Organocatalytic reactions of 3 hydroxy 2 pyrone and n arylsulfonyl 3 hydroxy 2 pyridone 4

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 aceta

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Chapter4

Experimental Section

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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

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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 H-atoms were put at calculated positions

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

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4.2.1 General procedure for Vinylogous Aldol Reaction of 3-hydroxy-2-pyrone and

aldehydes

To a 4 ml sample vial containing 1 (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)

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4.2.2 General procedure for Diels-Alder reaction of 3-hydroxy-2-pyrone and

N-mesityl-maleimide

To a 4 ml sample vial containing catalyst 8a (1.6 mg, 0.008 mmol, 0.1 eq.),

3-hydroxy-2-pyrone (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,

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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 4 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-2-pyridone and N-substituted-maleimides

N

OH O

N O

O

N O

HO +

To a 4 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

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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 9a 3

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 0 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

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1H 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)

13C NMR (125MHz 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 9b 4

N O OH

Br

N O OH

9b 4b

To a solution of 4b (198.9 mg, 0.679 mmol, 1.0 eq.) in CH2Cl2 (2 ml) was added

i-Pr2NH (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 5 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

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1H 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)

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 9c 5

N O OH

K 2 CO 3 , KI MeCN, reflux, 95%

N O O

Br

4b

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 2 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

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1H 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)

13C 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

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

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1H NMR (500 MHz CDCl3 ppm): δ 2.31 (s, 3H), 2.59 (s, 6H), 3.27 (d, 2H, J = 6.9 Hz), 5.12 (m, 1H), 5.14 (m, 1H), 5.86 (m, 1H), 6.19 (d, 1H, J = 7.6 Hz), 6.47 (s, 1H), 6.98 (s, 2H), 7.65 (d, 1H, J = 7.6 Hz)

FTIR (KBr): 658, 684, 1172, 1367, 1614, 1650, 2976, 3307 cm-1

HRMS (FAB) m/z 334.1122 (M+ H+), calc for C17H20NO4S 334.1108

4.2.9 Procedure for the synthesis of 9d

To a solution containing 9c (133.2 mg, 0.400 mmol, 1.0 eq.) dissolved in EtOAc (5 ml)

was added Pd/C (10 % by weight) Bubbling of hydrogen gas for 15 minutes and the reaction mixture was stirred for a further 4 hours under a positive atmosphere of hydrogen gas (balloon) The reaction mixture was filtered and flash column chromatography yielded the titled compound as a white solid

(9d) White solid, 90% yield m.p.: 156.5-157.50C

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1H NMR (500 MHz CDCl3 ppm): δ 0.94 (t, 2H, J = 7.6 Hz), 1.60 (sextet, 2H, J = 7.6 Hz), 2.31 (s, 3H), 2.48 (t, 2H, J = 7.6 Hz), 2.59 (s, 6H), 6.18 (d, 1H, J = 8.2 Hz), 6.42 (s, 1H), 6.98 (s, 2H), 7.64 (d, 1H, J = 8.2 Hz)

FTIR (KBr): 669, 1169, 1371, 1544, 1606, 1652, 2925, 2961, 3341 cm-1

HRMS (FAB) m/z 336.1266 (M+ H+), calc for C17H22NO4S 336.1264

4.2.10 Procedure for the synthesis of 9e 6

The procedure for the protection of the alcohol is the same as for the synthesis of 4b

White solid, 85% yield

1H NMR (500 MHz CDCl3 ppm): δ 0.04 (s, 6H), 0.92 (s, 9H), 2.30 (s, 6H), 2.57 (s, 6H),

6.39 (d, 1H, J = 8.2 Hz), 6.94 (s, 2H), 7.59 (d, 1H, J = 8.2 Hz)

13C NMR (125 MHz CDCl3 ppm): δ 18.8, 21.1, 22.5, 25.8, 109.8, 119.2, 122.2, 131.0, 131.8, 141.5, 144.6, 145.4, 156.2

FTIR (KBr): 681, 740, 1176, 1354, 1604, 1677, 2857, 2930 cm-1

LRMS (FAB) m/z 486.2 (M+H+); 488.2 (M+H+)

