ࡱ> lnkyA7 EbjbjUU "7|7|ZBl<<<8tI' $D "f f f A A A $$$$$$$$' *`$UA A A A A $f f 'A f f $A $\"l$f  dCB<Z$,l$'0I'@$,*5N*l$Supporting Information Synthesis and Determination of the Absolute Configuration of the Bicyclic Guanidine Core of Batzelladine A Sergio G. Duron and David Y. Gin* Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801 General Procedures. All reactions were performed in flame-dried modified Schlenk (Kjeldahl shape) flasks fitted with a glass stopper or rubber septa under a positive pressure of argon, unless otherwise noted. Air- and moisture-sensitive liquids and solutions were transferred via syringe or stainless steel cannula. Organic solutions were concentrated by rotary evaporation below 30 C at ca. 25 Torr. Flash column chromatography was performed employing 230-400 mesh silica gel. Thin-layer chromatography (analytical and preparative) was performed using glass plates pre-coated to a depth of 0.25 mm with 230-400 mesh silica gel impregnated with a fluorescent indicator (254 nm). Materials. Tetrahydrofuran, dichloromethane, toluene and ether were purified by passage through two packed columns of neutral alumina under an argon atmosphere. Triethylamine and acetonitrile were distilled from calcium hydride at 760 Torr. Chloroform was distilled from phosphorous pentoxide. Methyl alcohol was distilled from Mg/I2. . Instrumentation. Infrared (IR) spectra were obtained using a Perkin Elmer Spectrum BX spectrophotometer referenced to a polystyrene standard. Data are presented as frequency of absorption (cm-1). Proton and carbon-13 nuclear magnetic resonance (1H NMR or 13C NMR) spectra were recorded on a Varian 400, a Varian 500, or a Varian Inova 500 NMR spectrometer; chemical shifts are expressed in parts per million (d scale) downfield from tetramethylsilane and are referenced to residual protium in the NMR solvent (CHCl3: d 7.26). Data are presented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet and/or multiple resonances), integration, coupling constant in Hertz (Hz) and assignment.  EMBED ChemDraw.Document.4.5  (2S, 3S)-3-Benzyloxycarbonylamino-2-bromo-1,4-butyrolactone (7). To a solution of freshly prepared LDA (diisopropylamine (2.50 ml, 17.8 mmol, 2.1 equiv) and n-BuLi (1.6 M, 10.60 ml, 17.0 mmol, 2 equiv)) in 150 ml THF was added 3(S)-[(carbobenzyloxy)amino]-g-butyrolactone (2.00 g, 8.51 mmol, 1 equiv) in 50 ml of THF via cannula at -78 (C. The cloudy yellow reaction mixture was stirred for 2.5 h and then freshly distilled TMSCl (2.20 ml, 17.3 mmol, 2.0 equiv) was injected into the reaction vessel and stirred for 15 min. Bromine (880 ml, 17.1 mmol, 2.0 equiv) was injected into the clear colorless reaction mixture and stirred for an additional 10 min. The resulting red-orange solution was diluted with Et2O (300 ml) and washed with 1N HCl (200 ml), saturated aqueous NaHCO3 (2 x 250 ml), and saturated aqueous NaCl (200 ml). The