We report a mild palladium-catalyzed method for the selective allylation of 4-alkylpyridines in which highly basic pyridylic anions behave as soft nucleophiles.

We report a mild palladium-catalyzed selective dehydrogenation of 4-alkylpyridines that exploits their soft enolization to alkylidene dihydropyridines using allyl chloroformate under metal-free conditions. Treatment of these intermediates with a palladium catalyst liberates an alkylpyridylic anion and an allylpalladium(II) intermediate, which combine and undergo βhydride elimination to install a double bond. Importantly, the formation of gas byproducts makes the process very practical. Furthermore, the reaction tolerates a broad range of functional groups, including many that can be dehydrogenated using similar palladium-catalyzed reactions, and is selective for 4-alkylpyridines even in substrates bearing multiple pyridylic positions.

Bolstered by recent advances in bioinformatics, genetics, and enzyme engineering, the field of chemoenzymatic synthesis has enjoyed a rapid increase in popularity and utility. This Perspective explores the integration of enzymes into multistep chemical syntheses, highlighting the unique potential of biocatalytic transformations to streamline the synthesis of complex natural products. In particular, we identify four primary conceptual approaches to chemoenzymatic synthesis and illustrate each with a number of landmark case studies. Future opportunities and challenges are also discussed.

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