HRMS (FAB) m/z 486.0773 (M+ H+), calc for C20H29NO479BrSSi486.0764

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HRMS (FAB) m/z 488.0762 (M+ H+), calc for C20H29NO481BrSSi488.0744

A modified procedure for the Suzuki coupling was carried out

O-TBS-protected 9b (34.1 mg, 0.070 mmol, 1.0 eq.) and 4-chloro-phenyl boronic acid

(10.6 mg, 0.084 mmol, 1.2 eq.) were dissolved in 2-propanol (1 ml) The mixture was stirred for 30 minutes allowing complete dissolution of all solids Palladium acetate (0.8

mg, 0.0035 mmol, 0.05 eq.), tricyclohexylphosphine (2.0 mg, 0.0070 mmol, 0.10 eq.) and 2M aqueous sodium carbonate (70 µl) were added The reaction mixture was heated at reflux for 1.5 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 which was subjected to desilylation with BF3.Et2O The procedure for the desilylation of

the TBS group is the same as for the synthesis of 4b

(9e) White solid, 75% yield for 2 steps

m.p : 168.5-169.00C

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1H NMR (500 MHz CDCl3 ppm): δ 2.33 (s, 3H), 2.63 (s, 6H), 6.46 (d, 1H, J = 8.2 Hz), 6.95 (s, 1H), 7.01 (s, 2H), 7.42 (d, 2H, J = 8.8 Hz), 7.64 (d, 2H, J = 8.8 Hz), 7.76 (d, 1H,

J = 8.2 Hz)

13C NMR (125MHz CDCl3 ppm): δ 21.2, 22.6, 107.6, 120.8, 125.0, 128.8, 129.9, 130.8, 132.2, 132.5, 134.9, 141.4, 143.0, 145.2, 157.8

FTIR (KBr): 639, 681, 1169, 1367, 1616, 1650, 3309 cm-1

HRMS (FAB) m/z 404.0731 (M+H+), calc for C20H19NO435ClS 404.0718

4.2.11 General procedure for Diels-Alder reaction of

N-arylsulfonyl-4-substituted-3-hydroxy-2-pyridone and N-substituted-maleimides

The procedure is the same for the synthesis of the adducts 6a-j

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4.2.12 General procedure for Diels-Alder reaction of

N-arylsulfonyl-3-hydroxy-2-pyridone and alkyl vinyl ketones

0.080 mmol, 1.0 eq.) was added, followed by 0.2 ml of CHCl3 The reaction mixture was stirred for 15 min until a clear solution was obtained 0.5 ml of methyl vinyl ketone (excess) was then added The reaction mixture was capped and placed in a cryobath preset at -40oC After stirring for 48 hrs, the solvent was removed under reduced pressure and the residue was dissolved in 1 ml of CH2Cl2 It was washed with deionised water (1 ml), 1% HCl (1 ml) and deionised water (1 ml) again After drying with Na2SO4, the solvent was removed under pressure and purified using flash column chromatography to

give a mixture of endo and exo products (~ 3:1 by HPLC) in 85% yield

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4.2.13 General procedure for Michael reaction of

N-arylsulfonyl-3-hydroxy-2-pyridone and β-nitro styrenes

0.080 mmol, 1.0 eq.) was added, followed by 0.5 ml of solvent The reaction mixture was placed in a cryobath preset at 0oC and allowed to stir for an hour 1-nitro-2-(2-nitrovinyl)benzene (46.6 mg, 0.240 mmol, 3.0 eq.) was then added After stirring for 72 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 13a was obtained as a white solid in 75% yield

References

1) Ju, Y.; Varma, R S J Org Chem 2006, 71, 135

2) Böhm, M.; Lorthiois, E.; Meyyappan, M.; Vasella, A Helv Chim Acta 2003, 86,

3787–3817

3) Gnaim, J M.; Sheldon, R A Tetrahedron Lett 1995, 36, 3893

4) Fujisaki, S.; Eguchi, H.; Omura, A.; Okamoto, A.; Nishida, A Bull Chem Soc

Jpn 1993, 66, 1576

5) Moffett, R B J Org Chem 1963, 28, 2885

6) Littke, A F.; Dai, C.; Fu, G C J Am Chem Soc 2000, 122, 4020–4028

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4.3 Characterization of compounds

