A practical way to synthesize chiral fluoro-containing polyhydro-2H-chromenes from monoterpenoids

Abstract Conditions enabling the single-step preparative synthesis of chiral 4-fluoropolyhydro-2H-chromenes in good yields through a reaction between monoterpenoid alcohols with para-menthane skeleton and aldehydes were developed for the first time. The BF 3 ·Et 2 O/ H 2 O system is used both as a catalyst and as a fluorine source. The reaction can involve aliphatic aldehydes as well as aromatic aldehydes containing various acceptor and donor substituents. 4-Hydroxyhexahydro-2H-chromenes were demonstrated to be capable of converting to 4-fluorohexahydro-2H-chromenes under the developed conditions, the reaction occurs with inversion of configuration. 64

Effect of structure and acidity of acid modified clay materials on synthesis of octahydro-2H-chromen-4-ol from vanillin and isopulegol

The Prins cyclization of (−)-isopulegol with vanillin to form octahydro-2H-chromen-4-ol was studied in the presence of natural layered aluminosilicates modified by 0.5 mol/dm3 HCl, such as montmorillonite, kaolin, and metakaolin obtained by the calcination of kaolin at 650 °C. According to infrared spectroscopy using pyridine as probe molecule, the amount and strength of Brønsted acid sites depend on the type of clay and decrease in the following order HCl-montmorillonite > HCl-kaolin > HCl-metakaolin. The difference in Brønsted acidity and textural properties of clays affected the reaction rate and the selectivity towards octahydro-2H-chromen-4-o

Synthesis of octahydro-2H-chromen-4-ol from vanillin and isopulegol over acid modified montmorillonite clays: Effect of acidity on the Prins cyclization

Two calcium-rich natural layered aluminosilicates containing 90–95 wt.% montmorillonite were chemically activated using 0.125–3.0 M HCl solutions. Structural and textural properties were characterized by X-ray diffraction, elemental analysis and N2-adsorption/desorption analyses. According to infrared spectroscopy using pyridine as probe molecule, the amount of Brønsted acid sites increased when increasing HCl concentration. The catalytic performance of these materials was investigated in the Prins cyclization of (−)-isopulegol with vanillin to form octahydro-2H-chromen-4-ol, carried out in toluene at 35 °C. It was found that the amount of Brønsted acid sites and the microporosity of the catalysts are key factors for the control of the reaction rate and the selectivity towards octahydro-2H-chromen-4-o

A Novel Small Molecule Supports the Survival of Cultured Dopamine Neurons and May Restore the Dopaminergic Innervation of the Brain in the MPTP Mouse Model of Parkinson's Disease

We previously showed that monoterpenoid (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol 1 alleviates motor manifestations of Parkinson's disease in animal models. In the present study, we designed and synthesized monoepoxides of (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol 1 and evaluated their biological activity in the MPTP mouse model of Parkinson's disease. We also assessed the ability of these compounds to penetrate the blood-brain barrier (BBB). According to these data, we chose epoxide 4, which potently restored the locomotor activity in MPTP-treated mice and efficiently penetrated the BBB, to further explore its potential mechanism of action. Epoxide 4 was found to robustly promote the survival of cultured dopamine neurons, protect dopamine neurons against toxin-induced degeneration, and trigger the mitogen-activated protein kinase (MAPK) signaling cascade in cells of neuronal origin. Meanwhile, neither the survival-promoting effect nor MAPK activation was observed in non-neuronal cells treated with epoxide 4. In the MPTP mouse model of Parkinson's disease, compound 4 increased the density of dopamine neuron fibers in the striatum, which can highlight its potential to stimulate striatal reinnervation and thus halt disease progression. Taken together, these data indicate that epoxide 4 can be a promising compound for further development, not only as a symptomatic but also as a neuroprotective and neurorestorative drug for Parkinson's disease.Peer reviewe

A Newly Identified Monoterpenoid-Based Small Molecule Able to Support the Survival of Primary Cultured Dopamine Neurons and Alleviate MPTP-Induced Toxicity In Vivo

