# Potassium Bisulfite’s Role in Developing a Robust Platform for Enantioenriched N‑Alkylpyridinium Salts as Piperidine Precursors

## TL;DR

A new method using potassium bisulfite helps create chiral piperidine precursors, which are important in drug development.

## Contribution

A robust platform for synthesizing enantioenriched N-alkylpyridinium salts using potassium metabisulfite as a key additive.

## Key findings

- Potassium metabisulfite enhances the formation of pyridinium salts by deconjugating Zincke imines.
- High-throughput experiments show broad compatibility with various coupling partners.
- The method provides a general platform for generating stereoenriched piperidine precursors.

## Abstract

Piperidines are prominent scaffolds in medicinal chemistry.
However,
methods that incorporate chiral N-alkyl substituents
on piperidine remain limited. Here, we report a platform for the synthesis
of enantioenriched N-(α-chiral)­alkylpyridinium
salts from commercially available pyridines and enantiopure primary
amines; the resulting pyridinium salts serve as versatile precursors
to stereoenriched N-(α-chiral)­alkylpiperidines
via established reduction protocols. We discovered potassium metabisulfite
as a reaction additive that significantly enhanced the robustness
of the pyridinium formation reaction. Mechanistic and computational
studies reveal that potassium metabisulfite deconjugates Zincke imines,
enabling a lower-energy polar cyclization pathway to pyridinium formation
compared to a pericyclic one. We performed high-throughput experimentation
that demonstrated a broad scope for both coupling partners, providing
a robust, general platform for generating libraries of piperidine
precursors relevant to medicinal chemistry.