Synthetic Methods Involving Decarboxylative Coupling

涉及脱羧偶联的合成方法

基本信息

批准号：
7884260
负责人：
Jon A Tunge
金额：
$ 25.66万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2012-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Many syntheses of drugs and biologically active natural products utilize catalytic cross-coupling reactions as a key step. Cross-coupling reactions often require toxic, expensive, or highly basic reagents to effect formation of organometallic reaction intermediates via transmetalation. The theme of this proposal is the replacement of these undesirable reagents with ubiquitous carboxylic acids. Decarboxylative metalation of carboxylic acid derivatives potentially allows formation of useful organometallic intermediates under mild conditions and produces only non-toxic CO2 as a byproduct. Decarboxylative metalation is being applied to more efficient syntheses of medium- and large-ring ketones, homoallylic amines, functionally differentiated hexadienes, and various biologically important heterocycles including pyridines, azetidines, and piperidines. We have strong preliminary data that demonstrates that enolate, acetylide, amide, allyl, a-amino, and stabilized alkyl nucleophiles can be generated by catalytic decarboxylation of the corresponding carboxylates. We propose to develop synthetic methods based on decarboxylative metalation with a focus on activity, scope, and enantioselectivity. The classes of molecules being targeted for synthetic development have been chosen based on their synthetic flexibility or occurrence as common motifs in natural products and/or Pharmaceuticals. Thus, adaptation of the new strategies developed as a result of this proposal will ultimately contribute to the generation of novel therapeutic reagents to treat human disease.

描述（由申请人提供）：许多药物和生物活性天然产物的合成都利用催化交叉偶联反应作为关键步骤。交叉偶联反应通常需要有毒、昂贵或强碱性试剂来通过金属转移形成有机金属反应中间体。该提案的主题是用普遍存在的羧酸取代这些不需要的试剂。羧酸衍生物的脱羧金属化可能允许在温和条件下形成有用的有机金属中间体，并且仅产生无毒的二氧化碳作为副产物。脱羧金属化被应用于更有效地合成中环和大环酮、高烯丙基胺、功能差异化己二烯以及各种生物学上重要的杂环，包括吡啶、氮杂环丁烷和哌啶。我们有强有力的初步数据表明，烯醇化物、乙炔化物、酰胺、烯丙基、α-氨基和稳定的烷基亲核试剂可以通过相应的羧酸盐的催化脱羧来生成。我们建议开发基于脱羧金属化的合成方法，重点关注活性、范围和对映选择性。用于合成开发的分子类别是根据其合成灵活性或作为天然产物和/或药物中常见主题的出现而选择的。因此，根据该提案开发的新策略的适应最终将有助于产生治疗人类疾病的新型治疗试剂。