Synthetic studies on natural products using a new approach via Diels-Alder reaction and fragmentation reaction

Zaragozic酸是一类结构相关的真菌代谢物，1992年由三个独立的类群从不同的生物中分离出来，已被发现是角鲨烯合成酶和法尼基蛋白转移酶的有效抑制剂。这些化合物共享一个共同的2，8-二氧二环[3.2.1]辛烷核心，并且在两个亲脂侧链(例如扎拉戈齐酸A)上有所不同。许多关于它们的合成的报道反映了它们独特的结构和生物活性。它们最大的特征是含有六个连续的手性碳原子的高含氧亲水核心。已有几个研究小组报道了Zaragozic酸的全合成，然而，各种合成方法仍在继续研究。我们开发了一条新的合成路线，用于从呋喃衍生物中构建Zaragozic酸的核心部分。该合成包括2，5-二取代呋喃与二甲基Diels-Alder反应得到的7-氧双环[2.2.1]七-2，5-二烯衍生物的C(3)，C(4)，C(6)和C(7)位的区域和立体选择性引入氧官能团的两个关键步骤和7-氧双环[2.2.1]庚烷衍生物的Grob裂解-还原-碘缩醛反应得到2，8-二氧双环[3.2.1]辛烷环体系。此外，在猪肝酯酶(PLE)作用下，7-氧杂双环[2.2.1]-2，5-二烯衍生物中的对称酯以较高的产率得到半酯，产率为70%ee。

Zaragozic acids (squalestatins), a family of structurally related fungal metabolites isolated from different organisms by three independent groups in 1992, have been found to be potent inhibitors of squalene synthase and farnesyl-protein transferase. These compounds share a common 2,8-dioxabicyclo[3.2.1]octane core and differ in two lipophilic side chains (e.g., zaragozic acid A). A number of reports about their synthesis reflected their unique structures and biological activities. Their most characteristic feature is the highly oxygenated hydrophilic core bearing six contiguous chiral carbon atoms. Total syntheses of zaragozic acids have been reported by several groups, however, various synthetic approaches continue to be investigated. We developed a new synthetic route for construction of the core moiety of zaragozic acids from a furan derivative. This synthesis involves two crucial steps for the regio- and stereoselective introduction of oxygen functionalities into the C(3), C(4), C(6) and C(7) positions on 7-oxabicyclo[2.2.1]hepta-2,5-diene derivative which was obtained by Diels-Alder reaction of 2,5-disubstituted furan with dimethyl, and Grob fragmentation-reduction-iodo acetalization reaction of 7-oxabicyclo[2.2.1]heptane derivative to give 2,8-dioxabicyclo[3.2.1]octane ring system. In addition, hydrolysis of symmetrical esters in 7-oxabicyclo[2.2.1]hepta-2,5-diene derivative by pig liver esterase (PLE) gave half ester in good yield (70% ee).