SYNTHESIS OF BIOLOGICALLY ACTIVE COMPLEX MOLECULES

生物活性复合分子的合成

• 批准号: 6693389
• 负责人: Matthew D. Shair
• 金额: $ 20.84万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-01 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6693389
• 关键词: alkenes; alkyltransferase; antineoplastics; chemical addition; chemical synthesis; cyclization; enzyme inhibitors; ketones; organometallic compounds; stereochemistry

This revised grant application details our plans to utilize, based upon preliminary findings, a cascade reaction in which a vinyl organometallic addition to a ketone initiates an apparent anionic oxy-Cope rearrangement followed by a transannular cyclization. This three step tandem reaction is capable of converting simple cyclic 2-vinyl-beta-ketoesters to complex polycyclic structures in a single transformation. Bridgehead olefin-containing molecules, medium-size rings, and complex fused ring systems are all accessible using this reaction. On the basis of these results, our specific aims involve: (1) Elucidation of the mechanism of this process using stereochemical probes. (2) Studies to explore the generality of the cascade sequence with applications to the synthesis of bridgehead olefin- containing molecules, medium-size rings, and fused ring systems. The conversion of the medium-size ring systems to fused bicyclic structures via transannular cyclizations will also be explored. (3) Application of the cascade reaction to the total synthesis of the ras farnesyltransferase inhibitors CP-225,917 and CP-263,114. These molecules are currently undergoing testing as inhibitors of tumor progression and a concise synthetic route will provide access to variants for biological evaluation.

这项修订的赠款应用程序详细介绍了我们根据初步发现的计划，这是一种级联反应，其中乙烯基有机金属添加酮启动了明显的阴离子氧化氧化剂重排，然后进行了跨自环化。 这三个步骤的串联反应能够将简单的循环2-乙烯基 - 贝特酮酮转换为单个转换中的复杂多环状结构。 使用此反应，可以访问含纤维烯烃的分子，中型环和复杂的融合环系统。 根据这些结果，我们的具体目的涉及：（1）使用立体化学探针阐明该过程的机制。 （2）研究探索级联序列的通用性，并应用于含有桥头烯烃烯烃的合成，含有分子，中型环和融合环系统。还将探索中型环系统通过跨媒体自动化的融合双环结构的转化。 （3）将级联反应应用于RAS Farneyltransferase抑制剂CP-225,917和CP-263,114的总合成。这些分子目前正在接受测试，因为肿瘤进展的抑制剂，简洁的合成途径将为生物学评估提供访问。

项目成果

Dynamic kinetic resolution during a cascade reaction on substrates with chiral all-carbon quaternary centers.

• DOI: 10.1002/anie.200462039
• 发表时间: 2005-04
• 期刊: Angewandte Chemie
• 作者: K. Xu;G. Lalic;S. Sheehan;M. Shair