combined organic layers were dried with NaSO4, filtered and concentrated. The light yellow solid was purified by flash column chromatography (33% ethyl acetate in hexanes) to afford 7, (2.01 g, 6.40 mmol, 75%) as a white crystalline solid. Rf = .30 (50% ethyl acetate in hexanes); 1H NMR (500 MHz, CDCl3) ( 7.42-7.29 (m, 5H), 5.88-5.80 (m, 1H), 5.14-5.05 (m, 2H), 4.69-4.59 (m, 1H), 4.47-4.39 (m, 2H), 4.27 (br d, 1H, J = 9.3 Hz); 13C NMR (126 MHz, CDCl3) 171.7, 155.8, 135.7, 128.9, 128.8, 128.7, 128.6, 128.4, 71.0, 67.7, 56.9, 40.1 FTIR (thin film; NaCl) 3329, 1789, 1705, 1534 cm-1; HRMS-EI (m/z): [M]+ Calcd for C12H12NO279Br 312.9950, found 312.9945.  EMBED ChemDraw.Document.4.5  Vinylogous carbamate 9. Both 7 (2.62 g, 8.34 mmol, 1 equiv) and 2-thiopyrrolidinone (854 mg, 8.46 mmol, 1 equiv) were combined in a flask and dissolved in CH2Cl2. The solvent was removed to evenly mix the solids. The solid mixture was submerged in an oil bath set at 90 (C. The melt was stirred for 25 minutes and then the resulting residue was cooled to ambient temperature. To this brown residue was sequentially added 52 ml of chloroform, triphenylphosphine (2.63 g, 10.03 mmol, 1.2 equiv), and 52 ml triethylamine. The solution was stirred at reflux for 18 h. The reaction mixture was concentrated under reduced pressure, dissolved in a minimal amount of CH2Cl2, then directly loaded on a column of SiO2 and purified by flash column chromatography (gradient elution: 50% ethyl acetate in hexanes ( 67% ethyl acetate in hexanes) to afford vinylogous carbamate 9 (1.29 g, 4.27 mmol, 51%) as an off-white solid. Rf = 0.25 (67% ethyl acetate in hexanes); 1H NMR (mixture of E/Z isomers ~1:3, 500 MHz, CDCl3) ( (Z isomer) 7.87 (br s, 1 H), 7.40-7.30 (m, 5 H), ( 5.10 (s, 2H), 5.00-4.95 (m, 1 H), 4.93-4.88 (m, 1 H), 4.47-4.41 (m, 1 H), 4.15 (dd, 1 H, J=10.1, 1.8 Hz), 3.60-3.52 (m, 2H,), 2.64 (t, 2H, J=8.0 Hz), 2.08-2.00 (m, 2H); (E isomer) 6.71 (br s, 1 H), 7.40-7.30 (m, 5 H), 5.11 (s, 2H), 5.00-4.95 (m, 1 H), 4.93-4.88 (m, 1 H), 4.47-4.41 (m, 1 H), 4.00 (dd, 1 H, J=10.4, 2.2 Hz), 3.48-3.35 (m, 2H), 3.07 (t, 2H, J=8.1 Hz), 2.08-2.00 (m, 2H); 13C NMR (126 MHz, CDCl3) 165.6, 157.3, 152.2, 145.1, 133.0, 130.1, 128.1, 91.5, 69.0, 58.2, 51.4, 47.5, 34.5, 32.4, 21.8, 21.5; FTIR (thin film; NaCl) 3306, 2955, 1691, 1616, 1517, 1230, 1048 cm-1; HRMS (FAB) m/z: (M+H)+ Calcd for C16H18O4N2 303.1345, found 303.1345.  EMBED ChemDraw.Document.4.5  Tricyclic-Urea 10. To a solution of 9 (48 mg, 0.16 mmol, 1 equiv) and bis(p-nitrophenyl)carbonate (54 mg, 0.18 mmol, 1.1 equiv) in 2.5 ml THF was added NaH (60 % dispersion in mineral oil, 14 mg, 0.35 mmol, 2.2 equiv) at 0 (C (ice/water bath). The orange/yellow solution was stirred in the ice bath and allowed to reach ambient temperature and stirred for 4 d. The solution was concentrated under reduced pressure, dissolved in minimal CH2Cl2, then directly loaded on a silica gel