a concise total synthesis of (±)-cipadonoid b from ...a concise total synthesis of (±)-cipadonoid...

- S1 -

Supporting information

A Concise Total Synthesis of (±)-Cipadonoid B

from Synthetic Azedaralide

Jonathan M. Faber and Craig M. Williams*

School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, 4072, Queensland, Australia

[email protected]

Contents

General Experimental S1

Experimental Procedures and characterisation data of all new compounds S2-6

1H and

13C NMR Spectra for compounds 8, 9 and 11 S7-12

1H and

13C NMR Spectra for natural and synthetic Cipadonoid B 1 S13-14

1H and

13C NMR Spectra for Cipadonoid B diastereomers 15 and 16 S15-18

Supplementary Material (ESI) for Chemical CommunicationsThis journal is (c) The Royal Society of Chemistry 2011

- S2 -

General Experimental

1H and

13C NMR spectra were recorded with a Bruker AV300 (300.13 MHz; 75.47 MHz),

AV400 (400.13 MHz; 100.62 MHz), DRX500 (500.13 MHz; 125.77 MHz), in

deuterochloroform (CDCl3). Coupling constants are given in Hz and chemical shifts are

expressed as δ values in ppm. Low resolution electrospray ionisation mass spectrometry

measurements (LRESIMS) were recorded in positive ionization mode on a Bruker Esquire

HCT (High Capacity 3D ion trap) instrument with a Bruker ESI source. High resolution

electron impact ionisation (HREIMS) accurate mass measurements were recorded on a

Finnigan MAT 900XL-TRAP (EI 70 eV) using perfluorokerosene-H as reference calibrant.

High resolution electrospray ionisation (HRESIMS) accurate mass measurements were

recorded in positive mode on a Bruker MicrOTOF-Q (quadrupole – Time of Flight)

instrument with a Bruker ESI source using sodium formate as reference calibrant. GC/MS

data were recorded on a Shimadzu GC-17A VR.3, mass spectrometer. Column

chromatography was performed using distilled solvents either on silica gel (Flash Silica gel

230 – 400 mesh) or using a Biotage Isolera One (MPLC) with samples loaded onto a HP-SIL

SNAP flash cartridge. Dichloromethane (DCM), toluene and xylenes were freshly distilled

from calcium hydride before use. Melting points were determined on a Stuart SMP11 Melting

Point apparatus and are uncorrected. Fine chemicals were purchased from the Aldrich Chem.

Co. All compounds synthesised here-in were conducted in the racemic series.


- S3 -

(E)-Methyl 4,4-dimethyl-5-hydroxy-7-oxonon-2-enoate (8)

A stirring solution of (E)-methyl 4,4-dimethyl-5-oxopent-2-enoate (5.78 g, 37.0 mmol) in

freshly distilled DCM (185 mL) was cooled to -78 °C under argon. A solution of TiCl4 (20.35

mL, 40.7 mmol, 2M in DCM) was added dropwise, followed by the addition of 2-(tert-

butyldimethylsilyloxy)but-1-ene (7.18 g, 38.5 mmol) via cannula to the dark red solution.

The resultant mixture was stirred for 30 min. at -78 °C and quenched by the addition of sat.

NH4Cl (50 mL). The biphasic mixture was allowed to warm to r.t. and the separated aqueous

layer extracted with diethyl ether (3 x 100 mL). The combined organic layer was successively

washed with sat. NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in

vacuo. The residue was purified by flash chromatography (petroleum ether/ethyl acetate, 4:1)

to afford (E)-methyl 5-hydroxy-4,4-dimethyl-7-oxonon-2-enoate (4.00 g, 47%) as a

colourless oil. 1H NMR (500 MHz CDCl3): δ = 6.95 (d, J = 16.1 Hz, 1H), 5.77 (d, J = 16.1

Hz, 1H), 3.84 (dt, J = 10.4, 2.2 Hz, 1H), 3.68 (s, 3H), 3.17 (d, J = 3.2 Hz, 1H), 2.48 – 2.34

(m, 4H), 1.04 (s, 3H), 1.03 (s, 3H), 0.99 (t, J = 7.3 Hz, 3H); 13

C NMR (125 MHz, CDCl3): δ

= 212.2, 167.1, 154.7, 119.3, 73.4, 51.5, 43.9, 40.8, 36.8, 23.0, 22.1, 7.4; LRMS (ESI)

Calculated: (M+Na+): 251.13 Found: 251.09; HRMS (ESI) Calculated for C12H20O4Na+:

251.1259, Found: 251.1247.

