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）：Wortmannin是一种近五十年闻名的抗真菌和抗炎抗生素，仅屈服于一种消失的总体合成和一种来自氢化可的松的部分合成。除了其抗生素特性外，发现Wortmannin在1990年代初期是一种有效的磷脂酰肌醇3-激酶（PI 3-激酶）抑制剂。已经提出了PI 3-激酶作为抗癌靶标，因此，已经提出了对使用麦芽汁的使用来防止癌细胞的扩散。但是，由于沃尔特曼（Wortmannin）的一般毒性很高，因此保留磨牙的高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不可少的。考虑到这一点，我们的具体目的是开发一种不对称的磨牙总合成，其收敛性，灵活性和足够的简洁性最终促进了许多衍生物的合成，以进行进一步的生物学测试。我们提出的途径涉及分别形成分子的两半，然后通过Diels-Alder反应加入它们，以形成Wortmannin和B环的第四纪中心之一。由于这种关键的Diels-Aide反应在空间上很麻烦，因此对正确与二烯和二烯二烯的电子设备进行适当匹配的研究对于这项努力成功可能是必要的。如果成功的话，是一种对映选择性且较短的途径，那么将实现过去的合成，从而可以访问更多的Wortmannin类似物。