ORGANIC
LETTERS
2011
Vol. 13, No. 13
3482–3485
Diastereoselective Construction of
7-Methylenebicyclo[3.2.1]oct-3-en-2-one
Derivatives by Palladium-Catalyzed
Cyclization of Propargylic Acetates with
2-Oxocyclohex-3-enecarboxylates
Masahiro Yoshida,* Chiyuki Sugimura, and Kozo Shishido
Graduate School of Pharmaceutical Sciences, The University of Tokushima,
1-78-1 Sho-machi, Tokushima
Received May 10, 2011
ABSTRACT
The reaction of propargylic acetates with 2-oxocyclohex-3-enecarboxylates in the presence of a palladium catalyst is described. Substituted
7-methylenebicyclo[3.2.1]oct-3-en-2-ones were synthesized in a highly diastereoselective manner.
Palladium-catalyzed reactions of propargylic com-
pounds with nucleophiles have received considerable at-
tention and have been extensively studied due to their
versatile and specific reactivity.1 The reaction of pro-
pargylic compounds with bis-nucleophiles is one example
of the more successful chemical processes developed to
date.2 In this reaction, a substrate having two nucleophilic
moieties within the molecule reacted sequentially with the
π-propargylpalladium complex, resulting from pro-
pargylic compounds and palladium catalysts, to afford
the cyclized product. For example, we have recently re-
ported the reaction of propargylic carbonates with β-keto
esters,2i in which substituted tetrahydrobenzofuranones
having a quaternary carbon stereocenter were synthe
sized in a highly diastereoselective manner (Scheme 1).
Scheme 1. Palladium-Catalyzed Reaction of Propargylic
Carbonates with β-Keto Esters
(1) (a) Tsuji, J. Palladium Reagents and Catalysts: Innovations in
Organic Synthesis; Wiley: New York, 1995; pp 453. (b) Tsuji, J. Palladium
Reagents and Catalysts: New Perspectives for the 21st Century; Wiley:
England, 2004; pp 543. (c) Tsuji, J.; Mandai, T. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2589. (d) Guo, L.-N.; Duan, X.-H.; Liang, Y.-M. Acc.
Chem. Res. 2011, 44, 111 and references therein.
(2) (a) Tsuji, J.; Watanabe, I.; Minami, I.; Shimizu, I. J. Am. Chem.
Soc. 1985, 107, 2196. (b) Geng, L.-F.; Lu, X.-Y. Chin. J. Chem. 1993, 11,
91. (c) Labrosse, J.-R.; Lhoste, P.; Sinou, D. Tetrahedron Lett. 1999, 40,
9025. (d) Labrosse, J.-R.; Lhoste, P.; Sinou, D. Org. Lett. 2000, 2, 527.
(e) Damez, C.; Labrosse, J.-R.; Lhoste, P.; Sinou, D. Tetrahedron Lett.
2003, 44, 557. (f) Duan, X.-H.; Liu, X.-Y.; Guo, L.-N.; Liao, M.-C.; Liu,
W.-M.; Liang, Y.-M. J. Org. Chem. 2005, 70, 6980. (g) Yoshida, M.;
Higuchi, M.; Shishido, K. Tetrahedron Lett. 2008, 49, 1678. (h) Yoshida,
M.; Higuchi, M.; Shishido, K. Org. Lett. 2009, 11, 4752. (i) Yoshida, M.;
Higuchi, M.; Shishido, K. Tetrahedron 2010, 66, 2675.
Although various heterocyclic molecules can be synthe-
sized by this type of cyclization, no examples have been
reported on the construction of carbocyclic molecules,
presumably because of the difficulty in designing the bis-
nucleophiles.3 In planning our investigation of this reac-
tion, we focused on the nucleophilic activity of 2-oxocy-
clohex-3-enecarboxylates. By introducing a conjugated
enone system within the substrate, it was thought that
both the R-carbon of the keto ester moiety and the
r
10.1021/ol201243u
Published on Web 06/02/2011
2011 American Chemical Society