ARMED DISARMED EFFECTS AND ADAMANTYL EXPANSION OF SOME CAGED TRICYCLIC ACETALS EN-ROUTE TO TETRODOTOXIN

Transformation of the previously prepared tricyclic ketone 4 into an a dvanced intermediate, 2a, of the Kishi-Goto synthesis of tetrodotoxin requires, among other things, cleavage of the internal acetal. In our attempts to carry this out, we were confronted by two major obstacles, one resulting from armed/disarmed effects encountered during acid-cat alyzed acetolyses. Thus ester protecting groups proximal to the acetal moiety inhibited cleavage, e.g., 4 --> 8a and 7 --> 8b. Although the corresponding ether analogs 9a and 9b did undergo acetolysis, the prod ucts obtained, 10a and 10b, respectively, revealed the second obstacle , namely the proclivity of the caged systems to undergo adamantyl expa nsion. The latter result was found to depend upon the presence of prop erly positioned nucleophilic substituents. Thus 11b underwent adamanty l expansion to 12b but its C7 epimer 15 experienced facile cleavage to bicyclic product 16. As an alternative to solvolysis for cleavage of the internal acetal, reductive elimination was examined. For example, compound 28a, obtained from 4 by standard procedures, reacted with zin c to give, after protection and saponification, gamma,delta unsaturate d carboxylic acid 29a, which underwent smooth iodolactonization. Repla cing the iodide of this product with an hydroxyl (32a --> 32b) by a fr ee radical process has succeeded albeit in disappointing yield. Nevert heless the resulting hydroxy lactone is a promising synthon of the adv anced Kishi-Goto intermediate.