CAREER: Development and Applications of Catalytically Generated Activated Carboxylates

职业：催化生成的活化羧酸盐的开发和应用

• 批准号: 0934261
• 负责人: Jeffrey Bode
• 金额: $ 14.58万
• 依托单位: University of Pennsylvania
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0934261&HistoricalAwards=false
• 关键词: CAREER; Development; Applications; Catalytically; Generated

Intramolecular redox reactions of a-functionalized aldehydes mediated by N-heterocyclic carbenes (or heterocyclic ylides) lead to the catalytic generation of activated carboxylates, suitable for the synthesis of esters, amides, and other carboxylic acid derivatives under economical and environmentally friendly reaction conditions. The discovery of this novel reactivity, mediated by an organic catalyst, of a-heteroatomic and a,b-unsaturated aldehydes opens a broad range of mechanistically unique pathways for the synthesis of chiral carboxylic acid derivatives, including anti-b-hydroxyesters and b-amino peptides. The design and application of chiral heterocyclic salts for catalyzing this novel process will provide an enantioselective method for directly controlling the absolute stereochemistry concomitant with esterifications and peptide couplings, and has the potential to supplant traditional multi-step chiral auxiliary based methodologies. By developing means of effecting the direct, enantioselective synthesis of amides from a,b-didehydroamino aldehydes, a waste-free, atom-economical approach to the synthesis of poly-a-amino-peptides from achiral precursors will emerge. The unique reactivities of unsaturated aldehydes under these catalytic conditions will enable novel carbon-carbon bond forming processes, including new annulation reactions affording lactones, lactams, and cyclopentanones, thereby providing a long-sought method for the direct, intermolecular synthesis of hetero- and carbocycles from stable, readily available starting materials. Applications of these new reactions include the synthesis of (1) short, biologically active a- and b-peptides, (2) the kalafungin class of naturally occurring antibiotics, and (3) the antibiotic moiramide B, which is active against drug resistant bacterial strains.With the support of this CAREER award from the Organic and Macromolecular Chemistry Program, Professor Jeffrey W. Bode, of the Department of Chemistry and Biochemistry at the University of California, Santa Barbara, is developing new reactions catalyzed by simple organic molecules rather than by metals. This reaction chemistry not only offers promise of great chemical selectivity, but also represents an economical, environmentally friendly ("green") approach to organic synthesis, eliminating the use of potentially hazardous metals and greatly reducing waste generation. Professor Bode will exploit the newly discovered reaction chemistry for the synthesis of a variety of products, including biologically active polypeptides and antibiotics, demonstrating the potentially broad applicability of this chemistry in the synthesis of important products. He will also engage undergraduate students, both at UCSB and from local community colleges, in an alternative sophomore level organic laboratory course aimed at exposing them to hands-on training in the realities of inquiry and research based organic chemistry.

由N-杂环卡宾（或杂环叶立德）介导的α-官能化醛的分子内氧化还原反应可催化生成活化的羧酸盐，适合在经济且环境友好的反应条件下合成酯、酰胺和其他羧酸衍生物。这种由有机催化剂介导的a-杂原子和a,b-不饱和醛的新颖反应性的发现，为合成手性羧酸衍生物（包括抗b-羟基酯和b-氨基肽）开辟了广泛的机械独特途径。用于催化这一新过程的手性杂环盐的设计和应用将为直接控制酯化和肽偶联的绝对立体化学提供对映选择性方法，并有可能取代传统的多步骤手性辅助方法。通过开发从α,b-二脱氢氨基醛直接、对映选择性合成酰胺的方法，将出现一种从非手性前体合成聚-α-氨基肽的无废物、原子经济的方法。不饱和醛在这些催化条件下的独特反应活性将实现新型碳-碳键形成过程，包括产生内酯、内酰胺和环戊酮的新环化反应，从而为从稳定、易于获得的起始材料直接分子间合成杂环和碳环提供了一种长期寻求的方法。这些新反应的应用包括合成 (1) 短的生物活性 a 肽和 b 肽，(2) 天然存在的抗生素 kalafungin 类，以及 (3) 对耐药细菌菌株具有活性的抗生素 moiramide B。 在有机和高分子化学项目的职业奖的支持下，化学系的 Jeffrey W. Bode 教授 加州大学圣塔芭芭拉分校的生物化学系正在开发由简单有机分子而不是金属催化的新反应。这种反应化学不仅提供了良好的化学选择性，而且代表了一种经济、环保（“绿色”）的有机合成方法，消除了潜在危险金属的使用并大大减少了废物的产生。博德教授将利用新发现的反应化学来合成各种产品，包括生物活性多肽和抗生素，展示这种化学在重要产品合成中的潜在广泛适用性。他还将让加州大学圣巴巴拉分校和当地社区学院的本科生参加另一门二年级有机实验室课程，旨在让他们接受基于有机化学的探究和研究现实的实践培训。