CAREER: Development and Applications of Catalytically Generated Activated Carboxylates

N-杂环卡宾(或杂环叶立德)催化α-官能化醛的分子内氧化还原反应生成活性羧酸盐，适合于在经济和环境友好的反应条件下合成酯、酰胺和其他羧酸衍生物。A-杂原子和a，b-不饱和醛在有机催化剂作用下的这种新型反应性的发现，为手性羧酸衍生物的合成开辟了一系列独特的机理途径，包括抗羟基酯和b-氨基肽。手性杂环盐催化这一新过程的设计和应用将为直接控制伴随着酯化和多肽偶联的绝对立体化学提供一种对映体选择性的方法，并有可能取代传统的多步手性辅助方法。通过开发由a，b-二脱氢氨基醛直接、对映选择性合成酰胺的方法，将出现一种从非手性前体合成多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-碳键形成过程成为可能，包括生成内酯、内酰胺和环戊酮的新环化反应，从而为从稳定、容易获得的起始原料直接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、具有生物活性的a-和b-肽，(2)卡拉芬金类天然抗生素，以及(3)抗耐药细菌菌株的抗生素moiraamine B。在有机和大分子化学项目的这一职业奖项的支持下，加州大学圣巴巴拉分校化学和生物化学系的Jeffrey W.Bode教授正在开发由简单有机分子而不是由金属催化的新反应。这种反应化学不仅提供了很好的化学选择性，而且代表了一种经济、环境友好的(绿色)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，展示了该化学在合成重要产品方面潜在的广泛适用性。他还将邀请UCSB和当地社区大学的本科生参加另一门大二水平的有机实验室课程，旨在让他们接受基于探究和研究的有机化学现实的动手培训。

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.