Annulation Strategies Toward the Total Synthesis of Saxitoxin and Zetekitoxin AB

描述（由申请人提供）：新反应技术的发明对于开发用于复杂化学合成的简洁和新颖的策略至关重要。胍生物碱石房蛤毒素和泽特克毒素AB是有效的电压门控钠通道阻滞剂，提出了重大的合成挑战。最近的研究已经确定该通道是治疗多种癌症的潜在靶点。最少量（<1 mg）zetekitoxin AB（已知最有效的阻断剂之一）的分离阻碍了进一步的生物学表征。提出了一种立体选择性[4+2]-环化合成石房蛤毒素和zetekitoxin AB的模块化策略。最初的研究将涉及各种成环反应组分的制备，随后集中于成环反应的深入研究。将在（+）-石房蛤毒素的背景下探索初始化学。开发的战略的效用，然后将证明通过收敛的立体选择性合成zetekitoxin AB。公共卫生相关性：该提案描述了一种有效神经毒素zetekitoxin AB的合成途径。通过开发一种新的化学杂环化反应，该分子将以收敛的方式构建，从而可以随时制备用于生物测试的类似物。获得这种分子将进一步研究钠离子通道，并可能导致治疗癌症的新疗法。

DESCRIPTION (provided by applicant): The invention of new reaction technologies is vital to enable the development of concise and novel strategies for complex chemical synthesis. Guanidinium alkaloids saxitoxin and zetekitoxin AB are potent voltage-gated sodium channel blockers that pose significant synthetic challenges. Recent studies have identified this channel a potential target in the treatment of a variety of cancers. Isolation of a minimal quantity (<1 mg) of zetekitoxin AB, one of the most potent blockers known, has hampered further biological characterization. A modular strategy for the synthesis of saxitoxin and zetekitoxin AB via a stereoselective [4+2]-annulation is proposed. Initial studies will involve the preparation of various annulation reaction components, followed by intense investigation focused on the annulation reaction. The initial chemistry will be explored in the context of the (+)-saxitoxin. The utility of the strategy developed will then be demonstrated by a convergent stereoselective synthesis of zetekitoxin AB. PUBLIC HEALTH RELEVANCE: This proposal describes a synthetic route to the potent neurotoxin zetekitoxin AB. By developing a new chemical heteroannulation reaction, this molecule will be constructed in a convergent fashion, allowing the ready preparation of analogues for biological testing. Access to this molecule will further research on the sodium ion channel and potentially lead to new therapeutics for the treatment of cancer.