Faculty of Chemistry

by Andreas Schneider, Thomas B.. Lystbænk, Daniel Markthaler, Niels Hansen and Bernhard Hauer

Terpene synthesis is at the heart of organic synthesis and often represents the state-of-the-art in synthetic methodologies. A remaining challenge is the correct three-dimensional assembly of the terpene skeleton via cationic cyclization of abundant linear precursors. Nature has been using this strategy for eons by employing the catalytic excellence of terpene cyclases. In this paper, we harness the synthetic power of engineered squalene-hopene cyclases and demonstrate the chemoenzymatic synthesis of ten chiral (mero-)terpenes with up to five stereocenters and >99% ee and de.

Nature communications, 2024,  doi 10.1038/s41467/-024-448993

For further information please contact:
Prof. Bernhard Hauer
Institute of Biochemistry and Technical Biochemistry,
Department Technical Biochemistry
University of Stuttgart

by Patrick Probst, Jonas Groos, Dongren Wang, Alexander Beck, Katrin Gugeler, Johannes Kästner,
Wolfgang Frey, and Michael R. Buchmeiser

J. Am. Chem. Soc. 2024 146 (12), 8435-8446

For further information please contact:
Prof. Michael R. Buchmeiser
Institute of Polymer Chemistry
University of Stuttgart

by Yannick Stöckl*, Katrin Gugeler, Celine M. Holzwarth, Wolfgang Frey, Sascha Wegner, Birgit Claasen, Anna Zens, Dietrich Gudat, Christian P. Sindlinger, Johannes Kästner*, and Sabine Laschat

Organometallics 2024, 43, 3, 330–340.

Enantioenriched boron chelates show promising synthetic and luminescent properties; however, the challenging synthesis makes these compounds scarce. In our earlier work, we established a chirality transfer from boron O,N-chelates toward enantioenriched C,N-chelates. This methodology proved to be quite robust, in terms of yields and selectivity. However, unexpected steric effects on stereocontrol prompted a deeper investigation of the chirality transfer. In order to gain a holistic understanding of this process, we studied the structure of the O,N- and C,N-chelates as well as the stability of the dative B–N bonds. Furthermore, the proposed ate-complex as a reaction intermediate could be characterized using heteronuclear (2D) NMR spectroscopy. For this ate-complex, a tridentate O,N,N-chelate effect of the borate anion with the Li-cation was observed. Additional experiments indicated that the borate formation governs the stereoselectivity of chirality transfer. For a successful chirality transfer, an unprecedented S_N2-type breaking of the dative B–N bond with an organometallic nucleophile was identified by DFT calculations as the most likely reaction path. For other cases, decreased or inverse enantioselectivity was rationalized by a solvent-assisted pathway.

For further information please contact:
Prof. Sabine Laschat
Institute of Organic Chemistry
University of Stuttgart

Isomerization of terpenes is achieved by Brønsted and Lewis acids, but the resulting products are mixtures difficult to separate. We have now succeeded in developing a variant of the enzyme squalene-hopene cyclases that catalyzes this difficult isomerization with an unprecedented precision. We show how the fine-tuned control of the carbocation in the enzyme can increase the (+)-borneol selectivity from 1% to >90% (>99% de). In collaboration with the group of Sílvia Osuna, University of Girona, our combined experimental and computational data suggest that the orientation of key aromatic residues leads to a restructuring of the water network that facilitates the selective termination of the secondary isobornyl cation. This work extends our mechanistic understanding of carbocation rearrangements and sets the stage for a target-oriented skeletal reorganization of widely used terpenes.

by Julian Ludwig, Christian Curado-Carballada, Stephan C. Hammer, Andreas Schneider, Svenja Diether, Nico Kress, Sergi Ruiz-Barragán, Sílvia Osuna* and Bernhard Hauer*

Angew. Chemie 2024

For further information please contact:
Prof. Bernhard Hauer
Institute of Biochemistry and Technical Biochemistry,
Department Technical Biochemistry
University of Stuttgart

by Jan S. Florenski, Noah Schellander and Prof. Dr.-Ing. Elias Klemm

ChemCatChem 2024, e202301

For further information please contact
Prof. Elias Klemm
Institute of Technical Chemistry
University of Stuttgart

by S. Gergel, J. Soler, A. Klein, K. H. Schülke, B. Hauer, M. Garcia-Borràs and S. Hammer.

