Synthetic Methods Involving Decarboxylative Coupling

涉及脱羧偶联的合成方法

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/7316362
• 关键词: Alkanes; Alkylation; Amides; Amination; Amines; Area; Azetidines; Benign; Biological Factors; Carbamates; Carbon; Carbon Dioxide; Carboxylic Acids; Chemistry; Class; Complex; Condition; Coupling; Data; Decarboxylation; Development; Facility Construction Funding Category; Foundations; Future; Generations; Ketones; Metals; Methods; Mind; Object Attachment; Pharmacologic Substance; Pliability; Publishing; Reaction; Reagent; Research; Research Personnel; Route; Scheme; Series; Standards of Weights and Measures; Therapeutic; Work; animation; azetidine; base; carbanion; carboxylate; desire; driving force; drug synthesis; enolate; human disease; innovation; novel therapeutics; piperidine; programs; pyridine; small molecule

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以通过金属转移作用实现有机金属反应中间体的形成。该提案的主题是用普遍存在的羧酸取代这些不受欢迎的试剂。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CO2作为副产物。脱羧金属化正被应用于更有效地合成中环和大环酮，高烯丙基胺，功能分化的己二烯，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反应生成。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。已根据其合成灵活性或作为天然产物和/或药物中常见基序的出现选择了合成开发的目标分子类别。因此，由于该提议而开发的新策略的适应性将最终有助于产生治疗人类疾病的新型治疗试剂。