride (50 mL) in a water bath ‘was added truoromethanesutfonic acid (6.12 mL, 1.1 equiv) over 20 min. The resultant solution was Stired 20 min further, then added to a 0 °C solution of oxazolidinone (4)-72 (12.9 9, 62.6 mmo) in methylene chloride (50 ml), followed by Wethylamine (10 mL, 1.95 equiv), maintaining the intemal 12 reer rare J© 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III ja0116041 Supporting Info Page 13 temperature at 0 °C, The resultant solution was sited for 10 min, cooled to -78 °C, and treated wih a ee —ti—‘—™O——S—sr——s—CisS=sissCisésésts mitre was sired for 2h, warned fo 0 °C, and stived 1 h futher. Phosphate butler (pH 7, 55 ml) and ‘hen MeOH (160 mL) were stowiy added, and the solution was stired for 10 min. A solution of 30% HOOHMeCH (1:3, 200 mL) was siowly introduced and the resulting solution was sted for 1 h, then Soncentated in vacue, Th residue was then cssolved in 22 ELOACwator (500 mL). The aqueous layer was extracted with EtOAc 2.x 60 ml, and the combined organic solution was washed with 6% NaHCO3 (200 mi) then brine (200 mL), dried over MgSOx, and concentrated in vacuo. Flash chromatography, using ErOe-hexanes (1:25 then 1:4) as eluant, provided the aldol adduct as way soli, (26.4 9, 92%): {af$ = +90 (€0.94, CHC) IR (CHC) 3500 (w, bp), 2960 (m), 2005 (m), 2860 (7), 1785 (5), 1690 (rp, | rr™——“=*=EUUC'trtrtree Miz, CPCk) 87.52 m,4H),74- 7.1 11H), 4.681 (m1 H), 4.18 (m, 9H), 3.85 (m, 9H), 8.7 (6, 4 1), 3.26 (99. Y= 99, 104 He, 1H), 2.77 (6d, d= 0.5, 184 He, 1H), 4.79 m1 H), 1.69 fm 1H, 128 (@, Je 7.0.3 1), 1.04 (s, 9); '8C. NMR (125 MHz, COCK) 8 176.5, 159.1, 196.6, 196 2, 193.3, 129.7, 129.4, 128.9, 127-7, 127-4, 706, 66.1, 62.4, 55.3, 42.8. 37.8, 96.0, 26.8, 19.1, 11.3; high resolution mass spectrum (ESI) mvz 568.2502 [(M+Na)*; caled for CagHagNOgSiNa: 568.2495}, oh (+)-73 Hydroxyacid (+)-73. To a solution of the aldol adduct (264 g, 62.6 mmo) in THFwater (6:1, 120 ml) S10" was added 30% HOOH (31.0 ml, 273 mmo) and 1 N LIOH (110 mL, 110 mmo). ‘The resultant Solution was stired fort h at 0°C and then quenched with saturated NegSO3 (100 ml) end saturated Sausous NH,CI (100 mL). The aqueous layer was extractod with EtOAc (2 x 100 ml). The organic layers wore combined, washed with saturated NH,Cl (100 ml), dried over MgSO, and concentrated in vacuo, Flash chromatography, using E\OAc-hexanes-tiethyiamine (50:50:1) then EtOAc-acetic acid (60:1) as 13 SRR eee }© 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III ja0116041 Supporting Info Page 14 eluant, provided (+)-73 (17.1 g, 92% yield) as a clear cil: [el =+6.5 (c0.49, CHC): IR (CHClg) 3500 (br), 3015 (m), 2960 (5), 2945 (6), 2865 (), 1750 (m), 1710 (6), 1465 (my), 1490 (mn), 1300 (em), 1110 (6), 1078 (8), 820 (m), 700 (m) cmt; 1H NMR (500 MHz, CDCtg) 5 7.58 (mm, 4 H), 7.39 (m, 6H), 4.52 (br, 4 Hy, 4.18 (240, Y= 10.1, 48, 28 He, 1H), 3.85 (m, 2H), 2.68 (dg, J=72, 46 He, 1H), 1.79 (m, 1 Hy, 1.52 (m1), 2, 3H), 1.04 (8, 9H); 18 NMR (125 Miz, CDC) 8177.1, 138, 1.18 (4, 182.6, 130.0, 127.7, 728, 63.5, 44.8, 34.2, 26.7, 19.0, 11.5; high resolution mass spectrum (ES!) m/z 409.1796 [(MeNay*; Caled for CopHs904SiNa: 409.1811], (+)-74 Dloxanone (+)-74: To a solution of hydroxyacid (4)-78 (2.77 9, 7.12 mmo) in methylene chioride (7 imi) at 0 °C was aded hexamethycisiazane (1.78 mL, 1.1 equiv. The resutant mixture was stived ovemight at @, then concentrated in vacuo. To the bis-TMS compound was added 2,6 di-tbutyhd- imettyleyridine (146 mg, 0.1 equiv) and a solution of aldehyde 58 in methylene chloride (60 ml) via annua. Aller cooling f0 -78 °C, timethylsiyiiate (440 yl, 2.90 mmo) was added. The resultant solulon was sted at-78 °C for 6h, and treated with pyridine (1 mL), then concentrated in vacuo, Flash Chromatography using 10:1 sitcawater, using EtOAc-hexanes (1:9) as eluant, provided ()-74 2.73 9, (66% yield) as a clear oil: [of = +19 (60.50, CHC); IR (CHCl) 3085 (w), 2945 (s), 2890 (m), 2870 (), 1745 (8), 1465 (m), 1450 (), 1380 (mn), 1950 (m), 1840 (my), 1220 (), 1115 (6,980 (6), 700 (0) cor; 1H NMR (600 Miz, CDCI) 87.54 (m, 4H), 7.98 (m, 6 H), 5.76 (8, 1H), 4.20 (ddd, J = 7, 3.8, 3.8 Hz, 1H), 3.85 (ddd, J= 10.1, 10.1, 4.1 Hz, 1 H),3.77 (dda, = 10.0, 5.0, 5.0 Hz, 1 H), 2.65 (dq, J=7.2, 3.9 He, 1 TBE 1H), 1.72 (m 1H), 1.25 (4, J= 7.4, 3H), 1.08 (21 H)t.04 6, 9H; 190 NM (125 MHz, rrtr—~—~—~s—S—~s—S:sizCSsNCsSCSCSCS‘iS ‘i‘O‘SU)UNUUCiCSCsC=CSCiészs 5, 12.0, 11.0; high resolution mass spectrum (C) mz 579.9287 [(M¥H}*; caled for Coats 104Siz: 579.3326). 