CAREER: Development and Applications of Catalytically Generated Activated Carboxylates

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导致催化生成活性羧酸酯，其适用于在经济和环境友好的反应条件下合成酯、酰胺和其它羧酸衍生物。这种新的反应性的发现，由有机催化剂介导的，α-杂原子和α，β-不饱和醛打开了广泛的机械独特的途径，用于合成手性羧酸衍生物，包括抗-β-羟基酯和β-氨基肽。手性杂环盐的设计和应用为催化这一新的过程提供了一种直接控制伴随着异构化和肽偶联的绝对立体化学的对映选择性方法，并有可能取代传统的基于多步手性助剂的方法。通过开发从a，b-二脱氢氨基醛直接对映选择性合成酰胺的方法，将出现从非手性前体合成聚-a-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性将使新的碳-碳键形成方法成为可能，包括提供内酯、内酰胺和环戊酮的新的成环反应，从而提供了一种长期寻求的从稳定的、容易获得的起始材料直接分子间合成杂环和碳环的方法。这些新反应的应用包括合成（1）短的、具有生物活性的a-和b-肽，（2）卡拉芬净类天然存在的抗生素，和（3）抗生素moiramide B，其对耐药性细菌菌株具有活性。位于圣巴巴拉的加州大学化学和生物化学系的博德正在开发由简单有机分子而非金属催化的新反应。这种反应化学不仅提供了很大的化学选择性，而且代表了一种经济、环境友好（“绿色”）的有机合成方法，消除了潜在危险金属的使用，大大减少了废物的产生。Bode教授将利用新发现的反应化学合成各种产品，包括生物活性多肽和抗生素，证明这种化学在重要产品合成中的潜在广泛适用性。他还将从事本科生，无论是在UCSB和当地社区学院，在另一个大二水平的有机实验室课程，旨在让他们接触到实践训练的调查和研究为基础的有机化学的现实。

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.