Potent candidates for anti-diabetic and anti-proliferative a

51 Pages·2017·3.48 MB·English

Electronic Supplementary Material (ESI) for New Journal of Chemistry.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2017
Supporting Information for:
Synthesis and in vitro evaluation of zerumbone pendant derivatives: Potent
candidates for anti-diabetic and anti-proliferative activities
B. P. Dhanya,a, b Greeshma Gopalan,a, b T. R. Reshmitha,c Saranya J,b P. Sharathna, a, b I.G. Shibi,d P. Nisha*a,c and K. V.
Radhakrishnan*a,b
a Academy of Scientific and Innovative Research (AcSIR), CSIR-NIIST, Thiruvananthapuram-695019, India
b Organic Chemistry Section, National Institute for Interdisciplinary Science and Technology (CSIR), Thiruvananthapuram 695019, India
c Agroprocessing and Natural Products Division, National Institute for Interdisciplinary Science and Technology (CSIR), Thiruvananthapuram
695 019, India.
d Department of Chemistry, Sree Narayana College, Chempazhanthi, Thiruvananthapuram, Kerala, India.
E-mail: [email protected]
Table of Contents
General Methods S2
Experimental Procedures S2-S3
Screening of Parameters S4-S5
Mechanistic Proposal S5
Characterization of the Products S6-S23
1H NMR &13C NMR Spectra S24-S48
Anti-diabetic assays S49
MTT assay S 50
S1
General Methods:
All the chemicals were of the best grade commercially available and were used without
further purification. All the solvents were purified according to standard procedures; dry solvents
were obtained according to the literature methods and stored over molecular sieves. Analytical
thin layer chromatography was performed on glass plates coated with silica gel containing
calcium sulfate binder. Gravity column chromatography was performed using 60-120 or 100-200
mesh silica gel, mixtures of hexane-ethyl acetate were used for elution. Melting point was
determined on a Buchi melting point apparatus and is uncorrected. Proton nuclear magnetic
resonance spectra (1H NMR) were recorded on a Bruker AV 500 spectrophotometers (CDCl as
3
solvent). Chemical shifts for 1H NMR spectra are reported as δ, in units of parts per million
(ppm) downfield from SiMe (δ 0.0) and relative to the signal of chloroform-d (δ 7.25, singlet).
4
Multiplicities were given as: s (singlet); d (doublet); t (triplet); q (quartet); quin (quintet); dd
(double doublet); m (multiplet). Coupling constants are reported as J value in Hz. Carbon nuclear
magnetic resonance spectra (13C NMR) are reported as δ in units of parts per million (ppm)
downfield from SiMe (δ 0.0) and relative to the signal of chloroform-d (δ 77.03, triplet). Mass
4
spectra were recorded under ESI/HRMS at 61800 resolution using Thermo Scientific Exactive
mass spectrometer. IR spectra were recorded on Bruker Alpha FT-IR spectrometer.
Synthesis of 7-Bromo-2,9,9-trimethyl-6-methyl-6-methylenecycloundeca-2,10-dienone (2a)
NBS (0.90g, 5.0mmol) was added to a solution of zerumbone (1.0 g, 4.6 mmol) in
acetonitrile/H O (1:1, 15 mL) mixture, and stirred vigorously at room temperature for 1 min.
2
H O (30 mL) was poured into the solution, filtered immediately, and washed with H O several
2 2
times to afford 7-Bromo-2,9,9-trimethyl-6-methyl-6-methylenecycloundeca-2,10-dienone, 2a as
a colorless solid quantitatively
Synthesis of 6-acetoxymethyl- 2,9,9-trimethylcycloundeca-2,6,10-trienone (2b)
Sodium acetate (82.8 mg, 1.0 mmol) was added to a solution of 2a (200 mg, 0.67 mmol) in DMF
(20 mL) at room temperature and stirred for 16 h. The progress of the reaction was monitored by
TLC (hexane/ethyl acetate=3:2). The DMF solution was extracted with CH Cl (3x30 mL) and
2 2
S2
the combined organic extracts were washed with brine (2x30 mL), dried over anhydrous Na SO ,
2 4
and concentrated on a rotary evaporator. Chromatography on silica gel, eluting with a 2:1
mixture of hexane and ethyl acetate, afforded 6-acetoxymethyl- 2,9,9-trimethylcycloundeca-
2,6,10-trienone, (2b) as a colorless oil in 91% yield
.
