Oleg V. Larionov

Direct, Catalytic, and Regioselective Synthesis of 2-Alkyl-, Aryl-, and Alkenyl-Substituted N-Heterocycles from N-Oxides

A one-step transformation of heterocyclic N-oxides to 2-alkyl-, aryl-, and alkenyl-substituted N-heterocycles is described. The success of this broad-scope methodology hinges on the combination of copper catalysis and activation by lithium fluoride or magnesium chloride. The utility of this method for the late-stage modification of complex N-heterocycles is exemplified by facile syntheses of new structural analogues of several antimalarial, antimicrobial, and fungicidal agents.

Scalable, Metal- and Additive-Free, Photoinduced Borylation of Haloarenes and Quaternary Arylammonium Salts.

We report herein a simple, metal- and additive-free, photoinduced borylation of haloarenes, including electron-rich fluoroarenes, as well as arylammonium salts directly to boronic acids. This borylation method has a broad scope and functional group tolerance. We show that it can be further extended to boronic esters and carried out on gram scale as well as under flow conditions.

Oligosubstituted Pyrroles Directly from Substituted Methyl Isocyanides and Acetylenes

The formal cycloaddition of alpha-metallated methyl isocyanides 1 onto the triple bond of electron-deficient acetylenes 2 represents a direct and convenient approach to oligosubstituted pyrroles 3. The scope and limitations of this reaction (24 examples, 25-97% yield) are reported along with an optimization of the reaction conditions and a rationalization of the mechanism. In addition, a related newly developed Cu(I)-mediated synthesis of 2,3-disubstituted pyrroles by the reaction of copper acetylides derived from unactivated terminal alkynes with substituted methyl isocyanides is described (11 examples, 5-88% yield).

Palladium-Catalyzed C8-Selective C–H Arylation of Quinoline N-Oxides: Insights into the Electronic, Steric, and Solvation Effects on the Site Selectivity by Mechanistic and DFT Computational Studies

We report herein a palladium-catalyzed C–H arylation of quinoline N-oxides that proceeds with high selectivity in favor of the C8 isomer. This site selectivity is unusual for palladium, since all of the hitherto described methods of palladium-catalyzed C–H functionalization of quinoline N-oxides are highly C2 selective. The reaction exhibits a broad synthetic scope with respect to quinoline N-oxides and iodoarenes and can be significantly accelerated to subhour reaction times under microwave irradiation. The C8-arylation method can be carried out on a gram scale and has excellent functional group tolerance. Mechanistic and density functional theory (DFT) computational studies provide evidence for the cyclopalladation pathway and describe key parameters influencing the site selectivity.

Three-component reaction of small-ring cyclic amines with arynes and acetonitrile

A novel stereospecific three-component reaction of aziridines and azetidines with arynes and acetonitrile has been developed. The reaction affords N-aryl γ-aminobutyronitriles and δ-aminovaleronitriles that can be used as precursors and congeners of a number of bioactive compounds, such as pregabalin and lergotrile.

Additive- and Metal-Free, Predictably 1,2- and 1,3-Regioselective, Photoinduced Dual C–H/C–X Borylation of Haloarenes

We report herein a simple, additive- and metal-free, photoinduced, dual C-H/C-X borylation of chloro-, bromo-, and iodoarenes. The reaction produces 1,2- and 1,3-diborylarenes on gram scales under batch and continuous flow conditions. The regioselectivity of the dual C-H/C-X borylation is determined by the solvent and the substituents in the parent haloarenes.

Synthetic and mechanistic aspects of the regioselective base-mediated reaction of perfluoroalkyl- and perfluoroarylsilanes with heterocyclic N-oxides

The scope and mechanistic implications of the direct transformation of heterocyclic N-oxides to 2-trifluoromethyl-, and related perfluoroalkyl- and perfluoroaryl-substituted N-heterocycles has been studied. The reaction is effected by perfluoroalkyl- and perfluorophenyltrimethylsilane in the presence of strong base. In situ displacement of the para-fluoro substituent in the pentafluorophenyl ring and the methoxy group in 8-methoxyquinolines with additional nucleophiles allows for further site-selective refunctionalization of the N-heterocyclic products.

Catalytic diastereo- and enantioselective annulations between transient nitrosoalkenes and indoles.

Caught in transition: an efficient catalytic system is the key to the successful development of the first highly diastereo- and enantioselective annulation reaction between indoles and transient nitrosoalkenes. This robust reaction affords structurally unique architectures with up to three new chiral centers. The products can be readily elaborated into other indoline-based chiral heterocyclic motifs, including those of pyrrolidinoindoline alkaloids.

Heterocyclic N-Oxides – An Emerging Class of Therapeutic Agents

Heterocyclic N-oxides have emerged as potent compounds with anticancer, antibacterial, antihypertensive, antiparasitic, anti-HIV, anti-inflammatory, herbicidal, neuroprotective, and procognitive activities. The N-oxide motif has been successfully employed in a number of recent drug development projects. This review surveys the emergence of this scaffold in the mainstream medicinal chemistry with a focus on the discovery of the heterocyclic N-oxide drugs, N-oxide-specific mechanisms of action, drug-receptor interactions and synthetic avenues to these compounds. As the first review on this subject that covers the developments since 1950s to date, it is expected that it will inspire wider implementation of the heterocyclic N-oxide motif in the rational design of new medicinal agents.

Synthesis and biological activity of optimized belactosin C congeners

Successful biochemical studies of the natural products belactosin A and C as well as their more stable acylated derivatives have proved them to be powerful proteasome inhibitors and thereby potential candidates as pharmacologically relevant active compounds. In order to understand their structure-biological activity relations in detail and to find ways of improving their biological activity, four new modified belactosin congeners have been synthesized and tested. One of them (compound 6) turned out to be a more potent inhibitor against HeLa cells than the known proteasome inhibitor MG132.