Redefining Stereocontrol in Photo-Biocatalysis: Access to Heteroatom, Axial, and Planar Chirality

• Applicant: Dr. Tristan von Münchow
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 572739603

The central objective of this project is to advance innovative concepts for encoding novel catalytic mechanisms into enzymes by merging biocatalysis with photocatalysis. This interdisciplinary approach seeks to harness the power of visible light to drive novel enantioselective transformations. Recent work by the group of Prof. Paolo Melchiorre (host) has established a compelling proof-of-concept for enzyme-mediated asymmetric iminium ion photocatalysis independently of external cofactors, relying instead on the direct photoexcitation of reaction intermediates. While these early studies achieved high stereoselectivity, the full scope and synthetic potential of this emerging platform remain largely untapped. Hence, the discovery of novel reactivities forms the basis of my project, with the aim of developing and characterizing photo-biocatalytic new-to-nature transformations. This includes the enantioselective synthesis of chiral motifs beyond stereogenic sp³-carbon — such as heteroatom-centered, axial, or planar chirality. The selective synthesis of such architectures is of considerable significance due to their prevalence in biologically active molecules, pharmaceuticals, and advanced materials. Despite the significance of these complex chiral motifs, efficient and enantioselective approaches for their synthesis remain scarce. Developing photo-biocatalytic strategies under mild, sustainable conditions holds great potential. Notably, the radical disconnection strategies detailed within this proposal represent unique modes of bond construction, inaccessible via current asymmetric catalytic methods. In this context, high-throughput directed evolution workflows will be implemented to improve the activity, selectivity, and turnover numbers (TON) of the identified photoenzymes, thereby enhancing their synthetic applicability, expanding their scope, and increasing their operational robustness. Importantly, this research directly addresses a critical contemporary challenge: the sustainable synthesis of value-added molecules from readily available feedstocks, such as carboxylic acids. In doing so, it aligns with the principles of green chemistry by replacing toxic, transition-metal-based methods with biocatalytic processes powered by light — an environmentally friendly and renewable resource. Thus, this research aims to significantly expand the synthetic capabilities of photoenzymes and contribute to global sustainability efforts, including the UN Sustainable Development Goals and the European Green Deal.

• DFG Programme: WBP Fellowship
• International Connection: Italy
• Host: Professor Dr. Paolo Melchiorre