O O
CH COONa
Br 3
DMF,rt
2a
2b OAc
General Procedure for the Synthesis of zerumbone pendant derivatives
6-Acetoxymethyl- 2,9,9-trimethylcycloundeca-2,6,10-trienone (0.137 mmol) and vanillin
(0.137 mmol) were taken in a schlenk tube. Pd (dba) .CHCI (10 mol %), PPh (40 mol %) as
2 3 3 3
ligand, Cs CO (2.0 equiv.) as base were added followed by THF (2mL) and stirred the reaction
2 3
for 12 h at room temperature. After the completion of the reaction as monitored by TLC, the
reaction mixture was concentrated and the crude product was purified by column
chromatography on silica gel (100-200 mesh) and hexane: ethylacetate as the eluent to afford
the product as a crystalline solid.
S3
Table S1 Optimization Studies for a Suitable Catalyst System
O
O
OH
O
Pdcatalyst
Br
ligand,base,solvent,
CHO
temperature
O
2a Vanillin O
3a
4a
CHO
Entry Catalyst Ligand Base Solvent Yield (%)[e]
1 a - - Cs CO THF NR
2 3
2 a Pd (dba) . CHCl PPh K CO THF Trace
2 3 3 3 2 3
3 b Pd (dba) . CHCl PPh Cs CO THF 43
2 3 3 3 2 3
4 a Pd (dba) . CHCl PPh Cs CO CH CN 44
2 3 3 3 2 3 3
5 a Pd (dba) . CHCl PPh Cs CO THF 24
2 3 3 3 2 3
6 a Pd(OAc) PPh Cs CO THF Trace
2 3 2 3
7 a Pd(O C.CF ) PPh Cs CO THF 21
2 3 2 3 2 3
8 a Pd(PPh ) - Cs CO THF 24
3 4 2 3
9 a Pd (dba) PPh Cs CO THF 43
2 3 3 2 3
10 c Pd (dba) . CHCl PPh Cs CO THF Trace
2 3 3 3 2 3
11 d Pd (dba) . CHCl PPh Cs CO THF 46
2 3 3 3 2 3
12 e Pd(OAc) dppf NaH THF 10
2
S4
Reaction condition:
a :2a: 3a=1:1, Catalyst(10 mol%),Ligand (0.4 equiv.), Base (1equiv.), Solvent(2mL)
b: 2a: 3a=1:1Catalyst(10 mol%),Ligand (0.4 equiv.), Base (2 equiv.), Solvent (2mL)
c: 2a: 3a=1:2Catalyst(10 mol%),Ligand (0.4 equiv.), Base (1 equiv.), Solvent (2mL)
d: 2b: 3a=1:1Catalyst(10 mol%),Ligand (0.4 equiv.), Base (1 equiv.), Solvent (2mL)
e: Isolated Yield
Scheme 1: Proposed mechanism
O
O
Pd(0)
O
AcO
R
O
Reductiveelimination
O
Pd
OAc
Oxidativeaddition
AcOPd
O (-allylintermediate)
R
R
HO
S5
3-methoxy-4-(((1Z,5E,8E)-4,4,8-trimethyl-7-oxocycloundeca-1,5,8
trienyl)methoxy)benzaldehyde (4a)
O
O
O
CHO
Yield: 46 % as a white solid; R : 0.14 (1:3 EtOAc: hexane), mp: 185-190oC
f
IR (neat)  3268, 3032, 2958, 2953, 2857, 2366, 2336, 1651, 1498, 1467, 1366, 1268,
max:
1232, 1173, 1106, 1038, 823, 736, 703, 631, 570, 528 cm-1.
