Synthetic Methods Involving Decarboxylative Coupling

描述(申请人提供)：许多药物和生物活性天然产物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的、昂贵的或高度碱性的试剂来影响金属有机反应中间体的形成。这项提议的主题是用无处不在的羧酸取代这些不受欢迎的试剂。羧酸衍生物的脱羧基金属化可能允许在温和的条件下形成有用的有机金属中间体，并且只产生无毒的二氧化碳作为副产品。脱羧基金属化法正被应用于更有效地合成中环酮、高烯丙基胺、功能分化的己二烯以及各种重要的生物杂环，包括吡啶、氮杂环和哌啶。我们有强有力的初步数据表明，烯酸酯、乙炔、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催化脱羧基生成。我们建议开发基于脱羧基金属化的合成方法，重点关注活性、范围和对映体选择性。作为合成开发目标的分子类别是根据它们的合成灵活性或在天然产品和/或药物中作为常见基序出现的来选择的。因此，根据这一提议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。

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.