A Convergent Total Synthesis of (+)-Wortmannin

( )-渥曼青霉素的收敛全合成

• 批准号: 6737731
• 负责人: Ryan W Van De Water
• 金额: $ 4.3万
• 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 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6737731
• 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）： 渥曼青霉素是一种已知近五十年的抗真菌和抗炎抗生素，仅屈服于一种外消旋全合成和一种由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-激酶已被建议作为抗癌靶点，因此，人们对使用渥曼青霉素预防癌细胞增殖产生了兴趣。然而，由于渥曼青霉素的高一般毒性，保留渥曼青霉素高PI 3-激酶抑制特性但忽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收敛、灵活且足够简洁的渥曼青霉素不对称全合成，以最终促进多种衍生物的合成，用于进一步的生物测试。我们提出的路线涉及分别形成分子的两半，然后通过狄尔斯-阿尔德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-艾德反应在空间上很麻烦，因此研究如何正确匹配二烯和亲双烯体的电子学对于这一努力的成功可能是必要的。如果成功，将实现比过去的合成更短的对映选择性路线，从而能够获得比以前更多种的渥曼青霉素类似物。