Synthesis of cycloisodityrosine revisited: A selective ring forming process

An efficient synthesis of cycloisodityrosine was developed based on an intramol. nucleophilic arom. substitution reaction for the selective ring formation of a key biaryl ether intermediate. Cycloetherification of dipeptide I gave exclusively the (meta,para)-cyclophane II (R = OH, R1 = NO2, R2 = Me3CO2C, R3 = H) at the expense of the 15-membered (para,para)-cyclophane III as a result of an enthalpy controlled process. The (meta,para)-cyclophane II (R = OH, R1 = NO2, R2 = Me3CO2C, R3 = H) was easily transformed to N,N'-dimethyl cycloisodityrosine II (R = OMe, R1 = H, R2 = Me, R3 = Me), an important structural subunit of bouvardin and the RA series. [on SciFinder (R)]