A Direct Aldol Strategy toward B-Type Amphidinolides

B 型氨脒内酯的直接羟醛策略

• 批准号: 6937935
• 负责人: BRANDON TURUNEN
• 金额: $ 4.21万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2008-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6937935
• 关键词: antineoplastic antibiotics; antineoplastics; drug design /synthesis /production; drug discovery /isolation; glycosides; lactones; macrolide antibiotics; marine toxins; postdoctoral investigator

DESCRIPTION (provided by applicant): The amphidinolides are a family of complex macrolides exhibiting potent and unique antitumor activity. The B-type amphidinolides represent promising leads in the search for new chemotherapeutic agents. Unfortunately, these compounds, isolated from marine dinoflagellates, are only isolable in minute quantities. Although many groups have pursued their total synthesis, no synthetic route currently exists. A novel strategy proposed here investigates the use of the direct aldol reaction promoted by Trost's new dizinc catalysts. The unique nature of this aldol reaction may make possible the development of a sequential, catalytic, asymmetric aldol reaction. This sequential aldol process would allow for rapid, stereocontrolled assembly of the required C18-C22 triol moiety present in the B-type amphidinolides. Formation of the required 26-member macrolide has represented a formidable challenge for previous investigators. Macrocyclization via ring closing metathesis has emerged as a powerful method to allow access to molecules which otherwise may have remained unattainable. For that reason, it is proposed to form the elusive 26-member macrolide of amphidinolide B1 via ring closing metathesis (RCM).

描述（由申请人提供）： 两栖类药物是一个复杂的大花环的家族，表现出有效和独特的抗肿瘤活性。 B型两栖类醇代表着寻找新的化学治疗剂的有希望的铅。不幸的是，这些化合物（从海洋鞭毛藻中分离出来）仅在微量数量中分离出来。尽管许多群体都追求了他们的总合成，但目前尚无合成路线。这里提出的一种新策略调查了Trost新的Dizinc催化剂促进的直接藻反应的使用。该藻反应的独特性质可能使得有可能发展顺序，催化，不对称的藻反应。这种顺序的醛醇过程将允许B型载二醇中存在的所需C18-C22三元部分所需的C18-C22三元部分的快速立体控制组装。所需的26名成员大花环的形成代表了以前的研究者的巨大挑战。通过环闭合分解的大环化已成为一种强大的方法，可以允许访问分子，否则这些分子可能是无法实现的。因此，提议通过环闭合分解（RCM）形成两栖动物26成员的大花环。