482
C. O. Soulage et al. / Tetrahedron Letters 53 (2012) 480–483
O
O
OH
OMe
OMe
OH
MeO
MeO
O
O
AcO
i
O
RO
RO
RO
AcO
AcO
O
O
11
: R=Ac
: R=H
AcO
ii
Br
1
OH
OR
2
10
Scheme 2. Synthesis of cirsimarin (1). Reagents and conditions: (i) BnEt3NBr, NaOH, CHCl3/H2O (5:1), 60 °C, 4 h, 35%; (ii) CH3OH/Et3N/H2O, (8:1:1), RT, 24 h, 66%.
Figure 2. Lipolytic and antilipogenic activity of cirsimarin on isolated human adipocytes. Lipolysis (left) was measured as the amount of glycerol released by adipose cells.
Lipogenesis (right) was measured as the incorporation of [14C]-acetate into total lipids. Data are expressed as mean SD for n = 4 independent experiments. Different letters
indicate significant differences between the means at P <0.05 level. pD2 was calculated as ꢀlog (EC50 or IC50).
The organic layer was dried over Na2SO4, solvents were evaporated off and
the obtained residue was purified by column chromatography using a pentane/
Acknowledgments
EtOAc gradient (6:4 to 4:6) and gave the protected flavone
9 (7.92 g,
18.9 mmol, 71%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): d 8.03 (d,
J = 8.8 Hz, 2H, H-30), 7.41 (m, 5H, H-70, H-80, H-90), 7.20 (s, 1H, H-9), 7.19 (d,
J = 8.8 Hz, 2H, H-20), 6.71 (s, 2H, H-50), 3.94 (s, 3H, H-7), 3.80 (s, 3H, H-6), 3.76
(s, 3H, H-8); 13C NMR (75 MHz, DMSO-d6): 175.2, 160.9, 160.2, 157.4, 153.9,
151.6, 139.8, 136.6, 128.5, 127.8, 127.6, 123.2, 115.3, 112.0, 106.1, 97.3, 69.5,
61.9, 61.0, 56.4. Anal. Calcd for C25H22O6:C, 71.76; H, 5.30. Found: C, 71.54; H,
5.31.
Financial support from INSA-Lyon (BQR 2008 grant) is grate-
fully acknowledged. The authors also thank Dr. Sylvie Moebs for
her help with the manuscript. The authors gratefully acknowledge
Dr. Emilie Kalbacher (MD) for providing them with subcutaneous
abdominal fat biopsies.
8. To a solution of protected flavone 9 (0.501 g, 1.20 mmol) in dry CH2Cl2 (20 mL)
under N2, a BBr3 solution in CH2Cl2 (1 M, 1.20 mL, 1.20 mmol) was added and
the reaction was stirred at 0 °C for 1.5 h. CH3OH (60 mL) was added slowly and
the obtained solution was stirred at RT for 30 min and a solid precipitated.
Solvents were evaporated off and the obtained yellow solid was purified by
column chromatography using a CH2Cl2/CH3OH mixture (98:2). The obtain
residue was dissolved in a CH3OH/THF mixture (1:1, 50 mL), catalytic amounts
of Pd/C was added and the reaction was stirred under H2 for 1.5 h at RT. The
suspension was filtrated over a celite plug and solvents were evaporated off.
The obtained residue was crystallized from CH3OH (10 mL) and gave
cirsimaritin (2, 0.210 g, 0.67 mmol, 56%) as a yellow solid. 1H NMR (300 MHz,
DMSO-d6): d 12.93 (s, 1H, OH-6), 10.38 (s, 1H, OH-40), 8.00 (d, J = 8.8 Hz, 2H, H-
30), 6.94 (d, J = 8.8 Hz, 2H, H-20), 6.91 (s, 1H, H-9), 6.84 (s, 1H, H-3), 3.92 (s, 3H,
H-8), 3.73 (s, 3H, H-7); 13C NMR (75 MHz, DMSO-d6): 182.2, 164.0, 161.3, 158.6,
152.6, 152.1, 131.8, 128.5, 121.1, 116.0, 105.1, 102.7, 91.6, 60.0, 56.4. Anal.
Calcd for C17H14O6:C, 64.97; H, 4.49. Found: C, 64.74; H, 4.50.
Supplementary data
Supplementary data (1H NMR spectra of compounds 1, 2, 5, 9,
and 11 are available as well as the material and methods used
for the biological experiments) associated with this article can be
References and notes
1. Zarrouki, B.; Pillon, N. J.; Kalbacher, E.; Soula, H. A.; N’Jomen, G. N.; Grand, L.;
Chambert, S.; Geloen, A.; Soulage, C. O. Int. J. Obes. 2010, 34, 1566–1575.
