Intramolecular Thiol-yne Cyclisation as a Novel Strategy for Thioglycal

0 downloads 0 Views 2MB Size Report
Intramolecular Thiol-yne Cyclisation as a Novel Strategy for ... Unless otherwise stated, all reactions were carried out under a nitrogen atmosphere. All.
Electronic Supplementary Material (ESI) for ChemComm. This journal is © The Royal Society of Chemistry 2015

Intramolecular Thiol-yne Cyclisation as a Novel Strategy for Thioglycal Synthesis† Vincent Corcé,a Lauren McSweeney,a Aoife Malonea and Eoin M. Scanlan*a a School of Chemistry, Trinity Biomedical Sciences Institute, 152-160 Pearse Street,Trinity College, Dublin 2, Ireland.

E-mail: [email protected]

Supporting Information

Table of contents General information

S2

Experimental procedures

S2-S7

NMR spectra

S8-S18

S-1

Experimental General Information NMR spectra were recorded at room temperature on a Bruker Advance 400 spectrometer, 1H (400 MHz) and 13C (100 MHz). Chemical shifts are reported in parts per million (ppm); coupling constant are reported in units of Hertz (Hz). Mass spectrometry analysis was performed with a Q-Tof Premier Waters Maldi-quadrupole time-of-flight (Q-Tof) mass spectrometer equipped with Z-spray electrospray ionization (ESI) and matrix assisted laser desorption ionisation (MALDI) sources. Optical rotation measurements were recorded using a Rudolf Research Analytical Autopol IV instrument. Unless otherwise stated, all reactions were carried out under a nitrogen atmosphere. All UV reactions were carried out in a Luzchem photoreactor, LZC-EDU (110 V/60 Hz) containing 10 UV lamps (8 watts, UVA blacklight blue 400-315 nm). Analytical thin-layer chromatography was performed using Merck 60 F254 silica gel and visualised by UV irradiation and molybdenum staining. Purifications were performed by flash column chromatography on silica gel Kieselgel SI60 (40−63 μm) from Fluka. Dichloromethane and methanol were distilled from calcium hydride under nitrogen prior to use. Tetrahydrofuran was distilled from sodium / benzophenone under nitrogen prior to use. Dimethylformamide was used dry from sure sealed bottles. Reagents were purchased from Sigma and Carbosynth and used without further purification.

Experimental Procedures (2R,3R,4R)-1,3,4-tris(benzyloxy)hex-5-yn-2-ol (2) To a stirred solution of trimethylsilyldiazomethane (3.56 mL, solution 2 M in hexane, 7.13 mmol) in dry THF (60 mL) was added lithium diisopropylamide (14 mL, solution 1.02 M in THF/heptanes/ethylbenzene, 14.25 mmol) at -20 °C. After stirring for 1 hour at this temperature, the mixture was cooled to -78 °C and a solution of 2,3,5-tri-O-benzyl-D-arabinofuranose 1 (2.0 g, 4.75 mmol) in dry THF (40 mL) was added via syringe. The resulting mixture was allowed to warm to room temperature over a period of 8 hours. The reaction was quenched by the addition of water (10 mL) and diethyl ether (200 mL) was added. The organic layer was separated and the aqueous layer was extracted with diethyl ether (3x200 mL). The ethereal layers were combined, dried over MgSO4, and evaporated under reduced pressure. The residue was dissolved in MeOH (20 mL) and KF was added (2.76 g, 47.5 mmol).After being stirred for 2 hours at room temperature, the solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (100 mL) and water (100 mL). The organic phase was washed with water (2x50 mL), dried over MgSO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane 10% ethyl acetate) to afford 2 as a colourless oil (1.4 g, 70%). [α]D23: -29.8 (c = 1.06, CHCl3); Rf: 0.35 (hexane 10% ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 7.21 – 7.40 (m, 15H, Ph), 4.86 and 4.55 (AB system, J = 12 Hz, 2H, PhCH2O), 4.83 and 4.62 (AB system, J = 11.6 Hz, 2H, PhCH2O), 4.51 and 4.48 (AB system, J = 12 Hz, 2H, PhCH2O), 4.41 (dd, J = 2.2 Hz, J = 3.7 Hz, 1H, H-4), 4.08 – 4.16 (m, 1H, H-2), 3.75 (dd, J = 3.8 Hz, J = 7.3 Hz, 1H, H-3), 3.64 (dd, J = 3.3 Hz, J = 9.9 Hz, 1H, H-1), 3.59 (dd, J = 5.1 Hz, J = 9.9 Hz, 1H, H-1), 2.55 (d, J = 2.2 Hz, 1H, H-6); 13C NMR (100 MHz, CDCl ) δ 138.1, 137.3, 128.6, 128.5, 128.45, 128.4, 128.3 128.1, 128.0, 127.9, 3 127.8 (Ar-C), 80.5 (C-5), 80.1 (C-3), 76.2 (C-6), 74.5 (PhCH2), 73.5 (PhCH2), 71.1 (PhCH2), 70.7 (C1), 70.3 (C-2), 68.8 (C-4); HRMS (ESI+) for C27H28NaO4 [M + Na]+: calcd 439.1880 ; found 439.1880.

