GOALI: A General Strategy for Piperidine Synthesis Using Zincke Imine Intermediates

Colorado State University, Fort Collins CO

Investigators

Abstract

With the support of the Chemical Synthesis Program in the Division of Chemistry, Andrew McNally of Colorado State University and Matthew Maddess of the Process Research and Development Group at Merck (Rahway, NJ) are engaged in an academic-industrial collaboration to study a process to prepare saturated nitrogen heterocyclic of the piperidine family from simpler aromatic (unsaturated) nitrogen-containing compounds of the pyridine family. This endeavor is important, and has societal benefits, because piperidines are among the most widespread class of compounds used as pharmaceutical agents and large collections of pyridines are available as potential starting materials. The overall process involves the chosen planar pyridine being first unraveled into an acyclic molecule (a so-called 'Zincke imine') which is then recyclized into a reactive positively charged intermediate (a pyridinium salt) that is subsequently converted into the desired three-dimensional piperidine of interest. This academic-industrial collaboration involves fundamental reaction development accelerated by Merck's unique technological capabilities, including high-throughput experimentation (HTE) and artificial intelligence (AI) tools, and it is anticipated to lead to a suite of chemical reactions capable of generating previously inaccessible piperidines that may impact the development of new therapeutics. The broader impacts of the funded project extend to providing unique training opportunities for graduate students who will receive mentorship from both academic and industrial settings and gain direct experience of Merck's technologies during the project period. Piperidine is the most common nitrogenous heterocycle found in FDA approved pharmaceuticals; accordingly, synthetic methods that can access piperidine derivatives in an efficient and selective manner are potentially useful tools for drug development. The aim of this GOALI (Grant Opportunities for Academic Liaison with Industry) project is to develop and explore a new route to substituted piperidines that exploits a recently discovered Zincke-type pyridine ring-opening chemistry that offers significantly greater scope than previously known variants. Specifically, upon activation of pyridines as their N-triflyl salts, subsequent engagement with a suitable amine (e.g., dibenzylamine) results in efficient conversion to acyclic Zincke imines. These species will be ring-closed with (heteroaryl)anilines or aliphatic amines and the resulting N-substituted pyridinium salts converted into a diverse range of otherwise difficult to access substituted piperidines by hydrogenation processes or via stagewise reactions with nucleophiles and electrophiles. Throughout the investigation, Merck's notable technological capabilities, including high-throughput reaction screening, AI tools to assist with the optimization of enantioselective hydrogenation reactions, and computational expertise to probe the mechanistic details of the processes of interest, will be deployed to facilitate achievement of the project goals. New transformations of pyridinium salts, including those allowing access to three-dimensional scaffolds and atropisomeric piperidine derivatives, are also a focus of attention and, if successful, would provide an entirely new route into such axially chiral systems. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.