Enantioselective Total Syntheses of Methanoquinolizidine-Containing Akuammiline Alkaloids and Related Studies

Abstract

<p class="first" id="P1">The akuammiline alkaloids are a structurally diverse class of bioactive natural products isolated from plants found in various parts of the world. A particularly challenging subset of akuammiline alkaloids are those that contain a methanoquinolizidine core. We describe a synthetic approach to these compounds that has enabled the first total syntheses of (+)-strictamine, (−)-2( <i>S</i>)-cathafoline, (+)-akuammiline, and (−)- <b>Ψ</b>-akuammigine. Our strategy relies on the development of the reductive interrupted Fischer indolization reaction to construct a common pentacyclic intermediate bearing five contiguous stereocenters, in addition to late-stage formation of the methanoquinolizidine framework using a deprotection–cyclization cascade. The total syntheses of (−)- <b>Ψ</b>-akuammigine and (+)-akuammiline mark the first preparations of akuammiline alkaloids containing both a methanoquinolizidine core and vicinal quaternary centers. Lastly, we describe the bioinspired reductive rearrangements of (+)-strictamine and (+)-akuammiline to ultimately provide (−)-10-demethoxyvincorine and a new analogue thereof. </p><p id="P2"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/5c5d20c3-b54f-49b6-90fe-fdb90959c817/PubMedCentral/image/nihms-982936-f0001.jpg"/> </div> </p>