AVERMECTIN, TETRODOTOXIN, & RADICAL-ALDEHYDE CYCLIZATION

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Section E of this research proposal describes a variety of experiments designed to gain a better understanding of radical-aldehyde cyclization. Results, summarized in the Preliminary Work, reveal a curious mixture of successes and failures that show clearly that the early successes we reported were fortuitous. Nevertheless, using these successes as models, we have incorporated radical cyclization process into several reactions in Sections F, G, and H where syntheses of three different compounds are proposed. Mechanistic investigations are proposed to help us discover the factors that govern success or failure. Section F is concerned with various aspects of the chemistry of avermectin, a compound whose importance arises from its use as anti- helmenthic agent in livestock and from its potential for human clinical use. A new synthesis of the northern half is proposed based on the novel development in the chemistry of 2,3-unsaturated hexothiopyranosides. With respect to the southern half, our recent work shows that C4-exocyclic olefins are ideal precursors in that they allow coupling of the northern and southern halves, either via the eastern lactone or western diene, without compromising the delicate C2 sterocenter. This strategy also permits ready modification of the avermectin skeleton, since the 3,4-double bond can be "parked" outside during the processes. Therefore, structure activity studies will be facilitated. Phyllanthocin, whose synthesis is proposed in Section G, is an anti- tumor spiroacetal. Several syntheses of this compound have been reported, but they all begin with the cyclohexane residue as the anchor, and then proceed to elaborate the furanoid ring. We plan to reverse this approach by beginning with a furanose sugar and using the radical cyclization approach for establishing the cyclohexane ring. This will give the compound in optically active form, and the strategy is designed to explore the utility of the radical cyclization. A major new undertaking in Section H is the synthesis of tetrodotoxin. This substance displays unique biological activity in that it is specific for the identification and use of sodium ion channels in nerve tissue. However, current availability relies almost exclusively on isolation form the puffer fish. Only one synthesis of the compound, in racemic form, has been achieved. Our work is designed to provide the molecule in optically active form, and to facilitate our design we plan to exploit the chemistry developed in the reported synthesis at late stages. The early stages of our synthesis uses some novel chemistry of 1,6-anhydro sugars in order to lay the structural framework for assembling the condensed skeleton of tetrodotoxin.