Reaction Design for the Synthesis of Neuroactive Agents

描述（由申请人提供）：该提案是由对作为神经化学物质显示选择性活性的含氮化合物的化学的总体兴趣指导的。胍毒素，河豚毒素和石房蛤毒素，代表两个这样的目标，每个具有独特的分子结构和显着的效力，以阻止离子通过电压门控Na+通道。因此，这两种化合物都是神经生理学和离子通道研究中的宝贵工具。随着天然产物的标记和类似物结构的获得，对这些大的（260-280 kDa）和复杂的跨膜通道蛋白的结构和机制的询问将大大推进。然而，毒素或其变体的合成特别具有挑战性，因为这些分子内官能团的精细和密集定位。因此，已经设计了新的化学策略来帮助减少与合成这种类型的结构相关的困难。通过金属催化的C-H插入将饱和C-H键选择性转化为甲醇胺中心的方法是我们的方法的基础。胺官能团在天然产物和药物中的普遍存在使得这种化学广泛适用于学术和工业研究中遇到的问题。胺化反应可以用任何数量的具有仲、叔、烯丙基、苄基C-H键的起始材料进行，并且可以用于从简单的醇前体构建1，2-氨基醇或1，3-双官能化胺衍生物。此外，该方法是立体特异性的，从而能够从具有光学限定的叔中心的底物组装对映体纯的四取代的胺基。插入产物可以通过选择性亲核加成反应来操纵无数的胺衍生物。对于我们的目的，这些类型的反应将加快河豚毒素和石房蛤毒素以及选择毒素类似物的制备。这些化合物将用于研究Na+通道的分子工作，重点是了解通道孔的离子选择性区域。总的来说，这些研究受到离子通道蛋白在细胞中电信号传递的重要作用及其作为治疗中枢神经系统相关疾病的靶点的广泛认可的重要性的刺激。

DESCRIPTION (provided by applicant): This proposal is guided by an overarching interest in the chemistry of nitrogen-containing compounds that display selective activity as neurochemicals. The guanidinum toxins, tetrodotoxin and saxitoxin, represent two such targets, each having a unique molecular architecture and remarkable potency to block ion passage through voltage-gated Na+ channels. Accordingly, both compounds have been invaluable tools in neurophysiology and ion channel research. Efforts to interrogate the structure and mechanism of these large (260-280 kDa) and complex transmembrane channel proteins would be advanced greatly with access to labeled and analogue structures of the natural products. Synthesis of either toxin, or variants thereof, is made particularly challenging, however, because of the elaborate and dense positioning of functional groups within these molecules. Thus, new chemical strategies have been devised to help reduce the difficulties associated with synthesizing structures of this type. Methodology for the selective conversion of saturated C-H bonds to carbinolamine centers through metal-catalyzed C-H insertion underlies our approach. The prevalence of amine functional groups in natural products and pharmaceuticals makes this chemistry broadly applicable to problems encountered in both academic and industrial research. The amination reaction can be performed with any number of starting materials possessing secondary, tertiary, allylic, benzylic C-H bonds, and may be used to construct 1,2-amino alcohols or 1,3-difunctionalized amine derivatives from simple alcohol precursors. In addition, the process is stereospecific, thereby enabling the assembly of enantiopure tetrasubstituted amine groups from substrates possessing optically defined tertiary centers. Insertion products can be manipulated through selective nucleophilic addition reactions to myriad amine derivatives. For our purposes, these types of reactions will expedite the preparation of tetrodotoxin and saxitoxin as well as select toxin analogues. Such compounds will be used to examine the molecular workings of the Na+ channel with a focus on understanding the ion selectivity region of the channel pore. Collectively, these studies are stimulated by the essential role of ion channel proteins for electrical signaling in cells and their widely recognized importance as targets for treating central nervous system-related disorders.