a concise total synthesis of (±)-cipadonoid b from ...a concise total synthesis of (±)-cipadonoid...
TRANSCRIPT
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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
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
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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.
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(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
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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
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(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 =
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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.
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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
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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
Supplementary Material (ESI) for Chemical CommunicationsThis journal is (c) The Royal Society of Chemistry 2011
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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
Supplementary Material (ESI) for Chemical CommunicationsThis journal is (c) The Royal Society of Chemistry 2011
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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
Supplementary Material (ESI) for Chemical CommunicationsThis journal is (c) The Royal Society of Chemistry 2011
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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
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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
Supplementary Material (ESI) for Chemical CommunicationsThis journal is (c) The Royal Society of Chemistry 2011
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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)
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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)
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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
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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
Supplementary Material (ESI) for Chemical CommunicationsThis journal is (c) The Royal Society of Chemistry 2011
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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
Supplementary Material (ESI) for Chemical CommunicationsThis journal is (c) The Royal Society of Chemistry 2011
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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
Supplementary Material (ESI) for Chemical CommunicationsThis journal is (c) The Royal Society of Chemistry 2011