Methyl 2-(2,2,6-trimethyl-5-oxocyclohex-3-enyl)acetate (9)

Anhydrous toluene (15 mL) was added to potassium hydride (30% w/w in mineral oil, ~ 6.7

mL), the suspension briefly stirred, then left to settle for 10 min. The supernatant was

removed via syringe, and quenched with wet THF. This process was repeated twice and then

the remaining solid dried under reduced pressure, to give a free flowing powder (2.00 g,

49.87 mmol). (E)-Methyl 5-hydroxy-4,4-dimethyl-7-oxonon-2-enoate 8 (2.00 g, 9.51 mmol)

in anhydrous toluene (40 mL) was added dropwise via cannula to a stirring suspension of the

washed potassium hydride (2.00 g, 49.87 mmol) in toluene (400 mL) under an atmosphere of

argon at 0 °C. The suspension was stirred at 0 °C for 15 min., then allowed to warm to r.t.

and stirred for further 30 min. The reaction was quenched by the dropwise addition of a


- S4 -

solution of acetic acid (3 mL) in toluene (20 mL), to attain a neutral pH, followed by water

(50 mL). The layers were separated and the aqueous phase extracted with DCM (3 x 150

mL). The organic layers were combined, washed with sat. NaHCO3, dried over Na2SO4,

filtered and concentrated in vacuo to give a crude yellow oil. Column chromatography

(petroleum ether/ethyl acetate, 4:1) provided methyl 2-(2,2,6-trimethyl-5-oxocyclohex-3-

enyl)acetate as a clear oil (0.85 g, 46 %) as a mixture of diastereomers (22:78, syn:anti). The

product was placed in the freezer overnight, and the resultant crystals separated from the oil,

washed with petroleum ether and dried to give the pure anti isomer. 1H NMR (500 MHz

CDCl3): δ = 6.57 (d, J = 12.6 Hz, 1H), 5.85 (d, J = 12.6 Hz, 1H), 3.67 (s, 3H), 2.60 – 2.10 (m,

4H), 1.13 (s, 3H), 1.08 (d, J = 7.7 Hz, 3H), 1.01 (s, 3H); 13

C NMR (125 MHz, CDCl3): δ =

200.8, 173.7, 158.9, 125.9, 51.9, 46.3, 43.3, 42.0, 36.6, 28.0, 20.3, 11.8; LRMS (ESI)

Calculated: (M+Na+): 233.12 Found: 233.10; HRMS (ESI) Calculated for C12H18O3Na+:

233.1154, Found: 233.1144.

Methyl 2-(3-methoxy-2,6,6-trimethylcyclohexa-2,4-dien-1-yl)acetate (11)

To a solution of the cyclohex-2-enone 9 (169 mg, 0.8 mmol) in freshly distilled DCM (8

mL), in a sealed tube under argon was added 2,6-di-tert-butyl-4-methylpyridine (660 mg, 3.2

mmol), and methyl trifluoromethanesulfonate (376 µL, 3.4 mmol). The resultant mixture was

stirred at 90 °C for 4 hours. The reaction vessel was allowed to cool to room temperature and

diluted with ethyl acetate (75 mL) and washed with water (50 mL), sat. NaHCO3 solution (50

mL) and brine. The organic phase was dried with Na2CO3, filtered and concentrated in vacuo

to give a clear oil (0.97 g). The oil was purified by column chromatography (1:10 1:4

ethyl acetate:petroleum spirit) to give the titled compound (128 mg, 71 %) as a clear oil. 2,6-

Di-tert-butyl-4-methylpyridine was also recovered. 1H NMR (300 MHz CDCl3: δ = 5.78 (d,

J = 9.9 Hz, 1H), 5.37 (d, J = 9.9 Hz, 1H), 3.63 (s, 3H), 3.49 (s, 3H), 2.47 (dd, J = 7.5, 14.8

