Total Synthesis of Ganoapplanin Enabled by a Radical Addition/Aldol Reaction Cascade

Abstract

The total synthesis of the Ganoderma meroterpenoid ganoapplanin, an inhibitor of T-type voltage-gated calcium channels, is reported. Our synthetic approach is based on the convergent coupling of a readily available aromatic polyketide scaffold with a bicyclic terpenoid fragment. The three contiguous stereocenters of the terpenoid fragment, two of which are quaternary, were constructed by a diastereoselective, titanium-mediated iodolactonization. For the fusion of the two fragments and to simultaneously install the crucial biaryl bond, we devised a highly effective two-component coupling strategy. This event involves an intramolecular 6-exo-trig radical addition of a quinone monoacetal followed by an intermolecular aldol reaction. A strategic late-stage oxidation sequence allowed the selective installation of the remaining oxygen functionalities and the introduction of the characteristic spiro bisacetal structure of ganoapplanin.

Figure 1

Selected structures of Ganoderma meroterpenoids and their classification.

Scheme 1. (A) Proposed Biosynthesis of Ganoapplanin (7) and (B) Retrosynthetic Disconnections

Scheme 2. (A) Synthesis of Aldehyde 14 and a (B) Radical 1,4-Addition/Aldol Sequence

Scheme 3. Late-Stage Oxidations and Completion of the Synthesis of Ganoapplanin