14 Eat ears J 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III ja0116041 Supporting Info Page 15 om AO he Ties’ To asolution of dioxanone (+)-74 (8.02 g, 6.21 mmol in methylene chloride (60 ml) at ~78 °C was added obutylaluminum hydride (6.69 mL, 1.0 Min methylene chloride, 1.1 equiv). The reaction Imbture was sted al-78 °C for 80 min, and treated with pyridine (1.27 mL, 3 equiv), a solution of 4: dimethylaminopyridine (700 mg, 1.1 equiv) in methylene chloride (2 mL), and acetic anhydride (1.97 mb, 20.91mmol). The reaction mixture was warmed to -15 °C, sted for. h, treated with saturated NHI (50 int) then warmed to over 30 min, Saturated Rochelle’s sa (60 mL) was slowly added, and the solution ‘wes sted or 10 min. The aqueous layer was extracted with methylene chloride (8 x 50 mL), and the organic extracts were washed with cold 5% NaHSO4 (100 mL), NAHCO3 (100 mL), then brine (200 mt), Ged over MgSOs, and concentrated in vacuo. Flash chromatography using 10:1 silca-water, using E1OAc-hexanes (0:1 then 1:6) as eluant, provided the corresponding acetal acetate (2. 559, 77% yield) as 8 clea lt [aiS) = +8.5 (60.58, CHO); IR (CHCl) 2040 (8), 2860 (8), 1755 (6), 1745 (©), 1460 (mm), 1430 (9, 1390 (rm), 1870 (rm), 1950 (8), 1210 (6), 1160 (69,1100 (6), 1080 (6), 990 (6), 670 (en) om 1H NMR (500 MHz, COCIs) 5 7.63 (m, 4 H), 7.38 (m, 6 H), 6.87 (dd, = 2.5, 1.4H2,1H), 6.31 (4d, J= 1.4, 1H), 4.00 (m, 1H), 3.81 (dd, 14.8, 4.5, 1.1 Hz, 1 H), 3.72 (ddd, = 10.4, 6.1, 5.1 Hz,1 H), 2.13 (d, 0.8 Hz, 1 H), 1.89 (m, 1 H), 1.66 (m, 2H), 1.07 (5, 21H), 1.04 (s, 9H), 1.00 (dd, J= 6.8, 1.2 Hz, 3-H); 9¢ NMR (125 MH, CDCIg) 8 168.9, 195.6, 1387, 129.6, 127.7, 100.7, 95.8, 90.1, 86.8, 75.5, 59.7, 95.6, 34.9, 26.9, 21.0, 19.2, 18.5, 11.1, 5.2; high resolution mass spectrum (ES!) nv 646.3387 [(M+Na)*; caled for Ps Boal To. solution ofthe acetate (2.26 g, 3.53 mmol) in methylene chloride (40 ml) at -10 °C was added CapHs40sSigNa: 645.2408], Tes Znle (3:38 G, 10.6 mmo) then trimethytsliykiniophenol (1.34 mL, 2 equiv). The resultant solution was Stied for 10 min and fitered, The fitrale was washed with saturated Ba(OH)e solution (60 ml). The 15 Sea fo 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III ja0116041 Supporting Info Page 16 Saneous layer was extracted with methylene chiovide (50 mL), and the organi solution was washed with brine (30 mL), dried over MgSO4, and concentrated in vacuo. Flash chromatography, using Et,0- hexanes (1:98) as eluant, provided the corresponding phenylthicether (1.74 9, 77% yield) as a pale Yellow oil: [ali = +109 (c0.59, CHCIg); IR (CHCla) 2940 (), 2860 (s), 1460 (m), 1345 (w), 1210 (w), 1110. {S), 990s), 970 (m9), 880), 660 (m) em; H NMI (500 M2, CDCI) 87.67 (m, 4H), 7.48 (m, 2H), 7.39 (6H), 7.26 (m, 3H), 6.14 5, +H), 5:37 (5,1 H), 4.40(m, 1H), 881 (m, 1H), 3.79 (m, 1H), 1.83 (m, 2H), 1.81 (m1), 1.18 (6, J= 7.0 He, 3H), 1.07 (, 30H); 9 NMR (125 MHz, CDC) 8 136.6, 134.7, 133.7, 1917, 1296, 1289, 127.7, 127.2, 102.2, 90.4, 866, 85.3, 72.7, 59:7, 97.0, 35, 3, 26.9, 19.3, 18.6, *90, 1% hgh resouiten mass spectrum (O) mi 686.997 (0 + Nar cal for CeahegOsSSia 696.3084) mes ¢ _ (+)-80 Sutfone (+)-80. To a solution of phenythioether (1.42 9, 1.68 mmo) in methylene chloride eee —s——CS mg, 8 equiv). ‘The resutant solution was sited fr 1.5 h treated with saturated NaySO3 solution (20 mL), and diluted wih water (100 mL) and methylene chiovide (100 mL). The aqueous layer was extracted with methylene chloe (3 x 20 mL}: the organic solution was then washed with saturated NaHCO (100 ml) and brine {100m}, eed over MgSC4, and concenttated i vacuo. Flash chromatography, using Et0Ac-hexanes (1:19 then 1:5) as eluant, provided (+)-80 (1.09 g, 83% yield) as a clear oll, major product: [a2 = +68 (c O54, CHI}: IR (CHCis) 2860 (6), 2880 (3), 1460 (m), 1425 (m), 1955 (n), 1905 (m), 1205 (@), 1130 (6), MOSES) 1010 (mn, 760 (rs), 660), 610 (m) em"; 1H NMR (500 Me, COCK) 8 7.91 (4, Je 8.2 he, 2 H), 7.69 (m, 5H), 7.54 (t, 78Hz, 24), 7.40 (m, 6H), 6.41 (5, 1H), 4.76 (m, 1 H), 4.50 (6, 1 4), 3.78 (m, 2H), 2.66 (dq, 3, 2.7 He, 1H), 1.84 (m, 2H), 1.70 (m, 1 H), 1.21 (d, 1 Hz, 3H),1.07 (s, 9 H) 1.06 (6.214); SC NMR (125 Miz, CDcly) 5197.3, 15.6, 133.9, 1936, 1206, 129.0, 127.7, 127.6, 101.1, 16 EE IEIOSSS'SS'V CES © 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III ja0116041 Supporting Info Page 17 997, 86.2, 87.8, 73, 59.7, 35.2, 288, 26.9, 19.2, 185, 19.1, 11.0; high resolution mass spectrum (ESI) m/z 727.3305 [(M+Na)*; calcd for: ‘CagHsgOsSSizNa: 727.3285]. 