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...
Multicomponent reactions 9i.e., those that engage three or more starting materials to form a product that contains significant fragments of all of them), have been widely employed in the construction of compound libraries, especially in the context of diversity-oriented synthesis. While relatively less exploited, their use in target-oriented synthesis offers significant advantages in terms of synthetic efficiency. This review provides a critical summary of the use of multicomponent reactions for the preparation of active pharmaceutical principles.
Quinones can in principle be viewed as a double-edged sword in the treatment of neurodegenerative diseases, since they are often cytoprotective but can also be cytotoxic due to covalent and redox modification of biomolecules. Nevertheless, low doses of moderately electrophilic quinones are generally cytoprotective, mainly due to their ability to activate the Keap1/Nrf2 pathway and thus induce the expression of detoxifying enzymes. Some natural quinones have relevant roles in important physiological processes. One of them is coenzyme Q10, which takes part in the oxidative phosphorylation processes involved in cell energy production, as a proton and electron carrier in the mitochondrial respiratory chain, and shows neuroprotective effects relevant to Alzheimer’s and Parkinson’s diseases. Additional neuroprotective quinones that can be regarded as coenzyme Q10 analogues are idobenone, mitoquinone and plastoquinone. Other endogenous quinones with neuroprotective activities include tocopherol-derived quinones, most notably vatiquinone, and vitamin K. A final group of non-endogenous quinones with neuroprotective activity is discussed, comprising embelin, APX-3330, cannabinoid-derived quinones, asterriquinones and other indolylquinones, pyrroloquinolinequinone and its analogues, geldanamycin and its analogues, rifampicin quinone, memoquin and a number of hybrid structures combining quinones with amino acids, cholinesterase inhibitors and non-steroidal anti-inflammatory drugs.
The aza-vinylogous Povarov reaction between aromatic amines, α-ketoaldehydes or α-formylesters and α,β-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.
Several types of C4‐functionalized 4‐alkyl‐2‐aryl‐1,2,3,4‐tetrahydroquinolines underwent rearrangement of their functional groups to C3, with concomitant aromatization, by simple reflux in 1,2‐dichlorobenzene. The functional groups that were shown to undergo the C4 to C3 migration were –CH=CH‐Z (where Z = CO2Et, CN, NO2, COCH3, CH2OH) and –CH=C(Y)–Z (where Y = CN and Z = CO2Et or Y = Z = CN). On the other hand, the dimethylhydrazono group failed to migrate under thermal conditions but was shown to undergo a smooth dehydrogenation/C4 to C3 rearrangement/ dehydrogenation sequence at room temperature in the presence of DDQ, with a broad scope that includes 4‐alkyl‐2‐aryl‐ and 2‐acyl‐1,2,3,4‐tetrahydroquinolines. We also report a computational and experimental study of the mechanism of both reactions, which supports an unusual intramolecular aza‐ene pathway. The ready availability by this method of 2,3‐difunctionalized quinolines allowed the simple preparation of fused heterocyclic systems derived from the pyrrolo[3,4‐b]quinoline framework, using both reductive and non‐reductive domino processes.
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