packed column and purified by flash column chromatography (60% ethyl acetate in hexanes) to afford tricyclic-urea 10 (37 mg, 0.11 mmol, 71 %) as an off-white solid. Rf = 0.43 (67 % ethyl acetate in hexanes); [a]23D  275.4 (c 0.62, CHCl3); 1H NMR (500 MHz, CDCl3) ( 7.46-7.32 (m, 5 H), 5.32 (ABq, 2H, nA = 5.35, nB = 5.28, JAB=12.0 Hz), 5.09-5.03 (m, 1H), 4.85 (dd, 1 H, J=9.6, 7.5 Hz), 3.96 (dd, 1 H, J=9.5, 8.4 Hz,), 3.90-3.74(m, 2H), 3.18-2.93 (m, 2H), 2.20-2.05 (m, 2H,); 13C NMR (126 MHz, CDCl3) 167.2, 153.3, 151.2, 148.6, 134.8, 129.0, 128.5, 92.8, 72.0, 69.7, 54.7, 47.9, 28.8, 21.9; FTIR (thin film; NaCl) 2963, 1779, 1755, 1716, 1698 cm-1; HRMS (EI) m/z: [M]+ Calcd for C17H16N2O5 328.1059, found 328.1058.  EMBED ChemDraw.Document.4.5  Tricyclic-Urea 11. To a solution of 10 (2.12 g, 6.46 mmol) in 150 ml EtOAc was added a small scoop of 10% Pd/C (cat.). The reaction mixture was stirred at ambient temperature under an atmosphere of hydrogen gas (balloon) for 2.5 h then filtered through celite and washed with CH2Cl2 (500 ml). The product was concentrated under reduced pressure to afford pure unprotected tricyclic-urea 11 (1.25 g, 6.44 mmol, >99%) as a white solid. Rf = 0.20 (100 % EtOAc); [a]26D  390.3 (c 0.69, CHCl3); 1H NMR (500 MHz, CDCl3) ( 6.25 (br s, 1 H), 4.81 (m, 1H), 4.60 (dd, 1 H, J=8.3, 7.5 Hz), 3.99 (t, 1H, J=8.3 Hz), 3.83-3.69 (m, 2H), 3.14-2.91 (m, 2H) 2.18-2.03 (m, 2H); 13C NMR (126 MHz, CDCl3) 167.9, 153.9, 153.1, 91.2, 71.9, 50.9, 47.0, 29.0, 21.9; FTIR (thin film; NaCl) 3296, 2935, 1738, 1684 cm-1; HRMS (FAB) m/z: (M+H)+ Calcd for C9H10N2O3 195.0770, found 195.0770.  EMBED ChemDraw.Document.4.5  Alcohol 12. To a solution of 11 (620 mg, 3.20 mmol, 1 equiv) in 30 ml of MeOH was added sodium methoxide (516 mg, 9.55 mmol, 3 equiv) at 0 (C (ice/water bath). The light green solution was stirred for 1.5 h and then quenched with Dowex 50WX4-50 (H+ form, MeOH washed) until the reaction was neutral (pH paper). The mixture was filtered and concentrated under reduced pressure. The residue was loaded on a silica gel packed column and purified by flash column chromatography (5% MeOH in ethyl acetate) to afford alcohol 12 (614 mg, 2.72 mmol, 85 %) as a white solid. Rf = 0.13 (100 % EtOAc); [a]23D +168.9 (c 0.34, CHCl3); 1H NMR (500 MHz, CDCl3) d 5.75 (bs, 1H), 4.43-4.40 (m, 1H), 3.73 (s, 3H), 3.75-3.67 (m, 2H), 3.64 (dd, 1H, J=10.9, 3.4 Hz), 3.52 (dd, 1H, J=10.9, 7.6 Hz), 3.22 (ddd, 1H, J = 18.3, 8.6, 4.6 Hz), 3.06 (ddd, 1H, J = 18.3, 9.4, 8.8 Hz), 2.00 (m, 2H); 13C NMR (126 MHz, CDCl3) d 166.4, 155.9, 153.6, 94.5, 65.8, 54.4, 51.4, 46.9, 32.3, 21.4; FTIR (thin film; NaCl) 3339, 2950, 1674, 1650, 1436, 1394, 1338, 1311, 1249, 1187, 1101, 1073, 1037 cm-1; HRMS (FAB) m/z: (M+H)+ calc for C10H14N2O4 227.1032, found 227.1032.  