Total synthesis of (±)-caesalpinnone A and (-)-caesalpinflavan B, progress toward the total synthesis of (+)-alterbrassicicene C and (-)-alterbrassicicene B.

In 2017, caesalpinnone A was isolated alongside three congeners, caesalpinflavans A-C. Caesalpinnone A possesses an unprecedented oxa-bridged ring system and displays modest cytotoxicity against a variety of cancer cell lines including MFC-7. To explore the structural features and the aforementioned bioactivity, a synthesis of these natural products was developed. The latter entails an early stage Barluenga coupling to convergently cross-couple two hindered, functionalized arenes. The derived material was advanced by reduction, protecting group interchange, and a Claisen Schmidt condensation to furnish the remainder of the carbon skeleton. A late-stage allyl deprotection leads to a spontaneous, chemoselective oxa-Michael to complete the synthesis of (±)-caesalpinnone A in 7 steps from known materials.

Alterbrassicicene C and B were isolated alongside a number of family members in 2019 from Alternaria brassicola. The alterbrassicicenes belong to the brassicene family, which is part of the even larger fusicoccane terpenoid family. Several investigations of the fusicoccane family have revealed that numerous members possess remarkable biological activity. Structurally, alterbrassicicene C manifests an unprecedented tetracyclic 5/6/6/5 ring system that features three quaternary centers. In developing an asymmetric synthesis of the alterbrassicicene, we designed a reductive enzymatic desymmetrization that effectively delivers a versatile early intermediate. The route employed to advance this latter intermediate features a lithium-halogen exchange and ring closing metathesis to assemble the 5/8/5 parent scaffold in only 7-steps from known materials. A silver promoted, oxiranium-stabilized rearrangement serves to transfer stereochemistry across the 8- membered ring. While this latter chemistry was employed in efforts to complete alterbrassicicene B, the transannular ethereal bridge this rearrangement produces can also serve as a precursor from which one can initiate an oxa-Michael/retro-oxa-Michael cascade to deliver the alterbrassicicene C oxygen/carbon scaffold.