Structural relationship between the antioxidant melatonin and the non-benzodiazepine hypnotic zolpidem (ZPD) suggests possible direct antioxidant and neuroprotective properties of this compound. In the present work, these effects were analyzed for zolpidem and four of its synthesis intermediates. In vitro assays include lipid peroxidation and protein oxidation studies in liver and brain homogenates. Intracellular antioxidant effects were analyzed by evaluation of free radical formation prevention in HT-22 hippocampal cells treated with glutamate 10mM and measured by flow cytometer DCF fluorescence. The neuroprotective effect of these compounds was evaluated as neuronal death prevention of HT-22 cells treated with the same concentration of glutamate. Zolpidem was found to prevent induced lipid peroxidation in rat liver and brain homogenates showing figures similar to melatonin, although it failed to prevent protein oxidation. ZPD-I was the most effective out of the several zolpidem intermediates studied as it prevented lipid peroxidation with an efficiency higher than melatonin or zolpidem and with an effectiveness similar to estradiol and trolox. ZPD-I prevents protein oxidation, which trolox is known to be unable to prevent. When cellular experiments were undertaken, ZPD-I prevented totally the increase of intracellular free radicals induced by glutamate 10mM in culture medium for 12h, while zolpidem and ZPD-III partially prevented this increase. Also the three compounds protected hippocampal neurons from glutamate-induced death in the same conditions, being their comparative efficacy, ZPD-III > ZPD-I = ZPD.

The [32] cycloaddition of alkenyl Fischer carbene complexes 1 and 6 with diazomethane derivatives to give D 2 -pyrazoline carbenes 2, 4, and 7 is described. The conversion of (À)-8-phenylmenthol-derived carbenes 6 into pyrazoline esters 9 through a one-pot cycloaddition ± protection ± oxidation is presented as an expeditious route to enantiomerically pure 3-alkoxycarbonyl-D 2 -pyrazolines in good yields and in a highly regio-and diastereoselective manner. Pyrazolidines 13 were synthesized in excellent overall yields from 9 through pyrazolines 11 and 12, the diastereoselective reduction of CN bond being the key step. Azaprolines 16 and 17 were prepared in very good yields from epimeric trans-13 or cis-13 by oxidative deprotection of the silylated hydroxy group. In an alternative reaction, the pyrazolidine ring of 13 was reduced to obtain protected openchain 2,4-diamino alcohols 19 with three chiral centers.

The reaction of tert‐butylalkynyl chromium Fischer carbene complex 1 with nitrones 2 affords β‐enamino‐ketoaldehydes 4 by the light‐promoted rearrangement of the corresponding [3+2] cycloadduct carbene complexes 3. On the other hand, [3+2] cycloaddition of chiral nonracemic Fischer alkenyl carbene complexes 19 with nitrilimines 10 yields enantiomerically pure Δ2‐pyrazolines with high regio‐ and diastereoselectivity.

A new procedure for the synthesis of 1,3,4-trisubstituted and 1,4-disubstituted pyrrolidin-2-one derivatives in an enantioselective fashion is reported. The 1,3-dipolar cycloaddition of (+/-)-menthol and (-)-8-phenylmenthol derived Fischer alkoxy alkenyl carbene complexes with in situ generated functionalized azomethine ylides gives the corresponding cycloadducts as chelated tetracarbonyl Fischer carbene complexes. Only one regioisomer is detected in all cases, and the diastereoselectivity of the reaction is very high when (-)-8-phenylmenthol derived carbenes are employed. Oxidation and further transformation of the cycloadducts provide an easy access to pyrrolidin-2-ones. The anti-inflammatory and antidepressant drug (+)-Rolipram is readily prepared in four steps in a 20% overall yield by taking advantage of this newly developed methodology.

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