Regio- and Stereoselective Electrochemical Alkylation of Morita–Baylis–Hillman Adducts

Electrosynthesis is effectively employed in a general regio- and stereoselective alkylation of Morita–Baylis–Hillman compounds. The exposition of N-acyloxyphthalimides (redox-active esters) to galvanostatic electroreductive conditions, following the sacrificial-anode strategy, is proved an efficient and practical method to access densely functionalized cinnamate and oxindole derivatives. High yields (up to 80%) and wide functional group tolerance characterized the methodology. A tentative mechanistic sketch is proposed based on dedicated control experiments

Catalytic Enantioselective Addition of Indoles to Activated <i>N</i>‑Benzylpyridinium Salts: Nucleophilic Dearomatization of Pyridines with Unusual C‑4 Regioselectivity

The catalytic enantioselective dearomatization of pyridines with nucleophiles represents a direct and convenient access to highly valuable dihydropyridines. Available methods, mostly based on <i>N</i>-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 <i>N</i>-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

Nucleophilic Dearomatization of Pyridines under Enamine Catalysis: Regio‑, Diastereo‑, and Enantioselective Addition of Aldehydes to Activated <i>N</i>‑Alkylpyridinium Salts

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 <i>N</i>-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-<i>c</i>]­pyridines, the core structure of anticancer peptidomimetics

Organocatalytic Enantioselective Construction of Conformationally Stable C(sp²)–C(sp³) Atropisomers

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

Nucleophilic Dearomatization of Pyridines under Enamine Catalysis: Regio‑, Diastereo‑, and Enantioselective Addition of Aldehydes to Activated <i>N</i>‑Alkylpyridinium Salts

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 <i>N</i>-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-<i>c</i>]­pyridines, the core structure of anticancer peptidomimetics

Catalytic Enantioselective Hetero-[6+4] and -[6+2] Cycloadditions for the Construction of Condensed Polycyclic Pyrroles, Imidazoles, and Pyrazoles

The development of the first chemo-, regio-, and stereoselective hetero-[6+4] and -[6+2] cycloadditions of heteroaromatic compounds via amino aza- and diazafulvenes is presented. Pyrroles, imidazoles, and pyrazoles substituted with a formyl group react with an aminocatalyst to generate an electron-rich hetero-6π-component that reacts in a chemo-, regio-, and stereoselective manner with electron-deficient dienes and olefins. For the hetero-[6+4] cycloaddition of the pyrrole system with dienes, a wide variation of both reaction partners is possible, providing attractive pyrrolo-azepine products in high yields and excellent enantioselectivities (99% ee). The hetero-[6+4] cycloaddition reaction concept is extended to include imidazoles and pyrazoles, giving imidazolo- and pyrazolo-azepines. The same activation concept is successfully employed to include hetero-[6+2] cycloadditions of the pyrrole system with nitroolefins, giving important pyrrolizidine-alkaloid scaffolds. Experimental NMR and mechanistic studies allowed for the identification of two different types of intermediates in the reaction. The first intermediate is the result of a rapid formation of an iminium ion, which generates a hetero-6π aminofulvene intermediate as a mixture of two isomers. Density functional theory calculations were used to determine the mechanism and sources of asymmetric induction in the hetero-[6+4] and -[6+2] cycloadditions. After formation of the reactive hetero-6π-components, a stepwise addition occurs with the diene or olefin, leading to a zwitterionic intermediate that undergoes cyclization to afford the cycloadduct, followed by eliminative catalyst release. The stereoselectivity is controlled by the second step, and computations elaborate on the various substrate and catalyst effects that alter the experimentally observed enantioselectivities. The computational studies provided a basis for improving the enantioselectivity of the hetero-[6+2] cycloaddition

Fluorinated Biphenyl Phosphine Ligands for Accelerated [Au(I)]-Catalysis

Fluorinated JohnPhos-type ligands are proposed as accelerating tools in homogeneous gold­(I) catalysis, with PedroPhosAuCl (Cat1) as the most efficient one. The ligands as well as the corresponding gold complexes were synthesized in high yields and fully characterized also via single-crystal X-ray diffraction. A secondary interaction between the distal phenyl ring of the phosphane ligand and the metal center is identified as key for the fine-tuning of the overall catalytic performance of the complexes. In particular, kinetic as well as computational analysis revealed that by accommodating F atoms on the biphenyl pendant of the ligand, more reactive organo-gold intermediates are realized toward subsequent nucleophilic condensations. The gold-catalyzed indole-hydroarylation of 1,6-enynes and the intramolecular hydroindolynation of alkynes have been adopted as benchmark reactions to exemplify these accelerating effects

Catalytic Enantioselective Hetero-[6+4] and -[6+2] Cycloadditions for the Construction of Condensed Polycyclic Pyrroles, Imidazoles, and Pyrazoles

The development of the first chemo-, regio-, and stereoselective hetero-[6+4] and -[6+2] cycloadditions of heteroaromatic compounds via amino aza- and diazafulvenes is presented. Pyrroles, imidazoles, and pyrazoles substituted with a formyl group react with an aminocatalyst to generate an electron-rich hetero-6π-component that reacts in a chemo-, regio-, and stereoselective manner with electron-deficient dienes and olefins. For the hetero-[6+4] cycloaddition of the pyrrole system with dienes, a wide variation of both reaction partners is possible, providing attractive pyrrolo-azepine products in high yields and excellent enantioselectivities (99% ee). The hetero-[6+4] cycloaddition reaction concept is extended to include imidazoles and pyrazoles, giving imidazolo- and pyrazolo-azepines. The same activation concept is successfully employed to include hetero-[6+2] cycloadditions of the pyrrole system with nitroolefins, giving important pyrrolizidine-alkaloid scaffolds. Experimental NMR and mechanistic studies allowed for the identification of two different types of intermediates in the reaction. The first intermediate is the result of a rapid formation of an iminium ion, which generates a hetero-6π aminofulvene intermediate as a mixture of two isomers. Density functional theory calculations were used to determine the mechanism and sources of asymmetric induction in the hetero-[6+4] and -[6+2] cycloadditions. After formation of the reactive hetero-6π-components, a stepwise addition occurs with the diene or olefin, leading to a zwitterionic intermediate that undergoes cyclization to afford the cycloadduct, followed by eliminative catalyst release. The stereoselectivity is controlled by the second step, and computations elaborate on the various substrate and catalyst effects that alter the experimentally observed enantioselectivities. The computational studies provided a basis for improving the enantioselectivity of the hetero-[6+2] cycloaddition

Nickel Catalyzed Carbonylation/Carboxylation Sequence via Double CO₂ Incorporation

A carbonylation–carboxylation synthetic sequence, via double CO2 fixation, is described. The productive merger of a Ni-catalyzed cross-electrophile coupling manifold, with the use of AlCl3, triggered a cascade reaction with the formation of three consecutive C–C bonds in a single operation. This strategy traces an unprecedented synthetic route to ketones under Lewis acid assisted carbon dioxide valorization. Computational insights revealed a unique double function of AlCl3, and labeling (13CO2) experiments validate the genuine incorporation of CO2 in both functional groups