2s ey . Za 70 ps: Enol ether 70: To a deoxygenated ~78 °C solution of sufone (+}-80 (947 mg, 0.492 mmo) in THF (4 ml) was added mBuLi (1.5 Min hexane, 261 1, 1.1 equiv), and the resultant solution was stired for 45 imin.Inancther fask, a deoxygenated -78 °C solution of 1,t-chlorotodoethane (865 yL, @ equi) in THF (FL) was treated with -PrMigC! (1.9 M in hexane, 2.33 uL, 9 equiv) over 40 min. This solution was quickly ‘added via cannula tothe ithiated sulfone solution. The resultant mixture was sted at -78 °C for 70 min, ‘and warmed to 10 °C over 30 min, then saturated NaHCO (60 ml) and E1,0 (60 mL) were added. The ‘aqueous layer was extracted with EO (3 x20 mL}, and the organic solution was washed with brine (30 mL), dried over NazSOq, and concentrated in vacue. Fash chromatography using basic AljOs + 10% water, with pentano-E!,0 (1:0 to 70:30) as eluant, provided 70 (2.76 9, 95% yield) es a clear oh. For anatical purposes, flash chromatography using basic AlgO3 + 10% waler and HPr;O-hexane (1:49) as lant aforded tne pure Zisomer: [al = +39.8 (€0.48, CHe); (CHC) 2900 (6), 2805 (6), 1690 , "455 (), 1426 (m), 1360 (m), 1350 (m), 1330 (), 1190 (rm), 1110 (), 985 (8), 880 (mr), 820 (m), 735 (m), 795 (m), 700 () emt; HNMR (500 MHz, COCK) 8 7.76-7.70 (m, 4 H), 7:28-7:21 (m, 6 H), 5.96 (6,4 ), 448 (J= 6.7 He, 1H), 8.92 (dd, J= 8.7, 43,2.7 Hz, 1H), 3.79 (ddd, J= 13.6, 8.5, 5.0 Hz, 1H), 9.64 (C00, J= 106,58, 52 He, 1H), 1.82 (dq, J=7.0, 2.7 He, 1H) 1.79- 1.79 (1H), 161 (0, Je 67 He, 3 W182- 145 (1H), 1.12 (6, 9H), 1.11 1.09 (m, 21 H), 1.07 (4, J= 7.0 He, 8 Hy; SC NMR (125 MHz, COCK) 5153.9, 194.8, 199.0, 129.0, 127.1, 102.8, 102.2, 91.5, 85.5, 75.9, 593, 36.9, 344, 26.1, 184, 17.7, 126, 10.4, 8.7; high resolution mass spectrum (ESI) mz 591.9669 [(MsH)*: caled for Caghs503Siz: 591.3690}. 17 SE fe eee Eo J 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III ja0116041 Supporting Info Page 18 Ersomer: lal) = 48.9 (00.54, Cota); IR (CHCIg) 2940 (8), 2860 (6), 1685 (w), 1455 (m), 1425 (m), 1360 (im), 1845 (em), 1190 (m), 1110 (8), 1000 (r), 880 (m), 815 (mm), 790 (m), 680 (rm) cmt; 1H NMR (500 MHz, CDCl) 87.76: 7.72 (m, 4 H), 7.29 -7.29 (m, 6H), 5.98 (5,1 H), 8.11 (q, = 7.1 Hz, 1 H), 3.87 (ddd, J= 8.3, 3.9, 2.6 Hz, 1H), 3.79 (dda, 5.0.4.9, 4.9 Hz, 1 H), 9.68 (ddd, J= 10.6, 5.6, 5.0 Hz, 1 H), 2.28 (dq, J= 7.0, 2.6 Hz, 1H) 1.72- 88 (1H), 1.59 1.48 (m, 1H) 1.28 (0, J= 7.1 He, 3H), 1.14 (6, 9H), 1.11 - 109 (m, 21 H), 1.08 (6, J= 7.0 Hz, 3H); 19C NMA (125 Miz, COCK) § 154.1, 194.9, 183.1, 129.0, 127.1, 102.7, 102.2, $2.0, 854, 76.9, 59.5, 34.4, 31.5, 26.1, 184, 17.7, 11.1, 104, 9:1; high resolution mass Spectrum (ESI) m/z 591.9669 [(MsH)+; caled for OggHss0aSip: 591.9690), (74 Pyranone (+)-71: To a solution of enol ether 70 (274 mg, 0.469 mmc) in methylene chloride (10 muy S1778°0 was added MeaAICI (1.0M in hexane, 500 iL, 1.1 equiv). The resultant solution was sired for 10 min, placed in a water bath, stired for 3 min, and treated with triethylamine (1 mL) and saturated NaHCOg (20 mL), and diuted with methylene chloride. The aqueous layer was extracted with methylene hlorde (8 x 20 mL), and the organie solution was washed with brine (60 ml), died over MgSOq, and Concentrated in vacuo, Flash chromatography, using EtOAchexanes (1:18) as eluant, provided wrt (249 ma, 91% yield) as a clear cit (a4? = +90 (60.76, CHOk); Ft (CHC) 9080 (w), 2070 (9), 2985 (s), 7900 (m), 2675 (8), 2190), 1745 (3), 1465 (m), 1440 (m, 4960 (m), 1345 (mn), 1118 (6), 1098 (), 1085 (9), 1068 (8, 700 (s) om 1H NM (500 MHz, CDCl) 8 7.69 (m, 4 H), 7.96 (m, 6H), 3.85 (4, J= 10.8 He, 1H), 3.83 (m, 2H), 3.74 (m, 1H), 2.70 (da, = 10.8, 6.7 Hz, 1H), 2.98 (dq, = 7.2, 2.4 Hz, 1H), 1.91 (mm, 1 H), 1.62 (mm, 1H), 1.13 (4, J=7.2 He, 3H),1.11 (4, 6.7 Hz, 3 H), 1.08 (8, 21 H) 1.02 (s, 9-H); 19 NMR (125 Miz, COCs) § 207.5, 134.9, 199.2, 129.0, 104.9, 86.0, 78.9, 75.3, 7365, 59, 6, 49.6, 48.9, 48.3, 457, 26.2, 282, 26.1, 184, 17.8, 10.5, 9.8, 9.1; high resolution mass spectrum (Cl) mz 591,367 [(Ms+H)*; calcd for CasHs5O3Si: 591.3690), 18 © 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III ja0116041 Supporting Info Page 19 OnPS “on Tes To a solution of pyranone (+)-71 (246 mg, 0.417 mmol) in ethanol (5 mL) at -10 °C was added NaBHs (32 mg, 2 equiv). After 30 min, the reaction mixture was treated with saturated NH,Cl (10 mL) then saturated NaHCOg solution (40 mL) and then diluted with methylene chloride (40 mL). The aqueous layer was extracted with methylene chloride (3 x 20 mL), and the organic solution was dried over MgSOx, and concentrated in vacuo. Flash chromatography, using EtOAc-hexanes (1:9) as eluant, provided the corresponding alcohol (225 mg, 91% yield) as a clear oil: [a}@9 = +40 (c 1.08, CHCl); IR (CHCla) 3610 (w), £2950 (s), 2875 (s), 1465 (rm), 1430 (m), 1390 (er), 1110 (s), 1090 (s), 1065 (s), 1020 (s), 880 (m), 820 (m), 695 (s); 'H NMA (500 MHz, CDCl) 8 7.68 - 7.62 (m, 4 H), 7.38 - 7.31 (m, 6 H), 3.84 - 3.78 (m, 1H), 3.72 - 3.69 (m, 1H), 3.61 - 3.58 (m, 1 h), 3.38 - 3.32 (m, 1 H), 1.88 (dq, 1H), 1.80 - 1.76 (m, 1H), 1.74 - 1.66 (m1 HY, 1.65 - 1.60 (m, 1 H), 1.45 (d, J= 4.6 Hz, 1 H), 1.08 (4, J= 6.6 Hz, 3), 1.07 (6, 21 H), 1.08 (6, 9H), 0.88 (6, J=6.9 Hz, 3H); 19C NMR (125 MHz, CDCl) § 135.5, 134.0, 129.6, 127.7, 105.7, 85.7, 76.6, 75.5, 73.4, 60.4, 38.7, 38.5, 35.6, 29.7, 26.9, 19.3, 18.6, 13.8, 11.2, 5.7; high resolution mass spectrum (Ci) m/z 593.3858 [(M+H)*; caled for CagHs70gSiz: 59,3846). Son 8S (+87 To.a solution ofthe alcoho (120 mg, 0.219 mmol in THE (10 mL) at 0 0 was added KH (26 mg, 8 equiv), and DMB-CI (163 mg, 4 equ). The reaction mixture was sited 90 min and poured into brine (40 mL). The reaction mixture was then extracted with EtOAc (3 x 40 mL); the combined extracts were dried over MgS04 and concentrated in vacuo, Fash chromatography, using EtOAchexanes (1:12) as eluant, g2v6 (+-87 (161 ma, 99% yield) asa colorless ot: fal +40.1(¢0.75, CHC): IR (CHC) 2000 (@), 2080 (6), 2880 (w), 1590 (w), 1460 (w), 1280 (s) cmt; 1H NMR (500 MHz, CDCIg) 8 7.65 (m, 4 H), 7.39 (m, 6 H), 19 © 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III ja0116041 Supporting Info Page 20 6.90 (4, J=1.6 Hz, 1H), 6.85 (4d, J= 8.2, 1.5 Hz, 1H), 6.81 (4, J= 8.1 Hz, 11H), 4.54 (0, J= 11.2 Hz, 1H), 4.26 (d, J= 11.2, 1 H), 3.86 (5, 3H), 3.86 (s, 3H), 9.88 (mm, 1 H), 9.74 (ddd, J= 15.5, 10.4, 5.3 Hz, 1H), 8.64 (d, J= 10.5 Hz, 1 H), 3.55 (ddd, J= 6.4, 4.6, 2.9 Hz, 1 H), 3.09 (dd, J= 10.5, 4.6 Hz, 1H), 2.04 (mm, 1 H), 1.91 (m, 1H), 1.81 (1m, 1 H), 1.66 (m, 1 H), 1.05 (m, 2H), 0.92 (¢, J= 6.9 Hz, 3H); "SC NMR (125 MHz, CDCk) § 149.1, 148.7, 135.5, 134.0, 193.9, 191.1, 129.6, 127.7, 120.2, 111.2, 111.0, 105.9, 85.6, 82.9, 75.4, 73.7, 69.8, 60.6, 55.9, 55.8, 37.3, 35.7, 34.3, 29.9, 19.3, 18.6, 14.3, 11.2, 6.0; high resolution mass spectrum (Cl, NHg) m/z 765.4845 [(M+Na)*; caled for C4sHegOsSioNa: 765.4347], dove Toa solution of protected pyran (+)-87 (160 mg, 0.215 mmol) in THF (4.3 mL, 0.05 M) was added ‘TBAF (0.861 mL, 1.0 Min THF, 4 equiv); the reaction mixture was stitred 90 min and poured into brine (25 mL). The solution was extracted with EtOAc (@ x 25 mL), and the combined extracts were dried over MgSOq, and concentrated in vacuo. Flash chromatography, using EtOAc-hexanes (1:3 then 3:1) as eluant, gave the primary alcohol (74 mg, 99% yield) as an oil: [a] +62.9 (c 0.95, CHClg); IR (CHClg) 3400 (w), 3290 (w}, 2800 (s), 1510 (wv), 1460 (w), 1110 (s) cmt; 1H NMR (600 MHz, CDCl) 5 6.90 (d, J= 1.9 Hz, 1H), 6.86 (dd, J= 8.1 Hz, 1 H), 6.82 (4, J 3.1 Hz, 1H), 4.57 (4, 1.4 Hz, 1 H), 4.30 (4, 11.4, 1H), 3.88 (8, 3H), 9.87 (s, 3H), 3.78 (m, 2H), 3.73 (dd, J= 10.7, 2.1 Hz, 1H), 3.68 (dt, 5, 2.9 Hz, 1H), 3.13 (dd, '= 10.5, 4.6 Hz, 1H), 2.03 (m, 2 H), 1.89 (ddd, J= 10.5, 6.5, 4.1 Hz, 1 H), 1.55 (m, 2H), 1.05 (4, J= 65 Hz, 3H), 0.95 (4, =7.0 Hz, 3H); 19C NMA (125 MHz, CDCl) 8149.1, 148.7, 130.9, 120.2, 111.2, 111.0, 82.3, 81.6, 78.1, 73.4, 73.0, 69.9, 60.9, 56.0, 55.9, 36.8, 35.4, 34.8, 13.9, 6.0; high resolution mass spectrum (Cl, NH3) r7vz 371.1826 [(M+Na)*; caled for CaoHagOsNa: 371.1839] 20 EISSN er © 2001 American Chemical Society, J. Am. Chem. Soc., Smith,{II ja0116041 Supporting Info Page 21 Soot dae” Toa solution ofthe primary aleohol (62 mg, 0.178 mmol in DMF (1.8 mL) was added triethylamine (0.30 mi, excess), and tbutyidiphenyisiyichloride (0.138 mL, 3 equiv), the reaction mixture was stirred 2 hand poured into water (25 mL). The aqueous solution was extracted with E1,0 (8 x 25 mL), and the combined organic extracts were died over MgSO, and concentrated in vacuo. Flash chromatography, using EtOAc-hexanes (1:3) as eluant, gave the primary BPS ether (87 mg, 98% yield) as an oil: [ay22 #473 (C1.0, CHC\g); IR (CHCl) 2910 (8), 1250 (s) cmt; 1H NMR (600 MHz, CDC's) 5 7.64 (m, 4H), 7.40 (6H), 6.91 (4, = 1.6 He, 1H), 887 (dd, J= 82, 1.6 Hz, 1H), 6.89 (4, J=8.1 He, 1H), 457 d= 11.3 H2,1H), 429 (d, J= 11.3, 1H), 3.88 (6, 6H), 9.84 (m, 1H), 3.77 (m, 1H), 2.64 (4d, J= 10.8, 2.1 He, 1 4), 3.62 (m, 1H), 3.12 (dd, +1 Hz, 1H), 2.47 (4, J= 2.4 Hz, 1 H),2.07 (m, 4 H), 1.89 (m, 2H), 1.68 (ddd, J = 198, 0.1, 52Hz, 1H), 1.06 (d, J= 8.6 Hz, 9H), 1.05 (6, 9H), 0.99 (4, J= 6.9 Hz, 3H); 48C NMA (125 MHz, CDCl) § 149.1, 148.7, 195.5, 198.9, 191.1, 129.6, 127.7, 120.2, 111.2, 111.0, 82.8, 82.0, 75 7, 72°, 698, 60.5, 55.9, 5.8, 36.9, 35.8, 34.4, 26.8, 19.8, 13.9, 5.9; high resolution mass spectrum (cl, 'NHg) m/z 609.3022 [(M+Na)*; caled