1H NMR (CDCl , 500MHz): δ 9.85 (s, 1H), 7.43- 7.40 (m, 2H), 6.97 (d, J= 8Hz, 1H), 6.20 (d,
3
J= 16Hz, 1H), 6.07- 6.03 (m, 1H), 6.02 (d, J= 16.5 Hz, 1H), 5.58- 5.54 (m, 1H), 4.64 (brs, 1H),
4.51 (brs, 1H), 3.88 (s, 3H), 2.69 (brs, 1H), 2.58 (brs, 1H), 2.41- 2.34 (m, 1H), 2.30- 2.25 (m,
2H), 2.07- 2.05 (m, 1H), 1.78 (s, 3H), 1.28 (s,3H), 1.09 (s, 3H) ppm.
13C NMR (CDCl , 125MHz): δ 203.7, 190.5, 160.0, 153.6, 150.1, 148.9, 138.8, 134.6, 131.7,
3
130.4, 127.2, 126.3, 111.7, 109.1, 66.3, 55.5, 42.5, 37.3, 36.3, 24.8, 12.0 ppm.
HRMS (ESI): m/z Calcd for C H NaO : 391.18853, Found: 391.18878.
23 28 4
(2E,6Z,10E)-6-((4-methoxyphenoxy)methyl)-2,9,9-trimethylcycloundeca-2,6,10-trienone
(4b)
O
O
O
S6
Yield: 76 % as a white solid; R : 0.43 (1:3 EtOAc: hexane), mp: 110-115oC
f
IR (neat)  2924, 1742, 1652, 1508, 1462, 1365, 1226, 1106, 1038, 827, 625, 578 cm-1.
max:
1H NMR (CDCl , 500MHz): δ 6.83 (s, 4H), 6.08- 6.06 (m, 1H), 6.06 (d, J= 16.5 Hz, 1H), 6.02
3
(d, J= 16.5 Hz, 1H), 5.51-5.47 (m, 1H), 4.50 (d, J= 9.5 Hz, 1H), 4.31 (d, J= 9 Hz, 1H), 3.78 (s,
3H), 2.74- 2.72 (m, 1H), 2.60-2.58 (m, 1H), 2.47-2.42 (m, 1H), 2.32- 2.23 (m, 2H), 2.05- 2.03
(m, 1H), 1.83 (s, 3H), 1.27 (s, 3H), 1.10 (s, 3H) ppm.
13C NMR (CDCl , 125MHz): δ 203.9, 160.2, 154.0, 152.8, 149.3, 138.4, 135.9, 130.3, 127.4,
3
116.0, 115.5, 114.7, 65.8, 55.6, 42.4, 37.4, 36.2, 25.0, 12.2 ppm.
HRMS (ESI): m/z Calcd for C H NaO : 363.19361, Found: 363.23306.
22 28 3
(2E,6Z,10E)-2,9,9-trimethyl-6-(p-tolyloxymethyl)cycloundeca-2,6,10-trienone (4c)
O
O
Yield: 68 % as colourless liquid; R : 0.571 (1:3 EtOAc: hexane)
f
IR (neat)  2925, 2852, 2394, 2356, 1714, 1555, 1509, 1430, 1362, 1331, 1232, 1178,
max:
1102, 969, 816, 758, 702, 634, 574, 546 cm-1.
1H NMR (CDCl , 500MHz): δ 7.08 (d, J= 8.5 Hz, 2H), 6.79 (d, J= 8.5 Hz, 2H), 6.09- 6.07 (m,
3
1H), 6.07 (d, J= 16.5 Hz, 1H), 6.02 (d, J= 16 Hz, 1H), 5.52- 5.48 (m, 1H), 4.51 (d, J= 9.5 Hz,
1H), 4.34 (d, J= 9.5 Hz, 1H), 2.74- 2.72 (m, 1H), 2.60- 2.57 (m, 1H), 2.48- 2.43 (m, 1H), 2.31 (s,
3H), 2.28- 2.24 (m, 2H), 2.06- 2.03 (m, 1H), 1.83 (s, 3H), 1.27 (s, 3H), 1.10 (s,3H) ppm.
