Photochemical Skeletal Editing for Pyridine-to-Pyrrole, -Furan, and -Thiophene Conversion

Descrizione del progetto

Convertire le piridine in altri eterocicli

La piridina, il pirrolo, il furano e il tiofene sono composti eteroaromatici essenziali ampiamente utilizzati per la sintesi di farmaci complessi. L’interconversione diretta tra anelli eteroaromatici, che consiste essenzialmente nello scambio di atomi nella struttura centrale, dispone del potenziale di accelerare notevolmente la scoperta di nuovi farmaci, consentendo modifiche in fase avanzata senza la necessità di realizzare lunghe sintesi ex novo. Sostenuto dal programma di azioni Marie Skłodowska-Curie, il progetto PYR2HET mira a sviluppare una nuova piattaforma fotochimica in grado di trasformare le piridine in pirroli, furani e tiofeni. Il metodo sfrutta l’N-ossidazione della piridina e la luce visibile al fine di scomporre gli anelli piridinici in catene diene contenenti nitrile, elementi costitutivi versatili che possono quindi reagire con nitreni, ossigeno singoletto o zolfo per formare, rispettivamente, anelli pirrolici, furanici e tiofenici.

Obiettivo

Heteroaromatic like pyridines, pyrroles, furans, and thiophenes are privileged scaffolds in pharmaceuticals & agrochemicals. While functional group modifications are routine, direct interconversion between heteroaromatic rings typically requiring de novo synthesis . “Ring replacement” strategies could transform drug discovery by enabling late-stage modulations, yet no general methods exist for converting abundant pyridines into other heterocycles.

This project will pioneer a photochemical platform to directly convert pyridines into pyrroles, furans, and thiophenes. The approach exploits pyridine N-oxidation followed by visible-light-mediated deconstruction to nitrile-containing dienes. These intermediates will undergo divergent [4+1] cycloadditions with nitrenes, singlet oxygen, or sulfur to yield pyrroles, furans, and thiophenes, respectively.

The methodology will progress through: (1) development of pyridine-to-pyrrole transformation via Cu-catalysed nitrene insertion and rearrangement, (2) mechanistic elucidation, (3) extension to pyridine-to-furan and pyridine-to-thiophene conversions using singlet oxygen and elemental sulfur, and (4) demonstration of synthetic utility in late-stage ring replacement of drug molecules.

This disruptive strategy introduces the first general method for heteroaromatic-to-heteroaromatic replacement, a conceptually novel retrosynthetic paradigm. It transforms pyridines from static scaffolds into versatile precursors, enabling access to new heterocyclic space of high biological and industrial value.

Completion of this ambitious project at RWTH Aachen University will be supported by advanced mechanistic expertise, knowledge transfer, and dissemination, equipping the Researcher with unique skills at the interface of photochemistry, catalysis, and heteroaromatic synthesis and strongly enhancing her career trajectory toward independence.