Topologically Unique Scaffolds in Photoassisted Diversity Oriented Synthesis (PDO

描述（由申请人提供）：本提案的总体目标是开发一种新的合成方法，其中将高产率的光化学关键反应纳入多样性导向的拆分-合并组合合成。光化学提供了一系列壮观的骨架转化，但它们在高通量合成方法中的利用是微不足道的。 我们的目标是开发一种新的合成方法，用于快速获得由各种官能团和碳/杂环悬垂物装饰的拓扑多样的多环支架，该核心框架刚性或半刚性地保持在独特的空间配置中。快速获得这种拓扑结构多样的支架将通过关键的光化学步骤及其与基态反应的结合来实现，最突出的是最近发现的基于光质子氧化分解的合成序列。 在各种各样的官能团和/或杂环部分内实现明确定义的三维关系是合成药物化学的核心。一个广泛的目标是产生潜在的药效团，通过系统地采样的化学空间与多样化的核心结构增强了一系列的外围功能。从高通量化学的角度来看，该任务只能用一组不同的独特的核心支架来实现，这些支架以独特的3D模式悬挂各种功能性悬垂物。我们的photoprotolytic oxametathesis允许生成拓扑上前所未有的多环缩醛支架，严格显示各种杂环在一个明确的空间排列。关键的分裂和池实施这种合成策略的事实是，photoprotolytic序列提供几乎定量的产量。 公共卫生相关性：由光引发的光化学反应在构建不寻常的分子框架方面具有无与伦比的前景，并为快速获得困难的合成目标提供了途径。然而，除了一些具有里程碑意义的合成外，合成有机光化学仍然没有得到合成有机化学家的充分利用。这对于多样性导向合成（DOS）及其拆分和合并实施尤其如此，这与小分子的高通量合成和新的有前途的治疗剂的发现最相关。我们正在开发新的合成方法，使我们能够迅速获得大量新的药物样分子，这些分子将可用于生物筛选。并非不重要的是，光化学步骤使用光作为试剂，因此可能是环境友好的。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.