New Synthetic Routes to Phorbols and Ingananes

描述（由申请人提供）：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，以构建类似于天然产物的生物活性phorbol家族（tigliane骨架）中发现的融合碳环结构和结构相关的ingenol衍生物。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-l-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。这种基本的环结构策略将与其他合成方法相结合，以产生结构和功能上不同的phorbol和ingenol类似物。

DESCRIPTION (provided by applicant): 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-l-ols followed by a [3,3]-sigmatropic rearrangement of the resulting 2-alkylidene-tetrahydro-furan intermediates. This basic ring construction strategy will be coupled with other synthetic methodologies to generate structurally and functionally diverse analogues of phorbol and ingenol.