Organic Letters
Letter
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(6) Tejero, I.; Gonzalez-Lafont, A.; Lluch, J. M.; Eriksson, L. A. J. Phys.
As described herein, we successfully identified α-CP-RvE2 (α-
2) and β-CP-RvE2 (β-2) as stable equivalents of RvE2. To our
knowledge, this is first report using a cyclopropane ring for
bioisosteric stabilization of 1,4-diene- containing polyunsatu-
rated fatty acids against autoxidation.
Chem. B 2007, 111, 5684.
(7) (a) Ogawa, S.; Urabe, D.; Yokokura, Y.; Arai, H.; Arita, M.; Inoue,
M. Org. Lett. 2009, 11, 3602. (b) Kosaki, Y.; Ogawa, N.; Kobayashi, Y.
Tetrahedron Lett. 2010, 51, 1856. (c) Rodriguez, A. R.; Spur, B. W.
Tetrahedron Lett. 2012, 53, 1912.
In conclusion, we designed α-CP-RvE2 (α-2) and β-CP-
RvE2(β-2), which avoid the unstable bisallylic positions of RvE2,
as stable equivalents of RvE2 on the basis of computational
calculations. Efficient syntheses of α-2 and β-2 as well as RvE2
were achieved by adopting a convergent synthetic strategy in
which the key cyclopropane units 5a and 5b were provided via
Sonogashira coupling with bromomethylenecyclopropane 7a
and its enantiomer 7b, inspired by our previous work on
cyclopropane chemistry. The synthesized α-2 and β-2 were not
only much more stable than RvE2 against autoxidation but also
exhibited equal or much more anti-inflammatory activity than
RvE2, resulting in the identification of α-2 and β-2 as stable
equivalents of RvE2. This study presents a strategy using a
cyclopropane for bioisosteric stabilization of 1,4-diene structures
to overcome the instability of polyunsaturated compounds of
pharmacological importance.
(8) Gotz, K.; Liermann, J. C.; Thines, E.; Anke, H.; Opatz, T. Org.
Biomol. Chem. 2010, 8, 2123. For details, see the Supporting
(9) (a) Takahashi, H.; Kawakita, T.; Ohno, M.; Yoshioka, M.;
Kobayashi, S. Tetrahedron 1992, 48, 5691. (b) Ostwald, R.; Chavant, P.-
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Y.; Stadtmuller, H.; Knochel, P. J. Org. Chem. 1994, 59, 4143. For details,
̈
(10) For selected reviews, see: (a) Pellissier, H. Tetrahedron 2008, 64,
7041. (b) Bartoli, G.; Bencivenni, G.; Dalpozzo, R. Synthesis 2014, 46,
979.
(11) Enantioselective Simmons−Smith reaction of cis-olefins, see:
Charette, A. B.; Juteau, H.; Lebel, H.; Molinaro, C. J. Am. Chem. Soc.
1998, 120, 11943.
(12) Highly regio- and stereoselective synthesis of alkylidenecyclo-
propanes via asymmetric cyclopropanation of allenes: Chanthamath, S.;
Chua, H. W.; Kimura, S.; Shibatomi, K.; Iwasa, S. Org. Lett. 2014, 16,
3408.
(13) Enantio- and diastereoselective synthesis of cis-disubstituted
cyclopropyl alcohols: (a) Kim, H. Y.; Lurain, A. E.; García-García, P.;
Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 13138. (b) Kim, H.
Y.; Salvi, L.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2010, 132, 402.
(14) For recent reports of highly enantio- and cis-selective cyclo-
propanation of monosubstituted olefins, see: (a) Kanchiku, S.;
Suematsu, H.; Uchida, T.; Katsuki, T. Angew. Chem., Int. Ed. 2007, 46,
3889. (b) Suematsu, H.; Kanchiku, S.; Uchida, T.; Katsuki, T. J. Am.
Chem. Soc. 2008, 130, 10327.
ASSOCIATED CONTENT
* Supporting Information
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S
The Supporting Information is available free of charge on the
Detailed experimental procedures, calculation, oxidative
stability, and biological assay (PDF)
(15) For other enantio- and cis-selective cyclopropanations of
monosubstituted olefins, see: (a) Evans, D. A.; Woerpel, K. A.;
Hinman, M. M.; Faul, M. M. J. Am. Chem. Soc. 1991, 113, 726.
(b) Fantauzzi, S.; Gallo, E.; Rose, E.; Raoul, N.; Caselli, A.; Issa, S.;
Ragaini, F.; Cenini, S. Organometallics 2008, 27, 6143. (c) Minuth, T.;
Boysen, M. M. K. Synthesis 2010, 2010, 2799.
AUTHOR INFORMATION
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Corresponding Author
ORCID
(16) Sasaki, H.; Irie, R.; Hamada, T.; Suzuki, K.; Katsuki, T.
Tetrahedron 1994, 50, 11827.
Notes
(17) (a) Kawamura, S.; Unno, Y.; List, A.; Mizuno, A.; Tanaka, M.;
Sasaki, T.; Arisawa, M.; Asai, A.; Groll, M.; Shuto, S. J. Med. Chem. 2013,
56, 3689. (b) Kawamura, S.; Unno, Y.; Tanaka, M.; Sasaki, T.; Yamano,
A.; Hirokawa, T.; Kameda, T.; Asai, A.; Arisawa, M.; Shuto, S. J. Med.
Chem. 2013, 56, 5829.
(18) The best results in our investigation of Charette asymmetric
cyclopropanation with 9 as the substrate: Treatment of 9 with
Zn(CH2I)2·DME (6 equiv) and chiral dioxaborolane reagent (2
equiv) in CH2Cl2 at reflux gave 10 (32% yield, 60% ee).
(19) We previously confirmed the enantiomeric purity of the
intermediate 7b as >99% ee; see: Tanabe, M.; Watanabe, M.;
Hoshiya, N.; Mizuno, A.; Fukuda, H.; Arisawa, M.; Shuto, S. J. Org.
Chem. 2013, 78, 11714.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This work was supported by a Grant-in-Aid for Young Scientists
(B) (25860087, H.F.) and Scientific Research Grant (15H02495,
S.S.) from the Japan Society for the Promotion of Science and the
Sasakawa Scientific Research Grant from The Japan Science
Society.
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