Tanja Gulder’s research while affiliated with Saarland University and other places

The synthesis of carbocycles bearing consecutive all-carbon quaternary centers remains a formidable challenge in organic chemistry due to their steric congestion and synthetic inaccessibility. Herein, we report an efficient and sustainable photocatalytic strategy for the cyclization of polyenes to cyclopentane thioethers using 2,4,6-triphenylpyrylium tetrafluoroborate (TPT⁺) as a photocatalyst in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP). The transformation proceeds via a thiyl radical-initiated mechanism, forming multiple Csp³–Csp³ bonds and quaternary centers in a single step under mild conditions. The method tolerates a broad range of aliphatic and functionalized thiols and exhibits high yields and good diastereoselectivities, the latter strongly depending on the addressed mechanism of the transformation. Mechanistic investigations support a radical pathway initiated by thiol oxidation. This work highlights the potential of combining photocatalysis with microstructured solvent systems to facilitate polyene cyclizations. Overall, it provides a versatile platform for synthesizing sterically congested, biologically relevant carbocyclic frameworks.

Nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) are essential tools in natural and life sciences, but their low sensitivity often hampers their applicability. Photochemically induced dynamic nuclear polarization (photo-CIDNP) offers a versatile and mild method to overcome this limitation. Here, we report on structure-photo-CIDNP relationship studies in liquid-state NMR utilizing a holistic approach. We synthesized biomimetic tryptophan-flavin diads with varying linker lengths composed of conformationally rigid oligoproline units. The predominant polyproline II (PPII) helical structure ensures consistent donor-acceptor distances. Photo-CIDNP experiments revealed significant hyperpolarization effects, particularly in diads with six proline units, mimicking the spatial arrangement found in natural photoactive proteins. Our findings highlight the potential of these biomimetic diads to enhance nuclear hyperpolarization in NMR spectroscopy. This work provides valuable insights into the design of diads for efficient photo-CIDNP generation, paving the way for advanced studies in modern NMR and bio-MRI.

Dieser Trendbericht erläutert Erkenntnisse der letzten beiden Jahre aus der Sicht von Wissenschaftlerinnen und Wissenschaftlern des interdisziplinären, durch die DFG geförderten Konsortiums Transregio 325. Die Autorinnen und Autoren forschen vor allem zu chemischer Photokatalyse und beleuchten besonders Themen mit molekülchemischer Komponente.

Vanadium-dependent haloperoxidases (VHPOs) are biotechnologically valuable and operationally versatile biocatalysts. VHPOs share remarkable active-site structural similarities yet display variable reactivity and selectivity. The factors dictating substrate specificity and, thus, a general understanding of VHPO reaction control still need to be discovered. This work’s strategic single-point mutation in the cyanobacterial bromoperoxidase AmVHPO facilitates a selectivity switch to allow aryl chlorination. This mutation induces loop formation that interacts with the neighboring protein monomer, creating a tunnel to the active sites. Structural analysis of the substrate-R425S-mutant complex reveals a substrate-binding site at the interface of two adjacent units. There, residues Glu139 and Phe401 interact with arenes, extending the substrate residence time close to the vanadate cofactor and stabilizing intermediates. Our findings validate the long-debated existence of direct substrate binding and provide a detailed VHPO mechanistic understanding. This work will pave the way for a broader application of VHPOs in diverse chemical processes.

Inspired by natural cryptic halogenation in C,C-bond formation, this study developed a synthetic approach combining biocatalytic bromination with transition-metal-catalyzed cross-coupling. Using the cyanobacterial AmVHPO, a robust and sustainable bromination-arylation cascade was created. Genetic modifications allowed enzyme immobilization, enhancing the compatibility between biocatalysis and chemocatalysis. This mild, efficient method for synthesizing biaryl compounds provides a foundation for future biochemo cascade reactions harnessing halogenation as a traceless directing tool.

