Chapter Chapter4 Experimental Section 74 Chapter 4.1 General procedures and methods All reactions were performed in oven-dried round bottom flasks or glass vials. The flasks were fitted with rubber septa and reactions were conducted under a positive pressure of nitrogen, unless otherwise noted. Stainless steel syringes or cannulae were used to transfer air- and moisture-sensitive liquids. Analytical thin layer chromatography (TLC) was performed with Merck pre-coated TLC plates, silica gel 60F-254, layer thickness 0.25 mm. Flash column chromatography was performed using Merck 60 (0.040 – 0.063 mm) mesh silica gel. Commercial reagents were purchased from Sigma Aldrich, Fluka, Alfa Aesar or Lancaster, and used as received. All solvent distillation was done at 760 Torr. THF was distilled from sodium/benzophenone; diethyl ether was distilled from sodium wire; CH2Cl2 was distilled from calcium hydride. Proton nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) spectra were recorded on a Bruker AMX500 (500MHz) NMR spectrometer. Deuterated solvent used was CDCl3. Chemical shifts for protons were reported in parts per million (ppm) downfield from tetramethylsilane and are referenced to the NMR solvent (δ 7.26). Chemical shifts for carbon were reported in parts per million (ppm) downfield from tetramethylsilane and were referenced to the carbon resonances of the solvent (δ 77.0). Data were represented as follows: chemical shift, integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet) and coupling constants (J) in Hertz (Hz). Both low and high resolution mass spectra were 75 Chapter obtained on a Finnigan/MAT 95XL-T mass spectrometer in FAB mode. Infrared spectra were recorded on a BIO-RAD FTS 165 FTIR spectrometer. Enantiomeric excesses were determined using chiral HPLC analysis on Hewlett Packard Ti-series 1050 HPLC units. Optical rotations were recorded on a Jasco DIP-1000 polarimeter. Melting points were determined on a BUCHI B-540 melting point apparatus. Single crystal X-Ray diffraction studies were obtained on a Bruker-AXS Smart Apex CCD single-crystal diffractometer. Crystals were grown from iso-propanol and dichloromethane solutions and mounted on glass fibres. X-ray data were collected with a Bruker AXS SMART APEX diffractometer, using Mo-Kα radiation at room temperature, with the SMART suite of Programs(1). Data were processed and corrected for Lorentz and polarisation effects with SAINT(2), and for absorption effect with SADABS(3). Structural solution and refinement were carried out with the SHELXTL, suite of programs (4). The structure was solved by direct methods to locate the heavy atoms, followed by difference maps for the light, non-hydrogen atoms. All non-hydrogen atoms were generally given anisotropic displacement parameters in the final model. All Hatoms were put at calculated positions. 1. SMART version 5.628, 2001. Bruker AXS Inc., Madison, Wisconsin, USA 2. SAINT+ version 6.22a, 2001 Bruker AXS Inc., Madison, Wisconsin, USA 3. SADABS, version 2.10, 2001 G. W. Sheldrick, University of Göttingen 4. SHELXTL, Version 6.14, 2000, Bruker AXS Inc., Madison, Wisconsin, USA 76 Chapter 4.2 Typical experimental procedures 4.2.1 General procedure for Vinylogous Aldol Reaction of 3-hydroxy-2-pyrone and aldehydes. To a ml sample vial containing (11.1 mg, 0.10 mmol, 1.0 eq.), TBD (2.1 mg, 0.015 mmol, 0.15 eq.) was added, followed by 0.5 ml of DMSO. The reaction mixture was stirred for 15 minutes for complete