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.
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.
