Synthetic Methods Involving Decarboxylative Coupling

涉及脱羧偶联的合成方法

基本信息

批准号：
7316362
负责人：
Jon A Tunge
金额：
$ 25.73万
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品的合成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，昂贵或高基本的试剂来通过跨金属实现有机反应中间体的形成。该提案的主题是用无处不在的羧酸代替这些不良试剂。羧酸衍生物的脱羧金属可能会在轻度条件下形成有用的有机金属中间体，并仅产生无毒的二氧化碳作为副产品。脱羧金属化被应用于中型和大环酮，均匀胺，功能分化的六边形以及包括吡啶，偶氮胺和哌啶在内的各种生物学上重要的杂环的更有效合成。我们有强大的初步数据，这些数据表明，可以通过相应的羧酸盐的催化脱羧化来产生烯烃，乙酰胺，酰胺，烯丙基，A-氨基和稳定的烷基亲核试剂。我们建议开发基于脱羧金属的合成方法，重点是活动，范围和对映选择性。根据天然产物和/或药物的共同基序，选择了用于合成发展的分子类别的类别。因此，由于该提案而制定的新策略的适应最终将有助于产生新的治疗方法来治疗人类疾病。