dissolution of 1. The appropriate aldehyde (4 eq.) was next added and allowed to stir under room conditions. After the reaction is complete, 1ml of deionised water is added. The mixture was extracted with CHCl3 (3x1.5ml) till the product was transferred to the organic phase. The organic extracts are collected and dried using Na2SO4. The solvent was removed under reduced pressure and the residue was loaded onto a short silica gel column, followed by flash column chromatography (gradient elution with hexane:ethyl acetate: 9/1 to 1/1). Product VAP was obtained as a yellow liquid (75% yield). 77 Chapter 4.2.2 General procedure for Diels-Alder reaction of 3-hydroxy-2-pyrone and Nmesityl-maleimide. To a ml sample vial containing catalyst 8a (1.6 mg, 0.008 mmol, 0.1 eq.), 3-hydroxy-2pyrone (9.0 mg, 0.080 mmol, 1.0 eq.) was added, followed by 1.0 ml of solvent. The reaction mixture was placed in a cryobath preset at -50oC and allowed to stir for an hour. N-mesityl-maleimide (51.6 mg, 0.240 mmol, 3.0 eq.) was then added. After stirring for 20 hrs, the solvent was removed under reduced pressure and the residue was loaded onto a short silica gel column, followed by flash column chromatography (gradient elution with hexane:ethyl acetate: 9/1 to 1/1). Product 5a was obtained as a white solid in 73% yield (major isomer). 4.2.3 General procedure for the synthesis of amino indanol catalysts.1 1,4-dibromobutane (0.115 ml, 0.973 mmol, 1.2 eq.) was added to a mixture containing (1R,2S)-amino alcohol (121.0 mg, 0.811 mmol, 1.0 eq.), potassium iodide (26.9 mg, 78 Chapter 0.162 mmol, 0.2 eq.) and potassium carbonate (291.0 mg, 2.110 mmol, 2.6 eq.) in a sealed tube. 2ml of iso-propanol was added and the reaction tube capped. The mixture was refluxed at 80oC for 24hrs and then allowed to cool to room temperature. The mixture was poured into ml of deionized water and extracted with ethyl acetate. The organic extracts were dried with Na2SO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane:ethyl acetate (1:4), yielding 8a (0.1244 g) as a yellow liquid in 75% yield. 4.2.4 General procedure for Diels-Alder reaction of N-arylsulfonyl-3-hydroxy-2pyridone and N-substituted-maleimides. N O SO2Ar O + OH 4b: Ar = 2,4,6-Me3C6H2 (Mes) 4c: Ar = 3,5-Me2C6H3 4d: Ar = 2,3,4,5,6-Me5C6 N R O 10 mol% 8a CHCl3, 20h O N SO2Ar O HO O N R Ar = Mes, R = Ph, 6a Ar = Mes, R = Et, 6b Ar = Mes, R = Bn, 6c Ar = Mes, R = 4-OEtC6H4, 6d Ar = Mes, R = 4-MeC6H4, 6e Ar = Mes, R = 4-BrC6H4, 6f Ar = Mes, R = 3,4-Cl2C6H3, 6g Ar = 3,5-Me2C6H3, R = Ph, 6h Ar = 2,3,4,5,6-Me5C6, R = Ph, 6j To a ml sample vial containing catalyst 8a (1.0 mg, 0.005 mmol, 0.1 eq.), 4b (14.7 mg, 0.050 mmol, 1.0 eq.) was added, followed by 0.5 ml of CHCl3. The reaction mixture was placed in a cryobath preset at -500C and allowed to stir for an hour. N-phenyl maleimide (26.0 mg, 0.150 mmol, 3.0 eq.) was then added. After stirring for 18 hrs, the solvent was removed under reduced pressure and the residue was loaded onto a short silica gel 79 Chapter column, followed by flash column chromatography (gradient elution with hexane:ethyl acetate: 9/1 to 1/1). Product 6a was obtained as a white solid in 93% yield (21.7 mg) and 93% ee. 4.2.5 General procedure for the synthesis of N-arylsulfonyl-3-hydroxy-2-pyridone. Pyridones 4b, 4c and 4d were prepared according to the published procedure.2 4.2.6 Procedure for the synthesis of 9a3 To a solution of 4b (219.9 mg, 0.750 mmol, 1.0 eq.) in PhMe (6 ml) was added