1150
S. K. Vadivel et al. / Tetrahedron Letters 52 (2011) 1149–1150
O
OCO(CH2)2CH3
OCO(CH2)2CH3
Immobilized
OH
O
Candida antarctica
(Novozym 435)
OH
OH
OCO(CH2)2CH3
O
HO
HO
EDCI, DMAP
O
OCO(CH2)2CH3
2
1
84%
O
90%
Immobilized
Candida antarctica (Novozyme 435),
Ethanol
67%
OH
O
OH
O
3
2-Arachidonoylglycerol
Scheme 1.
14. Monteiro, J. B.; Nascimento, M. G.; Ninow, J. L. Biotechnol. Lett. 2003, 25, 641.
15. Pfeffer, J.; Freund, A.; Bel-Rhlid, R.; Hansen, C. E.; Reuss, M.; Schmid, R. D.;
Maurer, S. C. Lipids 2007, 42, 947.
16. Damstrup, M. L.; Jensen, T.; Sparso, F. V.; Kiil, S. Z.; Jensen, A. D.; Xu, X. J. Am. Oil
Chem. Soc. 2005, 82, 559.
butylacetate was easily removed under vacuum. We also noted the
formation of ethyl arachidonate (27%) as a side product. It is note-
worthy that there was no formation of 1-arachidonoylglycerol ob-
served in the reaction. The crude product was purified by a small
filter column of boric acid impregnated silica.22
17. Damstrup, M. L.; Jensen, T.; Sparso, F. V.; Kiil, S. Z.; Jensen, A. D.; Xu, X. J. Am. Oil
Chem. Soc. 2006, 83, 27.
In summary, the improved and practical synthesis of 2-AG was
successfully carried out without any isomerization of the more sta-
ble 1-arachidonoyl glycerol. The mild neutral conditions, easy sca-
lability, and removal of the volatile byproduct provide added
advantages to the current method for the synthesis of 2-
monoacylglycerides.
18. Irimescu, R.; Iwasaki, Y.; Hou, C. T. J. Am. Oil Chem. Soc. 2002, 79, 879.
19. Halldorsson, A.; Magnusson, C. D.; Haraldsson, G. G. Tetrahedron 2003, 59,
9101. NMR data for compound 1: 1H NMR (CDCl3, 500 MHz) d 4.12–4.27 (m,
4H), 4.03–4.12 (m, 1H), 2.20–2.41 (t, J = 7.4 Hz, 4H), 1.67 (sxt, J = 7.42 Hz, 4H),
0.96 (t, J = 7.32 Hz, 6H).
20. Magnusson, C. D.; Haraldsson, C. G. Tetrahedron 2010, 66, 2728.
21. Preparation of 2: To
a solution of 1,3-dibutanoylglyerol (1) (0.500 g,
2.45 mmol) and arachidonic acid (0.74 g, 2.45 mmol) in anhydrous
dichloromethane (10 mL) was added DMAP (2.4 g, 19.6 mmol) and EDCI
(1.88 g, 9.8 mmol). The resulting solution was stirred for 24 h. Cold water was
added to the reaction mixture and washed with 5% HCl. The aqueous layer was
extracted with dichloromethane and the combined organic extracts were
washed with water, brine, and dried over sodium sulfate. The reaction mixture
was subjected to flash chromatography (hexanes/acetone; 7:3) to afford pure
triglyceride as colorless oil (1.06 g, 88%). IR (neat) 3012, 2931, 1741, 1167,
Acknowledgment
One of the authors (S.K.V.) acknowledges the financial support
for this research from NIDA (R03 DA029184-01).
1094 cmÀ1 1H NMR (CDCl3, 500 MHz) d 5.30–5.45 (m, 8H), 5.23–5.30 (m, 1H),
;
References and notes
4.10–4.37 (m, 4H), 2.76–2.91 (m, 6H), 2.34 (t, J = 7.57 Hz, 2H), 2.30 (t,
J = 7.57 Hz, 4H), 2.12 (q, J = 7.16 Hz, 2H), 2.06 (q, J = 7.32 Hz, 2H), 1.68–1.75
(m, 2H), 1.60–1.68 (m, 4H), 1.23–1.42 (m, 6H), 0.91–0.99 (m, 6H), 0.84–0.91
(m, 3H); 13C NMR (CDCl3, 100 MHz) d 173.3, 172.8 (2C), 130.7, 129.2, 128.9,
128.8, 128.5, 128.3, 128.0, 127.7, 69.2, 62.3 (2C), 36.1 (2C), 33.8, 31.7, 29.5,
27.4, 26.7, 25.8 (3C), 24.9, 22.8, 18.5 (2C), 14.3, 13.8 (2C).
