Enantioselective catalytic Povarov reactions.

Catalytic asymmetric Povarov protocols have undergone an explosive growth, especially in the last ten years, since the first example was published in 1996. The use of chiral Lewis and Brønsted acids and dual strategies based on their combination with catalysts acting by hydrogen bond formation, as well as covalent aminocatalysis, are reviewed. More recent variations such as the nitroso Povarov reaction and interrupted Povarov reactions as a route to chiral scaffolds other than tetrahydroquinolines are also discussed.

Mechanochemical Aza-Vinylogous Povarov Reactions for the Synthesis of Highly Functionalized 1,2,3,4-Tetrahydroquinolines and 1,2,3,4-Tetrahydro-1,5-Naphthyridines.

The aza-vinylogous Povarov reaction between aromatic amines, α-ketoaldehydes or α-formylesters and α,ß-unsaturated dimethylhydrazones was carried out in a sequential three-component fashion under mechanochemical conditions. Following extensive optimization work, the reaction was performed on a vibratory ball mill operating at 20 Hz and using zirconium oxide balls and milling jar, and afforded 1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydro- 1,5-naphthyridines functionalized at C-2, C-4 and also at C-6, in the latter case. This protocol generally afforded the target compounds in good to excellent yields and diastereoselectivities. A comparison of representative examples with the results obtained under conventional conditions revealed that the mechanochemical protocol affords faster Povarov reactions in comparable yields using a solvent-less environment.

Synthesis of 1,4-Diazepanes and Benzo[b][1,4]diazepines by a Domino Process Involving the In Situ Generation of an Aza-Nazarov Reagent.

A step- and atom-economical protocol allowing the synthesis of 1,4-diazepanes and also tetrahydro- and decahydro-1,5-benzodiazepines is described. The method proceeds from very simple starting materials such as 1,2-diamines and alkyl 3-oxohex-5-enoates and can be performed under solvent-free conditions in many instances. The key event of this process was the generation in situ of an aza-Nazarov reagent and its subsequent intramolecular aza-Michael cyclization. An intermolecular version of the reaction was also established and applied to the synthesis of the first example of the pyrrolo[1,2-a][1,5]diazonine framework.

New types of reactivity of α,ß-unsaturated N,N-dimethylhydrazones: chemodivergent diastereoselective synthesis of functionalized tetrahydroquinolines and hexahydropyrrolo[3,2-b]indoles.

The indium trichloride-catalyzed reaction between aromatic imines and α,ß-unsaturated N,N-dimethylhydrazones in acetonitrile afforded 1,2,3,4-tetrahydroquinolines bearing a hydrazone function at C4 through a one-pot diastereoselective domino process that involves the formation of two C-C bonds and the controlled generation of two stereocenters, one of which is quaternary. This reaction constitutes the first example of an α,ß-unsaturated dimethylhydrazone that behaves as a dienophile in a hetero Diels-Alder reaction. The related reaction between anilines, aromatic aldehydes, and methacrolein dimethylhydrazone in CHCl(3) with BF(3)⋅Et(2)O as catalyst afforded polysubstituted 1,2,3,3a,4,8b-hexahydropyrrolo[3,2-b]indoles as major products through a fully diastereoselective ABB'C four-component domino process that generates two cycles, three stereocenters, two C-C bonds, and two C-N bonds in a single operation.

ITH14001, a CGP37157-Nimodipine Hybrid Designed to Regulate Calcium Homeostasis and Oxidative Stress, Exerts Neuroprotection in Cerebral Ischemia.

During brain ischemia, oxygen and glucose deprivation induces calcium overload, extensive oxidative stress, neuroinflammation, and, finally, massive neuronal loss. In the search of a neuroprotective compound to mitigate this neuronal loss, we have designed and synthesized a new multitarget hybrid (ITH14001) directed at the reduction of calcium overload by acting on two regulators of calcium homeostasis; the mitochondrial Na+/Ca2+ exchanger (mNCX) and L-type voltage dependent calcium channels (VDCCs). This compound is a hybrid of CGP37157 (mNCX inhibitor) and nimodipine (L-type VDCCs blocker), and its pharmacological evaluation revealed a moderate ability to selectively inhibit both targets. These activities conferred concentration-dependent neuroprotection in two models of Ca2+ overload, such as toxicity induced by high K+ in the SH-SY5Y cell line (60% protection at 30 µM) and veratridine in hippocampal slices (26% protection at 10 µM). It also showed neuroprotective effect against oxidative stress, an activity related to its nitrogen radical scavenger effect and moderate induction of the Nrf2-ARE pathway. Its Nrf2 induction capability was confirmed by the increase of the expression of the antioxidant and anti-inflammatory enzyme heme-oxygenase I (3-fold increase). In addition, the multitarget profile of ITH14001 led to anti-inflammatory properties, shown by the reduction of nitrites production induced by lipopolysaccharide in glial cultures. Finally, it showed protective effect in two acute models of cerebral ischemia in hippocampal slices, excitotoxicity induced by glutamate (31% protection at 10 µM) and oxygen and glucose deprivation (76% protection at 10 µM), reducing oxidative stress and iNOS deleterious induction. In conclusion, our hybrid derivative showed improved neuroprotective properties when compared to its parent compounds CGP37157 and nimodipine.

B-ring-aryl substituted luotonin A analogues with a new binding mode to the topoisomerase 1-DNA complex show enhanced cytotoxic activity.

Topoisomerase 1 inhibition is an important strategy in targeted cancer chemotherapy. The drugs currently in use acting on this enzyme belong to the family of the camptothecins, and suffer severe limitations because of their low stability, which is associated with the hydrolysis of the δ-lactone moiety in their E ring. Luotonin A is a natural camptothecin analogue that lacks this functional group and therefore shows a much-improved stability, but at the cost of a lower activity. Therefore, the development of luotonin A analogues with an increased potency is important for progress in this area. In the present paper, a small library of luotonin A analogues modified at their A and B rings was generated by cerium(IV) ammonium nitrate-catalyzed Friedländer reactions. All analogues showed an activity similar or higher than the natural luotonin A in terms of topoisomerase 1 inhibition and some compounds had an activity comparable to that of camptothecin. Furthermore, most compounds showed a better activity than luotonin A in cell cytotoxicity assays. In order to rationalize these results, the first docking studies of luotonin-topoisomerase 1-DNA ternary complexes were undertaken. Most compounds bound in a manner similar to luotonin A and to standard topoisomerase poisons such as topotecan but, interestingly, the two most promising analogues, bearing a 3,5-dimethylphenyl substituent at ring B, docked in a different orientation. This binding mode allows the hydrophobic moiety to be shielded from the aqueous environment by being buried between the deoxyribose belonging to the G(+1) guanine and Arg364 in the scissile strand and the surface of the protein and a hydrogen bond between the D-ring carbonyl and the basic amino acid. The discovery of this new binding mode and its associated higher inhibitory potency is a significant advance in the design of new topoisomerase 1 inhibitors.

Synthesis of polysubstituted, functionalized quinolines through a metal-free domino process involving a C4­C3 functional group rearrangement.

4-Alkyl-1,2,3,4-tetrahydroquinolines bearing a 4-vinyl unit ending in an electron-withdrawing group were efficiently transformed into polysubstituted, C(3)-functionalized quinolines upon heating in refluxing o-dichlorobenzene, in a domino reaction involving an unusual C(4)-C(3) functional group rearrangement.