13C NMR (CDCl , 125MHz): δ 203.5, 159.9, 156.6, 149.0, 138.5, 135.9, 130.3, 130.1, 129.9,
3
127.4, 114.3, 65.3, 42.4, 37.4, 36.3, 25.0, 20.5, 12.2 ppm.
HRMS (ESI): m/z Calcd for C H NaO : 347.19870, Found: 347.19887.
22 28 2
S7
4-methoxy-3-(((1Z,5E,8E)-4,4,8-trimethyl-7-oxocycloundeca-1,5,8-
trienyl)methoxy)benzaldehyde (4d)
O
O
O
OHC
Yield: 63 % as a white solid; R : 0.28 (1:3 EtOAc: hexane), mp: 85-90oC
f
IR (neat)  3351, 2960, 2864, 2724, 1686, 1645, 1588, 1510, 1439, 1395, 1342, 1269,
max:
1161, 1129, 1015, 865, 808, 754, 700, 638, 583 cm-1.
1H NMR (CDCl , 500MHz): δ 9.86 (s, 1H), 7.46-7.40 (m, 2H), 6.98 (d, J= 8.5Hz, 1H), 6.26 (d,
3
J= 16.5Hz, 1H), 6.06- 6.03 (m, 1H), 6.01 (d, J= 16.5Hz, 1H), 5.57- 5.54 (m, 1H), 4.57 (brs, 1H),
4.48 (brs, 1H), 3.89 (s, 3H), 2.67 (brs, 1H), 2.57 (brs, 1H), 2.45 (brs, 1H), 2.31- 2.25 (m, 2H),
2.07- 2.04 (m, 1H), 1.76 (s, 3H), 1.51(s, 6H) ppm.
13C NMR (CDCl , 125MHz): δ 202.4, 190.4, 160.3, 158.0, 155.0, 149.1, 138.0, 133.7, 130.2,
3
127.2, 122.4, 114.7, 66.1, 55.7, 42.7, 37.3, 36.5, 29.7, 24.9, 12.2 ppm.
HRMS (ESI): m/z Calcd for C H NaO : 391.18853, Found: 391.18878
23 28 4
(2E,6Z,10E)-2,9,9-trimethyl-6-(phenoxymethyl)cycloundeca-2,6,10-trienone (4e)
O
O
Yield: 33 % as a white solid; R : 0.571 (1:3 EtOAc: hexane), mp: 60-63oC
f
IR (neat)  3390, 2922, 1590, 1462, 1420, 1121, 1040, 856, 540 cm-1.
max:
S8
1H NMR (CDCl , 500MHz): δ 7.30-7.26 (m, 2H), 6.96- 6.93 (m, 1H), 6.88- 6.87 (m, 2H), 6.07-
3
5.98 (m, 3H), 5.51- 5.48 (m, 1H), 4.51 (brs, 1H), 4.37 (brs, 1H), 2.71 (brs, 1H), 2.56 (brs, 1H),
2.44- 2.41 (m, 1H), 2.30- 2.23 (m, 2H), 2.05- 2.03 (m, 1H), 1.82 (s, 3H), 1.26 (s, 3H), 1.08 (s,
3H) ppm.
13C NMR (CDCl , 125MHz): δ 203.7, 160.0, 158.7, 149.2, 138.5, 135.7, 130.5, 129.5, 127.4,
3
121.0, 114.5, 65.1, 42.5, 37.4, 36.3, 25.0, 12.2 ppm.
HRMS (ESI): m/z Calcd for C H NaO : 333.18305, Found: 333.18364.
21 26 2
3-ethoxy-4-(((1Z,5E,8E)-4,4,8-trimethyl-7-oxocycloundeca-1,5,8-
trienyl)methoxy)benzaldehyde (4f)
O
O
O
CHO
Yield: 23 % as colourless liquid; R : 0.314 (1:3 EtOAc: hexane)
f
IR (neat)  3384, 2922, 1586, 1514, 1468, 1425, 1367, 1317, 1266, 1120, 1038, 860, 661,
max:
617, 547 cm-1.
