Stereoselektive Cascade Aldol Reactions for Expeditious. Total Synthesis of Polyketide Natural Products

自2006年以来，Yamamoto教授的团队开创了一种通过超甲硅烷基烯醇醚的一锅级联Mukaiyama交叉羟醛缩合反应合成聚酮化合物的新方法，该方法允许非常有效，立体选择性和即时获得高度生物活性和药学相关的天然产物。这种强大的方法在一个反应中结合了多个步骤，产生复杂的产物，而不需要分离中间体或冗长的保护基团操作。因此，对这种特殊的新方法的进一步探索对于制药科学的发展以及经济和生态原因都具有最高的兴趣。本项目旨在开发和应用该方法，以简洁，快速合成生物活性天然产物。首先，将优化反应条件以在一锅中平稳地促进多个（≥ 3个）级联羟醛缩合反应。同时，交叉醛偶联反应，导致高度取代的多羟基醛将进行研究。接下来，将进行醛片段与3-氧代-1，5-二醇的偶联。最后，新的进展将应用于合成聚甲氧基二烯型天然产物和阿夫拉他汀A的聚酮片段。

A novel approach to polyketide synthesis via one-pot, cascade Mukaiyama cross-aldol reactions of super-silyl enol ethers is pioneered since 2006 by the group of Professor Yamamoto and allows for a remarkably efficacious, stereoselective and instant access to a highly bioactive and pharmaceutically relevant class of natural products. This powerful approach combines multiple steps in a single reaction, yielding complex products without the need of isolation of intermediates or lengthy protective group manipulations. Further exploration of this exceptional new method is therefore of the highest interest for progression of pharmaceutical sciences and for both economical and ecological reasons. This project aims at development and application of this process to a concise, expeditious synthesis of bioactive natural products. First, reaction conditions will be optimized to smoothly promote multiple (≥3) cascade aldol reactions in one pot. In parallel, crossaldehyde coupling reactions leading to highly substituted polyhydroxylated aldehydes will be studied. Next, coupling of aldehyde fragments to 3-oxo-1,5-diols will be performed. Finally, new developments will be applied to the synthesis of natural products of the Polymethoxydiene type and of a polyketide fragment of the Aflastatin A.