Enantioselective Total Synthesis of (−)-Novofumigatonin

We disclose the first and enantioselective synthesis of novofumigatonin, an ortholactone meroterpenoid natural product featuring an unprecedented 7/6/5/6/5/5 hexacyclic skeleton. On a strategic level, this was addressed by a highly convergent strategy that hinges on coupling of a complex neopentylic organolithium reagent and a highly hindered ketone. A unique approach to the ortholactone–acetal was required as it is not peripheral but embedded within the complex carbocyclic framework. This key challenge was addressed by orchestration of a condensation cascade triggered by the selective generation of an oxocarbenium ion. Tempering reactivity in the face of the densely functionalized skeleton proved key and culminated in the total synthesis of novofumigatonin. Of note, this represents the first study on the construction of such an embedded ortholactone, potentially useful for preparation of such motifs in the context of complex molecule synthesis.