NEW SYNTHETIC ROUTES TO PHORBOLS AND INGENANES

拟议研究的总体科学目标是开发和应用新的合成方法和策略来构建融合碳环结构，类似于在具有生物活性的佛波醇家族(tigliane骨架)中发现的天然产物和结构相关的吲哚衍生物。这些化合物中的一些是蛋白激酶C的强激活剂，该酶已被证明在细胞信号转导中发挥重要作用，而另一些这类成员则引发不同的生物反应，包括抗HIV和抗肿瘤活性。所提出的合成方法是基于一种独特而高效的串联序列，该序列包括适当取代的4-戊烯-1-醇的分子内环化反应，以及所得到的2-亚烷基四氢呋喃中间体的[3，3]-Sigmatrotic重排。这项研究的具体目标是：(A)评估串联环化-Claisen重排方法作为合成四环佛手体环体系的新途径的范围和局限性；(B)扩展该方法用于构建吲哚类似物；以及(C)开发高效制备多官能化起始材料的方法，结合基本的环构建策略，这些方法将用于合成结构和功能多样化的佛波醇和吲哚类似物。

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.