SYNTHESIS OF BIOLOGICALLY ACTIVE COMPLEX MOLECULES

生物活性复合分子的合成

• 批准号: 6490185
• 负责人: Matthew D. Shair
• 金额: $ 19.66万
• 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/6490185
• 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.

这份修订后的拨款申请详细说明了我们基于初步发现利用级联反应的计划，在该反应中，乙烯基有机金属与酮的加成引发明显的阴离子氧合重排，随后发生跨环环化反应。这种三步串联反应能够在一次转化中将简单的环状2-乙烯-β-酮酯转化为复杂的多环结构。桥头含烯烃分子、中等大小的环和复杂的稠环体系都可以通过这个反应获得。在这些结果的基础上，我们的具体目标包括：(1)利用立体化学探针阐明这一过程的机理。(2)探索级联序列的通用性及其在桥头含烯烃分子、中等尺寸环和稠环体系合成中的应用。还将探索通过跨环环化反应将中等大小的环系转化为稠合双环结构。(3)级联反应在ras法尼基转移酶抑制剂CP-225,917和CP-263,114全合成中的应用。这些分子目前正在作为肿瘤进展的抑制剂进行测试，一条简洁的合成路线将为生物学评估提供变异体。