Synthetic Methods Involving Decarboxylative Coupling

描述（由申请人提供）：许多药物和具有生物活性的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、昂贵的或高碱性的试剂来通过金属转化影响有机金属反应中间体的形成。这个建议的主题是用无处不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物。脱羧金属化反应被应用于更有效地合成中环和大环酮、同丙烯胺、功能分化的己二烯以及各种重要的生物杂环，包括吡啶、氮杂啶和哌啶。我们有强有力的初步数据表明，烯酸酯、乙酰基、酰胺、烯丙基、a-氨基和稳定的烷基亲核试剂可以通过相应的羧酸催化脱羧生成。我们建议发展基于脱羧金属化的合成方法，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在天然产物和/或药物中的合成灵活性或常见基序来选择的。因此，根据这一建议制定的新策略的适应将最终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.