i-Pr2NH (10.5 µl, 0.075 mmol, 0.10 eq). The solution was stirred for 15 minutes under room conditions. SO2Cl2 (79.0 µl, 0.975 mmol, 1.3 eq.) was added and the reaction was heated at 70 C for 30 minutes. After cooling to room temperature, deionised water (5 ml) was added and the mixture was diluted with EtOAc (10 ml). Extraction was done with additional EtOAc (2 x 10 ml). The organic extracts were dried over Na2SO4 and concentrated under reduced pressure. Purification of the crude using flash column chromatography yielded the product. (9a) White solid, 75% yield. m.p. : 182.5-183.50C 80 Chapter H NMR (500 MHz CDCl3 ppm): δ 2.32 (s, 3H), 2.58 (s, 6H), 6.36 (d, 1H, J = 8.2 Hz), 6.85 (s, 1H), 7.00 (s, 2H), 7.67 (d, 1H, J = 8.2 Hz). 13 C NMR (125 MHz CDCl3 ppm): δ 21.2, 22.5, 108.8, 120.8, 122.8, 130.4, 132.2, 141.4, 143.6, 145.4, 156.4. FTIR (KBr): 648, 685, 1123, 1174, 1365, 1618, 1638, 2978, 3269 cm-1. LRMS (FAB) m/z 328.2 (M+H+) HRMS (FAB) m/z 328.0402 (M+ H+), calc. for C14H15NO435ClS 328.0405 4.2.7 Procedure for the synthesis of 9b4 N SO2Mes O OH 4b N NBS, (i-Pr)2NH CH2Cl2, h, 78% Br OH SO2Mes O 9b To a solution of 4b (198.9 mg, 0.679 mmol, 1.0 eq.) in CH2Cl2 (2 ml) was added iPr2NH (9.5 µl, 0.068 mmol, 0.10 eq.). The solution was stirred for 15 minutes under ambient conditions. N-Bromosuccinimide (1.1 eq.) (132.9 mg in ml CH2Cl2) was added portionwise over a period of 30 minutes. Stirring was continued for an additional 30 minutes. Deionised water (5 ml) was added and the mixture was diluted with CH2Cl2 (10ml). Extraction was done with additional CH2Cl2 (2 x 10 ml). The organic extracts were dried over Na2SO4 and concentrated under reduced pressure. Purification of the crude using flash column chromatography yielded the above product. (9b) White solid, 78% yield. m.p. : 163.0-164.50C 81 Chapter H NMR (500 MHz CDCl3 ppm): δ 2.32 (s, 3H), 2.58 (s, 6H), 6.48 (d, 1H, J = 8.2 Hz), 7.00 (s, 2H), 7.61 (d, 1H, J = 8.2 Hz). 13 C NMR (125 MHz CDCl3 ppm): δ 21.2, 22.5, 110.8, 111.5, 120.8, 130.4, 132.2, 141.4, 145.3, 145.4, 155.7. FTIR (KBr): 642, 678, 1174, 1363, 1636, 2920, 3287 cm-1. LRMS (FAB) m/z 372.0 (M+H+); 374.0 (M+H+) HRMS (FAB) m/z 371.9888 (M+ H+), calc. for C14H15NO479BrS 371.9900 HRMS (FAB) m/z 373.9870 (M+ H+), calc. for C14H15N1O481BrS 373.9879 4.2.8 Procedure for the synthesis of 9c5 N SO2Mes O OH 4b N Br K2CO3, KI MeCN, reflux, 95% SO2Mes O O To a mixture containing 4b (139.6 mg, 0.476 mmol, 1.0 eq.), K2CO3 (197.5 mg, 1.429 mmol, 3.0 eq.) and KI (7.9 mg, 0.048 mmol, 0.10 eq.) was added MeCN (3 ml). Allyl bromide (45.3 µl, 0.524 mmol, 1.1 eq.), was next added and the reaction mixture was heated at reflux for hours. After cooling to room temperature, water (5 ml) was added. The mixture was diluted with EtOAc (10ml) and extracted with additional EtOAc (2 x 10 ml). The organic extracts were dried over Na2SO4 and concentrated under reduced pressure. Purification of the crude using flash column chromatography yielded the above product. White solid, 95% yield. 82 Chapter H NMR (500 MHz CDCl3 ppm): δ 2.26 (s, 3H), 2.57 (s, 6H), 4.44 (d, 2H, J = 5.7 Hz), 5.24 (dd, 1H, J = 1.3, 10.7 Hz), 5.32 (dd, 1H, J = 1.3, 22.7 Hz), 5.95 (ddd, 1H, J = 5.7, 10.7, 22.7 Hz), 6.17 (dd, 1H, J = 6.9, 7.6 Hz), 6.56 (dd, 1H, J = 1.3, 7.6 Hz), 6.92 (s, 2H), 7.73 (dd, 1H, J = 1.3, 6.9 Hz). 