NIH-National Institute of General Medical Sciences

Project 4

Organometallic Reactions in Parallel Synthesis

In this project, metal-mediated routes to library synthesis will be developed using several thematically related approaches. In the first, chemoselective transition metal-catalyzed multi-component coupling reactions will be used to construct multifunctional scaffolds, such as α-N-substituted amides, α,β-unsaturated-δ-lactones, and lactams; up to three elements of diversity can be introduced simultaneously during this initial operation. A series of tactical reaction combinations (e.g., intramolecular Diels–Alder reactions or organometallic coupling processes like the Heck reaction) will then be carried out on these main structures. A series of applications of these methods to libraries inspired by the structural cores of bioactive natural products and synthetic heterocycles will follow. In a different project, a recently developed palladium-catalyzed three-component coupling of imines or aldehydes with allenes and boronic acids to afford functionalized lactones and lactams will be investigated. This chemistry will be applied to libraries containing substituted tetrahydropyrans and piperidines related to cytotoxic natural product calyxin L. A second theme involves the conjunction of aromatic/heteroaromatic building blocks with reactants featuring complementary reactive functionalities. These reactions can be viewed as facile annulations able to construct libraries featuring multiple distinct heterocyclic scaffolds in a single step. The application of Pd thin film capillaries to facilitate these reactions will also be explored.

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