for CagHs OsSiNa: 609.3012], Moss J Pn, PS (+)-88 To assolution of hexamethyltin (0.90 mL) in THE was added methyl lithium (0.107 mb, 1.4 M FLO. 2 equiv) and the reaction mixture was stirred at -78 “C for 30 min, then added via cannula to copper ‘vanide (75 mg, excess) in THF (0.5 mL) at 0 °C, stired for 10 min and cooled to -78 °C. The BPS ether. atime (22 mg, 0.098 mmol) in THE (1.5 mL) was added vie cannul,stived 48 min and iodomethane (0.20 ints excess) was added, Alter 45 min, DMPU (0.20 mL) was added, the reaction was allowed to war tor and sted for 16h. The reaction mixture was then poured into saturated NH,CI (40 ml) and extracted with at Sere eee © 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III ja0116041 Supporting Info Page 2: EtOAc (3 x 40 mL). The combined extracts ‘were dried over MgSO4 and concentrated in vacuo. Flash chromatography, using EtOAc-hexanes-triethylamine (10:90:1) as eluant, gave (+)-88 (23 mg, 80% yield) 8 an oll with recovered starting material (6 mg): (al? +48.6 (¢ 1.15, CoH): IR (CCU) 2940 (6), 1510 (s), 1110 (8), 650 (8) emt; 1H NMR (500 Miz, CgDg) 5 7.87 (m, 4H), 7.34 (m, 6 H), 7.08 (4, = 1.9 Hz, 1H), 7.01 (dd, N18 He, 1H), 6.77 (4, J= 8.1 He, 1H), 5.88 (, 1 H), 4.89 (4, J= 11.5 Hz, 1H), 4.31 (4, Je 11.4 Hz, 1H), 4.02 (dad, = 10.0, 8, 4.9 Hz, 1H), 3.91 (m, 1 H), 3.60 (s, 3H), 3.57 (d, J= 10.2 He, 4 H), 3.54 (s, 3H), 3.26 (ad, = 10.3, 4.6 Hz, 1H), 2.12 (m, 1 H), 2.02 (m, 2H), 1.94 (s, 3H), 1.82 (m, 1H), 1.28 GOH, 119 6, J=68 He, 9H, 1.09 (4, J=64 He, 3H, 025 (6,0 Hy 180 BUR (125 Me, C505) 515541, 1604, 149.9, 1980, 1944, 1822, 1299, 1275, 1202, 1125, 1124, 01.2, 899, 752, 69.9, 814,658, 557,866, 85.1, 937, 27.2, 195, 180 14.2 6.6, 067. -9.0; high resolution mass spectum (Cl, NH) m/z 769.2976 [(M+Na)*; caled for C4gHsgOsSiSnNa: 789.2973}. Toa solution of siyt ether (+)-88 (44 mg, 0.058 mmo) in THF (1.6 mL) was added TBAF (0.115 mls 10M in THF, 2 equiv). The reaction mixture was stired 2h, poured into brine (25 mL), and extracted wih E1OAo (3 x 25 mL). The organic layer was dried over MgSOy, and concentrated in vacuo, Flash chromatography, using EtOAc-hexanes-trethylamine (25: 1) as eluant, gave the primary alcohol (30 179, 100% yield) as anol: fal} +75.5 (0.65, CH); (CCl) 3510 (4), 2950 (6), 1510 (w), 1270 (6), 1030 (8) or HNMR (600 MHz, C0) 87.07 (, v -9 Hz, 1H), 6.90 (dd, J= 8.1, 1.9 Hz, 1H), 6.76 (d, J= 8.1 Hz, 1H), 5.87 (6, 1H), 4.62 (, 11.5 Hz, 1H), 4.31 (4, J= 11.5 Hz, 1H), 3.73 (m, 2H), 3.60 (6, 3 H), 3.57 (m, 1H), 8.526, 9H), 3.50 (4, J= 10.4 Hz, 1H), 9.16 (dd, J= 10.4, 4.6 He, 1H), 1.98 (m3), 1.91 (83H), 1.42 (m, 1H), 1.17 (4, J= 6.9 Hz, 3H), 1.06 (4, J=6.5 Hz, 3H), 0.22 (s, 9-H); 18C NMR (125 MHz, CeDg) 5152.6, 180.4, 149.9, 192.0, 120.2, 112.4, 112.8, 91.1, 88.3, 777, 69.8, 61.2, 55.7, 35.8, 22 © 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III ja0116041 Supporting Info Page 23 95.2, 99.5, 18.9, 15.0, 8.0, -8.1; high resolution mass spectrum (Cl, NH) 551.1788 [(M+Na)*; calod for CagH4oOsSnNa: $51.1795} (+)-89 Toa solution of the primary alcohol (13 mg, 0.025 mmol) in DMSO (1 mL) was added triethytamine (0.05 mL, excess) and sulfur trioxide pyridine complex (12 mg, 3 equiv), the reaction mixture was stirred {or 1h and poured into water (20 mL). The reaction mixture was then extracted with EL,O (8 x 25 mL), and {he combined extracts were driad over MgSOg and concentrated in vacuo. Fiash chromatography, using tOAcrhexanes-trethyiamine (16:45:1) as eluant, gave ()-89 (12 mg, 82% yield) as anol. [of%? +66.7 (0 0.60, CoH): FR (CC) 2950 (6), 1725 (6), 1518 (w), 1090 (6), 670 (8) cm, 1H NMR (500 MHz, Cog) 8 952 (t. J= 1.8 Hz, 1 H), 7.06 (4, J= 1.9 Hz, 1H), 7.00 (dd, J=8.1, 1.9 Hz, 1 H), 6.76 (d, J= 8.0 Hz, 1H), 5.86 (s, 1H), 4.59 (4, J 1.5Hz, 1H), 3.79 (ddd, = 8.5, 6.7, 2.0 Hz, 1H), 3.61 (6, 3H), 3.52 (¢, 3H), 3.46 (s, 3H), 3.46 (d, 10.3 Hz, 1H), 9.14 (dd, = 10.4, 4.6 Hz, 1H), 2.51 (ddd, 167, 8.6, 1.9 Hz, 1 H), 2.01 (ddd, J= 18.7, 4.7, 1.8 Hz, 1H), 1.82 (m, 2H), 1.90 (6, 3H), 0.96 (4, J= 6.5 Hz, 3H), 0.95 (J= 6.9 He, 3H), 0.23 (s, 8 Hy; 19C NMR (125 MHz, CeDg) 8 199.5, 152.3, 150.4, 149.9, 181.9, 120.3, 112.4, 112.8, 91.0, 82.9, 73.4, 68.9, 55.7, $5.7, 47.0, 83.4, 33.3, $1.9, 18.9, 14.1, 6.3, -9.3; high resolution ‘mass spectrum (Cl, NHg) m/z 549.1629 [(M+Na)*; caled for Ca¢HagOsSnNa: 549,162} pres bors © 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III ja0116041 Supporting Info Page 24 Alkene (+)-90a: To a solution of phosphonium salt (-)-12 (44 mg, 0.048 mmol) in DMF (4 mL) was ‘added lithium hexamethyldsiazane (0.108 mL, 0.5 Min THF, 1.1 equiv) at 0 %C and stived 80 