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

• Published in: Journal of organic chemistry Vol. 69; no. 12; pp. 4227 - 4237
• Main Authors: Marchalín, Štefan, Cvopová, Katarína, Križ, Miroslav, Baran, Peter, Oulyadi, Hassan, Daïch, Adam
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 11.06.2004; Amer Chemical Soc
• Subjects: Calcium Channel Blockers - chemical synthesis; Calcium Channel Blockers - chemistry; Catalysis; Chemical Sciences; Chemistry; Chemistry, Organic; Crystallization - methods; Dihydropyridines - chemical synthesis; Dihydropyridines - chemistry; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Lactams - chemistry; Medicinal Chemistry; Models, Molecular; Organic chemistry; Physical Sciences; Preparations and properties; Science & Technology; Stereoisomerism; ANTAGONIST MODULATION ACTIVITIES; KINETIC RESOLUTION; AMINO-ACIDS; 1,4-DIHYDROPYRIDINES; LIPASE; INDUCED DYNAMIC RESOLUTION; PURE; CEPHALEXIN; VOLTAGE-CLAMP; NILVADIPINE; Solvent effect; Nitrogen heterocycle; Thiazole derivatives; Temperature effect; Chiral compound; Pyridine derivatives; Schiff base; Racemic; Thiophene derivatives; Aminoaldehyde; Chemical synthesis; Sulfur nitrogen heterocycle; Condensation reaction; Filtration; Crystallization; Solubility; Thiolactam; Imine; Aldehyde; Tricyclic compound; X ray diffraction; Hydrolysis; Cycloaddition; Sulfur heterocycle; Optical resolution; Aminothiol
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo049706s

(R)- and (S)-α-phenylethylamine (α-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)-α-PEA (7) or (S)-α-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.