The total syntheses of OF4949-El and OF4949-IV are detailed and a study of the unusual effects remote substituents may have on the rate of the key macrocyclization reaction leading to 17-membered cyclic tripeptides incorporating a diary1 ether linked meta-and paracyclophane structural subunit is described. OF4949-I -OF4949-IV (l-4). isodityrosinederived cyclic tripeptides isolated from Penicillium ruguloswnZ and identified in spectroscopic and chemical degradative studies, ' have been shown to exhibit potent aminopeptidase B inhibitory activity, immunopotentiating activity, and confirmed antitumor activity.' Since the agents luck cytotoxic activity but possess confirmed antitumor activity against solid IMC carcinoma and antimetastatic activity against the pulmonary metastases of Lewis lung carcinoma, the agents constitute a new, class of potentially useful antitumor agents that act as immunopotentiators and that may not display host antigenicity or toxicity.' Thus, OF4949-I -OF4949-IV constitute unique additions to a growing class of important biologically active isodityrosinederived' cyclic peptides now including K-13 (s>,&' piperazinomycin ('7),6.* and a series of bicyclic hexapeptide antitumor-antibiotics RA-I-VII (7-14).6> Herein we detail a total synthesis of OF4949-III (1) and OF4949-IV (2) based on our recently disclosed Ulhnann condensation that may be conducted under reaction conditions that permit incorporation of a selectively-protected Hz C&H *'NHAc Fl' R*