EMBED ChemDraw.Document.4.5  Acetate 13. To a solution of 12 (350 mg, 1.55 mmol, 1 equiv) in 15 ml of CH2Cl2 at 0 (C (ice/water bath) was sequentially added acetic anhydride (800 ml, 8.48 mmol, 5.5 equiv), triethylamine (660 ml, 4.74, 3 equiv) and a small crystal of DMAP. After 10 min. the reaction was warmed to ambient temperature and stirred for 5 h. The reaction mixture was concentrated to about 25 % volume, then loaded directly on a silica gel packed column and purified by flash column chromatography (100% ethyl acetate) to afford 13 (405 mg, 1.55 mmol, 98%) as a white solid. Rf = 0.42 (100% ethyl acetate); [a]26D +121.6 (c 0.40, CHCl3); 1H NMR (500 MHz, CDCl3) d 5.84 (br d, 1 H, J = 2.3 Hz), 4.56 (ABX, 1H, JAB = 11.0 Hz, JBX = 8.3 Hz, JAX = 3.1 Hz, nx = 2277.1), 4.02 (ABX, 1H, JAB = 11.0 Hz, JBX = 8.3 Hz, JAX = 3.1 Hz, na = 2006.0, nb = 1982.6), 3.97 (ABX, 1H, JAB = 11.0 Hz, JBX = 8.3 Hz, J = 3.1 Hz, na = 2006.0, nb = 1982.6), 3.71 (s, 3H), 3.74-3.65 (m, 2H), 3.22 (ddd, 1H, J = 18.5, 8.8, 4.6 Hz), 3.04 (dt, 1H, J = 18.5, 9.0 Hz), 2.05 (s, 3H), 2.09-2.00 (m, 1H), 1.99-1.90 (m, 1 H); 13C NMR (126 MHz, CDCl3) d 171.0, 165.9, 156.5, 152.8, 93.5, 66.8, 51.5, 51.2, 46.9, 32.3, 21.4, 21.0; FTIR (thin film; NaCl) 3272, 2952, 1744, 1687, 1648, 1447, 1437, 1395, 1338, 1314, 1245, 1224, 1105, 1040 cm-1; HRMS (FAB) m/z: (M+H)+ calc for C12H16N2O5 269.1137, found 269.1138.  EMBED ChemDraw.Document.4.5  O-Methylisourea 14. To a solution of urea 13 (204 mg, 0.76 mmol, 1 equiv) in 3 ml CH2Cl2 was added freshly distilled MeOTf (200 ml, 1.62 mmol, 2 equiv). The resulting solution was stirred at ambient temperature for 3 d. The reaction was quenched with dry triethylamine, loaded directly on a silica gel packed column and purified by flash column chromatography (50% ethyl acetate in hexanes) to yield O-methylisourea 14 (194 mg, 0.69 mmol, 90%) as a clear viscous oil. Rf = 0.28 (50 % ethyl acetate in hexanes); [a]26D +94.4 (c 0.58, CHCl3); 1H NMR (500 MHz, C6D6) d 5.19 (dd, 1H, J = 5.6, 3.8 Hz), 4.62 (dd, 1H, J = 10.6, 5.6 Hz), 4.25 (dd, 1H, J = 10.6, 3.9 Hz), 3.59 (s, 3H), 3.45 (s, 3H), 3.13 (m, 1H), 2.96 (ddd, 1H, J = 18.4, 6.8, 5.6 Hz), 2.87 (m, 1H), 2.59 (dt, 1H, J = 18.3, 9.3 Hz), 1.72 (s, 3H), 1.19 (m, 2H); 13C NMR (126 MHz, C6D6) d 170.7, 166.9, 156.6, 151.4, 94.1, 68.3, 56.2, 54.2, 50.9, 47.6, 31.6, 21.9, 21.0; FTIR (thin film; NaCl) 3469, 2952, 1742, 1673, 1650, 1438, 1397, 1342, 1210, 1129, 1092, 1041 cm-1; HRMS (FAB) m/z: (M+H)+ calc for C13H18N2O5 283.1294, found 283.1293.  EMBED ChemDraw.Document.4.5  Alcohol 15. To a solution of O-methylisourea 14 (195 mg, 0. 69 mmol, 1 equiv) in 10 ml MeOH at 0 (C (ice/water bath) was added NaOMe (114 mg, 2.11 mmol, 3 equiv). The reaction was stirred for 2.5 h and then loaded directly on a silica gel packed column and purified by flash column chromatography (5% MeOH in EtOAc) to afford alcohol 15 (164 mg, 0.68 mmol, 99%) as a clear viscous oil. Rf = 0.14 (5 % MeOH in EtOAc); [a]28D +111.1 (c 0.50, CHCl3); 1H NMR (500 MHz, C6D6) d 5.06 (dd, 1H, J = 6.1, 3.8 Hz), 3.97 (dd, 1H, J = 10.3, 3.8 Hz), 3.83 (dd, 1H, J = 10.3, 6.1 Hz), 3.54 (s, 3H), 3.44 (s, 3H), 3.12 (m, 1H), 2.96-2.83 (m, 2H), 2.58 (dt, 1H, J = 18.4, 9.3 Hz), 1.20 (m, 2H); 13C NMR (126 MHz, C6D6) 167.4, 156.3, 151.1, 94.8, 67.9, 59.0, 54.0, 50.8, 47.5, 31.6, 21.8; FTIR (thin film; NaCl) 3400, 2952, 1690, 1608, 1439, 1398, 1345, 1285, 1213 cm-1; HRMS (FAB) m/z: (M+H)+ calc for C11H15N2O4 241.1188, found 241.1188.  