Metal-Catalyzed Reactions for Organic Synthesis

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Linked publications & trials

Abstract

PROJECT SUMMARY This R35 program focuses on developing new synthetic methods for the construction and/or late-stage diversification of biologically active molecules. It encompasses a wide range of transformations across three topical areas – C–H functionalization, decarbonylative coupling, and new routes to fluorinated building blocks – but is unified by two central tenets. First, all of the targeted reactions are synthetically valuable, either because they provide access to unusual chemical space or streamline the synthesis of existing structures. Second, this work is guided by fundamental studies of reaction mechanisms and key organometallic intermediates. These studies are central to driving the design of new catalysts and the development of new transformations. Six projects (two in each topical area) are highlighted in this proposal to showcase how physical organic and organometallic chemistry guide reaction design and problem solving. In the area of C–H functionalization, a first project will leverage the Sanford group's extensive expertise in Pd-catalyzed C–H functionalization to derivatize strained cycloalkane benzene bioisosteres, which are of high interest in drug development. A second project will focus on photocatalytic methods for the C–H pyridination of (hetero)arenes. The emphasis here will be on both developing novel photocatalysts for these transformations and deploying the N-arylpyridinium products as building blocks for a multitude of downstream functionalization reactions. In decarbonylative coupling, a first project will pursue stereospecific couplings of chiral pool carboxylic acids by capitalizing on the stereoretentive CO de-insertion and reductive elimination steps of the catalytic cycle. A second project will deploy decarbonylative methods for the late-stage conversion of carboxylic acids to bioisosteres like tetrazoles and sulfonamides. The ability to swap -CO2H for these analogues in complex molecules will accelerate drug discovery by precluding the need for de novo synthesis of each derivative. Finally, in the area of fluorinated building blocks, a first project will develop a suite of new routes to (hetero)aryl fluorides. These structures are of immense importance in medicinal and radiochemistry, and the proposed reactions will address key limitations of existing synthetic methods. A second project will pursue reagents and catalysts for installing fluorinated sulfur and oxygen groups onto (hetero)arene cores. These substituents are gaining prominence in medical chemistry based on their attractive biological properties. This project will address the myriad of challenges associated with achieving selective metal-catalyzed couplings reactions of these groups.