The imidazoline I2 receptors (I2-IRs) are widely distributed in the brain, and I2-IR ligands may have therapeutic potential as neuroprotective agents. Since structural data for I2-IR remains unknown, the discovery of selective I2-IR ligands devoid of α2-adrenoceptor (α2-AR) affinity is likely to provide valuable tools in defining the pharmacological characterization of these receptors. We report the pharmacological characterization of a new family of (2-imidazolin-4-yl)phosphonates. Radioligand binding studies showed that they displayed a higher affinity for I2-IRs than idazoxan, and high I2/α2 selectivity. In vivo studies in mice showed that acute treatments with 1b and 2c significantly increased p-FADD/FADD ratio (an index of cell survival) in the hippocampus when compared with vehicle-treated controls. Additionally, acute and repeated treatments with 2c, but not with 1b, markedly reduced hippocampal p35 cleavage into neurotoxic p25. The present results indicate a neuroprotective potential of (2-imidazolin-4-yl)phosphonates acting at I2-IRs.Keywords: (2-Imidazolin-4-yl)phosphonates; imidazoline I2 receptors; neuroprotection;

•Microwave assisted method to access thioformamides.•A mechanism is proposed.•Different substituted thioformamides prepared in good yields.•Isocyanides and carbon disulfide furnish without solvent thioformamides.A new, fast, solvent-free and efficient method is provided to prepare thioformamides by reacting isocyanides derivatives, carbon disulfide and benzylamine under microwave irradiation.Download high-res image (88KB)Download full-size image

An efficient and user-friendly synthetic process involving the combination of multicomponent reaction methodology and microwave heating generates unprecedented (2-imidazolin-4-yl)phosphonates 1–18. This strategy presents a silver-catalysed, operationally simple and environmentally friendly transformation without the need of anhydrous atmosphere or additional solvents.

Bicyclic α-iminophosphonates were prepared via the first diastereoselective silver catalyzed [3 + 2] cycloaddition reaction of diethyl isocyanomethylphosphonate and diversely N-substituted maleimides. The reduction of the resulting imine by catalytic hydrogenation led to cyclic α-aminophosphonates, which are α-aminoester surrogates. The relative stereochemistry of the adducts was confirmed by X-ray crystallographic analysis of 4. The diastereoselectivity of the cycloaddition reaction was rationalised by theoretical studies.

A practical enantioselective protecting group-free four-step route to the key quinolizidinone 6 from phenylglycinol-derived bicyclic lactam 1 is reported. The Grignard addition reaction to 6 takes place stereoselectively to give 1-ethyl-4-substituted quinolizidines 4-epi-207I and 7–9. Following a similar synthetic sequence, 9a-epi-6 is also accessed. However, the addition of Grignard reagents to 9a-epi-6 proceeds in a non-stereoselective manner. In order to gain insight into the different stereochemical outcome in the two series, theoretical calculations on the iminium salts A and B have been performed. The study concludes that the addition of the hydride, which is the step that determines the configuration of the final products, occurs in a stereoelectronic controlled manner. The theoretical study is in agreement with the experimental results.

Readily available chiral primary 1,2-aminoalcohols and diamines have been explored as organocatalysts for a domino Michael–aldol reaction. Their application in this organocascade process afforded cyclohexanone A with high levels of reactivity (up to 91% yield) and stereoselectivity (>97:3 d.r., up to 93% ee). Depending on the acid cocatalyst different chiral species (cyclic secondary aminesvs. acyclic primary amines) might catalyse the process. In order to shed light on the catalytic activation, several experiments were carried out and a detailed possible reaction mechanism is proposed. Theoretical studies support the stereochemical outcome of the process.

The double cyclocondensation of symmetric pyridyl bis(oxoacids) 2b and 3b with (R)-phenylglycinol stereoselectively gave access to bis-phenylglycinol-derived oxazolopyrrolidine 9 and oxazolopiperidone 10, respectively. Application of the stereocontrolled cyclocondensation reaction to phenyl bis-γ-oxoacid 4b provided 11, which was converted to the corresponding enantiopure di(pyrrolidinyl)benzene 22. The absolute configuration of the new stereogenic centers generated in the key cyclocondenstion step was unambiguously established by X-ray crystallographic analysis.

