A Convergent Total Synthesis of (+)-Wortmannin

描述(申请人提供)：Wortmannin，一种已有近50年历史的抗真菌和抗炎抗生素，仅屈服于一次外消旋全合成和一次氢化可的松部分合成。除了其抗菌特性外，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-Kinase)抑制剂。PI-3-K已被认为是一种抗癌靶点，因此，人们对使用Wortmannin来防止癌细胞增殖感兴趣。然而，由于Wortmannin的高一般毒性，保留Wortmannin的高等电点3-激酶抑制特性而忽略其毒性的类似物被认为是任何潜在的药物应用所必需的。考虑到这一点，我们的具体目标是开发一种不对称的Wortmannin全合成方法，该方法收敛、灵活、足够简洁，最终有助于合成多种衍生物，用于进一步的生物测试。我们提出的路线包括分别形成分子的两个半部分，然后通过Diels-Alder反应将它们连接起来，形成Wortmannin的四个中心之一以及B环。由于这一关键的Diels-aide反应在空间上非常繁琐，为了这一努力的成功，很可能有必要研究如何正确匹配双烯和双烯基团的电子结构。如果成功，将实现对映体选择性和比过去的合成路线短得多的路线，允许获得比以前可能的更多种类的Wortmannin类似物。

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.