Scheme 1. Synthetic Strategy for (-)-Kainic Acid (1)
Scheme 2. Synthesis of RCM Precursor 12
functionalities could be carried out on monoprotected diol
4. Enantioselective synthesis of 4 would be possible by
reduction of the Evans aldol reaction15 product 5, available
from crotonic acid derivative 6 and acetaldehyde.
Preparation of the substrate for RCM reaction started with
the acylation of oxazolidinone 7 with crotonic anhydride16
(Scheme 2). A diastereoselective Evans aldol reaction
between crotonamide detivative 8 and acetaldehyde pro-
ceeded in the presence of 1.05 equiv of TiCl4 and 2.5 equiv
of i-Pr2NEt to give the aldol product 9 as a single isomer.17
After protection of the hydroxyl group as the TES ether, the
chiral auxiliary was reductively cleaved to provide homo-
allylic alcohol 10. Introduction of the glycine moiety was
then carried out by Mitsunobu reaction18 of 10 with Nosyl
(Ns)-activated glycine methyl ester 11.19 Exchanging the Ns
with the Boc group by the standard conditions was followed
by desilylation and acylation with acryloyl chloride to afford
the desired precursor 13 for RCM reaction.
(11) For selected examples, see: (a) Ueno, Y.; Tanaka, K.; Ueyanagi,
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R. J. K.; Raynham, T. M. Chem. Commun. 1999, 245. (s) Chevliakov, M.
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Due to the impracticality of the Mitsunobu reaction for
large-scale preparation, we examined a reductive amination
approach to incorporate the glycine moiety (Scheme 3).
Scheme 3. Reductive Amination Approach To Introduce the
Glycine Moiety
(12) Morita, Y.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2005, 7, 4337.
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28, 446. (b) Grubbs, R. H. Tetrahedron 2004, 60, 7117.
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Michael addition reaction, see: Yoo, S.-E.; Lee, S.-H.; Kim, N.-J.
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(15) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
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Treatment of the TBS-protected aldol product 14 with
DIBAL-H at -78 °C gave the corresponding hemiaminal
15 as a mixture of diastereomers in modest yield. Reductive
amination of 15 with glycine methyl ester hydrochloride
(16) Ho, G.-J.; Mathre, D. J. J. Org. Chem. 1995, 60, 2271.
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(18) Mitsunobu, O. Synthesis 1981, 1.
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Org. Lett., Vol. 9, No. 9, 2007