A Convergent Total Synthesis of (+)-Wortmannin

描述（由申请人提供）：Wortmannin，一种已知近50年的抗真菌和抗炎抗生素，仅屈服于氢化可的松的一次外消旋全合成和一次部分合成。除了其抗生素特性，wortmannin在20世纪90年代初被发现是一种有效的磷脂酰肌醇3-激酶（PI 3-激酶）抑制剂。PI 3-激酶已被认为是一个抗癌靶点，因此，对使用wortmannin来防止癌细胞增殖的兴趣已被提出。然而，由于wortmannin的高一般毒性，保留wortmannin的高PI 3-激酶抑制特性但忽略其毒性的类似物被认为是任何潜在药物应用所必需的。考虑到这一点，我们的具体目标是开发一种不对称的wortmannin全合成，它是收敛的，灵活的，并且足够简洁，最终有助于合成许多衍生物以进行进一步的生物学测试。我们提出的途径包括分别形成分子的两半，然后通过Diels-Alder反应将它们连接起来，形成wortmannin的一个四元中心和B环。由于这个关键的Diels-AIde反应在空间上是繁琐的，因此对二烯和亲二烯试剂的电子结构进行适当匹配的研究可能是这项努力成功的必要条件。如果成功，一个对映选择性和相当短的路线比过去的合成将实现，允许获得更多种类的wortmannin类似物比以前是可能的。

DESCRIPTION (provided by applicant): Wortmannin, an anti-fungal and anti-inflammatory antibiotic known for almost fifty years, has only succumbed to one racemic total synthesis and one partial synthesis from hydrocortisone. In addition to its antibiotic properties, wortmannin was found to be a potent phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor in the early 1990s. PI 3-kinase has been suggested as an anti-cancer target and as such, interest in the use of wortmannin for preventing the proliferation of cancer cells has been suggested. However, because of wortmannin's high general toxicity, analogs that preserve wortmannin's high PI 3-kinase inhibition properties but omit its toxicity have been deemed necessary for any potential drug applications. With this in mind, our specific aim is to develop an asymmetric total synthesis of wortmannin that is convergent, flexible, and of sufficient brevity to eventually facilitate the synthesis of numerous derivatives for further biological testing. Our proposed route involves separately forming two halves of the molecule and later joining them via a Diels-Alder reaction to form one of the quaternary centers of wortmannin as well as the B ring. As this key Diels-AIde reaction is sterically cumbersome, investigations into properly matching the electronics of the diene and dienophile are likely necessary for success in this endeavor. If successful, an enantioselective and considerably shorter route then the, past synthesis would be achieved, allowing access to a greater variety of wortmannin analogs then has been previously possible.