Abstract
Monoterpene alkaloids encompass distinct chemical diversity and wide-ranging bioactivity. Their compact complexity has made them popular as synthetic targets and has inspired many distinct strategies and tactics in the field of heterocyclic chemistry. This article documents the evolution of a synthetic program aimed at accessing the unusual sulfonamide-containing natural product altemicidin, which was generally believed to be a monoterpene alkaloid throughout our entire synthetic investigations but has recently been found to originate through an unexpected and quite disparate biosynthetic pathway. By leveraging a pyridine dearomatization/cycloaddition strategy, we developed a concise pathway to the 5,6-fused bicyclic azaindane core and, after significant experimentation, an ultimate synthesis of altemicidin itself. Tactics to productively manipulate the multiple functional groups present on this highly polar scaffold proved challenging but were eventually realized via several carefully orchestrated and chemoselective transformations-investments that paid dividends in the form of significantly shorter chemical synthesis. Surprisingly, the bond-forming logic between our presumed abiotic synthetic strategy to this alkaloid class and its subsequently identified biosynthetic pathway is eerily similar.