Synthesis of Optically Pure 1,4-Dihydropyridine Derivatives by Means of Diastereoisomeric Separation of the Hantzsch Intermediates Bearing (R)-1-Phenylethylamino Group

Kosugi, Yoshiyuki; Hori, Masanori; Nagasaka, Tatsuo

doi:10.3987/com-94-s(b)51

Cited by 14 publications

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“…The results of these modifications were found variable for different types of reactants. On the contrary, numerous protocols for the synthesis of asymmetric chiral DHPs were described, including resolution of a racemic mixture (He et al, 2010), asymmetric induction (Martín et al, 1995), or chemoenzymatic method (Kosugi et al, 1994). Synthesis of target symmetrical 1,4‐DHPs ( 4a‐h ) is illustrated in Scheme 1.…”

Section: Resultsmentioning

confidence: 99%

In vitro cytotoxicity and docking study of novel symmetric and asymmetric dihydropyridines and pyridines as EGFR tyrosine kinase inhibitors

et al. 2022

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Quinolines have a weighty effect as anticancer agents and 1,4‐DHPs have demonstrated efficacy as anticancer agents in several studies, as well. New hybrid models of symmetric and asymmetric 1,4‐DHPs and pyridines linked at C3 of 2‐chloroquinoline as a new anticancer scaffold, were designed and synthesized. Hantszch 1,4‐DHPs method was adopted for chemical synthesis. MTT assay was performed for the evaluation of cytotoxicity, and EGFR tyrosine kinase assay was performed to investigate binding to our selected compounds, measured by ELISA. The IC50 expressed in µM values revealed that compounds 4a,b, and 5i,k showed the best results against the tested four cell lines than the reference drug 5‐Flurouuracil. Compound 5k displayed the most potent cytotoxic activity with IC50 values in the low µM range (12.03 ± 1.51: 20.09 ± 2.16 µM), compared with 5‐Fu IC50 range (40.74 ± 2.46: 63.81 ± 2.69 µM). The incorporation of 2‐chloroquinoline at C3 to C4 of 1,4‐DHP could be proposed as an anticancer scaffold rather than its analogous pyridines. Ester fragments connected to 1,4‐DHPs ring as a lipophilic part are essential for anticancer activity. The chirality at C4 improved the anticancer activity. The hydrogen and halogen bond facilitated protein‐ligand binding mode and affinity.

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Section: Resultsmentioning

confidence: 99%

In vitro cytotoxicity and docking study of novel symmetric and asymmetric dihydropyridines and pyridines as EGFR tyrosine kinase inhibitors

et al. 2022

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“…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).…”

Section: Commentmentioning

confidence: 99%

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

et al. 2006

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“…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 1 , (ii) the enantioselective Hantzsch-type synthesis using chiral auxiliary on the DHP-nitrogen atom 2 ,, or the ester function 3 ,4b or (iii) the chemoenzymatic approaches by hydrolyzing the alkyl ester(s) function(s) at the position C 3 and/or C 5 of the 3,5-dialkyl-4-aryl-1,4-DHP carboxylate(s). ,, In all these reported methods, only the 1,4-DHP nucleus with a methyl group at the C 2 and C 6 positions was studied.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2004

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(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.

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Synthesis of Optically Pure 1,4-Dihydropyridine Derivatives by Means of Diastereoisomeric Separation of the Hantzsch Intermediates Bearing (R)-1-Phenylethylamino Group

Cited by 14 publications

References 0 publications

In vitro cytotoxicity and docking study of novel symmetric and asymmetric dihydropyridines and pyridines as EGFR tyrosine kinase inhibitors

In vitro cytotoxicity and docking study of novel symmetric and asymmetric dihydropyridines and pyridines as EGFR tyrosine kinase inhibitors

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

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

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