EMBED ChemDraw.Document.4.5  Triisopropylsilylether (17). To a solution of 8-bromo-1-octanol (16) (2.01g, 9.61 mmol, 1 equiv) and triisopropylsilylchloride (2.25 ml, 10.51 mmol, 1.1 equiv) in 50 ml CH2Cl2 was added imidazole (1.94 g, 28.50 mmol, 3 equiv) and a few crystals of DMAP. The reaction mixture was stirred at ambient temperature for 2 h. The mixture was then concentrated to 25 % volume and then loaded directly on a silica gel packed column and purified by flash column chromatography (4% ethyl acetate in hexanes) to afford 17 (3.31 g, 9.08 mmol, 94%) as a clear liquid. Rf = 0.80 (5 % ethyl acetate in hexanes); 1H NMR (500 MHz, C6D6) d 3.67 (t, 2H, J = 6.7 Hz), 3.40 (t, 2H, J = 6.7 Hz), 1.85 (quintet, 2H, J = 7.1 Hz), 1.53 (quintet, 2H, J = 7.1 Hz), 1.43 (quintet, 2H, J = 7.5 Hz), 1.38-1.24 (m, 6H), 1.14-0.99 (m, 21H).  EMBED ChemDraw.Document.4.5  Triphenylphosphonium bromide 18. PPh3 (6.68 g, 25.47 mmol, 1.1 equiv) and 17 (8.44 g, 23.14 mmol, 1 equiv) were dissolved in CH3CN (50 ml) and refluxed for 15 h. The resulting solution was concentrated to 25% volume, loaded directly on a silica gel packed column and purified by flash column chromatography (5% MeOH in CH2Cl2) to afford phosphonium salt 18 (8.58, 13.68 mmol, 59 %) as a white hygroscopic solid. Rf = 0.46 (10 % MeOH in CH2Cl2); 1H NMR (500 MHz, C6D6) d 7.83-7.64 (m, 15H), 3.74-3.65 (m, 2H), 3.57 (t, 2H, J = 6.5 Hz), 1.63-1.54 (m, 4H), 1.42 (quintet, 2H, J = 7.3 Hz), 1.26-1.14 (m, 6H), 1.06-0.94 (m, 21H); HRMS (FAB) m/z: (M-Br)+ Calcd for C35H52OSiPBr 547.3525, found 547.3525.  EMBED ChemDraw.Document.4.5  20. Oxalyl chloride (195 ml, 2.24 mmol, 1.1 equiv) was injected to a stirring solution of DMSO (165 ml, 2.32 mmol, 1.1 equiv) in 140 ml THF at  78 (C and stirred for 20 min. The solution was then warmed to  38 (C for 10 min. then cooled back to 78 (C. Alcohol 15 (489 mg, 2.04 mmol, 1 equiv) was dissolved in 40 ml THF, cooled to 78 (C and transferred to the activated sulfoxide solution via cannula and stirred for 10 min. at 78 (C. The solution was then warmed to 38 (C for 10 min. upon which triethylamine (1.40 ml, 10.04 mmol, 5 equiv) was added and stirred for 15 min. The solution was warmed to ambient temperature for 1 h then cooled back to 78 (C and stirred for 5 min. To the aldehyde solution was added via cannula a prepared ylide solution (made by mixing 18 (5.83 g, 9.30 mmol, 4.6 equiv) and KHMDS (1.80 g, 9.01 mmol, 4.4 equiv) in 100 ml of THF). The orange solution was stirred