S-2

S-((2S,3S,4R)-1,3,4-tris(benzyloxy)hex-5-yn-2-yl) ethanethioate (3) To a stirred solution of 2 (975 mg, 2.43 mmol) in dry dichloromethane (25 mL) was added pyridine (393 µL, 4.86 mmol). The reaction mixture was cooled to 0 °C with an ice bath and trifluoromethanesulfonic anhydride (614 µL, 3.65 mmol) was added dropwise. The reaction mixture was stirred for 2 hours at room temperature and the solution was filtered over a pad of silica and eluted with dichloromethane. The filtrate was evaporated under reduced pressure and dried under high vacuum. The crude triflate was solubilized in dry DMF (5 mL) and cooled to 0 °C with an ice bath. Potassium thioacetate (554 mg, 4.86 mmol) was added and the reaction mixture was stirred for 2 hours at 0 °C. The reaction mixture was diluted with diethyl ether (50 mL), washed with water (2x25 mL), brine (2x25 mL), dried over MgSO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane 10% ethyl acetate) to afford 3 (868 mg, 75%) as pale yellow oil. [α]D23: -1.55 (c = 0.1, CHCl3); Rf: 0.31 (hexane 20% diethyl ether); 1H NMR (400 MHz, CDCl3) δ 7.32-7.40 (m, 15H, Ph), 5.01 and 4.67 (AB system, J = 11.45 Hz, 2H, PhCH2O), 4.92 and 4.61 (AB system, J = 11.45 Hz, 2H, PhCH2O), 4.61 and 4.47 (AB system, J = 11.45 Hz, 2H, PhCH2O), 4.46 (m, 2H, H-4 and H-6), 4.32 (d, J = 8.38 Hz, 1H, H-3), 3.74 (t, J = 9.69 Hz, 1H, H-1), 3.62 (m, 1H, H-1), 2.65 (s, 1H, H-6), 2.36 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) 194.5 (C=O), 138.4, 137.9, 137.5, 128.3, 128.2, 128.1, 127.8, 127.6, 127.5, 127.4 (Ar-C), 79.6 (C-5), 79.1 (C-3), 76.7 (C-6), 75.4 (PhCH2), 73.1 (C-4), 72.5 (PhCH2), 71.4 (PhCH2), 69.6 (C-1), 45.2 (C-2); HRMS (ESI+) C29H30NaO4S [M + Na]+ : calcd 497.1763 ; found 497.1756.