4.3.1 Characterisation of Vinylogous Aldol Product

(VAP1) Yellow liquid, 75% yield

1H NMR (500 MHz CDCl3 ppm): δ 5.57 (s, 1H), 6.23 (d, 1H, J = 7.6 Hz), 6.66 (d, 1H, J = 7.6 Hz), 7.57 (d, 1H, J = 8.2 Hz), 7.69 (d, 1H, J = 8.2 Hz)

13C NMR (125 MHz CDCl3 ppm): δ 72.0, 103.6, 114.3, 127.4, 132.6

FTIR (film): 1079, 1216, 1410, 1520, 2974, 3019 cm-1

LRMS (FAB) m/z 242.0 (M-)

HRMS (FAB) m/z 242.0459 (M-), calc for C13H8NO4 242.0448

4.3.2 Characterisation of amino indanol catalysts

(8a) (1R,2S)-2,3-dihydro-1-(pyrrolidin-1-yl)-1H-inden-2-ol

Yellow liquid, 75% yield

1H NMR (500 MHz CDCl3 ppm): δ 1.70-1.79 (m, 4H), 2.54-2.59 (m,

2H), 2.74-2.77 (m, 2H), 2.58 (dd, 1H, J = 7.6, 16.4 Hz), 3.20 (dd, 1H, J = 7.6, 15.8 Hz), 4.27 (d, 1H, J = 7.6 Hz), 4.43 (dd, 1H, J = 7.6, 14.5 Hz), 7.17-7.33 (m, 4H)

13C NMR (125 MHz CDCl3 ppm): δ 23.4, 40.8, 50.5, 66.4, 70.3, 125.5, 126.2, 126.4, 128.4, 139.1, 141.9

N

OH

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(8d) (1R,2S)-2,3-dihydro-1-(isoindolin-2-yl)-1H-inden-2-ol

White crystalline solid, 73% yield

m.p : 88.0-89.0oC

1H NMR (500 MHz CDCl3 ppm): δ 2.89 (dd, 1H, J = 6.9, 7.6, 16.1 Hz), 3.28 (dd, 1H, J = 6.9, 7.6, 16.1 Hz), 4.03 (d, 1H, J = 10.7 Hz), 4.21 (d, 1H, J = 11.4 Hz), 4.48 (d, 1H, J = 6.9 Hz), 4.54 (q, 1H, J = 6.9, 14.5 Hz), 7.17-7.22 (m, 5H), 7.26-7.29

(m, 2H), 7.36-7.38 (m, 1H)

13C NMR (125 MHz CDCl3 ppm): δ 40.7, 56.0, 66.8, 70.8, 122.2, 125.5, 126.8, 126.8, 128.6, 139.1, 139.4, 141.7

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FTIR (KBr): 673, 744, 1119, 1171, 1286, 1359, 1636, 1659, 2941, 3122, 3399 cm-1 LRMS (FAB) m/z 294.1 (M+H+)

HRMS (FAB) m/z 294.0787 (M+ H+), calc for C14H16NO4S294.0795

(4c) White solid, 60% yield

m.p : 145.0-146.00C

1H NMR (500 MHz CDCl3 ppm): δ 2.41 (s, 6H), 6.25 (dd, 1H, J = 6.9, 7.6 Hz), 6.76 (dd, 1H, J = 1.3, 6.9 Hz), 7.31 (s, 1H), 7.66 (dd, 1H, J = 1.3, 7.6

Hz), 7.70 (s, 2H)

13C NMR (125MHz CDCl3 ppm): δ 21.2, 106.9, 114.2, 121.5, 127.0, 136.0, 136.9, 139.2, 147.2, 157.4

FTIR (KBr): 683, 806, 1119, 1174, 1254, 1297, 1402, 1429, 1627, 1651, 2923, 3302 cm-1 LRMS (FAB) m/z 280.2 (M+H+)

HRMS (FAB) m/z 280.0642 (M+ H+), calc for C13H14NO4S280.0638

(4d) White solid, 50% yield

m.p : 140.0-141.50C

1H NMR (500 MHz CDCl3 ppm): δ 2.26 (s, 6H), 2.30 (s, 3H), 2.52 (s, 6H),

6.29 (dd, 1H, J = 6.9, 7.6 Hz), 6.43 (s, 1H, OH), 6.79 (dd, 1H, J = 1.9, 6.9 Hz), 7.71 (dd, 1H, J = 1.9, 7.6 Hz)

