Enantioselective Total Synthesis of Two Aromatized Halicyclamines

The concise and divergent syntheses of the marine alkaloids (+)-tetradehydrohalicyclamine B and (-)-<i>epi</i>-tetradehydrohalicyclamine B are disclosed. Each synthesis requires ten steps and hinges on several key transformations including an enantioselective organocatalyzed Michael addition, a macrocyclic aza-Wittig ligation, and reagent-controlled stereodivergent lactam reductions to assemble their core molecular frameworks. This approach constitutes the first reported asymmetric syntheses of these natural products while importantly enabling the controlled assembly of the <i>trans</i> stereochemical relationship adorning the piperidine ring, a relative configuration that was previously inaccessible. The careful employment of highly oxidized starting materials served as an underpinning of this synthetic strategy, streamlining fragment assembly and alleviating the need for circuitous functional group interconversions or extraneous redox.