13 C NMR (125 MHz CDCl3 ppm): δ 21.0, 22.4, 69.9, 104.4, 114.0, 118.8, 122.7, 131.2, 131.8, 131.9, 141.1, 144.4, 149.6, 156.6. FTIR (KBr): 665, 688, 756, 1010, 1126, 1169, 1272, 1349, 1609, 1673, 2925 cm-1. LRMS (FAB) m/z 334.1 (M+H+) HRMS (FAB) m/z 334.1111 (M+ H+), calc. for C17H20N1O4S 334.1108 O-allyl-protected 4b was dissolved in N,N-dimethylaniline (1 ml). The solution was heated at 1900C for 30 minutes. After cooling to room temperature, 10 % HCl was added till the pH is neutral and the solution was diluted with EtOAc (10ml) and extracted with additional EtOAc (2 x 10 ml). The organic extracts were dried over Na2SO4 and concentrated under reduced pressure. Purification using flash column chromatography yielded the above product as a white solid. (9c) White solid, 75% yield. m.p. : 138.2-139.50C 83 Chapter Ar 26.972 ea :4 11 34 .8 VWD1 A, Wav elength=240 nm (JULIAN\T10043B0.D) mAU A51.422 re a: 40 94 100 80 60 40 20 10 20 VWD1 A, Wav elength=240 nm (JULIAN\T10037A1.D) 30 40 50 40 50 60 60 Ar 26.360 ea :1 91 22 mAU 500 400 300 A50.356 re a: 83 40 .0 200 100 0 10 20 30 (10h) White solid, 91% yield, 90% ee. [α]D28 : +67.0 (c 0.8, CHCl3) O O S O N m.p. O Br HO N O Et : 190.0-190.5oC H NMR (500 MHz CDCl3 ppm): δ 1.13 (t, 3H, J = 6.9 Hz), 2.31 (s, 3H), 2.58 (s, 6H), 3.24 (d, 1H, J = 8.2 Hz), 3.54 (q, 2H, J = 6.9, 14.5 Hz), 3.72 (dd, 1H, J = 4.4, 8.2 Hz), 4.18 (s, 1H), 5.80 (dd, 1H, J = 4.4, 6.3 Hz), 6.68 (d, 1H, J = 6.3 Hz), 6.99 (s, 2H). 13 C NMR (125 MHz CDCl3 ppm): δ 12.7, 21.1, 22.6, 34.4, 44.4, 48.1, 52.3, 78.4, 128.3, 129.2, 131.3, 132.3, 141.1, 145.0, 168.4, 171.8, 172.7. FTIR (KBr): 678, 1097, 1169, 1350, 1404, 1703, 2941, 2976, 3447 cm-1. 118 Chapter LRMS (FAB) m/z 497.1 (M+H+); 499.1 (M+H+) HRMS (FAB) m/z 497.0360 (M+ H+), calc. for C20H22N2O679BrS 497.0376 HRMS (FAB) m/z 499.0343 (M+ H+), calc. for C20H22N2O681BrS 499.0356 The enantiomeric excess was determined by chiral HPLC; CHIRALPAK AS-H (4.6 mm i.d. x 250 mm); hexane/2-propanol 10/90; flow rate 0.5 ml/min; temp 25 0C; detection UV 240 nm; retention time 17.6 (major) and 30.7 (minor). Ar 17.680 ea :6 04 90 .7 VWD1 A, Wav elength=240 nm (JULIAN\T10110B1.D) mAU 500 A30.215 re a: 60 47 6. 400 300 200 100 10 VWD1 A, Wav elength=240 nm (JULIAN\T10107A6.D) 15 20 25 30 25 30 35 40 45 35 40 45 Ar 17.611 ea :9 40 14 .3 mAU 800 700 600 500 400 300 A30.728 re a: 41 62 .1 200 100 0 10 15 20 119 Chapter (10j) White solid, 92% yield, 90% ee. [α]D28 : +84.8 (c 0.8, CHCl3) O O S O N m.p. O Br HO N O : 125.0oC H NMR (500 MHz CDCl3 ppm): δ 2.30 (s, 3H), 2.55 (s, 6H), 3.26 (d, 1H, J = 8.2 Hz), 3.74 (dd, 1H, J = 4.4, 8.2 Hz), 4.16 (s, 1H), 4.61 (d, 2H, J = 7.6 Hz), 5.75 (dd, 1H, J = 4.4, 6.3 Hz), 6.45 (d, 1H, J = 6.3 Hz), 6.96 (s, 2H), 7.27-7.35 (m, 5H). 13 C NMR (125 MHz CDCl3 ppm): δ 21.1, 22.5, 44.6, 48.1, 52.3, 78.3, 128.0, 128.2, 128.7, 129.0, 129.5, 131.3, 132.3, 134.8, 141.1, 144.9, 168.4, 171.7, 172.5. FTIR (KBr): 678, 1099, 1169, 1350, 1398, 1707, 2954, 3033, 3451 cm-1. LRMS (FAB) m/z 559.1 (M+H+); 561.1 (M+H+) HRMS (FAB) m/z 559.0511 (M+ H+), calc. for C25H24N2O679BrS 559.0533 HRMS (FAB) m/z 561.0516 (M+ H+), calc. for C25H24N2O681BrS 561.0513 The enantiomeric excess was determined by chiral HPLC; CHIRALCEL OD-H (4.6 mm i.d. x 250 mm); hexane/2-propanol 25/75; flow rate 0.5 ml/min; temp 25 0C; detection UV 240 nm; retention time 28.2 (major) and 45.4 (minor). 