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13C NMR (125 MHz CDCl3 ppm): δ 17.2, 18.1, 18.3, 106.5, 114.1, 121.2, 133.3, 135.4, 135.9, 142.5, 147.1, 157.6

HRMS (FAB) m/z 322.1121 (M+ H+), calc for C16H20N1O4S322.1108

4.3.4 Characterisation of Diels-Alder Products

(4d) White solid, 73% yield (major isomer), 90% ee

[α]D28 : +158.1 (c 0.21, CHCl3) m.p : 155.0-157.0oC

1H NMR (500 MHz CDCl3 ppm): δ 2.00 (s, 3H), 2.02 (s, 3H), 2.29 (s,

3H), 3.33 (d, 1H, J = 8.2 Hz), 3.97 (dd, 1H, J = 4.4, 8.2 Hz), 4.00 (s, 1H), 5.70 (m, 1H), 6.59 (dd, 1H, J = 5.0, 8.2 Hz), 6.67 (m, 1H), 6.94 (s, 1H), 6.95 (s, 1H)

13C NMR (125 MHz CDCl3 ppm): δ 17.8, 18.7, 21.0, 43.6, 46.7, 72.2, 75.1, 126.7, 128.9, 129.5, 129.6, 134.7, 135.4, 137.8, 140.0, 171.6, 171.8, 171.9

FTIR (KBr): 975, 1141, 1194, 1378, 1716, 1768, 2923, 2959, 3471 cm-1

HRMS (FAB) m/z 328.1271 (M+ H+), calc for C18H18NO5 328.1371

The enantiomeric excess was determined by chiral HPLC; CHIRALPAK OC-H (4.6 mm i.d x 250 mm); methanol/2-propanol 50/50; flow rate 0.5 ml/min; temp 25 0C; detection

UV 224 nm; retention time 14.0 min (minor) and 16.6 min (major)

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1H NMR (500 MHz CDCl3 ppm): δ 2.31 (s, 3H), 2.61 (s, 6H), 3.26

(d, 1H, J = 7.6 Hz), 3.91 (dd, 1H, J = 3.8, 8.2 Hz), 4.11 (s, 1H), 5.89 (m, 1H), 6.50 (dd, 1H, J = 1.3, 8.2 Hz), 6.56 (dd, 1H, J = 5.7,

8.2 Hz), 6.98 (s, 2H), 7.18-7.20 (m, 2H), 7.39-7.47 (m, 3H)

13C NMR (125MHz CDCl3 ppm): δ21.1, 22.6, 25.3, 44.6, 47.8, 51.4, 78.0, 126.2, 129.0, 129.1, 129.2, 131.1, 131.5, 132.2, 137.3, 141.0, 144.7, 170.5, 172.1, 172.5

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HRMS (FAB) m/z 467.1271 (M+ H+), calc for C24H23N2O6S467.1271

The enantiomeric excess was determined by chiral HPLC; CHIRALPAK AS-H (4.6 mm i.d x 250 mm); hexane/2-propanol 5/95; flow rate 0.7 ml/min; temp 25 0C; detection UV

240 nm; retention time 20.0 min (major) and 48.4 min (minor)

1H NMR (500 MHz CDCl3 ppm): δ 1.10 (t, J = 7.6 Hz), 2.30 (s, 3H), 2.26 (s, 6H), 3.09 (d, 1H, J = 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)

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13C 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, 132.2, 137.1, 141.0, 144.7, 170.6, 172.9, 173.3

FTIR (KBr): 675, 1102, 1137, 1171, 1232, 1346, 1686, 1736, 2943, 3438 cm-1

HRMS (FAB) m/z 419.1266 (M+H+), calc for C20H23N2O6S419.1271

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(6c) White solid, 90% yield, 89% ee

[α]D28 : +59.1 (c 2.8, CHCl3) m.p : 102.0-103.0oC

1H NMR (500 MHz CDCl3 ppm): δ 2.29 (s, 3H), 2.55 (s, 6H),

3.09 (d, 1H, J = 8.2 Hz), 3.72 (dd, 1H, J = 3.8, 8.2 Hz), 4.01 (s, 1H), 4.59 (d, 2H, J = 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)

