A Convergent Total Synthesis of (+)-Wortmannin

( )-渥曼青霉素的收敛全合成

• 批准号: 6938569
• 负责人: Ryan W Van De Water
• 金额: $ 2万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2005-12-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6938569
• 关键词: Diels Alder reaction; androstane compound; antifungal agents; antiinflammatory agents; cell proliferation; chemical synthesis; diene; enzyme inhibitors; phosphatidylinositol 3 kinase; postdoctoral investigator; stereochemistry

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.

描述（由申请人提供）：Wortmannin是一种已知近50年的抗真菌和抗炎抗生素，仅通过一种外消旋全合成和一种氢化可的松部分合成。除了其抗生素特性外，渥曼青霉素在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-激酶已被认为是抗癌靶点，因此，已提出对使用渥曼青霉素预防癌细胞增殖的兴趣。然而，由于渥曼青霉素的高一般毒性，保留渥曼青霉素的高PI 3-激酶抑制特性但省略其毒性的类似物被认为对于任何潜在的药物应用都是必要的。考虑到这一点，我们的具体目标是开发一种不对称的渥曼青霉素的全合成，是收敛的，灵活的，并足够简洁，最终促进许多衍生物的合成，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半，然后通过Diels-Alder反应将它们连接起来，形成渥曼青霉素的四元中心之一以及B环。由于这一关键的狄尔斯-艾德反应在空间上是麻烦的，因此对二烯和亲二烯体的电子学的适当匹配的研究对于这一奋进的成功可能是必要的。如果成功的话，将实现对映选择性和比过去的合成路线短得多的路线，从而允许获得比以前可能的更多种类的渥曼青霉素类似物。