New Resolution of 2-Formyl-1,4-DHP Derivatives Using CIDR Methodology. Facile Access to New Chiral Tricyclic Thiolactam

Abstract

(R)- and (S)-alpha-phenylethylamine (alpha-PEA: 7) have been used separately to resolve successfully a racemate 2-formyl-1,4-DHP derivative 4. The process was based on the difference of the solubility of both Schiff bases (6) since one of them crystallized out from the solution. These imines obtained by condensation of (R)-alpha-PEA (7) or (S)-alpha-PEA (7) with aldehyde (rac-4) were separated and analyzed by X-ray diffraction, and their exposition to an hydrochloric hydrolysis conditions led to the enantiopure (4R)-4 or (4S)-4 in excellent yields. Separate condensation of other chiral (8 and 13) and racemic (18) amino thiols as auxiliary with rac-4, (4S)-4, or (4R)-4 is accompanied by an in situ crystallization-induced dynamic resolution, whereby one distereomer of thiazole template selectively precipitates and can be isolated by simple filtration in 76-82% yield with dr > 99. The thiazole species isolated from this process resulted from an amino aldehyde condensation followed by a spontaneous thiol-imine cycloaddition. Finally, the racemate (+/-)-(4R,2'R)-19 and the diastereomerically pure homologous (4S,2'R)-23 and (4R,2'S)-20 (obtained in good yields (79-82%) from 2-aminoethanethiol (18) and 2-formyl-1,4-DHP derivative rac-4, (4S)-4, or (4R)-4, respectively) were converted conveniently in a one-pot procedure into newly tricyclic thiolactams in the DHP series in racemic ((+/-)-(6R,9bR)-21, 72% yield)) and enantiopure ((6S,9bR)-24, 71% yield); (6R,9bS)-24, 70% yield) forms.

(4S,1′R)-Diethyl 6-methyl-2-[(1′-phenylethylimino)methyl]-4-(2-thienyl)-1,4-dihydropyridine-3,5-dicarboxylate

“…The title compound precipitated as crystals while the diastereomer diethyl (4R,1 0 R)-6-methyl-2-[(1 0 -phenylethylimino)methyl]-4-(2-thienyl)-1,4-dihydropyridine-3,5-dicarboxylate remained in the filtrate. Full details of the synthetic procedure have been published by Marchalín et al (2004). Yellow prism-like single crystals were prepared by recrystallization from an ethanol solution (1:1).…”

“…Three general methods have been reported for the preparation of enantiomeric 4-aryl-1,4-DHPs: (i) the optical resolution of 1,4-DHP-monocarboxylic acids (Goldmann & Stoltefuss, 1991); (ii) chemoenzymatic hydrolysis of the alkyl ester groups at the C3 and C5 positions of substituted 1,4-DHPs (Sobolev et al, 2004); (iii) the enantioselective Hantzsch-type synthesis using a chiral auxiliary on the 1,4-DHP N atom or the ester group (Kosugi et al, 1994;Peri et al, 2000). In our case, the third method was applied (Marchalín et al, 2004) for the preparation of the title compound, (I).…”

(4R,1′S)-Diethyl 6-methyl-2-[(1′-phenylethylimino)methyl]-4-(2-thienyl)-1,4-dihydropyridine-3,5-dicarboxylate

“…Compound (I) precipitated as crystals, while the diastereomer diethyl (4S,1 0 S)-6-methyl-2-[(1 0 -phenylethylimino)-methyl]-4-(2-thienyl)-1,4dihydropyridine-3,5-dicarboxylate remained in the filtrate. Full details of the synthetic procedure have been published by Marchalín et al (2004). Yellow prism-like single crystals were prepared by recrystallization from an ethanol-water solution (1:1) .…”

Diisopropyl 1-(4-methoxyphenyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

“…For background to the pharmaceutical applications of 1,4-dihydropyridine derivatives, see: Gaveriya et al (2001); Shah et al (2000Shah et al ( , 2002; Marchalin et al (2004); Chhillar et al (2006).…”