Divergent Synthesis of and Structurally Related Monoterpenoid Indole Alkaloids: A Non-biomimetic Strategy.

ConspectusMonoterpenoid indole alkaloids constitute one of the largest natural product families, with over 3000 members reported to date. , a genus of about 30 species, is notable for its rich alkaloid diversity. These plants produce unique monoterpenoid indole alkaloids with intriguing structures and bioactive properties, making them a key focus in synthetic chemistry research over the years. Between 2015 and 2022, a new class of compounds belonging to the genus was isolated, including arboridinine, arborisidine, arboduridine, and arbornamine. Interestingly, a structurally related alkaloid named alstrostine G, which resembles the pentacyclic system of arbornamine, was isolated from in 2017. These five alkaloids feature complex polycyclic skeletons and dense stereocenters, drawing significant attention from the synthesis community upon their isolation. Biogenetically, these four alkaloids are derived from subincanadine E containing a medium-sized ring, which undergoes distinct pathways to yield the four alkaloids with distinct frameworks. Alstrostine G was proposed to be derived from stemmadenine, which resembles subincanadine E. Enzymes enable their biosynthesis with precise regio-, stereo-, and enantioselectivity. From a laboratory synthesis perspective, however, mimicking this biosynthetic pathway without the help of enzymes can be quite challenging. These facts suggest the need to devise an alternative synthetic strategy for the divergent synthesis of this class of monoterpenoid indole alkaloids. Besides our work, about nine impressive total syntheses or synthetic studies have been reported by seven research groups. However, prior studies mainly focused on an individual natural product, such as arboridinine, arborisidine, arbornamine, or alstratine A. Our group has achieved the collective total synthesis of all five alkaloids by a divergent and non-biomimetic strategy.In this Account, we summarize our recent endeavors on the divergent total synthesis of these five monoterpenoid indole alkaloids via a non-biomimetic strategy. In-depth structural analysis of the five alkaloids revealed their hidden topological connection. We consequently classified them into two categories: (1) arboridinine, arborisidine, and arboduridine with caged frameworks, which share a common tricyclic A/B/D ring system, and (2) arbornamine and alstrostine G, which feature a 1,1-disubstituted tetrahydro-β-carboline (THBC) core. For the first category, we initially reported a divergent racemic synthesis of skeletally distinct arboridinine and arborisidine. This strategy features a Michael and Mannich cascade process to efficiently assemble the common tricyclic A/B/D ring core, followed by site-selective late-stage diversification to access the unique tetracyclic frameworks of arboridinine and arborisidine. Subsequently, we constructed the enantioenriched tricyclic A/B/D ring system via an enantioselective Michael reaction of oxindole followed by intramolecular nucleophilic addition, enabling the first asymmetric total synthesis of arboduridine. For the second category, we developed a highly effective enantioselective monobenzoylation of 1,3-diols to construct the 1,1-disubstituted THBC core. This chemistry was successfully applied to the divergent asymmetric total synthesis of alstrostine G and arbornamine, which also features a cascade Heck/hemiamination reaction forging the pivotal pentacyclic core with high efficiency.