Nucleophilic Dearomatization of Pyridines and Applications in Natural Product Synthesis

Nucleophilic dearomatization receives attention for its ability to install stereogenicity within a molecule using few steps. Whilst using aromatic substrates as a starting material can be difficult due to the low reactivity, methods have been developed to utilized them as building blocks. Exploring into pharmaceuticals and natural products will show a common moiety in di/tetrahydro pyridine and piperidines. These moieties can be synthesized via nucleophilic dearomatization of pyridines. Pyridine provides an advantage in this reactivity due to the lone pairs of the N being available to react with electrophiles. Subsequently nucleophilic attack into an activated pyridine will dearomatize and install a nucleophile on a sp³ carbon which can be further functionalized to become natural products/pharmaceuticals. [1]

The Maimone group in 2021 utilized this reactivity in a 11 step synthesis to install fragments onto a diphydropyridine for a subsequent 1,3-dipolar cycloaddition to afford Altemicidin A. [2] The Reisman group in 2022 produced a tetracyclic core using nucleophilic dearomatization of pyridine with glutaryl chloride in a 4 step synthesis to isomatrine with an extra step to readily provide other members of the Lupin-type alkaloids. [3] The Wipf group accessed the core of Ergot Alkaloids using nucleophilic dearomatization of pyridine with subsequent heck coupling to provide lysergol and isolysergol in 5 steps. [4]

This seminar will show how nucleophilic dearomatization of pyridine can be used as a tool to access di/tetrahydropyridines as well as show the use of this reactivity in total synthesis.

[1] Pozo, C. Chem. Rev. 2024, 124, 1122–1246

[2] Maimone, T. J. J. Am. Chem. Soc. 2021, 143, 7935–7939

[3] Reisman, S. E. J. Am. Chem. Soc. 2022, 144, 15938–15943

[4] Wipf, P. Org. Lett. 2022, 24, 7255, 725946