Asymmetric synthesis and biological evaluations of (+)- and (-)-6-dimethoxymethyl-1,4-dihydropyridine-3-carboxylic acid derivatives blocking N-type calcium channels

  • Bioorg Med Chem Lett. 2011 Jun 1;21(11):3317-9. doi: 10.1016/j.bmcl.2011.04.007.
Takashi Yamamoto  1 ,  Seiji Ohno ,  Seiji Niwa ,  Munetaka Tokumasu ,  Masako Hagihara ,  Hajime Koganei ,  Shin-ichi Fujita ,  Tomoko Takeda ,  Yuki Saitou ,  Satoshi Iwayama ,  Akira Takahara ,  Seinosuke Iwata ,  Masataka Shoji
Affiliations
  • 1. Exploratory Research Laboratories, Ajinomoto Pharmaceuticals Co., Ltd, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa, Japan. [email protected]
PMID: 21514827 DOI: 10.1016/j.bmcl.2011.04.007
Abstract

An efficient asymmetric synthesis of 1,4-dihydropyridine derivatives is described. The key step is the stereoselective Michael addition using t-butyl ester of L-valine as a chiral auxiliary to achieve good ee (>95% for all the tested experiments) and moderate yield. With this method, (+)-4-(3-chlorophenyl)-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid cinnamyl ester was obtained and was characterized as a promising N-type calcium channel blocker with improved selectivity over L-type compared to its (-)- and racemic isomers.