Synthesis of anticancer agents using Prins cyclization

描述(申请人提供)：这项建议的目标是开发基于Prins环化的新反应，并将这些新反应应用于合成复杂的天然产品。正在开发的新方法包括第二代Mukaiyama Aldol Prins(MAP)与未活化的烯烃的反应。在烯酮和烯醇醚之间发现了一种新的级联环化反应，该反应将被研究。我们将研究Prins环化反应的机理，并研究2-氧杂环己烷重排的作用。由TMSBr环化促进的Prins环化反应中令人惊讶的轴向选择性将从力学和实际制备过程两个方面进行研究。基于这一新方法的合成包括花蕾素I的路线，这是第二代合成亮氨酸内酯A、拉索内酯A和肯德霉素的方法。白果内酯A和拉索内酯A都显示出对人类癌细胞株的强大细胞毒性，计划中的合成比已报道的这些重要化合物更简洁和有效。本文所描述的工作将推动合成化学的发展，并为有机化学家提供新的工具。这些工具将促进许多新结构的合成，这些结构可能是新的药物制剂的重要组成部分。

DESCRIPTION (provided by applicant): The goals of this proposal are to develop new reactions based on the Prins cyclization and to apply these new reactions to the synthesis of complex natural products. New methods to be developed include the second generation Mukaiyama aldol Prins (MAP) reaction with unactivated alkenes. A new cascade cyclization reaction between enones and enol ethers has been discovered that will be investigated. The mechanism of the Prins cyclization will be studied, and the role of 2-oxonia Cope rearrangements will be investigated. The surprising axial selective in Prins cyclizations promoted by TMSBr cyclization will be studied both mechanistically and as a practical preparative procedure. Syntheses based on this new methodology include routes to calyxin I, a second-generation synthesis of leucascandrolide A, lasonolide A and kendomycin. Both leucascandrolide A and lasonolide A have shown potent cytotoxicity against human cancer cell lines, and the planned syntheses are more concise and efficient than any yet reported for these important compounds. The work described herein will advance the state of synthetic chemistry and provide new tools for organic chemists. These tools will facilitate the synthesis of many new structures that may be important as new pharmaceutical agents.