Recent advancement and novel application of organocatalyzed aldol condensation reactions: A comprehensive review

Background: Aldol reactions play an important role in the development of organic synthesis-owing to their critical importance for the forming of carbon-carbon bonds while concurrently one or two chiral centers come into being. In the modern scenario, the Aldol condensation reaction has arisen as perhaps the most significant reaction for the formation of novel medicinal agents exhibits promising pharmacological activities. Objective: The purpose of this study is to present newer synthetic approaches through Aldol condensation reaction for the synthesis of diverse scaffolds to explore the promising various types of biological activities. Methods: Aldol condensation concerns the nucleophilic addition reaction of a ketone enolate to an aldehyde to form aldol or β- hydroxy ketone. Occasionally, the aldol addition product losing water molecule yields an α, β-unsaturated ketone. Results: Results showed that amino acids and all lengths of peptides are utilized as chiral catalysts. As of now, the arrangement of catalysts that have been accounted for is intensely one-sided towards proline. This is to some degree because of its exceptional status among the normally happening amino acids as an auxiliary amine and to its restricted underlying adaptability. Conclusion: The present study thus provides useful insight concerning the promising coherent way for the synthesis of prolinamide analogue of proline, through a direct asymmetric aldol condensation reaction. Thus, the current study summarizes various Aldol condensation reactions for the synthesis of novel agents as well as their promising pharmacological importance.

Enantioselective access to tricyclic tetrahydropyran derivatives by a remote hydrogen bonding mediated intramolecular IEDHDA reaction

Inverse-electron-demand-hetero-Diels-Alder reactions of alkenes with α,β-unsaturated keto compounds allow rapid access to the tetrahydropyran ring found in numerous natural products and bioactive molecules. Despite its synthetic interest, catalytic asymmetric versions of this process remain underdeveloped, especially regarding the use of non-activated alkenes reacting with α,β-unsaturated ketone or aldehyde, for which no report can be found in the literature. Herein, we describe the catalytic inverse-electron-demand-hetero-Diels-Alder reactions between neutral alkenes and an α,β-unsaturated ketones or aldehydes to produce a variety of trans-fused [5,6,8] tricyclic structures containing a central, chiral tetrahydropyran ring. This complex transformation, which is achieved using a chiral phosphoric acid, allows for the formation of four stereogenic centers in a single step with high regio-, diastereo- and enantioselectivity (up to 99% ee). Such level of stereocontrol could be achieved by a key remote double hydrogen atom bonding interaction between the linear substrate and the catalyst.

Tethered Aryl Groups Increase the Activity of Anti-Proliferative Thieno[2,3-b]Pyridines by Targeting a Lipophilic Region in the Active Site of PI-PLC

The compounds 2-amino-3-carboxamido-thieno[2,3-b]pyridines have demonstrated excellent anti-proliferative activity against human cancer cell lines, including the triple-negative breast cancer cell line MDA-MB-231. In this study, 81 novel thieno[2,3-b]pyridines were synthesised in four series to further improve their anti-proliferative activity, in particular by targeting an adjacent lipophilic pocket in the putative target enzyme phosphoinositide phospholipase C (PI-PLC). Overall, it was found that appending a propyl-aryl group at C-5 on 2-amino-3-carboxamido-thieno[2,3-b]pyridine resulted in compounds with potent biological activity, exhibiting IC50 values in the nanomolar range. The propyl linker could be an α,β-unsaturated ketone or a saturated propyl ketone, but the highest activity was obtained when allylic alcohols were the tether between thieno[2,3-b]pyridine and the appended aryl group, with compound 21r having IC50 values lower than 50 nM. Compounds with one extra carbon in the tether (i.e., a four-atom chain) were found to be considerably less active. Molecular modelling revealed this propyl tether places the newly introduced aryl ring in an untargeted lipophilic pocket within the active site of the phosphoinositide phospholipase C (PI-PLC) enzyme.

Design, Synthesis and Evaluation of Novel Derivatives of Curcuminoids with Cytotoxicity

Curcumin and curcuminoids have been discussed frequently due to their promising functional groups (such as scaffolds of α,β-unsaturated β-diketone, α,β-unsaturated ketone and β′-hydroxy-α,β-unsaturated ketone connected with aromatic rings on both sides) that play an important role in various bioactivities, including antioxidant, anti-inflammatory, anti-proliferation and anticancer activity. A series of novel curcuminoid derivatives (a total of 55 new compounds) and three reference compounds were synthesized with good yields using three-step organic synthesis. The anti-proliferative activities of curcumin derivatives were examined for six human cancer cell lines: HeLaS3, KBvin, MCF-7, HepG2, NCI-H460 and NCI-H460/MX20. Compared to the IC50 values of all the synthesized derivatives, most α,β-unsaturated ketones displayed potent anti-proliferative effects against all six human cancer cell lines, whereas β′-hydroxy-α,β-unsaturated ketones and α,β-unsaturated β-diketones presented moderate anti-proliferative effects. Two potent curcuminoid derivatives were found among all the novel derivatives and reference compounds: (E)-5-hydroxy-7-phenyl-1- (3,4,5-trimethoxyphenyl)hept-1-en-3-one (compound 3) and (1E,4E)-1,7-bis (3,4,5-trimethoxyphenyl)hepta-1,4-dien-3-one (compound MD12a). These were selected for further analysis after the evaluation of their anti-proliferative effects against all human cancer cell lines. The results of apoptosis assays revealed that the number of dead cells was increased in early apoptosis and late apoptosis, while cell proliferation was also decreased after applying various concentrations of (E)-5-hydroxy-7-phenyl-1- (3,4,5-trimethoxyphenyl)hept-1-en-3-one (compound 3) and (1E,4E)-1,7-bis (3,4,5-trimethoxyphenyl)hepta-1,4-dien-3-one (compound MD12a) to MCF-7 and HpeG2 cancer cells. Analysis of the gene expression arrays showed that three genes (GADD45B, SESN2 and BBC3) were correlated with the p53 pathway. From the quantitative PCR analysis, it was seen that (1E,4E)-1,7-bis (3,4,5-trimethoxyphenyl) hepta-1,4-dien-3-one (compound MD12a) effectively induced the up-regulated expression of GADD45B, leading to the suppression of MCF-7 cancer cell formation and cell death. Molecular docking analysis was used to predict and sketch the interactions of the GADD45B-α,β-unsaturated ketone complex for help in drug design.

