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Abstract A practical protocol for the first regiodivergent asymmetric addition of aryl and alkenyl organometallic reagents to substitutedN‐alkyl pyridinium heterocycles is described. The couplings proceed with high regiochemical and stereochemical selectivities, and provide access to chiral 1,2,3‐ and 1,3,4‐trisubstituted dihydropyridine products, controlled by judicious choice of nitrogen activating agent. To this end, a correlation was found between the parameterized size of the activating group and the C2/C4 regioselectivity in the couplings. The utility of the described chemistry was demonstrated in two concise asymmetric syntheses of (+)‐N‐methylaspidospermidine and (−)‐paroxetine. 

Many transition metal coordination complexes are known to undergo a structural change in response to a stimulus, like light, which can have a debilitating impact on properties of interest (e.g., quantum yield, stability, reactivity, etc.). This is particularly true for Cu(I) coordination complexes that suffer from short, excited-state lifetimes due to D2d to D2 distortion and solvent coordination. Here, we investigate the impact of strategic surface binding and the role of the surface binding motif on the excited state lifetime of Cu(I) complexes with carboxylate-functionalized N-phenylpyridin-2-ylmethanimine ligands. Relative to the solution, the excited state lifetime for the ZrO2-bound complexes increases 7-fold when either one ligand is bound or both ligands are bound through a flexible linker but 17-fold when both ligands are rigidly bound to the surface. With support from theoretical calculations, we attribute the dramatic increase in lifetime for the latter to the rigid binding strategy inhibiting the planarizing distortion and possible quenching via solvent coordination. These results lend further support to the idea that molecular immobilization via strategic surface binding is an effective strategy for inhibiting undesired molecular distortion. 

This article describes the first enantioselective synthesis of the Tasmanian marine alkaloid (+)-cylindricine B. The concise construction of the compound hinged on dearomative retrosynthetic logic combined with a tactical advance in the generation of congested, cyclic, alpha-tertiary amine centers. The scope of this key coupling reaction was explored in addition to providing a synthetic application for Cu-catalyzed enantioselective dearomatization of N-acyl-pyridiniums. The synthesis proceeds in five or six steps from commercially available starting materials. 

Recent developments in the isotopic labeling of heteroarenes may prove to be useful in the realms of biomedical science, materials chemistry, and fundamental organic chemistry. The use of the age-old Zincke reaction, or tactical variants thereof, has become particularly utilitarian in effecting single-atom nitrogen replacement in various azines to generate their desired isotopologues. This chemistry can be synthetically leveraged at an early stage for diversity-oriented heterocyclic labeling of pharmaceuticals and/or natural products. Additionally, given the prevalence of saturated azacycles in biologically relevant molecules, access to these isotopologues becomes relevant through dearomative retrosynthetic analysis from the corresponding 15N-labeled heteroarenes. 

A synthesis of the natural product thebaine is reported in eight steps from commercially available starting materials, hinging on the dearomatization and coupling of simple aromatic starting materials. This provides divergent access to two unnatural opioid derivatives and is aimed at the long-term development of synthetic opioid analogs of the “wonderdrug” Naloxone. Additionally, a formal enantioselective synthesis of all reported targets is disclosed that leverages a catalytic asymmetric dearomatization via anion-pairing catalysis. 

Covering: up to 2023