min. The feaction mixture was cooled to -20 °C and the aldehyde (25 mg, 1.1 equiv) in DMF (1 mL) was added via cannula. The reaction was stirred for 45 min, and poured into water (25 mL). The aqueous solution was extracted with EtOAc (8 x 25 mL); the combined extracts were dried over MgSOq and concentrated in vacuo. Flash chromatography, using EtOAc-hexanes-trithylamine (10:90:1) as eluant, gave (+)-90a (52 Mg, 95%, 20:1 or: [a}®P +98. (c 1.0, Cyt: IR (CCl) 8010 (6), 2950 (6), 1475 (6), 1110 (), 1080 (6), 670 (s) emt; 1H NMR (500 MHz, CgDg) 6 7.89 (m, 4 H), 7.38 (6, 1 H), 7.95 (m, 6 H), 7.04 (d, Je 1.7 He, 4 H), 6.98 (a9, J= 8.1, 1.7 Hz, 1H), 685 (de, J= 16.1, 86, 6:7 He, 1H), 675 (4, J= 16.1 Hz, 1 H), 5.87 (6, 1H), 5.21 (4, J= 11.3 Hz, 1H), 4.82 (s, 1H), 4.80 (s, 1 Hy, 4.56 (d, J= 11.5 Hz, 1H), 4.30 (m, 1 H), 4.24 (1H), 4.24 (4, J= 11.5 Hz, 1H), 4.18 (m, 1H), 4.12 (m, 1H), 3.98 (ddd, J= 13.6, 10.3, 7.0 Hz, 1H), 3.87 (ddd, 11.9, 10.8, 6.4 Hz, 1H), 3.60 (8, 3H), 3.69 (s, 9 H), 8.47 (d, J= 10.1 Hz, 1 H), 3.38 (mm, 1H), 8.11 (dd, J= 10.3, 4.6 Hz, 1H), 2.53 (m, 1H), 2.41 (dd, J= 18.4, 4.4 Hz, 1H), 2.28 (dd, J= 13.1, 4.0 Hz, 4 H), 2.22 (m, 2H), 2.18 (m, 2H), 2.02 (m, 4 H), 1.94 (5, 3H), 1.86 (m, 1 H), 1.78 (m, 1), 1.74 (m, 1H), 1.51 (m, 1H), 1.27 (8, 9H), 1.12 (4, 6.8 Hz, 3H), 0.98 (d, J= 6.5 Hz, 3 H), 0.96 (s, 9H), 0.12 (5, 9H), 0.04 (s, 3H), 0.03 (s, 3H); 19C NMR (125 MHz, C_Dg) 8161.0, 152.7, 160.4, 149.8, 144.7, 142.9, 196.0, 196.0, 195.6, 194.4, 194.4, 1940, 132.0, 129.1, 128.7, 120.2, 119.1, 1124, 112.3, 104, 91.1, 835, 83.4, 7786, 69.8, 69:3, 9.0, 68.7, 65.4, 61.1, 55.7, 85.7, 40.2, 2.8, 99.6, 395, 99.2, 37.1, 96.6, 24.2, 83.6, 27.2, 26.1, 19.5, 19.0, 18.3, 14.3, 6.0, -4.8, -9.0; high resolution mass spectrum (Cl, NHa) m/z 120.5428 [(M+Na)*; caled for CeqHgsOgNSipSnNa: 120.5465]. ePso NN To a solution of (+)-91 (15.2 g, 42.9 mmol) and 2,6-ditert-butyi-4-methylpyridi (127 g, 1.4 equiv) in methylene chloride (41 mL) was added methyl triflate (6.53 mL, 1.95 equiv). After 3 d, the Feaction mixture was diluted with EtzO (100 mL), fillered and concentrated in vacuo . Flash Chromatography, using EtOAc-hexanes (0:1 then 1:19) as eluant, afforded the secondary methyl ether 24 © 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III ja0116041 Supporting Info Page 25 (13.32 9, 84 % yield) as a clear olt: [0] -12.6 (¢ 1.38, CHa) IR (CHCl) 3060 (mm), 2890 (m), 2910 6). £2840 (8), 1460 (m), 1420 (m), 1100 (s, br), 990 (m), 910 (r) en; 1H NMA (600 Miz, CDCI) 8 7.67-7.64 (1m, 4), 7.39-7.31 (m, 6H), 5:80-5:70 (m, 1H), 5.05 (dd, J= 86, 1.9 Hz, 1H), 5.03 (dd, J= 1.2, 1.2 He, 1 H), 3.79 (dda, = 10.2, 7.2, 6.1 Hz, 1H), 3.72 (ddd, = 11.2, 5.8, 5.8 Hz, 1H), 3.46 (m, 1H), 3.30 (s, 3 ‘Hy, 2.25:2.20 (m, 2H), 1.71 (m, 2H), 1.04 (, 9H): 196 NMR (125 Miz, COOL) 8 135.6, 1348, 1340, 120.5, 127.6, 116.9, 60.5, 56.6, 37.9, 36.6, 27.0, 19.2; high resolution mass spectrum m/z 369.2257 IM*; caled for CagHs202Si: 369.2249]. Anal. Caled for CagHg202Si: C, 74.95; H, 8.75. Found: ©, 75. 25; H, 9.03, BPso (-)-92 AA solution of the secondary methyl ether (473 mg, 1.28 mmol) in methylene chloride (5 mL) was Cooled to -78 °C and a stream of ozone was bubbled through the solution until faint blue color persisted, ‘The mixture was treated with trionenyl phosphine (393 mg, 1.2 equiv) at -78 °C, and allowed to warn to rt ‘overnight, then concentrated in vacuo. Flash chromatography, using E1OAc-hexanes (1:7) as eluant, Provided (-)-82 (458.0 mg, 96% yield) as a colorless oll. {aff -2.9 (01.76, CHO); IR (CHC) 3060 (m), 2990 (m), 2920 (8), 2840 (s), 1716 (8), 1460 (m), 1420 (m), 1100 (8, be) crt; TH NMR (500 MHz, CDCI) & 9.78 (t, J= 2.3 Hz, 1H), 7.69-7.64 (m, 4H), 7.41-7.32 (m, 6 H), 3.95 (app g, 7 He, 1 H), 3.80 (ddd, J= 10.8, 7.4, 5.2 Hz, 1H), 3.72 (ddd, = 8.6, 5.6, 5.6 Hz, 1H), 9.92 (s, 3 H), 2.58-2.50 (m, 2 H), 1.86 (ddd, J= 144, 8.6, 5:6 Ha, 1 H), 1.76-1.70 (m, 1H), 1.06 (s, 9 H); 190 NMR (125 MHz, CDC4) 8 201.4, 135.5, 193.6, 129.7, 127-7, 73.6, 60.1, 56.9, 48.2, 36.7, 26.9, 19.2; high resolution mass spectrum m/z 988.2900 [M+NHg*; caled for CaoHaaNOgSi: 388.2908). Anal, Caled for CozHg9036i: C, 71.31; H, 8.16 oe (-)-94b TMS-Enyne (-)-94b. To a suspension of (3-trimethylsily-2-propynyi)-triphenylphosphonium bromide (6.00 g, 26 equiv, dried by stripping trom toluene) in 80 mL of THF was added at -78 “© n-butyl ithium 25 © 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III ja0116041 Supporting Info Page 26 (2.5 Min hexanes, 4.4 mL, 2.6 equiv). The dark red mixture was stirred for 1 h at - 78 °C, warmed for 30 min to - 30 °C, and recooted to - 78 °C, at which time a solution