for 1.5 h at 78 (C, then 19 h at 45 (C. The reaction mixture was warmed to ambient temperature and stirred for 0.5 h and then concentrated to 25% volume. The resulting mixture was diluted in 500 ml CH2Cl2, washed with DI H2O (250 ml) and saturated aqueous NaCl (250 ml), dried with sodium sulfate, filtered and concentrated. The resulting oil was purified by flash column chromatography (20% ethyl acetate in hexanes) to yield alkene 19 (855 mg, 1.69 mmol, 83 %) as a mixture of E:Z isomers (~1:9). The oil was dissolved in 25 ml EtOH and 10 % Pd/C (cat) was added to the solution. The reaction was stirred under an atmosphere of H2 for 2 h. The solution was filtered through a column of celite and concentrated to afford pure 20 (848 mg, 1.67 mmol, 99 % from 19, 82 % from 15) as a clear oil. Rf = 0.27 (20 % ethyl acetate in hexanes); [a]24D +61.7 (c 0.65, CHCl3); 1H NMR (500 MHz, CDCl3) d 4.49 (dd, 1H, J = 6.9, 4.3 Hz), 3.75 (s, 3H), 3.68 (s, 3H), 3.65 (t, 2H, J = 6.7 Hz), 3.72-3.62 (m, 1H), 3.47 (td, 1H, J = 10.2, 7.3 Hz), 3.19 (ddd, 1H, J = 18.1, 8.6, 3.1 Hz), 2.89 (dt, 1H, J = 18.4, 9.3 ), 2.07-1.87 (m, 1H), 1.98-1.87 (m, 1H), 1.58-1.39 (m, 4H), 1.37-1.23 (m, 12H), 1.15-1.05 (m, 21H); 13C NMR (126 MHz, CDCl3) d 167.7, 154.8, 150.7, 97.8, 63.7, 55.3, 54.1, 50.9, 47.6, 38.1, 33.3, 31.2, 30.0, 29.9, 29.9, 29.7, 26.0, 24.9, 22.1, 18.2, 12.2; FTIR (thin film; NaCl) 2931, 2865, 1702, 1687, 1619, 1463, 1439, 1392, 1332, 1286, 1210, 1104 cm-1; HRMS (FAB) m/z: (M+H)+ calcd for C28H52N2O4Si 509.3775, found 509.3770.  EMBED ChemDraw.Document.4.5  Carboxylic acid 24. A solution of NaOH/MeOH (800 ml, made by stirring 12.5 g NaOH in MeOH for 0.5 h at ambient temperature) was added to methyl ester 20 (14 mg, 0.028 mmol) in a resealable flask. The reaction vessel was sealed and the solution was stirred in a 65 (C oil bath for 21 h. The reaction was diluted with CH2Cl2 (250 ml) and washed with DI H2O (150 ml). The aqueous layer was extracted with CH2Cl2 (100 ml). The organic layers were combined and washed with saturated aqueous NaCl (150 ml), dried with sodium sulfate, filtered and concentrated to afford carboxylic acid 24 (11 mg, 0.022 mmol, 81%). Rf = 0.10 (67% ethyl acetate in hexanes); 1H NMR (500 MHz, CDCl3) d 4.51 (dd, 1H, J = 7.2, 4.4 Hz), 3.77 (s, 3H), 3.66 (t, 2H, J = 6.7 Hz), 3.69-3.63 (m, 1H), 3.49 (td, 1H, J = 10.0, 7.5 Hz), 3.19 (ddd, 1H, J = 18.3, 8.8, 3.1 Hz), 2.92 (dt, 1H, J = 18.6, 9.4 Hz ), 2.09-1.88 (m, 1H), 1.98-1.87 (m, 1H), 1.58-1.42 (m, 4H), 1.37-1.23 (m, 12H), 1.15-1.02 (m, 21H); 13C NMR (126 MHz, CDCl3) d 172.1, 156.8, 150.4, 97.0, 63.8, 55.3, 54.2, 47.8, 38.1, 33.3, 31.6, 30.1, 29.9, 29.7, 26.0, 24.9, 21.9, 18.2, 12.2; FTIR (thin film; NaCl) 3950, 2918, 2854, 1695, 1656, 1391, 1332, 1286, 1217, 1102 cm-1; HRMS (FAB) m/z: (M+H)+ calcd for C27H50N2O4Si 495.3618, found 495.3619.  