The general goal of this proposal is to develop a new synthetic methodology where high yielding photochemical key reactions are incorporated into a diversity-oriented split-and-pool combinatorial synthesis. Photochemistry offers a range of spectacular skeletal transformations, yet their utilization in high throughput synthetic methods is insignificant.
We aim to develop a new synthetic methodology for rapid access to topologically diverse polycyclic scaffolds decorated by various functional groups and carbo/heterocyclic pendants, rigidly or semi-rigidly held in a unique spatial configuration by this core framework. Expeditious access to such topologically diverse scaffolds will be realized via key photochemical steps and their combination with ground state reactions, most prominently - the recently discovered synthetic sequence based on photoprotolytic oxametathesis. Achieving a well-defined three-dimensional relationship within an assortment of functional groups and/or heterocyclic moieties is central to synthetic medicinal chemistry. A broad objective is to generate potential pharmacophores by systematically sampling the chemical space with diversified core structures augmented with a range of peripheral functionalities. From the high throughput chemistry standpoint this task can only be achieved with a diverse set of distinctive core scaffolds suspending a variety of functional pendants in a unique 3D pattern. Our photoprotolytic oxametathesis allows for the generation of topologically unprecedented polycyclic acetal scaffolds, rigidly displaying a variety of heterocycles in a well-defined spatial arrangement. Critical for the split-and-pool implementation of this synthetic strategy is the fact that the photoprotolytic sequence offers nearly quantitative yields.
Photochemical reactions initiated by light hold unparalleled promise for building unusual molecular frameworks and offer expeditious access to difficult synthetic targets. Yet, with the exception of a few landmark syntheses, synthetic organic photochemistry remains underutilized by synthetic organic chemists. This is especially true for diversity-oriented synthesis (DOS) and its split-and-pool implementation, which are most relevant to high-throughput synthesis of small molecules and discovery of new promising therapeutic agents. We are developing novel synthetic methodologies, enabling us to gain expeditious access to a massive number of new drug-like molecules, which will be available for biological screening. Not unimportant is the fact that photochemical steps use light as a reagent, and therefore could be environmentally friendly.
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