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The catalytic enantioselective dearomatization of pyridines with nucleophiles represents a direct and convenient access to highly valuable dihydropyridines. Available methods, mostly based on N-acylpyridinium salts, give addition to the C-2/C-6 of the pyridine nucleus, rendering 1,2-/1,6-dihydropyridines. Herein, we present an alternative approach to this type of dearomatization reaction, employing activated N-benzylpyridinium salts in combination with a bifunctional organic catalyst. Optically active 1,4-dihydropyridines resulting from the addition of the nucleophile (indole) to the C-4 of the pyridine nucleus are obtained as major products, rendering this method for nucleophilic dearomatization of pyridines complementary to previous approaches.

A novel and straightforward synthesis of highly substituted isoquinoline-5,8-dione fused tricyclic pyrazoles is reported. The key step of the synthetic sequence is a regioselective, Ag2 CO3 promoted, 1,3-dipolar cycloaddition of C-heteroaryl-N-aryl nitrilimines and substituted isoquinoline-5,8-diones. The broad functional group tolerability and mild reaction conditions were found to be suitable for the preparation of a small library of compounds. These scaffolds were designed to interact with multiple biological residues, and two of them, after brief synthetic elaborations, were analyzed by molecular docking studies as potential anticancer drugs. In vitro studies confirmed the potent anticancer effects, showing promising IC50 values as low as 2.5 μm against three different glioblastoma cell lines. Their cytotoxic activity was finally positively correlated to their ability to inhibit PI3K/mTOR kinases, which are responsible for the regulation of diverse cellular processes in human cancer cells.

Alkylideneindolenines are widely employed key electrophilic intermediates for the α-functionalization of the C-3 side chain of indoles. However, the reactivity of their extended (vinylogous) counterparts has not been carefully explored so far. These intermediates can undergo 1,4- or 1,6-addition with functionalization at α- or γ-position of the side chain, resulting in regioisomeric mixtures of products. This work demonstrates that a complete γ-regioselectivity can be achieved in the reaction of 3-indol-3-yl allylic alcohols with various nucleophiles. This process is catalysed by just 1 mol% zinc(II) triflate at room temperature and entails the 1,6-selective addition of the nucleophile to an extended protonated alkylideneindolenine generated in situ. Indoles, pyrroles, anilines and thiols can be efficiently used as nucleophilic partners for this reaction, delivering the corresponding 3-vinyl substituted, γ-functionalised indole products in moderate to good yields.

A new protocol for the enantioselective direct alpha-heteroarylation of aldehydes with isoquinoline N-oxides, via chiral enamine catalysis, has been successfully developed. High enantiomeric excesses and moderate to good yields were achieved for a variety of alpha-heteroarylated aldehydes.

Catalytic addition of chiral enamines to azinium salts is a powerful tool for the synthesis of enantioenriched heterocycles. An unprecedented asymmetric dearomative addition of aldehydes to activated N-alkylpyridinium salts is presented. The process exhibits complete C-4 regioselectivity along with high levels of diastereo- and enantiocontrol, achieving a high-yielding synthesis of a broad range of optically active 1,4-dihydropyridines. Moreover, the presented methodology enables the synthesis of functionalized octahydropyrrolo[2,3-c]pyridines, the core structure of anticancer peptidomimetics.

Nonbiaryl atropisomers are molecules defined by a stereogenic axis featuring at least one nonarene moiety. Among these, scaffolds bearing a conformationally stable C(sp2)–C(sp3) stereogenic axis have been observed in natural compounds; however, their enantioselective synthesis remains almost completely unexplored. Herein we disclose a new class of chiral C(sp2)–C(sp3) atropisomers obtained with high levels of stereoselectivity (up to 99% ee) by means of an organocatalytic asymmetric methodology. Multiple molecular motifs could be embedded in this class of C(sp2)–C(sp3) atropisomers, showing a broad and general protocol. Experimental data provide strong evidence of the conformational stability of the C(sp2)–C(sp3) stereogenic axis (up to t1/225 °C >1000 y) in the obtained compounds and show kinetic control over this rare stereogenic element. This, coupled with density functional theory calculations, suggests that the observed stereoselectivity arises from a Curtin–Hammett scenario establishing an equilibrium of intermediates. Furthermore, the experimental investigation led to evidence of the operating principle of central-to-axial chirality conversions.