1-deoxy-1-methylene-2,3,5-tri-O-benzyl-4-thio-L-xylofuranose (4) To a stirred solution of 3 (120 mg, 0.25 mmol) in MeOH (1 mL) was added a freshly prepared solution of sodium methoxide in methanol (1 mL). After being stirred for 1 h, the solution was neutralized with Dowex® H+ form. The resin was filtered off, washed thoroughly with MeOH and the filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane 5% ethyl acetate) to afford 4 (75 mg, 68%) as a colourless oil. [α]D22: -0.83 (c = 0.1, CDCl3); Rf: 0.25 (hexane 10% diethyl ether); 1H NMR (400 MHz, CDCl3) δ 7.29-7.38 (m, 15H, PhCH), 5.31 (s, 1H, C=CH2), 5.27 (s, 1H, C=CH2), 4.71 and 4.52 (AB system, J = 11.73 Hz, 2H, PhCH2O), 4.63 and 4.57 (AB system, J = 11.73 Hz, 2H, PhCH2O), 4.58 and 4.55 (AB system, J = 11.45 Hz, 2H, PhCH2O), 4.37 (d, J = 3.10 Hz, 1H, H-4), 4.20 (dd, J = 11.46 Hz, J = 7.03 Hz, 1H, H-2), 4.12 (t, J = 3.10 Hz, 1H, H-3), 3.91 (dd, J = 9.45 Hz, J = 7.03 Hz, 1H, H-1), 3.71 (dd, J = 9.45 Hz, J = 7.03 Hz, 1H, H-1); 13C NMR (100 MHz, CDCl3) δ 145.3 (C-5), 137.9, 137.8, 137.6, 128.3, 128.2, 127.8, 127.7, 127.6, 127.5, 127.5, 127.4 (Ar-C), 108.1 (C=CH2), 82.2 (C-3), 73.2 (PhCH2), 72.3 (PhCH2), 70.0 (PhCH2), 68.9 (C-1), 50.2 (C-2); HRMS (ESI+) C27H28NaO3S [M + Na]+ : calcd 455.1651 ; found 455.1652.

(2S,3S,4R)-1,3,4-tris(benzyloxy)hex-5-yn-2-yl 4-nitrobenzoate To a stirred solution of 2 (1.3 g, 3.12 mmol) in dry THF (25 mL) was added triphenylphosphine (1.64 g, 6.24 mmol) and 4-nitrobenzoic acid (782.12 mg, 4.68 mmol). The reaction mixture was cooled to 0 °C with an ice bath and diisopropyl azodicarboxylate (1.23 mL, 6.24 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 16 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel (hexane 10% diethyl ether) to afford the nitrobenzoate (1.59 g, 90%) as a colourless viscous oil. [α]D23: -31.8 (c = 0.27, CHCl3); Rf: 0.24 (hexane 20% diethyl ether); 1H NMR (400 MHz, CDCl3) δ 8.22 and 8.09 (AB system, J = 8.5 Hz, 4H, PhNO2), 7.19 – 7.38 (m, 15H, Ph), 5.66 – 5.76 (m, 1H, H2), 4.91 and 4.64 (AB system, J = 11.5 Hz, 2H, PhCH2O), 4.84 and 4.49 (AB system, J = 11.6 Hz,

S-3

2H, PhCH2O), 4.45 and 4.45 (AB system, J = 12.1 Hz, 2H, PhCH2O), 4.34 (dd, J = 2.1 Hz, J = 5.9 Hz, 1H, H-4), 4.04 (dd, J = 4.6 Hz, J = 5.5 Hz, 1H, H-3), 3.72 (dd, J = 5.4 Hz, J = 10.3 Hz, 1H, H-1), 3.65 (dd, J = 5.9 Hz, J = 10.3 Hz, 1H, H-1), 2.54 (d, J = 2.1 Hz, 1H, H-6) 13C NMR (100 MHz, CDCl3) δ 164.1 (C=O), 150.6 (CNO2), 138.1, 137.8, 137.2, 135.6, 131.1, 128.6, 128.5, 128.2, 128.1, 127.9, 127.8, 123.6 (Ar-C), 79.5 (C-5), 79.1 (C-3), 76.7 (C-6), 75.3 (PhCH2O), 73.7 (C-2), 73.3 (PhCH2O), 71.2 (PhCH2O), 69.6 (C-4), 67.9 (C-1); HRMS (ESI+) C34H31NNaO7 [M + Na]+ : calcd 588.1998 ; found 588.2000.