120 Chapter Ar 29.620 ea :1 11 17 VWD1 A, Wav elength=240 nm (JULIAN\T10123A4.D) mAU 500 A44.083 re a: 10 89 41 400 300 200 100 10 20 VWD1 A, Wav elength=240 nm (JULIAN\T10120A2.D) 30 40 50 60 50 60 Ar 28.218 ea :1 26 45 mAU 700 600 500 400 300 A45.382 re a: 62 36 .1 200 100 0 10 20 30 40 (10k) White solid, 89% yield, 87% ee. [α]D28 : +110.5 (c 0.7, CHCl3) O O S O N m.p. O HO N O : 139.0oC H NMR (500 MHz CDCl3 ppm): δ 2.31 (s, 3H), 2.61 (s, 6H), 2.91 (dd, 1H, J = 6.3, 6.9, 18.0 Hz), 3.01 (dd, 1H, J = 6.3, 6.9, 18.0 Hz), 3.26 (d, 1H, J = 8.2 Hz), 3.87 (dd, 1H, J = 3.8, 8.2 Hz), 4.03 (s, 1H), 5.01 (dd, 1H, J = 1.3, 17.0 Hz), 5.09 (dd, 1H, J = 1.3, 10.1 Hz), 5.645.72 (m, 1H), 5.83 (dd, 1H, J = 4.4, 6.3 Hz), 6.45 (d, 1H, J = 6.3 Hz), 6.99 (s, 2H), 7.137.15 (m, 2H), 7.39-7.47 (m, 3H). 121 Chapter 13 C NMR (125 MHz CDCl3 ppm): δ 21.1, 22.5, 33.6, 44.7, 48.0, 51.2, 79.1, 118.8, 121.4, 126.2, 129.1, 129.3, 131.1, 131.6, 132.2, 132.3, 141.0, 144.7, 148.8, 170.8, 172.1, 172.7. FTIR (KBr): 663, 752, 1098, 1169, 1350, 1384, 1717, 2957, 3453 cm-1. LRMS (FAB) m/z 507.1 (M+H+) HRMS (FAB) m/z 507.1586 (M+ H+), calc. for C27H27N2O6S 507.1584 The enantiomeric excess was determined by chiral HPLC; CHIRALPAK AS-H (4.6 mm i.d. x 250 mm); hexane/2-propanol 10/90; flow rate 0.5 ml/min; temp 25 0C; detection UV 240 nm; retention time 17.6 (major) and 38.6 (minor). Ar 17.598 ea :1 15 00 VWD1 A, Wav elength=240 nm (JULIAN\T10043C0.D) mAU 600 500 A39.210 re a: 11 69 51 400 300 200 100 10 VWD1 A, Wav elength=240 nm (JULIAN\T10037C1.D) 20 30 40 50 50 Ar 17.586 ea :1 71 35 mAU 1200 1000 800 600 A38.636 re a: 11 96 3. 400 200 0 10 20 30 40 122 Chapter (10m) White solid, 93% yield,83% ee. [α]D28 : +97.6 (c 0.7, CHCl3) O O S O N m.p. O HO N O : 185.0oC H NMR (500 MHz CDCl3 ppm): δ 0.85 (t, 3H, J = 7.6 Hz), 1.33-1.44 (m, 2H), 2.09-2.18 (m, 1H), 2.23-2.30 (m, 1H), 2.31 (s, 3H), 2.61 (s, 6H), 3.24 (d, 1H, J = 8.2 Hz), 3.87 (dd, 1H, J = 3.8, 8.2 Hz), 4.01 (s, 1H), 5.81 (dd, 1H, J = 4.4, 5.7 Hz), 6.16 (d, 1H, J = 5.7 Hz), 6.98 (s, 2H), 7.13-7.15 (m, 2H), 7.38-7.47 (m, 3H). 13 C NMR (125 MHz CDCl3 ppm): δ 13.6, 20.0, 21.1, 22.5, 31.3, 44.7, 48.1, 51.2, 79.2, 120.4, 126.1, 129.0, 129.3, 131.2, 131.7, 132.2, 141.0, 144.6, 150.3, 171.0, 172.2, 172.7. FTIR (KBr): 673, 1099, 1169, 1350, 1383, 1716, 2933, 2961, 3461 cm-1. LRMS (FAB) m/z 509.3 (M+H+) HRMS (FAB) m/z 509.1750 (M+ H+), calc. for C27H29N2O6S 509.1741 The enantiomeric excess was determined by chiral HPLC; CHIRALCEL OD-H (4.6 mm i.d. x 250 mm); hexane/2-propanol 50/50; flow rate 0.5 ml/min; temp 25 0C; detection UV 240 nm; retention time 22.7 (minor) and 36.8 (major). 123 Chapter Ar 22.367 ea :1 93 07 VWD1 A, Wav elength=240 nm (JULIAN\T10122B0.D) mAU 1400 A36.614 re a: 19 67 36 1200 1000 800 600 400 200 10 VWD1 A, Wav elength=240 nm (JULIAN\T10119B1.D) 20 30 40 50 50 Ar 36.800 ea :1 50 97 mAU 600 500 400 A22.714 re a: 14 24 0. 300 200 100 0 10 20 30 40 124 Chapter Determination of the Relative Configuration of 11a and 11b by 1H-1H 2D COSY NMR The structures of the Diels-Alder products were elucidated using NMR techniques. Chemical shifts of H5exo and H5endo protons were correlated with values in the literature.2 1H-1H COSY showed there is correlation between H5exo, H6endo and H6exo in the endo product; and correlation between H5endo, H6endo’and H6exo’ in the exo product. There is no correlation with H1 for both products. H5endo H5exo H6endo’ H6endo H6exo’ H6exo 125 Chapter R N R N O O H6exo' H6exo H1 HO H1 H5exo H6endo HO COMe H6endo' COMe H5endo endo product exo product Determination of the Relative Configuration of 11a and 11b by 1D NOE R N O H6exo 9.5% NOE H1 HO H5exo H6endo No NOE COMe endo product (major product), H5exo at 3.05ppm 126 Chapter R N O