of aldehyde (-)-92 (1.58 g, 4.26 mmol) in 5 mL of THF was added via cannula. The reaction was kept for 1 h at - 78 °C before warming to rt over 3 h. The reaction was quenched with saturated NHCl (25 mL) and water (150 ml), then diluted with E120 (150 mL). The aqueous phase was extracted with EtzO (2 x 100 mL); the combined organic layers were dried over MgSOq, and concentrated in vacuo. Flash chromatography, using EtOAc-hexanes (1:7) as eluant, afforded (-)-94b (1.910 g, 96.5 % yield) a5 a slighty yellow oll. E Isomer: fal® -20.2 (c 0.64, CHK); {CHCI) 3680 (1), 3510 (w), 3010 (s), 2895 (I), 1515 (m), 1480 (em, 1420 (m), 1290 (6), 925 (m, br), 720 (6, br), 670 (s, br) ont; 'H NMIR (500 MHz, CDCI) 6 7.69-7.65 (m, 4 H), 7.45-7.35 (rn, 6 H), 6.20 (dt, J= 16.0, 7.3 Hz, 1H), 5.55 (dt, = 16.0, 1.5 Hz, 1H), 3.82-3.76 (m, 1 H), 3.73-3.66 (m, 1H), 3.50-3.43 (m, 1H), 8.31 (5, 3H), 2.32-2.22 (m, 2H), 1.72-1.65 (m, 2H), 1.05 (s, 9 H), 0.2 (s, 9H); 13C NMR (125 MHz, CDCk) 5 141.7, 195.5, 133.8, 129.5, 127.6, 112.0, 103.9, 98.0, 76.9, 60.3, 56.7, 37.1, 367, 26.9, 19.2, 0.0; high resolution, mass spectrum m/z 465.2626 [(M+H)*; caled for Cagh41OzSip: 465.2645). Anal, Caled for CagH4qOzSiz: C, 72.96; H, 8.67. Found: C, 71.99; H, 8.72. OM e290 AF To a solution of the TMS enyne (3.60 g, 7.74 mmol) in methanol (10 mL) was added KzCO3 (100 ‘mg, 0.1 equiv). Alter stirring overnight, the mixture was diluted with water (50 mL) and Et,O (60 mL). The aqueous layer was extracted with E1,0 (2 x 50 mL). The combined organic layers were dried over MgSO4, and concentrated in vacuo. Flash chromatography, using E1,O-hexanes (1:7) as eluant, afforded the terminal enyne (2.91 g, 96 % yield) as a clear oil: (a}f} -20.2 (0.47, CHClg); IR (CHClg) $300 (m), 3010 (), 2930 (s), 2860 (m), 2090 (w, br), 1590 (m), 1470 (m), 1425 (m), 1205 (s, br), 1105, {8, br), 720 (s, br) emt; 4H NMR (500 MHz, CDCIg) 8 7.68-7.62 (m, 4H), 7.41-7.32 (m, 6 H), 6.20 (dt, J = 16.0 Hz, J= 7.3 Hz, 1H), 5.55 (ddl, J= 16.0 Hz, = 2.1 Hz, J= 1.5 Hz, 1H), 3.82-3.74 (m, 1 H), 8.72-3.66 (m, 1H), 8.50 (dd, J= 5.6, 5.6 Hz, 1H), 3.31 (6, 3H), 2.81 (4, J= 2.1 Hz, 1H), 2.96-2.22 (m, 2H), 1.72+1.63 (m, 2 H), 1.08 (6, 9 H): "3 NMR (125 MHz, CDCl) 6 142.5, 135.6, 184.8, 129.6, 127.6, 110.8, 82.3, 77.0, 76.0, 60.3, 56.8, 26 © 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III ja0116041 Supporting Info Page 27 37.2, 96.7, 26.9, 19. ; high resolution mass spectrum mvz 393.2257 [(M+H)t; caled for CosHsg02Si 393.2250]. Anal. Caled for CosHa202Si: C, 76.48; H, 8.22. Found: C, 76.54; H, 8.24. Mea, : epso_/ OH To a well-stired solution of AD-mix 8 (10 g) in 1:1 water-BuOH (70 mL) at 0 °C was added ‘methanesulfonamide (400 mg, 1 equiv) and the terminal enyne (1.29 g, 3.89 mmol) in one portion. After 72h stiring at 0 °C, sodium sulfite (10 g) was added, and the reaction mixture stirred for 1h. The mixture was then diluted with water (75 mL) and extracted with EtOAc (8x 160 mL). The combined organic layers ‘were washed with brine (15 mL), dried over MgSO, and concentrated in vacuo. Flash chromatography, Using EtOAc-hexanes (1:4 then 3:7) as eluant, afforded the enyne-diol (1.209 9, 73 % yield) as a slightly yellow oil. IR (CHCl) 3560 (rn, br), 2420 (m, br), 3905 (s), 3005 (s), 2930 (s), 2860 (6), 2890 (w, br), 1730 (w, br), 1465 (om), 1430 (rm), 1985 (m), 1265 (s), 1205 (s, br), 1110 (6, bx), 700 (s, br) emt; 1H NMR (500 MHz, CDCig) 67.65 (m, 4 H), 7.40 (m, 6 H), 4.18 (dd, |. 2.1 Hz, 1H), 3.90 (ddd, J: 1, 6.1, 3.0 Hz, 1H), 3.75 (mm, 3H), 9.44 (brs, 1 H), 3.34 (5, 3H), 2.95 (brs, 1H), 2.44 (d, J= 1 Hz, 1H), 1.95-1.65 (series of m, 4H), 1.07 (s, 9 H); 18 NMR (125 MHz, CDCIg) 5 135.5, 183.7, 129.6, 127.6, 82.2, 76.1, 74.2, 71. 66.1, 60.3, 56.8, 36.0, 35.5, 26.8, 19.1; high resolution mass spectrum m/z 427.2287 [(M+H)*; calod for CogHasO4Si: 427.2804), Anal. Caled for CagHs404S: C, 70.38; H, 8.03. Found: C, 70.1 8.34, Meo, BPs To stirred solution of the diol (1.431 g, 3.35 mmol) in methylene chloride (10 mL) was added 2,2- dimethoxypropane (1.04 g, 3 equiv) and pTSA (catalytic amount). After 2 h, 75 mL of saturated NaHCO Solution was added and the mixture was extracted with EtOAc (8x 100 mL). The combined organic layers were washed once with 15 ml of brine, dried over MgSOx, and concentrated in vacuo, Flash a7 © 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III ja0116041 Supporting Info Page 28 chromatography, using pentane-Et,0 (9:1) as eluant, alforded acetonide (1.217 g, 78 % yield) as a clear olka +7.7 (¢1.575, CHCig); IR (CHCIg) 3670 (w, bx), 3800 (), 3005 (8), 2990 (3), 2855 (6), 2990 (w), 1470 (tm), 1425 (m), 