Parkinson’s disease (PD) is the most common age-related movement disorder characterized by the progressive loss of nigrostriatal dopaminergic neurons. To date, PD treatment strategies are mostly based on dopamine replacement medicines, which can alleviate motor symptoms but do not slow down the progression of neurodegeneration. Thus, there is a need for disease-modifying PD therapies. The aim of this work was to evaluate the neuroprotective effects of the novel compound PA96 on dopamine neurons in vivo and in vitro, assess its ability to alleviate motor deficits in MPTP- and haloperidol-based PD models, as well as PK profile and BBB penetration. PA96 was synthesized from (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl) cyclohex-3-ene-1,2-diol (Prottremin) using the original three-step stereoselective procedure. We found that PA96: (1) supported the survival of cultured näive dopamine neurons; (2) supported the survival of MPP+-challenged dopamine neurons in vitro and in vivo; (3) had chemically appropriate properties (synthesis, solubility, etc.); (4) alleviated motor deficits in MPTP- and haloperidol-based models of PD; (5) penetrated the blood–brain barrier in vivo; and (6) was eliminated from the bloodstream relative rapidly. In conclusion, the present article demonstrates the identification of PA96 as a lead compound for the future development of this compound into a clinically used drug

Aldol Condensation of Cyclopentanone with Valeraldehyde Over Metal Oxides

Kinetics of the cross aldol condensation of valeraldehyde with cyclopentanone was investigated in a batch reactor under atmospheric pressure at 130 °C using heterogeneous metal modified oxides, such as CeO2–MgO, FeO–MgO, FeO–CaO as well as pristine CaO as catalysts. The catalysts were prepared either by evaporation impregnation or deposition precipitation methods and characterized by XRD, TEM, SEM, nitrogen adsorption, ammonia and CO2 TPD. The results revealed that an optimum amount of strong basic sites gives the highest ratio between cross condensation and self-condensation products of valeraldehyde. The highest yield of the desired product 2-pentylidenecyclopentanone (66%) was obtained with FeO–MgO prepared by the deposition precipitation methods.</p

Inhibition of DNA Repair Enzymes as a Valuable Pharmaceutical Approach

The DNA repair system plays a crucial role in maintaining the integrity of the genome [...

A practical way to synthesize chiral fluoro-containing polyhydro-2H-chromenes from monoterpenoids

Conditions enabling the single-step preparative synthesis of chiral 4-fluoropolyhydro-2H-chromenes in good yields through a reaction between monoterpenoid alcohols with para-menthane skeleton and aldehydes were developed for the first time. The BF3·Et2O/H2O system is used both as a catalyst and as a fluorine source. The reaction can involve aliphatic aldehydes as well as aromatic aldehydes containing various acceptor and donor substituents. 4-Hydroxyhexahydro-2H-chromenes were demonstrated to be capable of converting to 4-fluorohexahydro-2H-chromenes under the developed conditions, the reaction occurs with inversion of configuration

(1S,5R)-6,6-Dimethyl-4-(((1S,2S,5S)-2,6,6-trimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)methyl)bicyclo[3.1.1]hept-3-en-2-one

A simple and convenient procedure for the &gamma;, &beta;-dimerization of verbenone was developed. The dimer was obtained during aging with KOH without a solvent. The process proceeds as the formation of the extended enolate of verbenone and its Michael addition to other molecules of verbenone. The product yield was 82% after purification by column chromatography and recrystallization

(1<i>S</i>,5<i>R</i>)-6,6-Dimethyl-4-(((1<i>S</i>,2<i>S</i>,5<i>S</i>)-2,6,6-trimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)methyl)bicyclo[3.1.1]hept-3-en-2-one

A simple and convenient procedure for the γ, β-dimerization of verbenone was developed. The dimer was obtained during aging with KOH without a solvent. The process proceeds as the formation of the extended enolate of verbenone and its Michael addition to other molecules of verbenone. The product yield was 82% after purification by column chromatography and recrystallization