174741-86-7Relevant academic research and scientific papers
Armed/disarmed effects and adamantyl expansion of some caged tricyclic acetals en route to tetrodotoxin
Burgey, Christopher S.,Vollerthun, Roland,Fraser-Reid, Bert
, p. 1609 - 1618 (2007/10/03)
Transformation of the previously prepared tricyclic ketone 4 into an advanced 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-catalyzed 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 products obtained, 10a and 10b, respectively, revealed the second obstacle, namely the proclivity of the caged systems to undergo adamantyl expansion. The latter result was found to depend upon the presence of properly positioned nucleophilic substituents. Thus 11b underwent adamantyl 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 zinc to give, after protection and saponification, γ,δ unsaturated carboxylic acid 29a, which underwent smooth iodolactonization. Replacing the iodide of this product with an hydroxyl (32a → 32b) by a free radical process has succeeded albeit in disappointing yield. Nevertheless the resulting hydroxy lactone is a promising synthon of the advanced Kishi-Goto intermediate.
