Total Synthesis of Cytotoxic Garcinia Natural Products

描述（由申请人提供）：已显示藤黄属天然产物家族的许多成员对一系列癌细胞系显示出显著的细胞毒性。本研究的目标是开发一种短而有效的合成该家族的一员，高迪肖二酸G。该合成的关键步骤是一种新的一锅法，三组分偶联反应。这个序列，其中包括狄尔斯-阿尔德反应，羟醛缩合，和杂迈克尔加成，将允许非常容易的制备三环核心共同的藤黄。将该核心片段偶联到一个复杂但容易制备的酚片段上，将完成guadichaudiic acid G的全合成。此外，将该核心偶联至替代酚片段将允许快速获得该家族的其他成员，包括天然存在的羊肚菌酸和scortechinone B以及潜在无限数量的非天然类似物。以这种方式，将产生藤黄属类型产物的文库，并测定针对癌细胞系的细胞毒性，最终目标是鉴定具有上级生物活性的化合物。

DESCRIPTION (provided by applicant): Many members of the Garcinia family of natural products have been shown to display significant cytotoxicity against a range of cancer cell lines. The goal of the proposed research is to develop a short and efficient synthesis of a member of this family, gaudichaudiic acid G. A key step in the proposed synthesis is a novel one-pot, three component coupling reaction. This sequence, which involves a Diels-Alder reaction, aldol condensation, and hetero-Michael addition, will allow for the exceedingly facile preparation of the tricyclic core common to the Garcinia xanthonoids. Coupling of this core fragment to a complex but readily prepared phenolic fragment will complete the total synthesis of guadichaudiic acid G. In addition, coupling of this core to alternative phenolic fragments will allow rapid access to additional members of this family including naturally occurring morellic acid and scortechinone B as well as a potentially limitless number of unnatural analogues. In this way, a library of garcinia-type products will be generated and assayed for cytotoxicity against cancer cell lines with the ultimate goal being to identify a compound with superior biological activity.