Studies on the synthetic potential of novel heterocycle-forming cyclases

酶在有机化学中的应用具有很大的潜力。通过利用典型的酶特性（如高选择性和温和的反应条件），它们可以明显丰富当前的合成方法。表征和进一步开发新的酶类型成为有用的生物催化剂是实现这一目标的重要一步。一个有希望但迄今为止几乎没有开发的新生物催化剂来源是次级代谢。其酶对于化学酶促合成，特别是具有药理学相关性的复杂天然产物的合成具有高度吸引力。因此，这一领域的进展在有机化学、药理学和医学等不同领域引起了极大的兴趣。本项目的目的是研究和改进最近发现的一组环化酶的合成效用。这些催化分子内氧杂-迈克尔加成的羟基烯硫代手性，减少氧杂环。这类化合物的立体选择性合成仍然是一个挑战，迄今为止，这阻碍了其药理学潜力的充分利用。在对来自安地霉素生物合成的代表性环化酶AmbDH 3的研究中，我们已经显示了该酶的有希望的立体选择性和底物耐受性以及其反应到制备规模的可扩展性。将酶反应与仲醇的动态动力学拆分或去外消旋化系统偶联，立体中心，从非手性前体开始（工作包1）。在该项目的第二部分中，将开发含吡喃的天然产物（-）-中心珠蛋白的有效化学酶促全合成，其在关键步骤中使用AmbDH 3（工作包2）。在工作包1中开发的系统将在该合成路线中找到应用。通过利用这种环化酶类型的特定性质，将制备新的（-）-中心珠蛋白衍生物，这将是更难以获得使用已建立的方法。这些衍生物将在生物测定中对其活性特征进行检测。

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.