Studies on the synthetic potential of novel heterocycle-forming cyclases
Organic Molecular Chemistry - Synthesis and Characterisation
Final Report Abstract
This research project was concerned with the preparative-synthetic application of a newly discovered group of ring-forming enzymes that had only been biochemically characterised at the time of the proposal. These enzymes catalyse the so-called intramolecular oxa-Michael addition (IMOMA) which, when reacted with suitable substrates, leads to chiral oxygen heterocycles (CHCs). These are important structural elements of natural products and drugs that are often involved in their biological activity. Improving the synthetic methodology for their production is therefore desirable, and the so-called IMOMA cyclases, due to their high selectivity, have excellent potential to enable decisive progress in this field. In this project, the cyclase AmbDH3, which has been biochemically characterised by our group, was investigated for its integration into cascade processes in order to increase its synthetic value. First, a system for dynamic kinetic resolution of racemates was envisaged by combining the cyclase with transition metal-based catalysts. This approach was abandoned due to unavoidable side reactions of the metal catalysts with the precursors. Approaches to combine the cyclase with alcohol dehydrogenases, which should also allow dynamic kinetic resolution of racemates or deracemising cyclisation, could be established in principle but not fully elaborated within the time frame of the project. ADH cyclase cascades were successfully investigated in detail, allowing chiral SHZs with up to four stereocentres to be obtained from prochiral precursors in a single synthetic operation. These cascades were suitable for the preparation of different types of SHZ (tetrahydropyrans and tetrahydrofurans) with different substituent patterns and were also applicable on a preparative scale. In addition, it was shown that the obtained thioester SHZs can be easily converted into a variety of derivatives. The aim of the project was therefore achieved and, by integrating the cyclase AmbDH3 into enzyme cascades, a simple, flexible and efficient access to diverse chiral heterocycles with potential for natural product and drug synthesis has been created.
Publications
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Biocatalysts from Biosynthetic Pathways: Enabling Stereoselective, Enzymatic Cycloether Formation on a Gram Scale. ACS Catalysis, 10(9), 4973-4982.
Hollmann, Tim; Berkhan, Gesche; Wagner, Lisa; Sung, Kwang Hoon; Kolb, Simon; Geise, Hendrik & Hahn, Frank
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Step-Economic Synthesis of Biomimetic β-Ketopolyene Thioesters and Demonstration of Their Usefulness in Enzymatic Biosynthesis Studies. Organic Letters, 22(13), 4955-4959.
Wunderlich, Johannes; Roß, Theresa; Schröder, Marius & Hahn, Frank
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The ambruticins and jerangolids – chemistry, biology and chemoenzymatic synthesis of potent antifungal drug candidates. Natural Product Reports, 37(10), 1300-1315.
Hahn, Frank & Guth, Florian M.
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Cross-linking of a polyketide synthase domain leads to a recyclable biocatalyst for chiral oxygen heterocycle synthesis. RSC Advances, 11(33), 20248-20251.
Wagner, Lisa; Roß, Theresa; Hollmann, Tim & Hahn, Frank
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Studying a Bottleneck of Multimodular Polyketide Synthase Processing: the Polyketide Structure-Dependent Performance of Ketoreductase Domains. ACS Chemical Biology, 17(5), 1030-1037.
Schröder, Marius; Roß, Theresa; Hemmerling, Franziska & Hahn, Frank
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Towards understanding oxygen heterocycle-forming biocatalysts: a selectivity study of the pyran synthase PedPS7. Organic & Biomolecular Chemistry, 20(48), 9645-9649.
Wagner, Lisa; Stang, Jörg; Derra, Sebastian; Hollmann, Tim & Hahn, Frank
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Suzuki–Miyaura Reaction in the Presence of N-Acetylcysteamine Thioesters Enables Rapid Synthesis of Biomimetic Polyketide Thioester Surrogates for Biosynthetic Studies. Chemistry, 5(2), 1407-1418.
Derra, Sebastian; Schlotte, Luca & Hahn, Frank