(2S,3R,4R)-1,3,4-tris(benzyloxy)hex-5-yn-2-ol (5) To a stirred solution of the nitrobenzoate (1.2 g, 2.12 mmol) in MeOH (20 mL) was added a freshly prepared solution of sodium methoxide in methanol (2 mL). After being stirred for 2 h, the solution was neutralized with Dowex® H+ form. The resin was filtered off, washed thoroughly with MeOH and the filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane 30% diethyl ether) to afford 5 (870 mg, 98%), (88% over two steps), as a colourless oil. [α]D23: -28.1 (c = 0.18, CHCl3); Rf: 0.36 (hexane 50% diethyl ether); 1H NMR (400 MHz, CDCl3) δ 7.25 – 7.45 (m, 15H, Ph), 4.95 and 4.60 (AB system, J = 11.1 Hz, 2H, PhCH2O), 4.89 and 4.57 (AB system, J = 11.7 Hz, 2H, PhCH2O), 4.51 and 4.46 (AB system, J = 11.9 Hz, 2H, PhCH2O), 4.46 (dd, J = 2.1 Hz, J = 7.1 Hz, 1H, H-4), 4.22 (dt, J = 2.5 Hz, J = 6.1 Hz, 1H, H2), 3.79 (dd, J = 2.5 Hz, J = 7.1 Hz, 1H, H-3), 3.50 (dd, J = 6.2 Hz, J = 9.6 Hz, 1H, H-1), 3.45 (dd, J = 6.1 Hz, J = 9.6 Hz, 1H, H-1), 2.61 (d, J = 2.1 Hz, 1H, H-6) 13C NMR (100 MHz, CDCl3) δ 138.2, 138.1, 137.6, 128.6, 128.5, 128.4, 128.2, 128.0, 127.9 (Ar-C), 80.2 (C-5), 79.9 (C-3), 76.4 (C-6), 75.3 (PhCH2), 73.4 (PhCH2), 71.5 (PhCH2), 71.2 (C-1), 71.1 (C-4), 70.2 (C-2); HRMS (ESI+) C27H28NaO4 [M + Na]+ : calcd 439.1885 ; found 439.1883.

S-((2R,3S,4R)-1,3,4-tris(benzyloxy)hex-5-yn-2-yl) ethanethioate (6) To a stirred solution of 5 (800 mg, 1.92 mmol) in dry dichloromethane (19 mL) was added pyridine (310 µL, 3.84 mmol). The reaction mixture was cooled to 0 °C with an ice bath and trifluoromethanesulfonic anhydride (485 µL,m 2.88 mmol) was added dropwise. The reaction mixture was stirred for 2 hours at room temperature and the solution was filtered over a pad of silica and eluted with dichloromethane. The filtrate was evaporated under reduced pressure and dried under high vacuum. The crude triflate was solubilized in dry DMF (5 mL) and cooled to 0 °C with an ice bath. Potassium thioacetate (438.6 mg, 3.84 mmol) was added and the reaction mixture was stirred for 2 hours at 0 °C. The reaction mixture was diluted with diethyl ether (50 mL), washed with water (2x25 mL), brine (2x25 mL), dried over MgSO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane 5% ethyl acetate) to afford 6 (550 mg, 60%) as pale yellow oil. [α]D23: -52.8 (c = 0.2, CHCl3); Rf: 0.31 (hexane 20% diethyl ether); 1H NMR (400 MHz, CDCl3) δ 7.23 – 7.37 (m, 15H, Ph), 4.90 and 4.65 (AB system, J = 11.2 Hz, 2H, PhCH2O), 4.83 and 4.52 (AB system, J = 11.6 Hz, 2H, PhCH2O), 4.51 and 4.43 (AB system, J = 12.1 Hz, 2H, PhCH2O), 4.47 (dd, J = 2.1 Hz, J = 6 Hz, 1H, H-4), 4.34 – 4.40 (m, 1H, H-2), 3.95 (dd, J = 4.5 Hz, J = 6 Hz, 1H, H-3), 3.74 (dd, J = 6.9 Hz, J = 10.2 Hz, 1H, H-1), 3.62 (dd, J = 5.5 Hz, J = 10.2 Hz, 1H, H-1), 2.61 (d, J = 2.1 Hz, 1H, H-6)), 2.29(s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 194.7 (C=O), 138.3, 138.1, 137.4, 128.4, 128.3, 128.2, 127.9, 127.8, 127.6, 127.55, 127.5 (Ar-C), 81.5 (C-3), 80.3

S-4

(C-5), 76.3 (C-6), 75.2 (PhCH2), 72.8 (PhCH2), 71.1 (PhCH2), 70.8 (C-4), 68.8 (C-1), 44.9 (C-2), 30.6 (CH3); HRMS (ESI+) C29H30NaO4S [M + Na]+ : calcd 497.1763 ; found 497.1756.

