A New Approach to the Synthesis of Piperazinomycin and Bouvardin: Facile Access to Cycloisodityrosine <i>via</i> an Intramolecular S_NAr Reaction

Abstract

A new method for the synthesis of cycloisodityrosine atropisomers I (R1 = CO2Me, R2 = NHBoc), a 14-membered m,p-cyclophane, is reported. The synthesis hinged on an efficient macrocyclization procedure for biaryl ether formation based on an intramol. SNAr reaction. The cyclization conditions are much milder and the yield is much higher than those previously reported. Moreover, the presence of the NO2 function in I provides an opportunity to introduce not only the hydroxyl group found in natural products but also others such as amino acid amide for bioactivity evaluation. 3-Fluoro-4-nitrophenylalanine II was prepd. by alkylation of a chiral bislactim ether with 3-fluoro-4-nitrobenzyl bromide; secondary amine III resulting from the double alkylation was isolated as a minor product and characterized. A mechanism was proposed for its formation. [on SciFinder (R)]