3591
(MeOH–H2O, ethanol, CH2Cl2), isomerization to 1-Ara-Gl was observed, going near to completion in
one or more days even at low temperatures. The stable solid boronate ester 5 serves as an excellent
storage form of 2-Ara-Gl.
Cleavage of 5 is immediate and complete by dissolving in 85% MeOH–H2O with which it is eluted
through a C18 reverse phase LoBar chromatography column.12 2-Ara-Gl fractions elute without any 1-
Ara-Gl or phenylboronic acid (HPLC). The MeOH–H2O solution can be used as such, in the short term
before isomerization becomes significant, or can be partitioned between water and CH2Cl2, dried and
evaporated to a resin (86% yield) for longer term storage. The NMR spectra13 is in agreement with that
expected for the symmetrical 2-Ara-Gl and that reported6 and in contrast with 1-Ara-Gl independently
prepared from glycerol and arachidonic acid or from cleavage from the boronate ester 6.
The results presented here demonstrate that 2-arachidonylglycerol-1,3-phenylboronate ester 5 is a
versatile intermediate for the synthesis of 2-Ara-Gl that enables: (1) its chromatographic resolution
from its isomer 6, (2) its conversion to 2-Ara-Gl effectively and efficiently under very simple and mild
conditions; and (3) provides a means of stable storage for an as needed conversion to the unstable 2-Ara-
Gl. The approach suggests its application to the synthesis of other 2-acylglycerols.
Acknowledgements
The assistance of Dr. Lois E. Nice is gratefully acknowledged. This work was supported by the
National Institute on Drug Abuse on contract No. N01DA-6-7054.
References
1. 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.; Pertwee, R. G.; Griffin, G.; Bayewitch, M.; Barg, J.; Vogel, Z. Biochem. Pharmacol. 1995, 50,
83–90.
2. Mechoulam, R.; Fride, E.; Di Marzo, V. Eur. J. Pharmaco. 1998, 359, 1–18.
3. Di Marzo, V.; Bisogno, T.; De Petrocellis, L.; Melck, D.; Martin, B. R. Cur. Med. Chem. 1999, 6, 721–744.
4. Martin, J. B. J. Am. Chem. Soc. 1953, 75, 5483–5486.
5. Martin, J. B. J. Am. Chem. Soc. 1953, 75, 5482–5483.
6. Han, L.; Razdan, R. K. Tetrahedron Lett. 1999, 40, 1631–1634. A 1,3-disilyl ether of glycerol has recently been reported
for the synthesis of 2-Ara-Gl, for which the deblocking of the final intermediate proceeds under different conditions (low
temperature, n-Bu4NF, HOAc buffer, overnight) and yields than the phenylboronate ester of this work does (ambient
temperature, 85% MeOH–H2O, immediate).
1
7. 2-Arachidonyl-cis-1,3-O-benzylideneglycerol: H NMR (250 MHz, CDCl3) δ 7.52–7.48 (m, 2H, ArH2), 7.39–7.34 (m,
3H, ArH3), 5.55 (s, 1H, CHPh), 5.38 (m, 8H, vinyl H), 4.71 (s, 1H, 20-H), 4.28, 4.16 (d,d, 4H, J=13.5 Hz, eq./ax. 10/30-H),
2.82–2.77 (m, 6H, diallylic), 2.45 (t, 2H, J=7.6 Hz, 2-CH2), 2.18–2.00 (m, 4H, allylic-H), 1.75 (p, 2H, J=7.3 Hz, 3-CH2),
1.37–1.17 (m, 6H, 17-19-CH2), 0.88 (t, 3H, J=6.7 Hz, 20-CH3). 13C NMR (CDCl3) δ 173.6, 137.8, 130.4, 129.0, 128.9,
128.5, 128.3, 128.2, 127.9, 127.5, 126.0, 101.2, 69.4, 65.8, 33.7, 31.5, 29.3, 27.1, 26.5, 25.6, 24.7, 22.5. MS (DIP, 14 eV)
m/e 466 (M+).
1
8. 2-Arachidonylglycerol 1,3-phenylboronate ester: H NMR (300 MHz, CDCl3): δ 7.8 (dd, 2H, J=8.1, 1.5 Hz, phenyl),
7.44–7.36 (m, 3H, phenyl), 5.45–5.32 (m, 8H, vinyl), 5.18 (p, 1H, J=2.2 Hz, 20-CH), 4.28 (dd, 2H, J=12, 2.2 Hz, 10- and
30-CH[ax. or eq.]), 4.19 (dd, 2H, J=12, 2.2 Hz, 10- and 30-CH[eq. or ax.]), 2.84–2.76 (m, 6H, diallylic), 2.36 (t, 2H, J=7.8
Hz, 2-CH2), 2.13–2.01 (m, 4H, allylic), 1.69 (p, 2H, J=7.5 Hz, 3-CH2), 1.37–1.28 (m, 6H, 17–19 CH2), 0.88 (t, 3H, J=6.8
Hz, 20-CH3).
9. 1-Arachidonylglycerol 2,3-phenylboronate ester: 1H NMR (300 MHz, CDCl3): 7.28 (d, 2H, J=9 Hz, ArH2), 7.46 (d, 1H,
0
J=3 Hz, ArH), 7.38 (t, 2H, J=7.5 Hz, ArH2 ), 5.37 (m, 8H, vinyl H8), 4.80 (m, 1H, 20-H), 4.45 (t, 1H, J=9.1 Hz, 30-Ha), 4.30
(dd, 1H, J=4.0, 11.9 Hz, 10-Ha), 4.21 (dd, 1H, J=5.1, 11.9 Hz, 10-Hb), 4.14 (dd, 1H, J=9.1 Hz, 30-Hb), 2.86–2.75 (m, 6H, 7,