As demonstrated by earlier successes with enamines, nitrogen-activated C=C double bonds have considerable potential for use in the construction of various nitrogen-containing products. To expand the applications of this class of substrates, we focused on studying the reactivity of enamides and enecarbamates as promising representatives. Starting from the well-known Povarov reaction, we gradually developed other cycloaddition reactions and, more generally, an extended range of methods for α,β-difunctionalization. Our most recent work, which involves radical processes, has contributed to a significant increase in the diversity of scaffolds accessible from these nitrogenous substrates and is potentially applicable to various natural and bioactive synthetic targets. 1 Introduction 2 General Design 3 Asymmetric Brønsted Acid-Catalyzed α,β-Difunctionalization of Enamides 3.1 Intramolecular α,β-Difunctionalization of Enamides Through Cycloaddition Reactions 3.1.1 Povarov Reactions 3.1.2 Diels–Alder Reactions of 1-Azadienes 3.2 Intermolecular α,β-Difunctionalization of Enamides 3.2.1 Mannich Reactions 3.2.2 Addition to Azo Compounds 3.2.3 Halogenation Reactions 4 Radical Tandem Difunctionalization: β-Alkylation Followed by α-Functionalization of Enamides 4.1 Photoredox-Mediated Tandem α,β-Difunctionalization of Enamides 4.1.1 Oxyalkylation 4.1.2 Oxy-, Amino- and Carbotrifluoromethylation 4.2 Single-Electron Transfer-Mediated Tandem α,β-Difunctionalization of Enamides 5 Conclusion

The synthesis and structure–activity relationships associated with a series of 1,1-diarylethylene tubulin polymerization inhibitors 3 and 4 are described. The key step for their preparation involves a palladium-catalyzed coupling of N-arylsulfonylhydrazones with aryl halides, thus providing flexible and convergent access to tri- and tetrasubstituted 1,1-diarylolefins 3 and 4 related to isocombretastatin A-4 (isoCA-4). These compounds have been evaluated for tubulin polymerization inhibitory activity as well as for cytotoxic activity. The most potent compounds are 1,1-diaryl-2-methoxyethylenes 4b, 4d and 4e having a trisubstituted double bond. They exhibited good antiproliferative activity against various human cancer cell lines (GI₅₀ = 8–80 nM). Compounds 4b and 4e strongly inhibited tubulin polymerization with IC₅₀ values of 2 and 3 μM, respectively, and induced cell cycle arrest in the G₂/M phase in the K562 cell line. Docking studies in the colchicine binding site of tubulin allowed identification of residues most likely to interact with these inhibitors and explain their potent anti-tubulin activity.