EMBED ChemDraw.Document.4.5  25. To a solution of acid 24 (12 mg, 0.024 mmol, 1 equiv), BOP-Cl (14 mg, 0.056 mmol, 2.3 equiv) and 23 (45 mg, 0.11 mmol, 4.6 equiv) in 100 ml of CH2Cl2 was added triethylamine (11 ml, 0.079 mmol, 3.2 equiv). The reaction was stirred at ambient temperature for 18 h. The crude mixture was loaded directly on SiO2 and purified by flash column chromatography (25% ethyl acetate in hexanes) to afford 25 as a clear viscous oil (16 mg, 0.018 mmol, 75 %). Rf = 0.29 (40 % EtOAc in Hexane); 1H NMR (500 MHz, CDCl3) d 9.46 (bs, 1H), 9.26 (bs, 1H), 7.42-7.27 (m, 10H), 5.24 (s, 2H), 5.15 (s, 2H), 4.50 (dd, 1H, J = 6.6, 4.3 Hz), 4.06 (t, 2H, J = 6.6 Hz), 4.02 (t, 2H, J = 7.2 Hz), 3.76 (s, 3H), 3.65 (t, 2H, J = 6.6 Hz), 3.61 (ddd, 1H, J = 10.3, 7.5, 2.5 Hz), 3.41 (td, 1H, J = 10.0, 7.4 Hz), 3.11 (ddd, 1H, J = 18.2, 8.6, 3.0 Hz), 2.82 (dt, 1H, J = 18.3, 9.3 Hz), 1.94-1.90 (m, 1H), 1.89-1.82 (m, 1H), 1.71-1.18 (m, 20H), 1.11-1.02 (m, 21H); 13C NMR (126 MHz, CDCl3) 167.0, 164.2, 160.8, 156.2, 154.6, 150.7, 137.2, 134.9, 129.0, 128.62, 128.5, 128.1, 128.0, 97.8, 69.1, 67.2, 63.7, 63.2, 55.4, 54.1, 47.6, 44.6, 38.1, 33.3, 31.3, 30.1, 29.9, 29.7, 26.3, 26.0, 25.9, 25.0, 22.0, 18.2, 12.2; FTIR (thin film; NaCl) 3389, 2929, 2855, 1719, 1700, 1687, 1615, 1507, 1457, 1254, 1101 cm-1; HRMS (FAB) m/z: (M+H)+ calcd for C48H73N5O8Si 876.5307, found 876.5308.  EMBED ChemDraw.Document.4.5  26. To a solution of 25 (15 mg, 0.017 mmol) in 1 ml CH3CN was added 3 drops of an HF solution (49% in H2O). The reaction was stirred at ambient temperature for 0.5 h and then quenched with 5 drops of brine and 10 drops of ammonium hydroxide. The biphasic mixture was diluted with 100 ml ethyl acetate and washed with brine (50 ml). The brine layer was further extracted with ethyl acetate (2 x 25 ml). The combined organic layers were dried with sodium sulfate, filtered and concentrated. The resulting oil was purified by flash column chromatography (50% ethyl acetate in hexanes) to afford 26 (12 mg, 0.017 mmol, 97%) as a clear oil. Rf = 0.29 (67 % EtOAc in Hexane); 1H NMR (500 MHz, CDCl3) d 9.46 (bs, 1H), 9.26 (bs, 1H), 7.41-7.27 (m, 10H), 5.24 (s, 2H), 5.14 (s, 2H), 4.50 (dd, 1H, J = 6.8, 4.6 Hz), 4.05 (t, 2H, J = 6.5 Hz), 4.02 (t, 2H, J = 7.5 Hz), 3.76 (s, 3H), 3.64-3.58 (m, 3H), 3.41 (td, 1H, J = 10.2, 7.2 Hz), 3.11 (ddd, 1H, J = 18.3, 8.7, 3.1 Hz), 2.82 (dt, 1H, J = 18.4, 9.5 Hz), 1.99-1.90 (m, 1H), 1.90-1.80 (m, 1H), 1.72-1.21 (m, 20H); 13C NMR (126 MHz, CDCl3) 167.1, 164.2, 160.8, 156.2, 154.6, 150.7, 137.2, 134.9, 129.0, 128.6, 128.5, 128.1, 128.0, 97.8, 69.1, 67.2, 63.3, 55.3, 54.1, 47.6, 38.1, 33.0, 30.0, 29.9, 29.7, 29.6, 25.9, 24.9, 22.1; FTIR (thin film; NaCl) 3386, 3287, 2927, 2853, 1718, 1695, 1609, 1508, 1441, 1395, 1332, 1206, 1100 cm-1; HRMS (FAB) m/z: (M+H)+ calcd for C39H53N5O8 720.3972, found 720.3969.  