The direct regioselective oxidation of internal alkenes to ketones poses an important synthetic challenge. Now, directed evolution of a cytochrome P450 enzyme affords a ketone synthase that can efficiently oxidize internal arylalkenes directly to ketones with high chemo- and regioselectivity.

Nature Catalysis 2023

For further information please contact:
Prof. Bernhard Hauer
Institute of Biochemistry and Technical Biochemistry,
Department Technical Biochemistry
University of Stuttgart

by L. W. Zimmermann, R. Aghaei Hakkak, M. Ranjbar, Th. Schleid: "Crystal Structures and Thermal Analyses of Three New High-Energy Hydrazinium Hydro-closo-Borates"
Int. J. Hydrog. Energy 2024, 49, 1469–1477.

For further information please contact
Prof. Thomas Schleid
Institute of Inorganic Chemistry
University of Stuttgart

The paper "Prolinyl Nucleotides Drive Enzyme-Free Genetic Copying of RNA" from Prof. Richert was nominated for the cover of Angewandte (vide infra). It shows that long reads of mixed sequence RNA can be achieved with an amino acid as leaving group.

Angew. Chem. Int. Ed.2023, e202307591

For further information please contact:
Prof. Clemens Richert
Institute of Organic Chemistry
University of Stuttgart

by Shubhadeep Chandra, Dr. Arijit Singha Hazari, Dr. Qian Song, David Hunger, Dr. Nicolás I. Neuman, Prof. Dr. Joris van Slageren, Prof. Dr. Elias Klemm, Prof. Dr. Biprajit Sarkar.

For further information please contact:
Prof. Biprajit Sarkar
Institute of Inorganic Chemistry
University of Stuttgart

by Jona T. Schelle, William Lepottevin and Bernhard Hauer

Oxyfunctionalization reactions are of great interest in organic chemistry and industry. Rieske non-heme iron oxygenases, such as cumene dioxygenase, have shown significant potential for these reactions. However, scaling up oxygenase-catalyzed reactions can be challenging due to their reliance on molecular oxygen. In this study, we optimized the reaction set-up and oxygen uptake for cumene dioxygenase-catalyzed biotransformations and successfully scaled up the reaction volume from 1 mL to 200 mL. Our results demonstrate the applicability of our set-up for product isolation and characterization.

Chemie Ingenieur Technik 95,5: 607 – 611 (2023)

For further information please contact:
Prof. Bernhard Hauer
Institute of Biochemistry and Technical Biochemistry,
Department Technical Biochemistry
University of Stuttgart

by Benjamin Aberle,  Daniel Kowalczyk,  Simon Massini,  Alexander-N. Egler-Kemmerer,  Sebastian Gergel,  Stephan Hammer,  Bernhard Hauer

Terpenes are natural compounds with diverse applications, but the available carbon scaffolds are limited by their biosynthesis from five carbon precursors. To gain access to non-natural terpenoids, we identified and engineered methyltransferases for late-stage C-methylation of unactivated alkenes. The engineering resulted in a 55-fold improvement of conversion of (E,E)-farnesol with > 99% selectivity. In total, five non-natural terpenoids were produced and isolated using this biocatalytic method. This opens new avenues for the modification of the carbon scaffold of terpenes.

Angewandte Chemie int. Ed.

For further information please contact:
Prof. Bernhard Hauer
Institute of Biochemistry and Technical Biochemistry,
Department Technical Biochemistry
University of Stuttgart

by Andreas Schneider; Christian Curado; Thomas B. Lystbaek; Sílvia Osuna; Bernhard Hauer

Angewandte Chemie: DOI number​ 10.1002/anie.202301607

The synthetic power of terpene cyclases is of broad academic as well as industrial interest as it can cut down synthetic routes to complex cyclic terpenes to essentially one step. However, these enzymes usually lack catalytic turnovers and stability under the new-to-nature conditions. Teaming up with the BioCompLab, Girona of Silvia Osuna, we showcase the synergy of tailoring the active site and entrance tunnel of the squalene-hopene cyclase for the stereocontrolled cationic cyclization of E,E-homofarnesol to (–)-ambroxide with >100.000 total turnovers.

For further information please contact:
Prof. Bernhard Hauer
Institute of Biochemistry and Technical Biochemistry,
Department Technical Biochemistry
University of Stuttgart