ORGANIC
LETTERS
2005
Vol. 7, No. 19
4181-4183
Expedient Synthesis of Potent
Cannabinoid Receptor Agonist
(−)-CP55,940
Noriaki Itagaki, Tsutomu Sugahara, and Yoshiharu Iwabuchi*
Graduate School of Pharmaceutical Sciences, Tohoku UniVersity,
Aobayama, Sendai 980-8578, Japan
Received July 5, 2005
ABSTRACT
A stereocontrolled synthesis of (−)-CP55,940, a potent cannabinoid receptor agonist, has been attained using a novel aldolization/retro-
aldolization interconversion strategy, in which a temporarily generated chiral aldol motif plays essential roles.
Molecules that exhibit inherent stereoelectronic preferences
render their derivatives versatile in organic synthesis.
Bicyclo[3.n.1]alkane (n ) 2, 3) frameworks are representa-
tive of such structural elements that elicit distinguished
diastereofacial preferences. Therefore, continuing effort has
been devoted to realyzing their efficient assembly.1-4
In the preceding Letter,5 we reported a highly enantioselec-
tive synthesis of both enantiomeric forms of endo-8-hydroxy-
bicyclo[3.3.1]nonan-2-one (2) based on the organocatalytic
direct asymmetric intramolecular aldolization of σ-symmetric
3-(4-oxocyclohexyl)-propionaldehyde (1). In this Letter, we
report the use of this process in devising an expedient route
for the synthesis of the potent cannabinoid receptor agonist
(-)-CP55,940 (3),6 the use of which is growing in various
branches of the life sciences7 (Scheme 1).
The chiral building block 2 that is destined to constitute
(-)-(1R,3R,4R)-CP55,940 was secured from σ-symmetric
keto-aldehyde 18 in 68% yield with 99% de and 94% ee by
treatment with cis-4-TBDPSroxy-D-proline (25 mol %) in
(1) For synthesis of bicyclo[3.2.1]octanes, a review: (a) Rodriguez, J.;
Filippini, M.-H. Chem. ReV. 1999, 99, 27. Selected recent examples: (b)
Kosugi, H.; Sugiura, J.; Kato, M. Chem. Commun. 1996, 2743. (c) Toyota,
M.; Wada, T.; Fukumoto, K.; Ihara, M. J. Am. Chem. Soc. 1998, 120, 4916.
(d) Nagata, H.; Miyazawa, N.; Ogasawara, K. Org. Lett. 2001, 3, 1737. (e)
Langer, P.; Holtz, E.; Saleh, N. N. R. Chem. Eur. J. 2002, 8, 917. (f)
Orugunty, R. S.; Wright, D. L.; Battiste, M. A.; Helmich, R. J.; Abboud,
K. J. Org. Chem. 2004, 69, 406.
(2) For selected utility of bicyclo[3.2.1]octanes, see: (a) Nagata, H.;
Miyazawa, N.; Ogasawara, K. Chem. Commun. 2001, 1094. (b) Hanada,
K.; Miyazawa, N.; Ogasawara, K. Org. Lett. 2002, 4, 4515. (c) Miyazawa,
N.; Tosaka, A.; Hanada, K.; Ogasawara, K. Heterocycles 2003, 59, 491
and references therein. (d) Gutke, H.-J.; Braun, N. A.; Spitzner, D.
Tetrahedron 2004, 60, 8137.
(3) For synthesis of bicyclo[3.3.1]nonanes, reviews: (a) Peter, J. A.
Synthesis 1979, 321. (b) Butkus, E. Synlett 2001, 1827. Selected examples:
(c) Nicolaou, K. C.; Pfefferkorn, J. A.; Cao, G.-Q.; Kim, S.; Kessabi, J.
Org. Lett. 1999, 1, 807. (d) Aoyagi, K.; Nakamura, H.; Yamamoto, Y. J.
Org. Chem. 1999, 64, 4148. (e) Byeon, C.-H.; Hart, D. J.; Lai, C.-S.; Unch,
J. Synlett 2000, 119. (f) Barluenga, J.; Ballesteros, A.; Santamar´ıa, J.; de la
Ru´a, R. B.; Rubio, E.; Toma´s, M. J. Am. Chem. Soc. 2000, 122, 12874. (g)
Takagi, R.; Nerio, T.; Miwa, Y.; Matsumura, S.; Ohkata, K. Tetrahedron
Lett. 2004, 45, 7401.
(4) For selected utility of bicyclo[3.3.1]nonanes, see: (a) Buno, F.;
Tenaglia, A. J. Org. Chem. 2000, 65, 3869. (b) Gambacorta, A.; Tofani,
D.; Lupattelli, P.; Tafi, A. Tetrahedron Lett. 2002, 43, 2195. (c) Shibuya,
M.; Taniguchi, T.; Takahashi, M.; Ogasawara, K. Tetrahedron Lett. 2002,
43, 4145.
(5) See preceding Letter: Itagaki, N.; Kimura, M.; Sugahara, T.;
Iwabuchi, Y. Org. Lett. 2005, 7, 4185.
(6) Johnson, M. R.; Melvin, L. S., Jr., U.S. Patent 4,371,720, July 28,
1981.
(7) (a) Di Marzo, V.; Matias, I. Nat. Neurosci. 2005, 8, 585. (b) Begg,
M.; Pacher, P.; Ba´tkai, S.; Osei-Hyiaman, D.; Offerta´ler, L.; Mo, F. M.;
Kunos, G. Pharmacol. Ther. 2005, 106, 133. (c) Goutopoulos, A.;
Makryannis, A. Pharmacol. Ther. 2002, 95, 103.
(8) Mori, K.; Takayama, S.; Kido, M. Bioorg. Med. Chem. 1994, 2, 395.
10.1021/ol051570c CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/18/2005