NEW SYNTHETIC ROUTES TO PHORBOLS AND INGENANES

该研究的总体科学目标是开发和应用新的合成方法和策略，以构建类似于天然产物的生物活性磷家族（tigliane骨架）和结构相关的ingenol衍生物中的融合碳环结构。其中一些化合物是蛋白激酶C的强激活剂，已被证明在细胞信号转导中起主要作用，而这类化合物的其他成员则引发不同的生物反应，包括抗hiv和抗肿瘤活性。所提出的组装tigliane环体系的合成策略依赖于一种独特且高效的串联序列，该序列涉及适当取代的4-戊烷-1-醇的分子内环化，然后对所得到的2-烷基烯四氢呋喃中间体进行[3,3]-异位重排。本研究的具体目标是：(A)评估串联环合- claisen重排方法作为四环磷体环体系的新途径的范围和局限性；(B)将此方法扩展到ingenol类似物的构建和(C)开发有效制备多功能化起始材料的方法，这些起始材料与基本环构建策略相结合，将用于生成结构和功能多样化的佛博尔和ingenol类似物。

The overall scientific goal for the proposed research is to develop and apply novel synthetic methods and strategies toward the construction of fused carbocyclic structures analogous to those found in the biologically active phorbol family (tigliane skeleton) of natural products and structurally related ingenol derivatives. Some of these compounds are strong activators of the enzyme protein kinase C which has been shown to play a major role in cellular signal transduction, while other members of this class elicit different biological responses, including anti-HIV as well as anti-tumor activity. The proposed synthetic strategy for the assembly of the tigliane ring system relies on a unique and highly efficient tandem sequence that involves the intramolecular cyclization of appropriately substituted 4-pentyn-1-ols followed by a [3,3]-sigmatropic rearrangement of the resulting 2-alkylidenetetrahydrofuran intermediates. The specific goals for this research are: (A) to assess the scope and limitations of the tandem cyclization-Claisen rearrangement methodology as a novel route to the tetracyclic phorboid ring system; (B) to extend this methodology for the construction of ingenol analogues and (C) to develop methods for the efficient preparation of polyfunctionalized starting materials which, coupled with the basic ring construction strategy, will be used to generate structurally and functionally diverse analogues of phorbol and ingenol.