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简洁和新颖的复杂化学合成策略至关重要。胍类生物碱石蛤毒素和泽曲霉毒素AB是有效的电压门控钠通道阻滞剂，对合成构成重大挑战。最近的研究已经确定这一通道是治疗多种癌症的潜在靶点。极少量（< 1mg）的zetekitoxin AB（已知最有效的阻滞剂之一）的分离阻碍了进一步的生物学表征。提出了一种通过立体选择性[4+2]环合成蛤蚌毒素和泽曲霉毒素AB的模块化策略。最初的研究将包括制备各种环化反应组分，随后是对环化反应的深入研究。最初的化学反应将在(+)-蛤蚌毒素的背景下进行探讨。该策略的实用性将通过zetekitoxin AB的聚合立体选择性合成来证明。公共卫生相关性：该建议描述了一种合成强效神经毒素zetekitoxin AB的途径。通过开发一种新的化学异环反应，该分子将以聚合方式构建，从而可以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.