Selective Halogenation Reactions for the Synthesis of Chiral Bioactive Small Molecules

 描述(申请人提供)：本建议的目标是开发新的选择性化学方法，以实现选择性二卤化、卤代官能化和二卤化物衍生化反应，这些反应可用于合成复杂的、具有生物活性的小分子。近2,000种含有氯或溴的立体合成中心的化合物已经被表征，虽然在迫切的医疗需求领域(如抗癌、抗生素)显示了生物活性，但由于来自自然来源的不可靠供应以及缺乏系统的手性有机卤素合成的选择性方法，对生物活性的治疗潜力和物理基础的进一步研究一直受到阻碍。初步研究结果表明，金属路易斯酸、亲电卤化剂和配体的模块组合能够在各种含醇的烯烃底物上选择性地进行二溴、溴氯化、二氯化和卤醚化反应。本研究的第一个目标是将这一策略充分发展到催化剂控制的化学、区域、非对映和对映选择性重卤化和卤代官能化反应。这项研究的第二个目的是将这一策略扩展到合成卤代生物活性小分子。这项研究的第三个目标是确定允许通过立体定向碳-杂原子和碳-碳键形成反应对浓缩的二卤化物进行衍生化以选择性合成生物活性小分子的条件。这一贡献意义重大，因为它将使许多班级能够选择性地准备 用于进一步生物学评价的手性卤代化合物和非卤代化合物。创新源于开发一种通用的、可调的方法学平台，以实现多种类别的手性卤化小分子的可预测和选择性制备。

 DESCRIPTION (provided by applicant): The goal of this proposal is to develop new selective chemical methods for achieving selective dihalogenation, halofunctionalization, and dihalide derivatization reactions that can be used for the synthesis of complex, biologically active small molecules. Nearly 2,000 compounds containing either a chlorine- or bromine-bearing stereogenic center have been characterized, and while biological activity has been demonstrated in areas of pressing medical need (e.g. anticancer, antibiotic), further investigation into the therapeutic potential and physical basis for bioactivity has been hindered by an unreliable supply from natural sources as well as by a lack of selective methods for systematic chiral organohalogen synthesis. Preliminary findings indicate that the modular combination of metal Lewis acid, electrophilic halogenating agent, and ligand is capable of effecting selective dibromination, bromochlorination, dichlorination, and haloetherification on a variety of alcohol-containing alkene substrates. The first aim of this research is the full development of this strategy to catalyst-controlled chemo-, regio-, diastereo-, and enantioselective dihalogenation and halofunctionalization reactions. The second aim of this research is the extension of this strategy for the synthesis of halogenated bioactive small molecules. The third aim of this research involves identifying conditions that will allow for the derivatization of enriched dihalides for the selective synthesis of bioactive small molecules through stereospecific carbon-heteroatom and carbon-carbon bond-forming reactions. This contribution is significant because it will enable the selective preparation of numerous classes of chiral halogenated and non-halogenated compounds for further biological evaluation. Innovation stems from developing a general, tunable, methodological platform to enable the predictable and selective preparation of numerous classes of chiral halogenated small molecules.