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

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 11; pp. 3317 - 3319
• Main Authors: Yamamoto, Takashi, Ohno, Seiji, Niwa, Seiji, Tokumasu, Munetaka, Hagihara, Masako, Koganei, Hajime, Fujita, Shin-ichi, Takeda, Tomoko, Saitou, Yuki, Iwayama, Satoshi, Takahara, Akira, Iwata, Seinosuke, Shoji, Masataka
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01-06-2011; Elsevier
• Subjects: 1,4-Dihydropyridine derivative; Animals; Asymmetric synthesis; Biological and medical sciences; calcium channel blockers; calcium channels; Calcium Channels, N-Type - drug effects; Carboxylic Acids - chemical synthesis; Carboxylic Acids - chemistry; Carboxylic Acids - pharmacology; Cell Line, Tumor; Dihydropyridines - chemical synthesis; Dihydropyridines - chemistry; Dihydropyridines - pharmacology; Humans; isomers; Medical sciences; Methyl Ethers - chemical synthesis; Methyl Ethers - chemistry; Methyl Ethers - pharmacology; Miscellaneous; Molecular Structure; N-type calcium channel blocker; Neuropharmacology; Pharmacology. Drug treatments; Protein Binding - drug effects; Rats; Stereoisomerism; Structure-Activity Relationship; Structure–activity relationships; 1,4-Dihydropyridine derivative; N-type calcium channel blocker; Asymmetric synthesis; Structure–activity relationships; Enantiomer(+); Structure activity relation; Carboxylic acid; Chlorine Organic compounds; N-type calcium channel; Ionic channel; Dihydropyridine derivatives; Antagonist; Structure-activity relationships
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.04.007

The novel asymmetric synthesis is reported for the preparation of optically pure (+)-4-(3-chlorophenyl)-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3,5-dicarboxilic acid cinnamyl ester ((+)-
3) as a promising blocker for the N-type calcium channels.
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.