1-deoxy-1-methylene-2,3,5-tri-O-benzyl-4-thio-D-arabinofuranose (7) To a stirred solution of 6 (91 mg, 0.21 mmol) in MeOH (1 mL) was added a freshly prepared solution of sodium methoxide in methanol (1 mL). After being stirred for 1 h, the solution was neutralized with Dowex® H+ form. The resin was filtered off, washed thoroughly with MeOH and the filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane 5% ethyl acetate) to afford 7 (83 mg, 91%) as a colourless oil. [α]D22: +16.2 (c = 0.2, CHCl3); Rf: 0.25 (hexane 10% diethyl ether); 1H NMR (400 MHz, CDCl3) δ 7.24 – 7.42 (m, 15H, Ph), 5.32 (bs, 1H, C=CH2), 5.24 (bs, 1H, C=CH2), 4.70 (d, PhCH2O); 4.65 (s, 2H, PhCH2O), 4.48 – 4.57 (m, 3H, PhCH2O), 4.39 (d, 1H, J = 3.6 Hz, H-2), 4.08 (t, 1H, J = 3.2 Hz, H-3), 3.77 – 3.86 (m, 2H, H-5 and H-4), 3.52 – 3.62 (m, 1H, H-5); 13C NMR (100 MHz, CDCl3) δ 145.0 (C-1), 138.1, 137.8, 137.7, 128.5, 128.4, 127.9, 127.8, 127.75, 127.7, 127.6 (Ar-C), 107.8 (C=CH2), 86.9 (C-2), 83.4 (C-3), 73.1 (PhCH2O), 72.0 (C-5), 71.9 (PhCH2O), 71.6 (PhCH2O), 51.3 (C-4); HRMS (ESI+) C27H28NaO3S [M + Na]+ : calcd 455.1651 ; found 455.1652. (2R,3S,4R)-1,3,4-tris(benzyloxy)hex-5-yne-2-thiol (8) To a stirred solution of 6 (130 mg, 0.274 mmol) in dry THF (3 mL) was added methyllithium (1 ml solution 0.88 M in diethyl ether, 0.877 mmol) at -78 °C. The reaction mixture was warmed to -50 °C and stirred for 3 hours. The reaction was cooled to -78 °C, quenched by addition of aqueous HCl 1 M (3 mL) and diluted with diethyl ether (30 mL). The etheral layer was washed with water (2x10 mL), dried over MgSO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane 5% diethyl ether) to afford 8 (60 mg, 50%) as colourless oil. [α]D22: -59 (c = 0.1, CHCl3); Rf: 0.25 (hexane 10% diethyl ether); 1H NMR (400 MHz, CDCl3) δ 7.24 – 7.43 (m, 15H, Ph), 5.02 and 4.66 (AB system, J = 11 Hz, 2H, PhCH2O), 4.89 and 4.58 (AB system, J = 11.8 Hz, 2H, PhCH2O), 4.69 – 4.74 (m, 1H, H-4), 4.52 and 4.49 (AB system, J = 11.9 Hz, 2H, PhCH2O), 3.79 – 3.89 (m, 2H, H-1 and H-3), 3.69 (dd, J = 4.5 Hz, J = 9.5 Hz, 1H, H-1), 3.34 – 3.45 (m, 1H, H-2), 2.58 (d, J = 2.1 Hz, H-6), 1.86 (d, J = 9.84 Hz, 1H, SH); 13C NMR (100 MHz, CDCl3) δ 138.3, 138.1, 137.4, 128.5, 128.4, 128.3, 128.2, 128.1, 127.9, 127.6 (Ar-C), 83.6 (C-3), 80.9 (C-5), 75.8 (C-6), 75.7 (PhCH2), 73.1 (PhCH2), 71.1 (C-1), 71.0 (PhCH2), 69.5 (C-4), 40.4 (C-2); HRMS (ESI+) C27H28NaO3S [M + Na]+ : calcd 455.1651 ; found 455.1673.