13C 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, 132.2, 135.1, 136.9, 141.0, 144.7, 170.5, 172.8, 173.0

FTIR (KBr): 674, 1101, 1167, 1347, 1399, 1704, 2950, 3445 cm-1

The enantiomeric excess was determined by chiral HPLC; CHIRALPAK AS-H (4.6 mm i.d x 250 mm); 2-propanol; flow rate 0.9 ml/min; temp 25 0C; detection UV 240 nm; retention time 21.8 min (major) and 81.7 min (minor)

N

O

O O

S

O

Trang 26

1H NMR (500 MHz CDCl3 ppm): δ 1.41 (t, 3H, J = 6.9 Hz), 2.30 (s, 3H), 2.60 (s, 6H), 3.23 (d, 1H, J = 8.2 Hz), 3.88 (dd, 1H, J = 4.4, 8.2 Hz), 4.03 (q, 2H, J = 6.9, 13.9 Hz), 4.13 (s, 1H), 5.86-5.88 (m, 1H), 6.48-6.49 (m, 1H), 6.54 (dd, 1H, J = 5.7, 8.2 Hz), 6.93 (d, 2H, J

S

O

OEt

Trang 27

13C 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, 123.4, 127.3, 128.9, 131.6, 132.2, 137.2, 141.0, 144.7, 159.2, 170.5, 172.4, 172.8

The enantiomeric excess was determined by chiral HPLC; CHIRALCEL OC-H (4.6 mm i.d x 250 mm); methanol/2-propanol 80/20; flow rate 0.5 ml/min; temp 25 0C; detection

UV 240 nm; retention time 16.4 min (minor) and 20.5 min (major)

Trang 28

101

(6e) White solid, 95% yield, 94% ee

[α]D28 : +98.5 (c 1.0, CHCl3) m.p : 201.0oC

2.60 (s, 6H), 3.25 (d, 1H, J = 8.4 Hz), 3.90 (dd, 1H, J = 4.2, 8.4 Hz), 4.09 (s, 1H), 5.87-5.91 (m, 1H), 6.50 (dd, 1H, J = 1.0, 7.7 Hz), 6.56 (dd, 1H, J = 5.6, 8.0 Hz), 6.98 (s, 2H), 7.06 (d, 2H, J = 8.0 Hz), 7.25 (d, 2H, J =

8.0 Hz)

13C NMR (125MHz 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, 132.2, 137.2, 139.3, 141.0, 144.7, 170.5, 172.2, 172.7

FTIR (KBr): 674, 821, 1105, 1172, 1357, 1389, 1514, 1686, 1732, 1786, 2943, 3460 cm-1 LRMS (FAB) m/z 481.2 (M+H+)

N

O

O O

S

O

Trang 29

3.27 (d, 1H, J = 8.2 Hz), 3.92 (dd, 1H, J = 4.4, 8.2 Hz), 4.14 (s, 1H), 5.87-5.89 (m, 1H), 6.50 (dd, 1H, J = 1.3, 8.2 Hz), 6.55 (dd, 1H, J = 5.7, 7.6 Hz), 6.98 (s, 2H), 7.09 (d, 2H, J = 8.8 Hz), 7.58 (d, 2H, J = 8.8 Hz)

13C NMR (125MHz CDCl3 ppm): δ 21.1, 22.6, 25.3, 44.6, 47.8, 51.3, 78.0, 123.0, 127.6, 128.9, 130.0, 131.4, 132.2, 132.4, 137.3, 141.0, 144.8, 170.4, 171.8, 172.2

S

O

Br

Trang 30

103

LRMS (FAB) m/z 545.0 (M+H+); 547.0 (M+H+)

HRMS (FAB) m/z 545.0380 (M+H+), calc for C24H22N2O679BrS545.0376

HRMS (FAB) m/z 547.0384 (M+H+), calc for C24H22N2O681BrS547.0356

The enantiomeric excess was determined by chiral HPLC; CHIRALPAK AS-H (4.6 mm i.d x 250 mm); hexane:2-propanol 5/95 ; flow rate 0.7 ml/min; temp 25 0C; detection UV

2.86

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