Hz, 1H), 2.26 (t, J = 6.5 Hz, 1H), 2.13 (dd, J = 5.7, 15.0 Hz, 1 H), 1.66 (s, 3H), 1.04 (s, 3H),

0.96 (s, 3H); 13

C NMR (100 MHz, CDCl3): δ = 174.4, 146.6, 137.2, 119.9, 116.6, 57.4, 51.6,

47.2, 35.0, 32.9, 26.4, 24.5, 14.7; GC/MS m/z (%) 224.2 (M+•

, 13.0%), 152.2 (13.5), 151.1

(100), 149.1 (34.5), 136.2 (35.8), 135.2 (11.6), 121.1 (12.5), 119.2 (12.7), 105.2 (11.9), 91.1


- S5 -

(32.7), 79.1 (14.3), 77.1 (19.7), 43.1 (11.1), 41.1 (22.5); HRMS (EI) Calculated for

C13H20O3: 224.1412, Found: 224.1415

A solution of methyl 2-(3-methoxy-2,6,6-trimethylcyclohexa-2,4-dien-1-yl)acetate 11 (284

mg, 1.27 mmol), azedaralide 2 (82.5 mg, 0.32 mmol) and a crystal of p-toluenesulfonic acid

in dry xylenes (3.1 mL) was stirred for 4 hours at 180 °C in a sealed tube under argon.

Following cooling to room temperature, the reaction mixture was diluted with DCM (50 mL)

and washed with saturated NaHCO3 solution, brine, dried over Na2SO3 and concentrated to

give a yellow oil. Purification using MPLC (1:4 ethyl acetate:petroleum spirit), gave 1 (28.8

mg, 20.1 %), 15 (6.3 mg, 4.4 %) and 16 (21.7 mg, 15.1 %).

Compound 1 (±)-Cipadonoid B: white amorphous solid

1H NMR (500 MHz CDCl3: δ = 7.43 (m, 1H), 7.37 (m, 1H), 6.67 (d, J = 10.0 Hz, 1H), 6.39

(d, J = 1.5 Hz, 1H), 6.00 (s, 1H), 5.91 (d, J = 10.5 Hz, 1H), 5.48 (d, J = 1.5 Hz, 1H), 5.29 (s,

1H), 5.01 (s, 1H), 3.69 (s, 3H), 2.83 (dd, J = 6.0, 4.5 Hz, 1H), 2.43 (m, 3H), 2.04 (dq, J =

15.5, 3.0 Hz, 1H), 1.74 (m, 1H), 1.38 (td, J = 14.0, 4.5 Hz, 1H), 1.11 (s, 9H), 1.06, (dt, J =

13.5, 4.5 Hz, 1H), 0.97 (s, 3H); 13

C NMR (100 MHz, CDCl3): 203.5, 174.1, 166.2, 166.0,

159.1, 143.4, 142.7, 141.1, 127.0, 121.4, 120.4, 111.6, 110.1, 79.9, 52.1, 50.7, 47.6, 43.6,

39.3, 37.1, 31.7, 30.2, 29.5, 24.0, 21.1, 21.0, 18.5; LRMS (ESI) Calculated: (M+Na+):

475.21, Found: 475.20; HRMS (ESI) Calculated for C27H32O6Na+: 475.2091, Found:

475.2089.

Compound 15: slightly yellow oil

1H NMR (500 MHz CDCl3:

1H NMR (500 MHz CDCl3: δ = 7.50 (m, 1H), 7.41 (m, 1H),

6.47 (d, J = 10.5 Hz, 1H), 6.44 (d, J = 1.5 Hz, 1H), 5.94 (s, 1H), 5.83 (d, J = 10.0 Hz, 1H),

5.25 (s, 1H), 5.18 (s, 1H), 4.71 (s, 1H), 3.70 (s, 3H), 3.14 (t, J = 5.5 Hz, 1H), 2.68 (dd, J =


- S6 -

16.5, 4.5 Hz, 1H), 2.54 (m, 2H), 1.88 (m, 1H), 1.81 (m, 1H), 1.73 (m, 1H), 1.29 (ddd, J =

13.5, 6.5, 3.5 Hz, 1H), 1.20 (s, 3H), 1.07 (s, 3H), 1.05 (s, 3H), 0.96 (s, 3H); 13