1. Di Marzo, V.; Petrosino, S. Curr. Opin. Lipidol. 2007, 18, 129.
2. Lambert, D. M.; Fowler, C. J. J. Med. Chem. 2005, 48, 5059.
3. Goparaju, S. K.; Ueda, N.; Yamaguchi, H.; Yamamoto, S. FEBS Lett. 1998, 422, 69.
4. Mechoulam, R.; Ben-Shabat, S.; Hanus, L.; Ligumsky, M.; Kaminski, N. E.;
Schatz, A. R.; Gopher, A.; Almog, S.; Martin, B. R.; Compton, D. R., et al Biochem.
Pharmacol. 1995, 50, 83.
5. Sugiura, T.; Kishimoto, S.; Oka, S.; Gokoh, M. Prog. Lipid. Res. 2006, 45, 405.
6. Sugiura, T.; Kodaka, T.; Nakane, S.; Miyashita, T.; Kondo, S.; Suhara, Y.;
Takayama, H.; Waku, K.; Seki, C.; Baba, N.; Ishima, Y. J. Biol. Chem. 1999, 274,
2794.
7. Sugiura, T.; Kondo, S.; Kishimoto, S.; Miyashita, T.; Nakane, S.; Kodaka, T.;
Suhara, Y.; Takayama, H.; Waku, K. J. Biol. Chem. 2000, 275, 605.
8. Martin, J. B. J. Am. Chem. Soc. 1953, 75, 5483.
9. Han, L. N.; Razdan, R. K. Tetrahedron Lett. 1999, 40, 1631.
10. Seltzman, H. H.; Fleming, D. N.; Hawkins, G. D.; Carroll, F. I. Tetrahedron Lett.
2000, 41, 3589.
22. Preparation of 2-arachidonoyl glycerol (3): Triglyceride
2
(0.050 g,
0.102 mmol) and anhydrous ethanol (0.7 mL) were stirred at room
temperature and the reaction was started by the addition of Novozym 435
(75 mg) and the reaction mixture was stirred for 1 h and the starting material
was completely consumed. An additional 50 mg was added and the reaction
mixture was stirred for another 1 h. After completion of the reaction the
enzyme was filtered off and washed with ether and the solvent was evaporated
and the crude product was purified by plug of boric acid impregnated silica gel
(hexanes/acetone; 9:1–3:2) to afford analytically pure 2-AG (0.026 g, 67%) as a
colorless oil. IR (neat) 3420, 3012, 2927, 1736, 1456, 1378, 1277, 1152 cmÀ1
;
1H NMR (500 MHz, CDCl3) d 5.37–5.49 (m, 8H), 4.93 (p, 5.0 Hz, 1H), 3.84 (t,
J = 5.0 Hz, 4H), 2.79–2.88 (m, 6H), 2.39 (t, J = 7.5 Hz, 2H), 2.13 (q, J = 7.0 Hz, 2H),
2.06 (q, J = 7.0 Hz, 2H), 2.00 (br t, J = 5.5 Hz, 2H), 1.72 (p, J = 7.2 Hz, 2H), 1.30–
1.40 (m, 6H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) d 174.1, 130.7,
129.3, 128.9, 128.8, 128.5, 128.3, 128.1, 127.8, 75.2, 62.5 (2C), 33.8, 31.7, 29.6,
27.4, 26.7, 25.8, 25.8, 25.8, 24.9, 22.8, 14.3.
11. Stamatov, S. D.; Stawinski, J. Tetrahedron Lett. 2002, 43, 1759.
12. Nakamura, K.; Yamanaka, R.; Matsuda, T.; Harada, T. Tetrahedron: Asymmetry
2003, 14, 2659.
13. Matsuda, T.; Yamanaka, R.; Nakamura, K. Tetrahedron: Asymmetry 2009, 20,
513.