EMBED ChemDraw.Document.4.5  Alcohol 21. O-Methylisourea 20 (31 mg, 0.061 mmol, 1 equiv) was dissolved in 1.5 ml THF and cooled to 0 (C (ice/water bath). A 1M TBAF solution (170 ml, 0.170 mmol, 2.8 equiv) was injected into the reaction mixture and stirred for 1h. The reaction mixture was then warmed to ambient temperature, stirred for 0.5 h, and then more TBAF (15 ml, 0.015 mmol, 0.25 equiv) was added. The solution was stirred for 0.5 h and then directly loaded on a silica gel packed column and purified by flash chromatography (hexane:EtOAc 1:2) to afford alcohol 21 (21 mg, 0.060 mmol, 98%) as a clear viscous oil. 21: Rf = 0.25 (75 % EtOAc in Hexane); 1H NMR (500 MHz, CDCl3) d 4.50 (dd, 1H, J = 7.0, 4.6 Hz), 3.76 (s, 3H), 3.69 (s, 3H), 3.67-3.61 (m, 3H), 3.46 (m, 1H), 3.17 (ddd, 1H, J = 18.2, 8.7, 3.1 Hz), 2.88 (dt, 1H, J = 18.5, 9.3 Hz), 2.05-1.97 (m, 1H), 1.97-1.86 (m, 1H), 1.60-1.21 (m, 16H); FTIR (thin film; NaCl) 3400, 2928, 2853, 1699, 1682, 1614, 1438, 1393, 1337, 1288, 1211, 1104 cm-1; HRMS (FAB) m/z: (M+H)+ calcd for C19H31N2O4 353.2440, found 353.2441.  EMBED ChemDraw.Document.4.5  Guanidiniumformate 22. Ammonium acetate (130 mg, 1.69 mmol, 27 equiv) was added to a solution of alcohol 21 (22 mg, 0.063 mmol, 1 equiv) in MeOH (7 ml). The reaction mixture was cooled in an ice/water bath and NH3 (gas) was bubbled through the reaction mixture for 10 min. The flask was sealed and heated to 60 (C for 35 h. The solution was cooled to ambient temperature and argon was bubbled through the reaction mixture to remove excess NH3. The mixture was concentrated, dissolved in a minimal amount of MeOH and loaded directly on a silica gel packed column and purified by flash chromatography (CH2Cl2:MeOH:H2O:HCOOH 85:15:0.5:0.5). The fractions containing the desired product were combined and concentrated. The resulting oil was dissolved in CH2Cl2 and filtered to remove any dissolved SiO2. The CH2Cl2 was removed under reduced pressure to afford guanidiniumformate 22 (14 mg, 0.037 mmol, 58%) as a colorless viscous oil. 22. Rf = 0.25 (CH2Cl2:MeOH:H2O:HCOOH 85:15:0.5:0.5 ); [a]D23 = +28.3 (c = 0.20, MeOH); 1H NMR (500 MHz, CD3OH) d 4.38 (t, 1H, J = 6.0 Hz), 3.81 (td, 1H, J = 9.2, 2.9 Hz), 3.76 (s, 3H), 3.66 (td, 1H, J = 9.7, 7.5 Hz), 3.54 (t, 2H, J = 6.7 Hz), 3.31 (ddd, 1H, J = 18.2, 8.5, 3.0 Hz), 2.97 (dt, 1H, J = 18.3, 9.5 ), 2.27-2.19 (m, 1H), 2.15-2.04 (m, 1H), 1.59-1.46 (m, 4H), 1.44-1.26 (m, 12H); FTIR (thin film; NaCl) 3563-2478, 2927, 2855, 1694, 1653, 1595, 1534, 1436, 1349, 1269, 1194, 1105 cm-1; HRMS (FAB) m/z: (M+H)+ calcd for C18H31N3O3 338.2444, found 338.2445. Submitted: Org. Lett. Duron and Gin* PAGE  SPAGE 3 =>R`           F H  " 0 2     56]j[x> CJUVaJ jUOJQJnHtHOJQJH*H*nHo(tHnHtH nHo(tH5655OJQJ\5\:CJE  $dha$$dha$ $  dha$$`a$ ^`$da$ ^`DIJKMO` 68  rs89:;abvwyz>Q5\ jUjZ> CJUVaJ jU]6 jdH* 6H*]H*OJQJ j OJQJ\6]\5J%&de*+_`rt+-l p .!0!2!6!OJQJ j\ j-UjJ*> CJUVaJ jU6 jdH* 6H*]6]5 jH*N##((B00::BBGGKKLOP\\Yf|fvjnnu"v$dha$$dha$6!:!J!L!b!d!l!n!!!!!!!!!!" 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