Synthesis of thyroxine: Biomimetic studies

Article abstract of DOI:10.1139/v97-105

The biomimetic oxidative coupling of the ethyl ester of N-acetyl-3,5- diiodotyrosine (1) to yield the ethyl ester of N-acetylthyroxine (2) has been investigated. A putative mechanism involving phenolic coupling to yield an intermediate aryloxydienone (7) followed by an E2 elimination for loss of the side chain has been proposed. Oxidative couplings with analogous 4- substituted 3,5-diiodophenols indicate that a number of mechanisms are possible; these include quinone methide intermediates and S(N)2 substitutions in the intermediate aryloxydienones. Rearomatization of the intermediate aryloxydienones is a strong driving force for the loss of the side chains. The results indicate that 3,5-diiodo-4-aryloxydienones are good leaving groups in E2 and S(N)2 mechanisms. The synthetic method provides a facile synthesis of thyroxine analogues from readily available 4-substituted 3,5- diiodophenols. The biomimetic oxidative coupling of the ethyl ester of N-acetyl-3,5-diiodotyrosine (1) to yield the ethyl ester of N-acetylthyroxine (2) has been investigated. A putative mechanism involving phenolic coupling to yield an intermediate aryloxydienone (7) followed by an E2 elimination for loss of the side chain has been proposed. Oxidative couplings with analogous 4-substituted 3,5-diiodophenols indicate that a number of mechanisms are possible; these include quinone methide intermediates and S_N2 substitutions in the intermediate aryloxydienones. Rearomatization of the intermediate aryloxydienones is a strong driving force for the loss of the side chains. The results indicate that 3,5-diiodo-4-aryloxydienones are good leaving groups in E2 and S_N2 mechanisms. The synthetic method provides a facile synthesis of thyroxine analogues from readily available 4-substituted 3,5-diiodophenols.