C NMR (100

MHz, CDCl3): δ = 202.2, 173.8, 166.5, 164.9, 155.4, 143.2, 143.1, 141.2, 124.5, 120.7,

120.1, 113.1, 110.0, 79.9, 54.7, 52.2, 48.5, 43.5, 39.5, 37.4, 32.7, 31.4, 31.0, 23.0, 22.0, 18.7,

17.6; LRMS (ESI) Calculated: (M+Na+): 475.21, Found: 475.20; HRMS (ESI) Calculated

for C27H32O6Na+: 475.2091, Found: 475.2094.

Compound 16: colourless crystals (MeOH); mp 195 – 196 °C; 1H NMR (500 MHz CDCl3: δ

= 7.51 (m, 1H), 7.39 (t, J = 1.5 Hz, 1H), 6.59 (d, J = 10.0 Hz, 1H), 6.46 (m, 1H), 5.82 (d, J =

10.0 Hz, 1H), 5.74 (s, 1H), 5.49 (s, 1H), 5.42 (d, J = 1.5 Hz, 1H), 5.39 (s, 1H), 3.69 (s, 3H),

2.92 (dd, J = 8.1, 3.0 Hz, 1H), 2.63 (dd, J = 6.3, 3.3 Hz, 1H), 2.45 (dd, J = 8.5, 17.0 Hz, 1H),

2.37 (dd, J = 17.0, 2.5 Hz, 1H), 2.19 (td, J = 13.0, 4.0 Hz, 1H), 1.99 (dq, J = 4.2, 14.7 Hz,

1H), 1.69 (m, 1H), 1.19 (s, 3H), 1.13 (dt, J = 4.2, 13.5 Hz, 1H), 1.07 (s, 3H), 1.02 (s, 3H),

0.96 (s, 3H); 13

C NMR (100 MHz, CDCl3): 203.1, 174.5, 166.2, 165.6, 158.8, 143.4, 142.7,

141.2, 127.8, 122.0, 120.4, 112.3, 110.2, 79.9, 52.1, 47.0, 44.1, 39.6, 37.0, 31.7, 29.4, 29.3,

24.4, 22.1, 19.4, 18.4; LRMS (ESI) Calculated: (M+Na+): 475.21 Found: 475.20; HRMS

(ESI) Calculated for C27H33O6+: 453.2272, Found: 453.2272.


