Potassium Bisulfite’s Role in Developing a Robust Platform for Enantioenriched N‑Alkylpyridinium Salts as Piperidine Precursors
Jake D. Selingo, Jacob R. King, Barbara Pio, Andrew J. Neel, Yu-Hong Lam, Robert S. Paton, Matthew L. Maddess, Andrew McNally
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.
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…
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Taxonomy
TopicsAdvanced Synthetic Organic Chemistry · Coordination Chemistry and Organometallics · Catalytic C–H Functionalization Methods