1H NMR (CDCl , 500MHz): δ 9.84 (s, 1H), 7.42- 7.39 (m, 2H), 6.98 (d, J= 8 Hz, 1H), 6.30 (d,
3
J= 16.5Hz, 1H), 6.04- 6.00 (m, 2H), 5.57- 5.53 (m, 1H), 4.60 (brs, 1H), 4.51 (brs, 1H), 4.14-
4.10 (q, 2H), 2.69 (s, 1H), 2.56 (brs, 1H), 2.45- 2.43 (m, 1H), 2.32- 2.26 (m, 2H), 2.06- 2.01(m,
1H), 1.77 (s, 3H), 1.41 (t, J= 7Hz, 3H), 1.27 (s, 3H), 1.11 (s, 3H) ppm.
13C NMR (CDCl , 125MHz): δ 203.8, 190.4, 160.5, 153.7, 149.5, 148.5, 138.9, 134.5, 131.7,
3
130.4, 127.3, 126.0, 112.0, 110.2, 66.6, 64.2, 42.5, 37.4, 36.6, 24.8, 14.6, 12.2 ppm.
HRMS (ESI): m/z Calcd for C H NaO : 405.20418, Found: 405.20346.
24 30 4
. (2E,6Z,10E)-6-((biphenyl-2-yloxy)methyl)-2,9,9-trimethylcycloundeca-2,6,10-trienone (4g)
S9
O
O
Yield: 76 % as colourless liquid; R : 0.571 (1:3 EtOAc: hexane)
f
IR (neat)  3372, 3059, 2962, 2929, 2870, 1897, 1709, 1646, 1504, 1479, 1457, 1434, 1388,
max:
1366, 1267, 1223, 1119, 1054, 1007, 973, 912, 834, 754, 735, 700, 614, 566 cm-1.
1H NMR (CDCl , 500MHz): δ 7.53- 7.51 (m, 2H), 7.43- 7.40 (m, 2H), 7.36- 7.31 (m, 3H), 7.10-
3
7.09 (m, 1H), 7.03 (d, J= 5.5 Hz, 1H), 6.04- 6.02 (m, 1H), 5.99 (d, J= 16.5 Hz, 1H), 5.75 (d, J=
16.5 Hz, 1H), 5.43- 5.40 (m, 1H), 4.67 (brs, 1H), 4.16 (brs, 1H), 2.66 (brs, 1H), 2.38- 1.99 (m,
5H), 1.69 (s, 3H), 1.24 (s, 3H), 1.08 (s, 3H) ppm.
13C NMR (CDCl , 125MHz): δ 203.2, 159.2, 155.6, 149.3, 138.3, 136.2, 131.0, 129.4, 128.8,
3
128.5, 127.8, 127.3, 126.9, 127.3, 126.9, 65.9, 42.2, 37.4, 35.2, 24.4, 11.7 ppm.
HRMS (ESI): m/z Calcd for C H NaO : 409.21435, Found: 409.21418.
27 30 2
2-(((1Z,5E,8E)-4,4,8-trimethyl-7-oxocycloundeca-1,5,8-trienyl)methoxy)benzaldehyde (4h)
O
O
CHO
Yield: 28% as viscous liquid; R : 0.40 (1:3 EtOAc: hexane)
f
IR (neat)  3341, 2923, 2855, 1588, 1422, 1366, 1318, 1119, 1040, 858, 669, 618, 524 cm-
max:
1.
1H NMR (CDCl , 500MHz): δ 10.5 (s, 1H), 7.87 (dd, J1= 7.5 Hz, J2=1.5 Hz, 1H), 7.57- 7.54
3
(m, 1H), 7.09- 7.06 (m, 1H), 7.00 (d, J= 8.5 Hz, 1H), 6.10- 6.08 (m, 1H), 6.04 (d, J= 16.5 Hz,
S10