Investigation of biological activities and antioxidant effects of newly synthesized α-β substituted unsaturated ketone benzofuran derivatives

Effects of benzofuran-derived α - β unsaturated ketone-derived compounds, which are newly synthesized and not previously subjected to biological activity testing have been evaluated. The pour test compounds were determined for in vitro antioxidant activity using models namely 1,1-Dihenyl-2-picrylhydrazyl radical (DPPH*) and Lipid Peroxidation (LPO) scavenging methods. Lipophilic vitamins and phytosterols analysis was carried out on an HPLC instrument. The fatty acids in the lipid extract were converted to methyl esters and then analyzed by gas chromatography (GC). Our results show that 1a, 2a, 2c coded substances used at 20 µL and 30 µL concentrations have more DPPH free radical scavenging activity than quercetin used as standard. Whereas the amount of LPO was significantly decreased in Quercetin and Resveratrol groups and 1a coded substance compared to the control and FR groups (p < 0.0001). 1c coded substance partially increased the amount of GSH (p < 0.01). When effects of 1b, 2c coded substances on lipophilic vitamins and phytosterol profile in S. Cerevisiae yeast cell were examined; the amounts of α-tocopherol, δ- tocopherol, vitamin K1, and Stigmasterol increased in all groups compared to the control. When effects of 1c, 2a coded substances on lipophilic vitamins and phytosterol profile in S. Cerevisiae Yeast Cell were examined; the amounts of α- tocopherol, vitamin K1, and Stigmasterol increased compared to the control group.

Synthesis of Enantiopure ω-(4-Fluorophenyl) 6,11-Methylene Lipoxin B4 Methyl Ester

The synthesis of Lipoxin B4 analogs (LXB4) to gain access to stabilized inflammation resolving compounds is an active field of research. Focusing on variation and stabilization of the conjugated E,Z,E,E C6–C13 tetraene moiety of natural LXB4, a methylene bridge introduced between C6 and C11 suppresses any Z/E isomerization of the C8–C9 olefin. Furthermore, rapid ω-oxidation (C20) should be avoided by replacing the C18-C20 segment by an aromatic moiety. Optically active C1–C12 building blocks were accessed from cycloheptatriene 1-carbonester (C6–C11, C21) and glutaryl chloride (C1–C5) as described earlier. The ω-segment had been generated via a five-step sequence starting from 4-arylbutanoic acid. Horner key olefination enabled assembly of the carbon backbone. A final five step sequence including a chelate Cram reduction of the unsaturated ketone moiety afforded the target ω-aryl 6,11-methylene-LXB4 methyl ester.

Synthesis of the Trans-Syn-Trans Perhydrobenzo[f]chromene Ring System

<p>A stereoselective synthesis of the <i>trans</i>-<i>syn</i>-<i>trans </i>perhydrobenzo[<i>f</i>]chromene skeleton is presented. The target compound <b>3 </b>was achieved in six steps starting from the (<i>S</i>)-(+)-Wieland-Miescher ketone. Key steps include the sp² alkylation at the a-carbon of an unsaturated ketone, Birch-type reductive alkylation, and an acid-catalyzed cyclization. </p>

Synthesis of the Trans-Syn-Trans Perhydrobenzo[f]chromene Ring System

<p>A stereoselective synthesis of the <i>trans</i>-<i>syn</i>-<i>trans </i>perhydrobenzo[<i>f</i>]chromene skeleton is presented. The target compound <b>3 </b>was achieved in six steps starting from the (<i>S</i>)-(+)-Wieland-Miescher ketone. Key steps include the sp² alkylation at the a-carbon of an unsaturated ketone, Birch-type reductive alkylation, and an acid-catalyzed cyclization. </p>

Coumarin-Chalcone Hybrids as Inhibitors of MAO-B: Biological Activity and In Silico Studies

Fourteen coumarin-derived compounds modified at the C3 carbon of coumarin with an α,β-unsaturated ketone were synthesized. These compounds may be designated as chalcocoumarins (3-cinnamoyl-2H-chromen-2-ones). Both chalcones and coumarins are recognized scaffolds in medicinal chemistry, showing diverse biological and pharmacological properties among which neuroprotective activities and multiple enzyme inhibition, including mitochondrial enzyme systems, stand out. The evaluation of monoamine oxidase B (MAO-B) inhibitors has aroused considerable interest as therapeutic agents for neurodegenerative diseases such as Parkinson’s. Of the fourteen chalcocumarins evaluated here against MAO-B, ChC4 showed the strongest activity in vitro, with IC50 = 0.76 ± 0.08 µM. Computational docking, molecular dynamics and MM/GBSA studies, confirm that ChC4 binds very stably to the active rMAO-B site, explaining the experimental inhibition data.