There is a perpetual need for efficient and mild methods to integrate deuterium atoms into carbon frameworks through late‐stage modifications. We have developed a simple and highly effective synthetic route for hydrogen isotope exchange (HIE) in aromatic compounds under ambient conditions. This method utilizes catalytic amounts of hexafluorophosphate (PF6⁻) in deuterated 1,1,1,3,3,3‐hexafluoroisopropanol (HFIP‐d1) and D2O. Phenols, anilines, anisoles, and heterocyclic compounds were converted with high yields and excellent deuterium incorporations, which allows for the synthesis of a wide range of deuterated aromatic compounds. Spectroscopic and theoretical studies show that an interactive H‐bonding network triggered by HFIP‐d1 activates the typically inert P−F bond in PF6⁻ for D2O addition. The thus in situ formed DPO2F2 then triggers HIE, offering a new way to deuterated building blocks, drugs, and natural‐product derivatives with high deuterium incorporation via the activation of strong bonds.

There is a perpetual need for efficient and mild methods to integrate deuterium atoms into carbon frameworks through late‐stage modifications. We have developed a simple and highly effective synthetic route for hydrogen isotope exchange (HIE) in aromatic compounds under ambient conditions. This method utilizes catalytic amounts of hexafluorophosphate (PF6−) in deuterated 1,1,1,3,3,3‐hexafluoroisopropanol (HFIP‐d1) and D2O. Phenols, anilines, anisoles, and heterocyclic compounds were converted with high yields and excellent deuterium incorporations, which allows for the synthesis of a wide range of deuterated aromatic compounds. Spectroscopic and theoretical studies show that an interactive H‐bonding network triggered by HFIP‐d1 activates the typically inert P‐F bond in PF6‐ for D2O addition. The thus in‐situ formed DPO2F2 triggers then HIE, offering a new way to deuterated building blocks, drugs, and natural‐product derivatives with high deuterium incorporation via the activation of strong bonds.

There is a perpetual need for efficient and mild methods to integrate deuterium atoms into carbon frameworks through late-stage modifications. We have developed a simple and highly effective synthetic route for hydrogen isotope exchange (HIE) in aromatic compounds under ambient conditions. This method utilizes catalytic amounts of hexafluorophosphate (PF6−) in deuterated 1,1,1,3,3,3-hexafluoroisopropanol (HFIP-d1) and D2O. Phenols, anilines, anisoles, and heterocyclic compounds were converted with high yields and excellent deuterium incorporations, which allows for the synthesis of a wide range of deuterated aromatic compounds. Spectroscopic and theoretical studies show that an interactive H-bonding network triggered by HFIP-d1 activates the typically inert P-F bond in PF6 for D2O addition. The thus in-situ formed DPO2F2 triggers then HIE, offering a new way to deuterated building blocks, drugs, and natural-product derivatives with high deuterium incorporation via the activation of strong bonds.

This work presents a novel microfluidic screening setup with real-time analytics for investigating reactions with immobilised biocatalysts. The setup combines microreactor technology, multi-reactor integration, and online (chip-)LC/MS analysis in a sequential automated workflow. We utilized in-house manufactured fused-silica glass chips as reusable packed-bed microreactors interconnected as individual tube reactors. The potential of this setup was showcased by conducting and optimising a biocatalytic aromatic bromination reaction as the first proof of concept using immobilised vanadium-dependent haloperoxidase from Curvularia inaequalis (CiVHPO). The fusion of a HaloTagTM to CiVHPO was used for efficient and mild covalent linkage of the enzyme onto chloroalkane-functionalized particles. Then, the biotransformation was continuously monitored with automated LC/MS data acquisition in a data-rich manner. By further developing the automation principle, it was possible to sequentially screen multiple different connected packed-bed microreactors for reaction optimization while using only miniature amounts of reactants and biocatalyst. Finally, we present a fast and modular chipHPLC solution for online analysis to reduce the overall solvent consumption by over 80%. We established a modern microfluidic platform for real-time reaction monitoring and evaluation of biocatalytic reactions through automation of the reactant feed integration, flexible microreactor selection, and online LC/MS analysis.

This work presents a novel microfluidic screening setup with real-time analytics for investigating reactions with immobilised biocatalysts. The setup combines microreactor technology, multi-reactor integration, and online (chip-)LC/MS analysis in a...