H6exo' H1 COMe H6endo' 5.0% NOE HO H5endo No NOE exo product (minor product), H5endo at 3.18ppm (11a) + (11b) White solid, 85% yield, both isomers not O O S O N O HO separable by flash column chromatography. O S O N endo isomer : 1H NMR (500 MHz CDCl3 ppm): δ 2.09 O HO O (ddd, 1H, J = 1.9, 4.4, 12.9 Hz), 2.30 (s, 3H), 2.31 (s, 3H), 2.38 (ddd, 1H, J = 3.8, 9.5, 13.2 Hz), 2.59 (s, 6H), 3.05 (dd, 1H, J = 4.4, 9.5 Hz), 3.94 (s, 1H), 5.41-5.44 (m, 1H), 6.15-6.17 (m, 1H), 6.51 (dd, 1H, J = 4.4, 9.5 Hz), 6.96 (s, 2H). exo isomer : 1H NMR (500 MHz CDCl3 ppm): δ 2.00 (ddd, 1H, J = 2.5, 10.7, 13.2 Hz), 2.23 (s, 3H), 2.29 (s, 3H), 2.26-2.29 (m, 1H, overlap with methyl peaks), 2.64 (s, 6H), 3.18 (dd, 1H, J = 5.0, 10.7 Hz), 3.86 (s, 1H), 5.39-5.42 (m, 1H), 6.35 (dd, 1H, J = 1.9, 8.2 Hz), 6.55 (dd, 1H, J = 5.7, 8.2 Hz), 6.97 (s, 2H). LRMS (FAB) m/z 364.1 (M+H+) 127 Chapter HRMS (FAB) m/z 364.1204 (M+ H+), calc. for C18H22NO5S 364.1213 The enantiomeric excess was determined by chiral HPLC; CHIRALPAK IC (4.6 mm i.d. x 250 mm); flow rate 0.5 ml/min; temp 25 0C; detection UV 240 nm. A gradient eluent was used: 0-40 min, hexane/2-propanol 80/20; 40-45 min, hexane/2-propanol 80/20 increased polarity to 60/40; 45 to end hexane/2-propanol 60/40. Major product retention time 30.8 and 35.5 min, 90% ee. Minor product retention time 74.9 and 87.1 min, 90% ee. 75.642 600 35.242 31.056 VWD1 A, Wav elength=240 nm (JULIAN\T1027301.D) mAU 89.902 500 400 300 200 100 20 VWD1 A, Wav elength=240 nm (JULIAN\T10253B0.D) 40 60 40 60 80 30.815 mAU 600 500 400 87.105 300 100 74.882 35.545 200 0 20 80 128 Chapter (12a)+ (12b) White solid, 85% yield, both isomers not separable by flash column chromatography. O O S O N O O S O N endo isomer : 1H NMR (500 MHz CDCl3 ppm): δ O HO O HO 1.03 (t, 3H, J = 7.6 Hz), 2.02 (ddd, 1H, J = 1.9, 4.4, 13.2 Hz), 2.41 (q, 2H, J = 7.6, 14.5 Hz), 2.44-2.46 (m,1H), 2.28 (s, 3H), 2.57 (s, 6H), 3.02 (dd, 1H, J = 4.4, 9.5 Hz), 3.96 (s, 1H), 5.40-5.42 (m, 1H), 6.14-6.15 (m, 1H), 6.51 (dd, 1H, J = 5.7, 8.2 Hz), 6.94 (s, 2H). LRMS (FAB) m/z 378.1 (M+H+) HRMS (FAB) m/z 378.1366 (M+ H+), calc. for C19H24NO5S 378.1370 The enantiomeric excess was determined by chiral HPLC; CHIRALPAK IC (4.6 mm i.d. x 250 mm); flow rate 0.5 ml/min; temp 25 0C; detection UV 240 nm. A gradient eluent was used: 0-40 min, hexane/2-propanol 80/20; 40-45 min, hexane/2-propanol 80/20 increased polarity to 60/40; 45 to end hexane/2-propanol 60/40. Major product retention time 23.9 and 26.7 min, 90% ee. Minor product retention time 61.8 and 65.4 min, 90% ee. 129 Chapter 1750 26.043 23.648 VWD1 A, Wav elength=240 nm (JULIAN\T1027502.D) mAU 1500 1250 1000 750 250 62.966 60.047 500 10 20 VWD1 A, Wav elength=240 nm (JULIAN\T1026300.D) 30 40 50 60 30 40 50 60 23.864 mAU 1750 1500 61.768 1250 1000 750 250 65.384 26.706 500 0 10 20 4.3.5 Characterisation of Michael products. N NO2 OH NO2 SO2Mes (13a) White solid, 75% yield, 96% ee. O [α]D28 : +10.3 (c 0.3, CHCl3) m.p. : 146.0-147.0oC H NMR (500 MHz CDCl3 ppm): δ 2.32 (s, 3H), 2.56 (s, 6H), 5.07 (dd, 1H, J = 7.6, 14.5 Hz), 5.19 (dd, 1H, J = 8.2, 14.5 Hz), 5.51 (t, 1H, J = 7.6 Hz), 6.19 (d, 1H, J = 7.6 Hz), 6.86 (s, 1H), 7.00 (s, 2H), 7.47-7.50 (m, 1H), 7.54-7.55 (m, 1H), 7.59-7.62 (m, 1H), 7.647.66 (d, 1H, J = 7.6 Hz), 7.92-7.93 (m, 1H). 