Asymmetric synthesis of 1,4-disubstituted 3-methylidenedihydroquinolin-2(1 H )-ones

Pięta, Marlena; Kędzia, Jacek; Wojciechowski, Jakub; Janecki, Tomasz

doi:10.1016/j.tetasy.2017.03.010

Cited by 3 publications

(3 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Taking into consideration both great the potential of 3‐alkylidene(arylidene)‐2,3‐dihydroquinolin‐4(1 H )‐ones 1 as cytotoxic agents and their synthetic utility, we decided to develop a new route leading to these compounds, based on the well recognized Horner–Wadsworth–Emmons (HWE) methodology which enables the introduction of the exo ‐alkylidene bond onto the carbo‐ or heterocyclic ring. [ ][ ] This methodology has been successfully applied in our laboratory for the synthesis of various 1‐oxo‐2‐alkylideneheterocycles and very recently in the asymmetric synthesis of 3‐methylidenedihydroquinolin‐2(1 H )‐ones . In this report, we demonstrate that HWE approach can be effectively applied to the synthesis of 2‐substituted 3‐methylidene‐1‐tosyl‐2,3‐dihydroquinolin‐4(1 H )‐ones 11 .…”

Section: Introductionmentioning

confidence: 80%

“…In turn, ketones 10 were mixtures of cis and trans isomers and configurational assignments were made on the bases of characteristic 3 J (H2,H3) coupling constants, which were in the range of 4.4 – 4.6 Hz for cis isomers and 1.2 – 1.4 for trans isomers. Analogous differences in the 3 J (H3,H4) coupling constants in cis ‐ and trans ‐4‐substituted‐3‐phosphoryl‐2,3‐dihydroquinolin‐2(1 H )‐ones [ ][ ] and 4‐substituted‐3‐phosphorylchroman‐2‐ones [ ][ ] are well documented and were attributed to the trans ‐diaxial arrangement of the phosphoryl group and substituent in position 4 in trans ‐isomers. Inspection of the molecular models of cis ‐ and trans ‐3‐(diethoxyphosphoryl)‐2,3‐dihydroquinolin‐4(1 H )‐ones 10 revealed great conformational similarity of these compounds to 3‐phosphorylquinolin‐2‐ones and 3‐phosphorylchroman‐2‐ones, including trans ‐diaxial arrangement of the phosphoryl group and substituent in position 2 in trans ‐ 10 .…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Synthesis of 3‐Methylidene‐1‐tosyl‐2,3‐dihydroquinolin‐4(1H)‐ones as Potent Cytotoxic Agents

Koszuk

Bartosik

Wojciechowski

et al. 2018

Chemistry & Biodiversity

Self Cite

View full text Add to dashboard Cite

An efficient synthetic strategy to 3-methylidene-2,3-dihydroquinolin-4(1H)-ones variously substituted in position 2 has been developed. The title compounds were synthesized in the reaction sequence involving reaction of diethyl methylphosphonate with methyl 2-(tosylamino)benzoate, condensation of thus formed diethyl 2-oxo-2-(2-N-tosylphenyl)ethylphosphonate with various aldehydes followed by successful application of the obtained 3-(diethoxyphosphoryl)-1,2-dihydroquinolin-4-ols as Horner-Wadsworth-Emmons reagents for the olefination of formaldehyde. Also, enantioselective approach to the target compounds has been evaluated using 3-dimenthoxyphosphoryl group as a chiral auxiliary. Single X-ray crystal analysis of (2S)-3-(dimenthoxyphosphoryl)-2-phenyl-1-tosyldihydroquinolin-4-ol revealed the presence of strong resonance-assisted hydrogen bond (RAHB). The obtained 3-methylidene-2,3-dihydroquinolin-4(1H)-ones were then tested for their cytotoxic activity against two leukemia cell lines NALM-6 and HL-60 and a breast cancer MCF-7 cell line. All compounds showed very high cytotoxic activity with the IC values mostly below 1 μm in all three cancer cell lines. The selected analogs were also tested on human umbilical vein endothelial cells (HUVEC) and on human mammary gland/breast cells (MCF-10A) to evaluate their influence on normal cells. Since one of the most serious problems in cancer chemotherapy is the development of drug resistance, the mRNA levels and activity of ABCB1 transporter considered to be the most important factor engaged in drug resistance, were evaluated in MCF-7 cells treated with two selected analogs. Both compounds were strong ABCB1 transporter inhibitors that could prevent efflux of anticancer drugs from cancer cells.

show abstract

Section: Introductionmentioning

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Synthesis of 3‐Methylidene‐1‐tosyl‐2,3‐dihydroquinolin‐4(1H)‐ones as Potent Cytotoxic Agents

Koszuk

Bartosik

Wojciechowski

et al. 2018

Chemistry & Biodiversity

Self Cite

View full text Add to dashboard Cite

show abstract

“…In this report, we present a new, general synthetic method for obtaining variously substituted 3-methylidenechroman-4-ones 14 , based on the (well-recognized in our laboratory) Horner–Wadsworth–Emmons approach for the construction of exo -methylidene bond [29,30,31]. All obtained 3-methylidenechroman-4-ones 14 were evaluated in terms of their cytotoxic activity against three human cancer cell lines: promyelocytic leukemia HL-60, NALM-6, and breast adenocarcinoma cell line MCF-7.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Cytotoxic Evaluation of 3-Methylidenechroman-4-ones

et al. 2019

Self Cite

View full text Add to dashboard Cite

In the search for new anticancer agents, a library of variously substituted 3-methylidenechroman-4-ones was synthesized using Horner–Wadsworth–Emmons methodology. Acylation of diethyl methylphosphonate with selected ethyl salicylates furnished 3-diethoxyphosphorylchromen-4-ones which were next used as Michael acceptors in the reaction with various Grignard reagents. The adducts were obtained as the mixtures of trans and cis diastereoisomers along with a small amount of enol forms. Their relative configuration and preferred conformation were established by NMR analysis. The adducts turned up to be effective Horner–Wadsworth–Emmons reagents giving 2-substituted 3-methylidenechroman-4-ones, which were then tested for their possible cytotoxic activity against two leukemia cell lines, HL-60 and NALM-6, and against MCF-7 breast cancer cell line. All new compounds (14a–o) were highly cytotoxic for the leukemic cells and showed a moderate or weak effect on MCF-7 cells. Analog 14d exhibited the highest growth inhibitory activity and was more potent than carboplatin against HL-60 (IC50 = 1.46 ± 0.16 µM) and NALM-6 (IC50 = 0.50 ± 0.05 µM) cells. Further tests showed that 14d induced apoptosis in NALM-6 cells, which was mediated mostly through the extrinsic pathway.

show abstract

Enantioselective synthesis of 5-methylidenedihydrouracils as potential anticancer agents

et al. 2019

View full text Add to dashboard Cite

Asymmetric synthesis of 1,4-disubstituted 3-methylidenedihydroquinolin-2(1 H )-ones

Cited by 3 publications

References 11 publications

Synthesis of 3‐Methylidene‐1‐tosyl‐2,3‐dihydroquinolin‐4(1H)‐ones as Potent Cytotoxic Agents

Synthesis of 3‐Methylidene‐1‐tosyl‐2,3‐dihydroquinolin‐4(1H)‐ones as Potent Cytotoxic Agents

Synthesis and Cytotoxic Evaluation of 3-Methylidenechroman-4-ones

Enantioselective synthesis of 5-methylidenedihydrouracils as potential anticancer agents

Contact Info

Product

Resources

About