Synthesis of anticancer agents using Prins cyclization

描述（由申请人提供）：本提案的目标是开发基于普林斯环化的新反应，并将这些新反应应用于复杂天然产物的合成。新开发的方法包括与未活化烯烃的第二代Mukaiyama aldol Prins （MAP）反应。烯酮和烯醇醚之间发现了一种新的级联环化反应，并将对其进行研究。研究了Prins环化的机理，并探讨了2-氧离子Cope重排的作用。TMSBr环化所促进的普林斯环化中令人惊讶的轴向选择性将从机理和实际制备过程两方面进行研究。基于这种新方法的合成包括花萼素I的合成路线，花萼素I是第二代合成的亮色红素内酯a， lasonolide a和kendomycin。亮色木犀内酯A和lasonolide A都显示出对人类癌细胞系的强细胞毒性，并且计划的合成比迄今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，这些新结构可能是重要的新药物制剂。

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.