Divergent Total Synthesis of the Harziane Diterpenoids

The harziane family of diterpenoid natural products possesses a stereochemically dense 6/5/7/4 tetracyclic framework that is structurally distinct among secondary metabolites. Indeed, members contain up to six contiguous stereocenters, three all-carbon quaternary centers, and an array of differential oxidation patterns across the nearly 50 members that have been isolated since the inaugural member was first reported in 1992. Herein we report a concise strategy, guided both by quaternary center analysis as well as common intermediate logic, that has led to the synthesis of three family members with distinctive stereochemical and oxidation patterns as well as the proposed structure of a fourth; all were accessed in just 1-3 steps from that common, late-stage intermediate, and three of these structures have been prepared for the first time. Four other natural products were obtained formally from that same material. Key operations include (1) a Au(I)-catalyzed cycloisomerization reaction to forge their unique bicyclo[5.2.0]nonane framework, (2) a strategic semi-Pinacol ring contraction that sets the stage for formation of the final ring system, and (3) a suite of late-stage site- and chemo-selective redox reactions using synthetic handles on two different halves of the molecule that, when properly orchestrated, smoothly complete the targets.