Electrolytic Macrocyclizations: Scalable Synthesis of a Diazonamide‐Based Drug Development Candidate

Abstract

An electrochemical method to synthesize the core macrolactam of diazonamides is described. Large ring-forming 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 aconcise,scalable preparation of DZ-2384;arefined analog of diazonamideAs lated for clinical development as ac ancer therapeutic.

Synthetic Organic Electrochemical Methods Since 2000: On the Verge of a Renaissance

“…300 Nucleophilic attack of the phenol onto the indolyl radical cation elicited a macrocyclization, furnishing DZ-2384, a diazonamide analog of therapeutic potential against various types of cancers. Notably, the reaction has been reliably performed above 60 g scale on a similar substrate, attesting the utility of anodic arene oxidation.…”

Recent Advances in the Electrochemical Synthesis and Functionalization of Indole Derivatives

“…It is worthy of note that Harran and co‐workers in the early 2015 developed an electrochemical macrocyclization protocol for the concise, scalable preparation of DZ‐2384 138 , a refined analogue of diazonamide A slated for clinical development as a cancer therapeutic (Scheme ) . Mechanistically distinct from the macrocyclization using the chemical oxidant PhI(OAc) 2 , this electrochemical transformation was initiated by oxidation at the indole moiety of 137 rather than at the phenol, thus the formation of spirocyclohexadienone by‐products frequently observed under chemical conditions was circumvented.…”

External oxidant-free electrooxidative [3 + 2] annulation between phenol and indole derivatives

“…In analogous to the natural bias, the oxidative [3 + 2] annulation between phenols and indoles usually gives benzofuro[2,3-b]indolines. Over the past decade, different reaction protocols for the synthesis of benzofuro[2,3-b]indoline moiety have been developed by Harran 37 , 40 , Danishefsky 41 , Vincent 42 , 43 , and others 44 – 46 . In contrast, attempts on phenol–indoles coupling for the synthesis of benzofuro[3,2-b]indolines have rarely succeeded 47 .…”