130 Chapter 13 C NMR (125 MHz CDCl3 ppm): δ 21.2, 22.5, 39.5, 75.1, 107.0, 121.4, 124.7, 125.4, 129.3, 129.6, 130.5, 131.3, 132.3, 133.5, 141.4, 144.4, 145.4, 149.5, 157.0. FTIR (KBr): 670, 1133, 1173, 1368, 1528, 1556, 1615, 1651, 2945, 3279 cm-1. LRMS (FAB) m/z 488.2 (M+H+) HRMS (FAB) m/z 488.1130 (M+ H+), calc. for C22H22N3O8S 488.1122 The enantiomeric excess was determined by chiral HPLC; CHIRALCEL OD-H (4.6 mm i.d. x 250 mm); hexane/2-propanol 75/25; flow rate 0.5 ml/min; temp 25 0C; detection UV 240 nm; retention time 43.5 and 57.2 min. 41.482 VWD1 A, Wav elength=240 nm (JULIAN\T1025901.D) 55.924 mAU 200 150 100 50 0 10 20 30 40 30 40 50 60 70 80 60 70 80 57.193 VWD1 A, Wav elength=240 nm (JULIAN\T1025400.D) mAU 350 300 250 200 150 43.473 100 50 0 10 20 50 131 Chapter N O2 N SO2Mes (13b) White solid, 75% yield, 80% ee. O [α]D28 : +1.0 (c 0.3, CHCl3) OH NO2 m.p. : 165.0-166.0oC H NMR (500 MHz CDCl3 ppm): δ 2.32 (s, 3H), 2.57 (s, 6H), 5.01 (t, 1H, J = 8.2 Hz), 5.06 (dd, 1H, J = 8.2, 13.2 Hz), 5.14 (dd, 1H, J = 6.9, 13.2 Hz), 6.13 (d, 1H, J = 8.2 Hz), 6.92 (s, 1H), 7.00 (s, 2H), 7.54-7.57 (m, 1H), 7.66-7.67 (m, 1H), 7.70 (d, 1H, J = 8.2 Hz), 8.18-8.19 (m, 1H). 13 C NMR (125 MHz CDCl3 ppm): δ 21.2, 22.6, 43.7, 75.7, 106.1, 121.9, 122.7, 123.3, 124.4, 130.3, 130.4, 132.3, 133.9, 138.8, 141.5, 144.2, 145.5, 148.7, 156.9. FTIR (KBr): 680, 1139, 1173, 1364, 1532, 1553, 1622, 1656, 2978, 3300 cm-1. LRMS (FAB) m/z 488.2 (M+H+) HRMS (FAB) m/z 488.1122 (M+ H+), calc. for C22H22N3O8S 488.1122 The enantiomeric excess was determined by chiral HPLC; CHIRALCEL OD-H (4.6 mm i.d. x 250 mm); hexane/2-propanol 50/50; flow rate 0.5 ml/min; temp 25 0C; detection UV 240 nm; retention time 15.1 and 21.1 min. 132 Chapter Ar 42.924 ea :8 21 83 .8 VWD1 A, Wav elength=240 nm (JULIAN\Y T102793.D) mAU 64.801 250 200 150 100 50 10 20 VWD1 A, Wav elength=240 nm (JULIAN\T10240A1.D) 30 40 30 40 50 60 70 80 80 Ar 64.829 ea :7 10 38 .9 mAU 160 140 120 100 80 A45.046 re a: 73 11 .4 60 40 20 0 10 20 50 60 70 133 [...]... = 4. 4, 8 .2 Hz), 4. 14 (s, 1H), 5. 82 (dd, 1H, J = 4. 4, 6 .3 Hz), 6 .44 (dd, 1H, J = 6 .3 Hz), 6.98 (s, 2H) 13 C NMR ( 125 MHz CDCl3 ppm): δ 12. 7, 21 .1, 22 .6, 34 .3, 44 .2, 48 .2, 51 .3, 78 .3, 1 23 . 5, 131 .3, 1 32 .3, 139 .0, 141 .1, 145 .0, 168.5, 1 72. 0, 1 72. 7 FTIR (KBr): 6 64, 1099, 1170, 122 9, 135 1, 140 4, 17 03, 29 45 , 29 77, 34 50 cm-1 LRMS (FAB) m/z 4 53. 1 (M+H+) HRMS (FAB) m/z 4 53. 0889 (M+ H+), calc for C20H2 2N2 O 635 ClS... (m, 1H), 6 .48 -6 .49 (m, 1H), 6. 54 (dd, 1H, J = 5.7, 8 .2 Hz), 6. 93 (d, 2H, J = 9.5 Hz), 6.98 (s, 2H), 7.07 (d, 2H, J = 9.5 Hz) 99 Chapter 4 13 C NMR ( 125 MHz CDCl3 ppm): δ 14. 7, 21 .1, 22 .6, 25 .3, 44 .4, 47 .7, 51 .4, 53. 4, 63. 7, 78.0, 115.0, 1 23 . 4, 127 .3, 128 .9, 131 .6, 1 32 .2, 137 .2, 141 .0, 144 .7, 159 .2, 170.5, 1 72. 4, 1 72. 8 FTIR (KBr): 6 74, 1 137 , 1171, 1 23 2 , 1 34 6, 140 8, 1686, 1 736 , 29 43 , 29 74, 34 38 cm-1 LRMS... (s, 2H), 7.06 (d, 2H, J = 8.0 Hz), 7 .25 (d, 2H, J = 8.0 Hz) 13 C NMR ( 125 MHz CDCl3 ppm): δ 21 .1, 21 .2, 22 .6, 44 .5, 47 .8, 51 .4, 78.0, 125 .9, 128 .4, 128 .9, 129 .9, 131 .5, 1 32 .2, 137 .2, 139 .3, 141 .0, 144 .7, 170.5, 1 72. 2, 1 72. 7 FTIR (KBr): 6 74, 821 , 1105, 11 72, 135 7, 138 9, 15 14, 1686, 1 7 32 , 1786, 29 43 , 34 60 cm-1 LRMS (FAB) m/z 48 1 .2 (M+H+) HRMS (FAB) m/z 48 1.1 43 5 (M+H+), calc for C25H2 5N2 O6S 48 1.1 42 8 The... (s, 2H), 7.09 (d, 2H, J = 8.8 Hz), 7.58 (d, 2H, J = 8.8 Hz) 13 C NMR ( 125 MHz CDCl3 ppm): δ 21 .1, 22 .6, 25 .3, 44 .6, 47 .8, 51 .3, 78.0, 1 23 . 0, 127 .6, 128 .9, 130 .0, 131 .4, 1 32 .2, 1 32 .4, 137 .3, 141 .0, 144 .8, 170 .4, 171.8, 1 72. 