2. (a) Marais, J. P. J.; Ferreira, D.; Slade, D. Phytochemistry 2005, 66, 2145–2176; (b)
Chu, H. W.; Wu, H. T.; Lee, Y. J. Tetrahedron 2004, 60, 2647–2655.
9. (a) Kondo, T.; Oyama, K.; Yoshida, K. Angew. Chem., Int. Ed. 2001, 40, 894–897;
(b) Oyama, K.; Kondo, T. Tetrahedron 2004, 60, 2025–2034.
10. Kleine, H. P.; Weinberg, D. V.; Kaufman, R. J.; Sidhu, R. S. Carbohydr. Res. 1985,
142, 333–337.
3. For previous reports of the synthesis of cirsimaritin, see: (a) Ahluwalia, V. K.;
Malik, B. K.; Seshadri, T. R. Indian J. Chem.
B 1976, 14, 592–593; (b)
Ramasubramanian, A.; Ravi, P.; Ramesh, P. Indian J. Chem. B 1988, 27, 182.
4. Combes, S.; Finet, J. P.; Siri, D. J. Chem. Soc. Perkin Trans. 1 2002, 38–44.
5. Kavvadias, D.; Sand, P.; Youdim, K. A.; Qaiser, M. Z.; Rice-Evans, C.; Baur, R.;
Sigel, E.; Rausch, W. D.; Riederer, P.; Schreier, P. Br. J. Pharmacol. 2004, 142,
811–820.
11. 2,3,4,6-Tetra-O-acetyl-
and cirsimaritin (2, 0.101 g, 0.32 mmol) were dissolved in CH3Cl (1.5 mL). To
this mixture solution of benzyltriethylammonium bromide (0.104 g,
a-D-glucopyranosyl bromide (10, 0.526 g, 1.28 mmol)
a
0.38 mmol) in aqueous NaOH (1.25 M, 0.3 mL) was added and the reaction
was vigorously stirred at 60 °C for 4 h. The mixture was washed by aqueous
NaOH (1.25 M, 2 ꢂ 5 mL), saturated NH4Cl solution (2 ꢂ 5 mL) and then water
(5 mL). The organic layer was dried over Na2SO4, solvents were evaporated off
and the obtained orange oil was purified by column chromatography using a
pentane/EtOAc (1:1). Protected flavone glucoside 11 (72 mg, 0.11 mmol, 35%)
was obtained as a white solid. 1H NMR (300 MHz, DMSO-d6): d 12.82 (s, 1H,
OH-6), 8.13 (d, J = 9.0 Hz, 2H, H-30), 7.19 (d, J = 9.0 Hz, 2H, H-20), 7.00 (s, 1H, H-
3), 6.96 (s, 1H, H-9), 5.79 (d, J = 7.9 Hz, 1H, H-100), 5.44 (t, J = 9.6 Hz, 1H, H-300),
5.12 (dd, J = 9.8 Hz, J = 7.9 Hz, 1H, H-200), 5.04 (t, J = 9.8 Hz, 1H, H-400), 4.32 (m,
1H, H-500), 4.25–4.05 (m, 2H, H-600), 3.93 (s, 3H, H-8), 3.74 (s, 3H, H-7), 2.03,
2.03, 2.02, 1.98 (4s, 4 ꢂ OAc); 13C NMR (75 MHz, DMSO-d6): 182.3, 170.0,
169.6, 169.3, 169.1, 163.1, 159.1, 158.8, 152.7, 152.0, 132.0, 128.4, 125.0, 116.6,
6. See Kalinin, A. V.; da Silva, A. J. M.; Lopes, C. C.; Lopes, R. S. C.; Snieckus, V.
Tetrahedron Lett. 1998, 39, 4995–4998. and references therein.
7. To
a solution of phenol 5 (6.07 g, 26.8 mmol) in pyridine (150 mL), acid
chloride 7 (13.07 g, 53.0 mmol) was added under N2 and the reaction was
stirred at RT for 15 h. Freshly powdered KOH (12 g, 213.9 mmol) was then
added and the obtained mixture was heated to 70 °C for 3 h. After cooling, the
reaction was poured into an ice cold HCl (4%, 1 L) solution which was then
extracted with EtOAc (3 ꢂ 300 mL). The combined organic layers were washed
using
a
saturated NaHCO3 solution (2 ꢂ 200 mL) before being dried over
Na2SO4 and evaporated to dryness. The obtained yellow solid was dissolved in
AcOH (150 mL) and concentrated H2SO4 (10 mL) was added. The reaction was
heated at 80 °C for 1.5 h and then poured in ice cold water (700 mL). The
solution containing
a
precipitate was extracted by EtOAc (3 ꢂ 300 mL).