Structure Revision of Hexacyclinol / Total Synthesis pt. III: Synthesis
Porco, Su, Lei, Bardhan and Rychnovsky. ACIEE, 2006, Early View. DOI: 10.1002/anie.200602854.
So the dust has settled – and it looks like Rychnovsky was right. But lets disregard the controversy for now, and look at the synthesis. John Porco’s approach to this reassigned structure bears relations to his work on the similar natural product, panepophenanthrin.
This work hinges on the fact that both targets are actually dimeric; however, in the case of Hexacyclinol, a further cyclisation has occured to deliver the product. Thus, they created the monomer in four steps from the literature, and noticed spontaneous cyclisation immediately, using TREAT-HF to perform the deprotection of the TES group. This funky reagent is Et3N.3HF, and is apparently a far safer fluorinating agent than the more common HF.py.
So with the monomer in hand, they left it sitting around neat for 3 days, and acheived a 87% yield of dimer (my kind of reaction). The final cyclisation was promoted by K-10 clay, acting as a Lewis acid, delivering hexacyclinol in 99%. Nice! And in far fewer steps than La Clair’s “synthesis”…
For more about TREAT-HF, have a look here.