2 FTIR (KBr): 6 74, 1099, 1167, 1 34 8, 138 6, 149 1, 1716, 29 57, 34 47 cm-1 1 02 Chapter 4 LRMS (FAB) m/z 545 .0 (M+H+); 547 .0 (M+H+) HRMS (FAB) m/z 545 . 038 0 (M+H+), calc for C24H2 2N2 O679BrS... 6.50-6. 52 (dd, 1H, J = 1 .3, 8 .2 Hz), 6.55-6.58 (dd, 1H, J = 5.7, 7.6 Hz), 6.99 (s, 2H), 7.10-7. 12 (m, 1H), 7 .36 -7 .37 (m, 1H), 7. 52- 7. 54 (m, 1H) 13 C NMR ( 125 MHz CDCl3 ppm): δ 21 .1, 22 .6, 44 .7, 47 .8, 51 .3, 78.0, 125 .3, 128 .0, 129 .0, 130 .2, 131 .4, 1 32 .3, 133 .3, 133 .4, 137 .4, 141 .1, 144 .9, 170 .3, 171 .4, 171.9 FTIR (KBr): 6 74, 1101, 1168, 1 34 9, 137 8, 147 6, 1 720 , 29 53, 34 20 cm-1 LRMS (FAB) m/z 535 .1 (M+H+); 537 .1... = 8 .2 Hz), 3. 51 (q, 2H, J = 6.9, 7.6 Hz), 3. 72 (dd, 1H, J = 3. 8, 8 .2 Hz), 4. 03 (s,1H), 5.78-5.81 (m, 1H), 6 .36 -6 .37 (m, 1H), 6 .44 (dd, 1H, J = 5.7, 8 .2 Hz), 6.96 (s, 2H) 96 Chapter 4 13 C NMR ( 125 MHz CDCl3 ppm): δ 12. 7, 21 .1, 22 .5, 34 .2, 44 .4, 47 .7, 51 .3, 77.9, 128 .6, 131 .6, 1 32 .2, 137 .1, 141 .0, 144 .7, 170.6, 1 72. 9, 1 73. 3 FTIR (KBr): 675, 11 02, 1 137 , 1171, 1 23 2 , 1 34 6, 1686, 1 736 , 29 43 , 34 38 cm-1 LRMS... for C25H2 5N2 O6S 48 1.1 42 8 The enantiomeric excess was determined by chiral HPLC; CHIRALPAK AS-H (4. 6 mm i.d x 25 0 mm); 2- propanol; flow rate 0.9 ml/min; temp 25 0C; detection UV 24 0 nm; retention time 21 .8 min (major) and 81.7 min (minor) 98 Chapter 4 Ar 22 .49 4 ea :1 43 11 1 VWD1 A, Wav elength = 24 0 nm (JULIAN\Y T8162B0.D) mAU 40 30 89. 133 Ar ea :1 32 72 3 20 10 0 20 VWD1 A, Wav elength = 24 0 nm (JULIAN\Y... 29 . 649 600 500 40 0 30 0 20 0 100 0 0 5 10 15 20 25 30 35 min 21 .38 3 VWD1 A, Wav elength = 24 0 nm (JULIAN\Y T8091A1.D) mAU 600 500 40 0 30 0 30 . 6 24 20 0 100 0 0 5 10 15 20 25 30 35 min (6j) White solid, 96% yield, 88% ee [α]D28 : +0.9 (c 0 .4, CHCl3) O O S O N m.p 1 O HO N O : 2 13. 4 -21 4. 60C H NMR (500 MHz CDCl3 ppm): δ 2. 25 (s, 6H), 2 .30 (s, 3H), 2. 53 (s, 6H), 3. 25 (d, 1H, J = 8 .2 Hz), 3. 92 (dd, 1H, J = 4. 4,... CDCl3 ppm): δ 17 .2, 18.1, 18 .3, 106.5, 1 14. 1, 121 .2, 133 .3, 135 .4, 135 .9, 1 42 . 5, 147 .1, 157.6 FTIR (KBr): 649 , 7 43 , 1119, 1166, 121 4, 135 4, 139 3, 1 622 , 1655, 29 24, 32 87 cm-1 LRMS (FAB) m/z 32 2. 2 (M+H+) HRMS (FAB) m/z 32 2. 1 121 (M+ H+), calc for C16H2 0N1 O4S 32 2. 1108 4 .3. 4 Characterisation of Diels-Alder Products O (4d) White solid, 73% yield (major isomer), 90% ee O O HO N O [α]D28 : +158.1 (c 0 .21 ,... 6.9 Hz), 5. 74- 5.76 (m, 1H), 6. 14- 6.16 (m, 1H), 6 .21 (dd, 1H, J = 5.7, 8 .2 Hz), 6. 94 (s, 2H), 7 .26 -7 . 32 (m, 5H) 13 C NMR ( 125 MHz CDCl3 ppm): δ 21 .1, 22 .5, 25 .3, 42 . 9, 44 .5, 47 .7, 51 .3, 77.9, 128 .2, 128 .5, 128 .6, 129 .0, 131 .5, 1 32 .2, 135 .1, 136 .9, 141 .0, 144 .7, 170.5, 1 72. 8, 1 73. 0 FTIR (KBr): 6 74, 1101, 1167, 1 34 7, 139 9, 17 04, 29 50, 34 45 cm-1 LRMS (FAB) m/z 48 1.1 (M+H+) HRMS (FAB) m/z 48 1. 140 4 (M+H+), . 7 .22 -7 . 24 (m, 2H), 7 .33 -7 . 34 (m, 2H). 13 C NMR ( 125 MHz CDCl 3 ppm): δ 23 . 6, 40 .1, 50.5, 75 .3, 75 .3, 125 .4, 126 .3, 126 .3, 128 .1, 140 .1, 141 .4. FTIR (film): 10 83, 122 0, 141 5, 1 533 , 29 60, 30 10. 93 13 C NMR ( 125 MHz CDCl 3 ppm): δ 21 .3, 22 .5, 106 .3, 1 14 .3, 121 .7, 131 .0, 1 32 .2, 141 .3, 145 .1, 147 .2, 157.7. FTIR (KBr): 6 73, 744 , 1119, 1171, 128 6, 135 9, 1 636 , 1659, 29 41 , 31 22 , 33 99 cm -1 MHz CDCl 3 ppm): δ 21 .2, 22 .5, 108.8, 120 .8, 122 .8, 130 .4, 1 32 .2, 141 .4, 1 43 . 6, 145 .4, 156 .4. FTIR (KBr): 648 , 685, 11 23 , 11 74, 136 5, 1618, 1 638 , 29 78, 32 69 cm -1 . LRMS (FAB) m/z 32 8 .2 (M+H + )