Studies on the synthetic potential of novel heterocycle-forming cyclases

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The application of enzymes in organic chemistry has great potential. By exploiting typical enzyme properties (such as high selectivity and mild reaction conditions), they can clearly enrich the current synthetic methodology. The characterisation and further development of novel enzyme types into useful biocatalysts is an important step towards this goal. A promising but so far barely tapped source of new biocatalysts is the secondary metabolism. Its enzymes are highly attractive for chemoenzymatic synthesis, especially of complex natural products with pharmacological relevance. Progress in this area is therefore of great interest in such diverse fields as organic chemistry, pharmacology and medicine.The aim of this project is to study and improve the synthetic utility of a recently discovered group of cyclases. These catalyse intramolecular oxa-Michael additions of hydroxy enethioates to chiral, reduced oxygen heterocycles. The stereoselective synthesis of this class of compounds is still a challenge, which has hitherto prevented the full exploitation of their pharmacological potential. In studies of the representative cyclase AmbDH3 from the ambruticin biosynthesis, we have already shown a promising stereoselectivity and substrate tolerance of this enzyme as well as a scalability of its reactions to the preparative scale.Based on this, the enzyme reaction is to be coupled to a dynamic kinetic resolution or a deracemisation system of secondary alcohols in order to allow the production of chiral oxygen heterocycles with up to three stereogenic centers, starting from achiral precursors (work package 1). In the second part of the project an efficient chemoenzymatic total synthesis of the pyran-containing natural product (-)-centrolobin will be developed, which uses AmbDH3 in the key step (work package 2). The system developed in work package 1 will find an application in this synthetic route. By exploiting the specific properties of this cyclase type, novel (-)-centrolobin derivatives are to be prepared, which would be much more difficult to access using established methods. These derivatives will be tested in biological assays regarding their activity profile.