- S7 -

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

0.977

0.992

1.007

1.031

1.043

1.197

2.348

2.369

2.378

2.383

2.392

2.406

2.422

2.458

2.462

2.492

2.496

3.163

3.169

3.681

3.833

3.838

3.849

3.854

5.756

5.788

6.935

6.967

7.240

3.7

83

6.0

67

2.0

35

4.0

41

0.9

12

3.1

70

0.9

90

0.9

92

1.0

00


- S8 -

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

7.42

22.06

23.03

29.59

36.77

40.77

43.91

51.45

73.37

76.74

77.00

77.25

119.25

154.74

167.08

212.33


- S9 -

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

1.011

1.077

1.084

1.089

1.132

2.271

2.293

2.298

2.300

2.303

2.305

2.312

2.316

2.449

2.476

3.673

5.846

5.866

6.560

6.580

7.240

3.3

34

3.4

47

3.4

62

3.2

97

1.1

96

3.0

25

0.9

30

1.0

02


- S10 -

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

11.76

20.31

27.99

34.73

36.58

43.29

45.65

51.88

77.00

125.91

158.90

173.68

200.77


- S11 -

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

0.955

1.042

1.663

2.095

2.114

2.145

2.164

2.234

2.256

2.277

2.431

2.455

2.481

2.505

3.488

3.489

3.627

5.353

5.385

5.765

5.797

7.240

3.0

74

3.0

90

3.0

64

1.0

66

1.0

29

1.0

59

2.8

15

3.0

02

0.9

82

1.0

00


- S12 -

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

14.73

24.48

26.36

32.92

34.96

47.24

51.58

57.40

76.68

77.00

77.32

116.57

119.88

137.19

146.64

174.43


- S13 -

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

1.068

1.076

1.085

1.107

1.347

1.355

1.374

1.383

1.402

1.411

1.524

1.701

1.710

1.714

1.724

1.728

1.731

1.741

1.744

1.751

1.754

1.758

1.768

1.772

1.781

2.011

2.019

2.025

2.033

2.042

2.050

2.055

2.063

2.387

2.396

2.401

2.410

2.415

2.420

2.429

2.435

2.447

2.468

2.481

2.824

2.833

2.836

2.845

3.691

5.013

5.015

5.016

5.287

5.475

5.479

5.899

5.919

6.003

6.393

6.394

6.397

6.398

6.661

6.681

7.240

7.367

7.370

7.374

7.435

7.436

7.438

3.1

69

1.2

96

9.1

03

1.0

58

1.0

70

1.0

81

3.1

44

1.0

23

2.9

37

1.0

00

0.9

93

0.9

98

0.9

92

0.9

54

0.9

71

1.0

00

0.8

83

0.8

99

Cipadonoid B (1) (500 MHz, CDCl3)

(Natural)


- S14 -

30405060708090100110120130140150160170180190200 ppm

18.50

20.97

21.13

23.97

29.50

30.18

31.74

37.11

39.27

43.60

47.57

50.71

52.13

76.69

77.00

77.32

79.90

110.07

111.62

120.45

121.38

127.01

141.06

142.75

143.37

159.10

166.02

166.13

174.13

203.47

Cipadonoid B (1) (125 MHz, CDCl3)

(Natural)


- S15 -

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

1.272

1.278

1.285

1.293

1.300

1.305

1.312

1.700

1.708

1.722

1.730

1.735

1.750

1.757

1.782

1.789

1.794

1.801

1.810

1.817

1.823

1.831

1.840

1.845

1.852

1.863

1.871

1.884

1.892

1.901

1.913

2.507

2.515

2.519

2.527

2.532

2.564

2.575

2.662

2.670

2.694

2.703

3.130

3.141

3.152

3.699

4.715

5.184

5.245

5.247

5.824

5.845

5.942

6.442

6.444

6.446

6.447

6.466

6.487

7.240

7.414

7.417

7.497

7.498

7.500

3.1

15

3.1

97

3.2

30

3.2

99

2.2

20

1.6

03

2.6

75

2.2

60

1.0

21

1.0

16

2.9

63

0.9

92

1.0

05

0.9

91

1.0

05

0.9

44

1.0

00

1.0

10

0.9

20

0.8

86


- S16 -

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

17.63

18.66

21.96

23.02

30.94

31.40

32.65

37.35

39.48

43.47

48.55

52.22

54.73

77.00

79.95

109.97

113.12

120.12

120.70

124.50

141.16

143.06

143.23

155.41

164.87

166.52

173.81

202.24


- S17 -

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

1.149

1.193

1.538

1.646

1.655

1.659

1.667

1.672

1.676

1.681

1.685

1.688

1.693

1.697

1.702

1.710

1.714

1.723

1.961

1.969

1.978

1.986

1.991

1.999

2.008

2.016

2.157

2.165

2.184

2.192

2.210

2.218

2.342

2.347

2.377

2.381

2.422

2.439

2.456

2.473

2.621

2.628

2.633

2.640

2.916

2.921

2.933

2.937

3.689

5.392

5.420

5.424

5.488

5.735

5.809

5.829

6.460

6.461

6.463

6.465

6.581

6.601

7.240

7.385

7.388

7.391

7.506

7.507

7.509

7.511

7.512

3.2

02

3.2

40

3.1

82

1.2

12

3.1

89

1.0

81

1.0

71

1.0

74

1.0

58

1.0

46

1.0

26

1.0

33

3.0

73

1.0

22

1.0

13

1.0

13

0.9

82

0.9

96

1.0

00

1.0

32

0.9

33

0.9

37


- S18 -

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

18.44

19.39

22.05

24.40

29.30

29.42

31.73

37.02

39.61

44.11

46.96

52.10

77.00

79.85

110.15

112.34

120.45

121.97

127.76

141.20

142.74

143.41

158.77

165.60

166.22

174.45

203.10


a concise total synthesis of (±)-cipadonoid b from ...a concise total synthesis of (±)-cipadonoid...

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