A concise synthesis of (-)-aplyviolene facilitated by a strategic tertiary radical conjugate addition.

TLDR: This work reports the first total synthesis of aplyviolene, and undesirable aspects of this first-generation synthesis are the lengthy preparation of the cis-perhydroazulene unit and the need to remove the extraneous ketone carbonyl group from the product of the fragment-coupling step.

Abstract: Aplyviolene (1) and macfarlandin E (2, Figure 1A) are representative of the more complex members of the rearranged spongian diterpene class of natural products.[1,2] These diterpenes are structurally defined by attached cis-perhydroazulene and 6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one fragments. The substantial challenge in assembling these structures centers on the construction of the sensitive bicyclic lactone subunit and the formation of the C8–C14 σ-bond joining the two ring systems, a challenge augmented by the quaternary nature of C8.[3] We previously reported preparation of the lactone subunits of 1 and 2 by the synthesis of truncated congeners 3 and 4 (Figure 1A),[4] as well as the first total synthesis of aplyviolene (outlined in Figure 1B).[5] In this latter effort, the key C8–C14 σ-bond was formed by Michael addition of tertiary enolate 5 to enone 6.[6] Subsequent elaboration of product 7 provided intermediate 8, which was converted to (−)-aplyviolene along the lines of our earlier synthesis of 3. Undesirable aspects of this first-generation synthesis are the lengthy preparation of the cis-perhydroazulene unit and the need to remove the extraneous ketone carbonyl group from the product of the fragment-coupling step.