1380 (m), 1205 (s, by), 1105 (s, br), 695 (s, be) cmt; TH NMR (500 MHz, COCK) & 7.68-7.62 (m, 4 H), 7.43-7.37 (m, 6 H), 4.25 (dd, J= 7.5, 2.0 Hz, 1H), 4.19 (ddd, J= 7.8, 7.7, 4.2 He, 1H), 8.71-8.60 (m, 2H), 3.60-3.56 (m, 1 H), 3.93 (s, 3H), 2.48 (4, J= 2.1 Hz, 1H), 1.90-1.70 (series of m, 4 H), 1.45 (6, SH), 1.38 (6, 3 H), 1.07 (s, 9H); 19C NMR (125 MHz, CDClg) 8 195.6, 133.8, 129.6, 127.6, 109.9, 80.8, 79.0, 75.3, 74.4, 70.6, 60.3, $7.0, 37.9, 37.0, 27.2, 26.9, 26.1, 19.2; high resolution mass spectrum m/z 487.2617 [(M+H)*; caled for C2gHaq04Si: 467.2618]. Anal. Caled for CasHsg04Si: C, ll Meo, epsa_J 6. (+)-95 72.06; H, 8.21. Found: C, 71.93; H, 8.49, To a.solution of acetonide (2.80 , 6.00 mmol) in THF (35 mL) at -78 °C was added dropwise f- butylthium (1.7M in pentane, 3.68 mL, 1.03 equiv) until a yellow color persisted. After 30 min, methyl lodide (1.87 mL, 5 equiv) was added, the mixture was kept at - 78 °C for another 60 min, and then allowed {0 reach overnight. Saturated NHC! (50 mL) and water (150 mL) were added and the mixture was extracted with E1,0 (8.x 100 mL). The combined organic layers were dried over MgSOq and concentrated in vacuo. The product was converted into the subsequent alcohol without further purification. For anaiytical purposes, flash chromatography, using E1,O-hexanes (1:9) as eluant, afforded (+)-95 as a clear Olt fo} +104 (61.28, CHOI); IR (CHC's) 3670 (w, br), $800 (rm), 3000 (6), 2920 (6), 2850 (s), 2900 (m), 1516 (=), 1470 (m), 1420 (rn), 1200 (s, br), 1105 (6, br), 720 (6, br) cmv; 1H NMR (500 MHz, CDCI) 8 7-68-7.62 (m, 4 H), 7.43-7.34 (m, 6H), 4.18 (da, J=7.9, 2.0 Hz, 1H), 4.10 (ddd, J= 8.6, 8.0, 3.6 Hz, 1H), 3.81-3.74 (rm, 2 H), 3.65-3.60 (m, 1 H), 3.34 (5, 3H), 1.84 (4, J=2.0 Hz, 3H), 1.85-1.65 (series of m, 4 H), 1.48 (S, 3H), 1.39 (6, 3H), 1.06 (s, 9H); '9C NMR (125 MHz, CDCl) 8 135.6, 133.9, 129.6, 127.6, 109.2, 28 e ae a : © 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III ja0116041 Supporting Info Page 29 82.9, 787, 75.6, 75.3, 71.2, 60.4, 57.1, 97.6, 37.1, 27.2, 26.9, 264, 19.2, 8.7; high resolution mass spectrum m/z 481.2774 [(MsH}*; caled for CagH¢1O4Si: 481.2774]. Anal. Caled for CogHaaO4Si: C, 72.46; H, 8.39. Found: C, 72.48; H, 8.43. ‘To a solution of acetonide (4)-95 (6.0 mmol in THF (60 mL) was added TBAF (1 Min THF, 12 mL, 2 equiv) and the reaction was stired al for t/h, Water (200 mL) and methylene chloride (200 mi) were added, and the aqueous phase was extacted win methylene chloride (@ x 100 mL). The combined organic layers were cried over MgSO, and concentrated in vacuo. Flash chromatography, using EIOAC- hexanes (2:3 then 4:1) as eluant, afforded the primary alcohol (1.46 g, 100 % yield over 2 steps) as a clear ol: fa +43 (c1.19, CHC) IR (CHCIg) 9860 (w, bx), 3610 (w, br, 9480 (m, br, 3005 (8), 2895 (6), 2930 (6), 2040 (w), 1460 (m), 1420 (r), 1980 (8) 1870 (6), 1210 (6, br), 1160 (6) 1070 (s, i), 905 (8), 715 (8 BD) come; 1H NMR (600 MHz, CDCl) 6 4.18 (da, J= 8.1, 2.0 He, 1H), 4.04 (ddd, J= 8.8, 8.4, 3.6 Hz, 1H), 3.80 (86, 41.8, 7.4, 4.5 Hz, 1 H), 3.79 (ddd, J = 11.4, 6.5, 4.9 Hz, 1 H), 3.64-3.58 (rm, 1H), 3.41 (6, 3H), 2.25 (6 br, 1H, OH), 1.95+1.85 (n, 2H), 1.85 (4, Y= 2.0 Hz, 3H), 1-75 (mn, 1H), 1.65 (mm, 1H), 1.43 (6S 19, 1.97 (6, 3H); 19C NM (125 MHz, COCK) 5 109.4, 63.2, 78.6, 77,7, 753, 71.1, 602, 87.3, 36.9, 96.2, 27.1, 26.4, 87; high resolution mass spectrum me 243.1591 [(M+H)*; calod for CraHza04: 243.1596]. Anal. Caled for C1gHoaO4: C, 64.44; H, 9.15. Four i] Y “Toa solution ofthe primary aloohol (63.3 mg, 0.261 mmol) in MeCN (8 mL) at r was added TEMPO , 64.09; H, 9.06. MeO, (6 mg, 0.15 equiv), pH = 7 butfer (2 mL), NaCiOe (148 mg, 5 equiv), and 5% NaOCl (catalytic amount). ‘Additional 5% NaOCi (catalytic amount) and NaCiOp (60 mg) were added every 2 h until TLC indicated 29 CE SSSSSESSS'S'S'S'S5= === © 2001 American Chemical Society, J. Am. Chem. Soc., Smith,III ja0116041 Supporting Info Page 30 consumption of starting material. Aller 9h, 15 drops of 8 NNaOH were added, follomed by addition of Saturated NegSOs solution (16 ml). After sting for 0 min, the aqueous layer was extracted with EtzO (4 X25 mL). The aqueous layer was acicified to pH over EtOAc with 1 NHCI (20 mL}. The aqueous layer was extracted with E1OAc (4 x 50 ml); the EtOAc extracts were dried over MgSOg and concentrated in vacuo to afford the acid 96. Toa solution of acid 96 (61.3 mg, 0.229 mmo) in methylene chloride ($ mL) was added FeClye6 '40 (31.6 mg, 0.62 equiv). After 40 min, the reaction was quenched with saturated NaHOOs (20 ml) and

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