(2S,3S,4R)-1,3,4-tris(benzyloxy)hex-5-yne-2-thiol (9) To a stirred solution of 3 (200 mg, 0.422 mmol) in dry THF (4 mL) was added methyllithium (1.0 mL solution 0.16 M in diethyl ether, 1.35 mmol) at -78 °C. The reaction mixture was warmed to -50 °C and stirred for 3 hours. The reaction was cooled to -78 °C, quenched by addition of aqueous HCl 1 M (3 mL) and diluted with diethyl ether (30 mL). The etheral layer was washed with water (2x10 mL), dried over MgSO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane 5% diethyl ether) to afford 9 (58 mg, 32%) as a colourless oil. Rf: 0.25 (hexane 10% diethyl ether); 1H NMR (400 MHz, CDCl3) δ 7.24-7.36 (m, 15H, Ph), 4.96 and 4.61 (AB system, J = 11.45 Hz, 2H, PhCH2O), 4.85 and 4.56 (AB system, J = 11.45 Hz, 2H, PhCH2O), 4.42 (AB system, J = 11.45 Hz, 2H, PhCH2O), 4.10 (dd, J = 8.12 Hz, J = 1.95 Hz, 1H, H3), 3.44-3.55 (m, 3H, H-1, H-2, H-4), 2.57 (d, J = 2.24 Hz, 1H, H-6), 1.68 (d, J = 10.16 Hz, 1H, SH); 13C NMR (100 MHz, CDCl3) δ 138.6, 137.9, 137.7, 128.4, 128.3, 128.2, 127.9, 127.8, 127.7, 127.6,

S-5

127.5 (Ar-C), 80.2 (C-5), 79.2 (C-3), 76.5 (C-6), 75.3 (PhCH2), 73.6 (C-4), 72.8 (PhCH2), 72.7 (PhCH2), 71.6 (C-1), 40.1 (C-2); HRMS (ESI+) C27H28NaO3S [M + Na]+ : calcd 455.1651 ; found 455.1673.

General Procedure for Radical Cyclisation To a degassed solution of thiol (57.2 mg, 0.132 mmol) in dry DMF (264 μL) was added 2,2dimethoxy-2-phenyl-acetophenone (6.8 mg, 26.4 μmol) and 2-methylbenzophenone (4.8 μL, 26.4 μmol). The solution was placed in a UV oven and irradiated for 1 h without agitation at 20 °C. DMF was removed in vacuo and the products were isolated by flash column chromatography on silica gel (hexane 5% ethyl acetate).

1-deoxy-1-methylene-2,3,5-tri-O-benzyl-4-thio-D-arabinofuranose (7) Starting from thiol 8, general procedure for radical cyclisation was applied. Only 7 and 8 were observed in the product mixture. Results at four different concentrations are tabulated below. Concentration

DMF volume

% Conversiona

% 5-exo

% 6-endo

1M

0.115 mL

40

100

0

0.5 M

0.23 mL

45

100

0

0.1 M

1.15 mL

58

100

0

0.05 Mb

2.3 mL

-

-

-

Conversion determined by 1H-NMR bReaction was incomplete at this concentration, accurate conversion could not be determined. a

S-6

Tri-O-benzyl-5-thioglucal (17) Starting from thiol 9, general procedure for radical cyclisation was applied. Following purification by column chromatography, 4 was isolated as a colourless oil (19 mg, 33%), 17 was isolated as a pale yellow oil (12.7 mg, 22%); [α]D22: -0.32 (c = 0.1, CDCl3) 1H NMR (400 MHz, CDCl3) δ 7.39-7.29 (m, 15H, Ph), 6.37 (d, J = 10.09 Hz, 1H, H-5), 5.85 (dd, J = 4.93 Hz, J = 10.09 Hz, 1H, H-6), 4.71-4.50 (m, 6H, PhCH2O), 3.98 (m, 1H, H-3), 3.91 (t, J = 4.66 Hz, 1H, H-4), 3.76 (dd, J = 6.31 Hz, J = 8.99 Hz, 1H, H-1), 3.67 (td, J = 2.08 Hz, J = 6.97 Hz, 1H, H-2), 3.63 (t, J = 8.03, 1H, H-1); 13C NMR (100 MHz, CDCl3) δ 138.3, 137.8, 128. 2, 127.9, 127.7, 127.6 (Ar-C), 124.5 (C-5), 118.3 (C-6), 72.9 (PhCH2), 72.4 (C-3), 72.1 (PhCH2), 70.8 (PhCH2), 70.1 (C-4), 68.7 (C-1), 40.4 (C-2); HRMS (ESI+) C27H28NaO3S [M + Na]+ : calcd 455.1651 ; found 455.1652.

