Daniel P. O'Malley

Synthesis of 1,9‐Dideoxy‐pre‐axinellamine

Dimeric pyrrole imidazole alkaloids such as the massadines, axinellamines, and palau amines, are marinederived natural products that represent a great opportunity to advance fundamental chemical synthesis (Figure 1). At the heart of their structure is a daunting stereochemical puzzle embedded in a fully substituted cyclopentane framework with spiro-fused and pendant guanidine-containing heterocycles. The extremely high nitrogen content of these molecules tests the limits of chemoselectivity control in synthesis. Their diverse and ornate architectures notwithstanding, the biochemical pathways to these interesting alkaloids may well be intimately related. The existence of such an interrelationship, if unearthed, could potentially simplify an approach to their chemical synthesis. It was recently postulated that all of the members of this natural product family can be traced back to the same hypothetical progenitor: “pre-axinellamine” (4, Figure 1), by varying modes of ring closure. Herein we delineate a simple pathway to arrive at 1,9-dideoxy-pre-axinellamine (5, axinellamine numbering used herein), a reduced form of that key intermediate (i.e. 4), which represents the complete carbogenic skeleton of natural products 1–3. Lessons learned during the total synthesis of simpler dimeric pyrrole-imidazole alkaloids and forays into a purely biomimetic route to 5 led us to target the trihalogenated building block 6. As outlined in Figure 1, this simplified core is pre-programmed with all of the requisite functionality and stereochemistry for elaboration to 5. In essence, construct 6 can be viewed as a minimal foundation for the synthesis of the carbogenic skeleton of 1–4. The experimental validation of this vision is documented in Scheme 1.