Chiral non-racemic bicyclic lactams derived from phenylglycinol have been appointed as key building blocks for the preparation of enantiopure nitrogen compounds. The removal of the chiral inductor leading to substituted piperidones by using air or oxygen in basic media is presented.(6S)-1-[(1R)-2-Hydroxy-1-phenylethyl]-6-[1-(methoxymethyl)indol-3-yl]piperidin-2-oneC23H26N2O3[α]D22=+25.5 (c 2.56, CHCl3)Source of chirality: (R)-phenylglycinolAbsolute configuration: (6S)(3R,6R)-6-Allyl-3-ethyl-1-[(1S)-2-hydroxy-1-phenylethyl]piperidin-2-oneC18H25NO2[α]D22=-63.1 (c 1.25, CHCl3).Source of chirality: (S)-phenylglycinolAbsolute configuration: (3R,6R)3,3-Diallyl-1-[(1S)-2-hydroxy-1-phenylethyl]piperidin-2-oneC19H25NO2[α]D22=+1.4 (c 1.0, MeOH)Source of chirality: (S)-phenylglycinolAbsolute configuration: (1S)(6S)-[1-(Methoxymethyl)indol-3-yl]piperidin-2-oneC15H18N2O2[α]D22=-55.5 (c 0.6, MeOH)Source of chirality: (R)-phenylglycinolAbsolute configuration: (6S)(5S,6S)-6-Allyl-5-ethylpiperidin-2-oneC10H17NO[α]D22=-23.7 (c 2.0, CHCl3)Source of chirality: (S)-phenylglycinolAbsolute configuration: (3S,6S)(3R,6R)-6-Allyl-3-ethylpiperidin-2-oneC10H17NO[α]D22=+20.1 (c 0.63, MeOH)Source of chirality: (S)-phenylglycinolAbsolute configuration: (3R,6R)(3S,6R)-6-Allyl-3-ethylpiperidin-2-oneC10H17NO[α]D22=-5.4 (c 0.7, MeOH)Source of chirality: (S)-phenylglycinolAbsolute configuration: (3S,6R)

Bicyclic α-iminophosphonates were prepared via the first diastereoselective silver catalyzed [3 + 2] cycloaddition reaction of diethyl isocyanomethylphosphonate and diversely N-substituted maleimides. The reduction of the resulting imine by catalytic hydrogenation led to cyclic α-aminophosphonates, which are α-aminoester surrogates. The relative stereochemistry of the adducts was confirmed by X-ray crystallographic analysis of 4. The diastereoselectivity of the cycloaddition reaction was rationalised by theoretical studies.

The double cyclocondensation of symmetric pyridyl bis(oxoacids) 2b and 3b with (R)-phenylglycinol stereoselectively gave access to bis-phenylglycinol-derived oxazolopyrrolidine 9 and oxazolopiperidone 10, respectively. Application of the stereocontrolled cyclocondensation reaction to phenyl bis-γ-oxoacid 4b provided 11, which was converted to the corresponding enantiopure di(pyrrolidinyl)benzene 22. The absolute configuration of the new stereogenic centers generated in the key cyclocondenstion step was unambiguously established by X-ray crystallographic analysis.

Readily available chiral primary 1,2-aminoalcohols and diamines have been explored as organocatalysts for a domino Michael–aldol reaction. Their application in this organocascade process afforded cyclohexanone A with high levels of reactivity (up to 91% yield) and stereoselectivity (>97:3 d.r., up to 93% ee). Depending on the acid cocatalyst different chiral species (cyclic secondary aminesvs. acyclic primary amines) might catalyse the process. In order to shed light on the catalytic activation, several experiments were carried out and a detailed possible reaction mechanism is proposed. Theoretical studies support the stereochemical outcome of the process.

A practical enantioselective protecting group-free four-step route to the key quinolizidinone 6 from phenylglycinol-derived bicyclic lactam 1 is reported. The Grignard addition reaction to 6 takes place stereoselectively to give 1-ethyl-4-substituted quinolizidines 4-epi-207I and 7–9. Following a similar synthetic sequence, 9a-epi-6 is also accessed. However, the addition of Grignard reagents to 9a-epi-6 proceeds in a non-stereoselective manner. In order to gain insight into the different stereochemical outcome in the two series, theoretical calculations on the iminium salts A and B have been performed. The study concludes that the addition of the hydride, which is the step that determines the configuration of the final products, occurs in a stereoelectronic controlled manner. The theoretical study is in agreement with the experimental results.