of a wide variety of physiological functions such as anti-
nociception, brain development, memory, retrograde neuronal
communication, control of movement, cardiovascular and
Scheme 1. Retrosynthetic Analysis of the Solid-Phase
Synthesis of Anandamide Analogues
5
immune regulation, and cellular proliferation. Small mol-
ecules affecting ECS activity have the potential to be
6
therapeutic agents for the treatment of diverse pathologies,
including neurodegenerative disorders, nociceptive alter-
ations, and malignant tumors. Hence, structure-activity
relationship (SAR) studies of anandamide analogues are
7
beginning to emerge. Most of the structural modifications
have focused on alteration of the ethanolamido headgroup.
For example, substituents at the 2-position have shown an
8
enhancement of metabolic stability, whereas introduction
of electronegative groups, such as halogen atoms or unsatur-
ated three-carbon substituents in the headgroup, results in
increased receptor binding affinity but reduced biochemical
stability. Reversal of the carbonyl and NH groups results in
higher metabolic stability; however, the receptor binding
affinity is somewhat decreased compared to that of anan-
formation that was successfully applied in solution-phase
reactions to obtain skipped polyyne compounds.
Key to our synthesis of AEA analogues was the C-C bond
forming reaction to install the consecutive diynes. To explore
and mimic this reaction on solid support, we commenced
with the solution-phase reaction of ester 7 with 4-chloro-
9
damide. The effect of chain length and branching of the
1
0
pentyl moiety of AEA has also been reported. More
recently, research on analogues of arachidonic acid has
revealed that there is no correlation between effects on
activity of the fatty acid amidohydrolase (FAAH) and on
the anandamide transport system (ANT).
1
2
but-2-yn-1-ol (8). Using the conditions shown in Scheme
2 afforded diyne 9 in high yield (93%).
The availability of AEA analogues should prove to be
useful for future in vitro and in vivo studies aimed at
delineating AEA’s mode of action and potential therapeutic
applications. Herein we report the first solid-phase synthesis
of anandamide analogues, which features copper-mediated
Scheme 2. Key Coupling Reaction Mediated by CuI in
Solution Phase
11
coupling reactions between terminal alkynes and propargyl
halides and a cleavage step that provides diversification of
the headgroup. Scheme 1 shows a retrosynthetic analysis of
our approach wherein Wang resin is employed as the solid
support. As shown, diversity at the headgroup would be
accomplished when the substrate is cleaved by acid, alcohol,
or amine to provide acid, ester, or amide, respectively.
Noteworthy would be the repetitive Cu-mediated C-C bond
Our successful solid-phase synthesis of target 4 is il-
lustrated in Schemes 3 and 4. Thus, 5-hexynoic acid was
quantitatively anchored to Wang resin via an ester linkage.
The resulting resin-bound alkyne 6 was anticipated to react
with alcohol 8 similarly to the solution-phase reaction
between 7 and 8. However, this Cu-mediated coupling
reaction on solid-support was sluggish due to the presence
of multiple phases. Consequently, alternative conditions were
investigated, and subsequently it was found that when 10
equiv of 8 reacted with resin-bound terminal alkyne 6 in the
presence of 3 equiv of CuI and 3 equiv of NaI in 9 mL of
DMF per gram of resin, yields greater than 90% could be
achieved. The resultant propargyl alcohol 10a was quanti-
tatively converted to the corresponding bromide 10b using
(
3) Hanus, L.; Abu-Lafi, S.; Fride, E.; Breuer, A.; Vogel, Z.; Shalev, D.
E.; Kustanovich, I.; Mechoulam, R. Proc. Natl. Acad. Sci. U.S.A. 2001,
8, 3662.
9
(
(
4) Martin, B. R. J. Pharmacol. Exp. Ther. 2002, 301, 790.
5) Lopez-Rodriguez, M. L.; Viso, A.; Ortega-Gutierrez, S.; Fowler, C.
J.; Tiger, G.; de Lago, E.; Fernandez-Ruiz, J.; Ramos, J. A. J. Med. Chem.
003, 46, 1512 and the references therein.
2
(
6) (a) Pertwee, R. G. Expert Opin. InVest. Drugs 2000, 9, 1553. (b)
Baker, D.; Pryce, G.; Croxford, J. L.; Brown, P.; Pertwee, R. G.; Huffman,
J. W.; Layward, L. Nature 2000, 404, 84. (c) Galve-Roperh, I.; Sanchez,
C.; Cortes, M. L.; del Pulgar, T. G.; Izquierdo, M.; Guzman, M. Nat. Med.
2
000, 6, 313. (d) Pertwee, R. G. Curr. Med. Chem. 1999, 6, 635.
7) (a) Palmer, S. L.; Khanolkar, A. D.; Makriyannis, A. Curr. Pharm.
(
Des. 2000, 6, 1381. (b) Pop, E. Curr. Opin. Chem. Biol. 1999, 3, 418. (c)
Khanolkar, A. D.; Makriyannis, A. Life Sci. 1999, 65, 607.
3 4
Ph P/CBr at temperatures from -40 to 0 °C. The C-C
(8) (a) Adams, I.; Ryan, W.; Singer, M.; Razdan, R. K.; Compton, D.
bond-forming reaction was repeated, but now using propargyl
alcohol to afford a triynol 11a, which was transformed to
propargyl bromide 11b. The final alkyne addition was
accomplished using the same coupling conditions, however,
with various alkynes to provide diversity on the tail ends of
tetrayne 5 (Scheme 3).
R.; Martin, B. R. Life Sci. 1995, 56, 2041. (b) Adams, I. B.; Ryan, W.;
Singer, M.; Thomas, B. F.; Compton, D. R.; Razdan, R. K.; Martin, B. R.
J. Pharmacol. Exp. Ther. 1995, 273, 1172. (c) Sheskin, T.; Hanus, L.;
Shager, J.; Vogel, J.; Mechoulam, R. J. Med. Chem. 1997, 40, 659.
(
9) Lin, S.; Khanolkar, A. D.; Fan, P.; Goutopoulos, A.; Qin, C.;
Papahadjis, D.; Makriyannis, A. J. Med. Chem. 1998, 41, 5353.
10) Ryan, W. J.; Banner, W. K.; Wiley, R. M.; Razdan, R. K. J. Med.
Chem. 1997, 40, 3517.
11) (a) Jeffery, T.; Gueugnot, S.; Linstrumelle, G. Tetrahedron Lett.
992, 33, 5757. (b) Lapitskaya, M. A.; Vasiljeva, L. L.; Pivnitsky, K. K.
Synthesis 1993, 65. (c) Durand, S.; Parrain, J.-L.; Santelli, M. Synthesis
998, 1015.
(
(
Attempts to reduce tetrayne 5 with the Schwartz reagent
1
or DIBALH on the resin were not successful. Thus, tetrayne
1
3
1
5 was cleaved using TFA (50% in CH
2
Cl
2
)
3
and AlMe /
1674
Org. Lett., Vol. 6, No. 10, 2004