Electrolytic Macrocyclizations :S calable Synthesis of aD iazonamide- Based Drug Developmen tC andidate**

An electrochemical method to synthesize the core macrolactam of diazonamides is described. Large ring-form- ing dehydrogenation is initiated by anodic oxidation at ag raphite surface .T he reaction requires no tailoring of the substrate and occurs at ambient temperature in aqueous DMF in an undivided cell open to air .T his unique chemistry has enabled ac oncise ,s calable preparation of DZ-2384 ;a refined analog of diazonamid eAs lated for clinical development as ac ancer therapeutic. I ti sn ot uncommon to observe internal cross-links between electron-rich aromatic side chains in peptide-derived natural products .T hese bonds rigidify structure and often improve pharmacological properties .P roducts of net dehydrogenation are frequently encountered, wherein C¢ Cb onding occurs at the expense of two aryl C¢ Hb onds .E xamples include oxygenated biphenyls (1) derived from tyrosine oxidations and bis-indoles resultant from tryptophan oxidations. (2) Some time ago we began studying as tructure that contains al inkage hybrid of the above two ;n amely diazonamide A( 1 , Figure 1), (3) wherein at yrosine residue has internally bonded to an adjacent tryptophan. Th e3 -linked o-phenolic 3H-indole in that case exists as its aminal tautomer ;g iving ac ore motif that was unknown at the time it was first described in diazonamides. (4) Structure 1 drew intense interest from the synthetic community and methods were forged to prepare the natural product. (5-7) Assembling the core of the molecule was ap articular challenge. (7 ,8 ) Among solutions to the problem, ours was an attempt to parallel biosynthesis .W ef ound that PhI(OAc)2 would mediate the conversion of peptidyl deriv- ative 2 (Figure 2, R = o-NO2PhSO2 )t oi someric aminals 3a and 4a . (5c) Th ed irectness of the construction was valuable, particularly as our interest in the pharmacology of diazon- amides increased. (9) Numerous congeners of the natural product were prepared and those molecules fueled early in vivo experiments. (10) As rodent models made clear that