David E. Stephens

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.

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.

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.

Insights into the mechanistic and synthetic aspects of the Mo/P-catalyzed oxidation of N-heterocycles

A Mo/P catalytic system for an efficient gram-scale oxidation of a variety of nitrogen heterocycles to N-oxides with hydrogen peroxide as terminal oxidant has been investigated. Combined spectroscopic and crystallographic studies point to the tetranuclear Mo4P peroxo complex as one of the active catalytic species present in the solution. Based on this finding an optimized catalytic system has been developed. The utility and chemoselectivity of the catalytic system has been demonstrated by the synthesis of over 20 heterocyclic N-oxides.

Concise Total Synthesis of Trichodermamides A, B, and C Enabled by an Efficient Construction of the 1,2-Oxazadecaline Core

We report herein a facile and efficient method of the construction of the cis-1,2-oxazadecaline system, distinctive of (pre)trichodermamides, aspergillazine A, gliovirin, and FA-2097. The formation of the 1,2-oxazadecaline core was accomplished by a 1,2-addition of an αC-lithiated O-silyl ethyl pyruvate oxime to benzoquinone, which is followed by an oxa-Michael ring-closure. The method was successfully applied to the concise total synthesis of trichodermamide A (in gram quantities) and trichodermamide B, as well as the first synthesis of trichodermamide C.

Assessment of Novel Curcumin Derivatives as Potent Inhibitors of Inflammation and Amyloid-β Aggregation in Alzheimer’s Disease

Alzheimers disease (AD) is the most common neurodegenerative disorder affecting the elderly population worldwide. Brain inflammation plays a key role in the progression of AD. Deposition of senile plaques in the brain stimulates an inflammatory response with the overexpression of pro-inflammatory mediators, such as the neuroinflammatory cytokine. interleukin-6. Curcumin has been revealed to be a potential agent for treating AD following different neuroprotective mechanisms, such as inhibition of aggregation and decrease in brain inflammation. We synthesized new curcumin derivatives with the aim of providing good anti-aggregation capacity but also improved anti-inflammatory activity. Nine curcumin derivatives were synthesized by etherification and esterification of the aromatic region. From these derivatives, compound 8 exhibited an anti-inflammatory effect similar to curcumin, while compounds 3, 4, and 10 were more potent. Moreover, when the anti-aggregation activity is considered, compounds 3, 4, 5, 6, and 10 showed biological activity in vitro. Compound 4 exhibited a strong anti-aggregation effect higher than curcumin. Monofunctionalized curcumin derivatives showed better bioactivity than difunctionalized compounds. Moreover, the presence of bulky groups in the chemical structure of curcumin derivatives decreased bioactivity.

Transition Metal-Catalyzed C–H Functionalization of Heterocyclic N-Oxides

Transition metal-catalyzed C–H-functionalization reactions of heterocyclic N-oxides are reviewed. Arylation, alkenylation, alkylation, cyanation, amidation, and sulfonylation reactions of azine, azole, and non-aromatic N-oxides are discussed with an emphasis on the regioselectivity of the C2–H, as well as distal C–H functionalization, of heterocyclic N-oxides. The review primarily focuses on the advances from the past decade.

Antiviral Activity of Novel Quinoline Derivatives against Dengue Virus Serotype 2

Dengue virus causes dengue fever, a debilitating disease with an increasing incidence in many tropical and subtropical territories. So far, there are no effective antivirals licensed to treat this virus. Here we describe the synthesis and antiviral activity evaluation of two compounds based on the quinoline scaffold, which has shown potential for the development of molecules with various biological activities. Two of the tested compounds showed dose-dependent inhibition of dengue virus serotype 2 in the low and sub micromolar range. The compounds 1 and 2 were also able to impair the accumulation of the viral envelope glycoprotein in infected cells, while showing no sign of direct virucidal activity and acting possibly through a mechanism involving the early stages of the infection. The results are congruent with previously reported data showing the potential of quinoline derivatives as a promising scaffold for the development of new antivirals against this important virus.