S-7

150

140

130

120

6.0 5.5

110

5.0

100

S-8 4.5

90

4.0

80

3.5

70

1.00

6.5 1.00 1.00 0.96

7.0 0.99

7.5 0.94 1.02 1.01 0.85 2.08 0.95

14.92

8.0

80.475 80.056 76.150 74.550 73.532 71.149 70.746 70.265 68.772

13C

138.121 137.262 128.573 128.544 128.454 128.391 128.341 128.088 128.001 127.914 127.866

4.882 4.852 4.847 4.818 4.706 4.634 4.605 4.567 4.537 4.508 4.495 4.465 4.422 4.416 4.412 4.407 4.142 4.129 4.123 4.115 4.103 3.762 3.752 3.744 3.734 3.657 3.648 3.632 3.624 3.616 3.603 3.592 3.579 2.561 2.556

7.343 7.337 7.332 7.321 7.315 7.301 7.288

1H

NMR spectrum of compound 2 (CDCl3, 400 MHz)

ffffffffffffffff OH BnO BnO OBn 2

3.0

60

2.5

50

ppm

NMR spectrum of compound 2 (CDCl3, 100 MHz)

ffffffffffffffff OH BnO

BnO OBn

2

ppm

1H

NMR spectrum of compound 3 (CDCl3, 600 MHz)

SAc

BnO BnO

OBn 3

13C

NMR spectrum of compound 3 (CDCl3, 150 MHz)

BnO

SAc

BnO OBn 3

S-9

1H

NMR spectrum of compound 4 (CDCl3, 600 MHz)

BnO

S

BnO

OBn 4

13C

NMR spectrum of compound 4 (CDCl3, 150 MHz)

BnO

S

BnO

OBn 4

S-10

170

160

150

140

130

120

110

S-11 5.0

100

4.5

90

4.0

80 0.82

5.5 1.04 1.01

6.0 1.01

6.5

79.544 79.132 76.710 75.288 73.673 73.279 71.206 69.586 67.954

7.0 1.04 1.02 1.04 1.01 2.06 0.99

7.5 1.00

14.39

8.0

138.070 137.831 137.205 135.597 131.059 128.563 128.459 128.222 128.094 127.932 127.876 123.562

1.87 1.91

8.5

150.621

13C

164.040

5.737 5.724 5.712 5.699 4.930 4.901 4.855 4.826 4.657 4.628 4.511 4.482 4.474 4.444 4.421 4.391 4.356 4.351 4.341 4.336 4.058 4.047 4.044 4.033 3.741 3.727 3.715 3.702 3.670 3.656 3.645 3.630 2.540 2.535

7.322 7.298 7.279 7.273 7.256 7.248 7.239 7.233

8.236 8.215 8.108 8.086

1H

NMR spectrum of nitrobenzoate (CDCl3, 400 MHz)

ffffffffffffffff

BnO

3.5 3.0

70

2.5

BnO

60

50

NO2

O O

BnO OBn

ppm

NMR spectrum of compound nitrobenzoate (CDCl3, 100 MHz)

ffffffffffffffff

O O

BnO OBn

ppm

NO2

145

140

135

130

125

80.249 79.968 76.452 75.266 73.427 71.467 71.144 71.075 70.239

120

115

5.5

110

5.0

105

100

S-12 4.5

95

4.0

90

85

80 0.91

6.0 2.10

6.5 1.00

7.0 0.99

7.5 1.99 2.96

0.98 0.99

14.00

8.0

128.552 128.538 128.487 128.215 127.991 127.873

13C

138.178 138.072 137.566

4.965 4.937 4.911 4.881 4.618 4.595 4.590 4.566 4.527 4.497 4.478 4.470 4.461 4.455 4.440 4.239 4.232 4.223 4.217 4.208 4.202 3.807 3.801 3.789 3.783 3.521 3.506 3.497 3.482 3.469 3.454 3.446 3.430 2.611 2.606

