Chemo-enzymatic Synthesis of Structurally Complex Sorbicillin-Derived Natural Products and Non-Natural Analogd

在过去的几年里，我们小组首次利用SorbC化学酶合成山梨霉素类天然产物，使几乎所有的（杂）二聚体和简单杂化化合物都具有高度的区域和立体选择性，从而对其合成有效性做出了重要贡献。虽然这些合成路线比以前的纯化学全合成快得多，效率也高得多，但仍然存在一些局限性：在经典的间歇过程中，山梨比西林通常不完全转化为山梨比西林醇，再加上在所有合成过程中观察到的不需要的二聚体副产物的形成，不仅导致有时需要苛刻的色谱纯化，而且重要的是，无论特定的目标结构如何，最大收率都在30%左右（±5%）。这对于目前处理的所有目标化合物都是可以接受的，这些化合物是在山梨糖醇氧化后直接在原位生成的。然而，这些限制对于所需的后续多阶段合成转化为更复杂的代表，以及通过山梨糖醇与高度功能化的反应伙伴反应形成的物质来说是有问题的，这些反应伙伴不能简单地大量过量使用。这尤其适用于大量物质的生产，用于详细的生物学表征和化合物的衍生化，例如优化生物活性或安装分子探针以阐明作用机制。在本研究项目中，我们将有针对性地解决这些问题，应用所开发的方法建立第一个立体选择性的复杂山梨醇类化合物的全合成，从而为广泛的生物医学和机制后续研究奠定基础。具体而言，我们计划：•固定化SorbC，在流动反应器中持续进行氧化脱芳，并通过适当的反应控制形成高选择性产物•通过Diels-Alder环加成反应与复杂的亲二烯试剂或多阶段后续化学反应，首次立体选择性合成杂化山梨脂类化合物•通过Michael加成反应，首次立体选择性合成杂化山梨脂类化合物•最初的工作是为了阐明分子的作用模式，最初使用抗生素Rezishanon A的例子

The development of the first chemo-enzymatic syntheses of sorbicillinoid natural products using SorbC in our group over the last few years has enabled highly regio- and stereoselective access to almost all (hetero-)dimeric and simple hybrid compounds of this class and has thus made an important contribution to their synthetic availability. While these synthetic routes are significantly faster and more efficient than previous, purely chemical total syntheses, some limitations remain: the usually incomplete conversion of sorbicillin to sorbicillinol in classical batch processes, combined with the formation of undesired dimeric by-products observed in all syntheses, not only leads to the need for sometimes demanding chromatographic purifications, but importantly also to maximum yields of around 30% ( ± 5%), regardless of the specific target structure. This was acceptable for all target compounds tackled so far, which are generated directly in situ after the oxidative production of sorbicillinol. However, these limitations are problematic for required subsequent multi-stage synthetic transformations to even more complex representatives, as well es for substances that are formed via a reaction of sorbicillinol with highly functionalized reaction partners that cannot simply be used in large excess. This applies in particular to the production of larger amounts of substances for detailed biological characterization and to the derivatization of the compounds, e.g. to optimize biological activities or to install molecular probes to elucidate mechanisms of action. In this research project, we will solve these problems in a targeted manner, apply the developed methodology to establish the first stereoselective total syntheses of complex sorbicillinoids and thus lay the foundation for extensive biomedical and mechanistic follow-up investigations. Specifically, we are planning: • Immobilization of SorbC and continuous implementation of the oxidative dearomatization in flow reactors with subsequent highly selective product formation through suitable reaction control • Development of the first stereoselective synthesis of hybrid sorbicillinoids from Diels-Alder cycloaddition reactions with complex dienophiles or with multi-stage subsequent chemistry • Development of first stereoselective total syntheses of hybrid sorbicillinoids from Michael addition reactions with multi-stage subsequent chemistry • Initial work to towards elucidation of molecular modes of action, initially using the example of the antibiotic Rezishanon A