7.374 7.372 7.363 7.358 7.346 7.338 7.329 7.316 7.312 7.303

1H

NMR spectrum of compound 5 (CDCl3, 400 MHz)

ffffffffffffffff OH BnO BnO OBn 5

3.5 3.0

75

70

2.5

65

2.0

60

ppm

NMR spectrum of compound 5 (CDCl3, 100 MHz)

ffffffffffffffff OH BnO

BnO OBn

5

ppm

200

190

180

170

160

150

140

130

120

110

S-13 4.5

100

4.0

90

3.5

80

70

3.0

60

50 2.88

5.0

30.626

5.5 0.89

6.0

44.884

6.5 1.02 1.00

7.0 1.00

0.99 1.01 1.02 1.97 1.00 1.02 1.03

15.05

7.5

81.492 80.355 76.283 75.236 72.850 71.125 70.779 68.867

13C

138.260 138.109 137.402 128.346 128.327 128.209 127.988 127.782 127.589 127.554 127.517

194.700

4.916 4.888 4.843 4.814 4.668 4.640 4.538 4.527 4.509 4.497 4.480 4.475 4.465 4.460 4.448 4.418 4.396 4.382 4.379 4.370 4.367 4.353 3.965 3.954 3.950 3.939 3.759 3.742 3.734 3.716 3.641 3.627 3.615 3.601 2.608 2.603 2.297

7.330 7.316 7.307 7.296 7.290 7.284

1H

NMR spectrum of compound 6 (CDCl3, 400 MHz)

ffffffffffffffff SAc BnO BnO OBn 6

2.5

40

2.0 ppm

NMR spectrum of compound 6 (CDCl3, 100 MHz)

ffffffffffffffff SAc BnO

BnO OBn

6

30

ppm

170

160

150

140

130

120

110

100

90

S-14 4.5

80

70

60 0.93

5.0 1.75

5.5

51.286

6.0 0.89

6.5 0.93 1.68 2.71 0.90

7.0

73.133 72.022 71.984 71.043

7.5 0.90 0.91

8.0

86.869 83.438

13.81

8.5

107.820

13C

145.021 138.031 137.833 137.766 128.446 128.390 127.929 127.843 127.751 127.725 127.678

5.322 5.240 4.721 4.691 4.655 4.560 4.548 4.530 4.522 4.492 4.404 4.395 4.091 4.084 4.075 3.845 3.826 3.821 3.814 3.795 3.789 3.603 3.578 3.572 3.546

7.359 7.345 7.335 7.323 7.305 7.292

1H

NMR spectrum of compound 7 (CDCl3, 400 MHz)

ffffffffffffffff

BnO

4.0 3.5

50

3.0

40

30

S

BnO OBn

7

2.5

BnO

20

ppm

NMR spectrum of compound 7 (CDCl3, 100 MHz)

ffffffffffffffff S BnO

7

OBn

10 ppm

160

150

140

130

120

110

100

4.5

90

S-15

80

4.0

70

3.5

60

3.0

50

40

0.93

5.0

0.84

5.5

40.372

6.0 1.00

6.5 1.00

7.0 1.95

7.5

0.97 0.98 0.94 1.07 0.99 2.09

13.39

8.0

83.579 80.972 75.814 75.725 73.056 71.196 71.013 69.513

13C

138.300 138.058 137.436 128.443 128.411 128.384 128.266 128.143 127.908 127.639

5.037 5.009 4.904 4.874 4.724 4.719 4.714 4.709 4.679 4.652 4.591 4.562 4.547 4.517 4.502 4.472 3.881 3.870 3.863 3.852 3.838 3.827 3.711 3.700 3.687 3.676 3.431 3.420 3.407 3.402 3.395 3.390 3.377 3.366 2.586 2.581 1.872 1.848

7.380 7.362 7.346 7.343 7.318 7.310

1H

NMR spectrum of compound 8 (CDCl3, 400 MHz)

ffffffffffffffff SH BnO BnO OBn 8

2.5 2.0

30

ppm

NMR spectrum of compound 8 (CDCl3, 100 MHz)

ffffffffffffffff SH BnO

BnO

OBn

8

20

ppm

1H

NMR spectrum of compound 9 (CDCl3, 400 MHz)

SH

BnO BnO

OBn 9

13C

NMR spectrum of compound 9 (CDCl3, 100 MHz)

BnO

SH

BnO OBn 9

S-16

1H

NMR spectrum of compound 17 (CDCl3, 600 MHz)

BnO

S

BnO OBn 17

13C

NMR spectrum of compound 17 (CDCl3, 150 MHz)

BnO

S

BnO OBn 17

S-17

HSQC spectrum of compound 17 (CDCl3, 150 MHz)

BnO

S

BnO OBn 17

S-18