A Unified Synthetic Strategy toward Hexahydrofuro[3,2- b ]benzofuranone Natural Products: Total Syntheses of (−)-Trichodermaketone A, the Reported Structure of (−)-Trichodermaketone B, and (−)-Trichodermaketone E from D-Mannose

Abstract We report herein a unified strategy for the total syntheses of three bioactive polyketides from Trichoderma fungus: (−)-trichodermaketone A, the reported structure of (−)-trichodermaketone B, and (−)-trichodermaketone E. These molecules showcase a unique hexahydrofuro[3,2-b]benzofuranone (5/5/6 tricyclic) core structure bearing four contiguous stereocenters around the A-ring and either a C(2)- or C(4)-stereocenter with a hydroxyl group in the C-ring. To date, no syntheses of these compounds or their framework have been previously reported. The hexahydrofuro[3,2-b]benzofuranone framework and the four A-ring stereocenters were assembled in one convergent step from an enantiospecific interrupted Garcia Gonzalez reaction between 1,3-cyclohexadione and an alkyl sugar derivative derived from D-mannose. The central hexahydrofuro[3,2-b]benzofuranone precursor enabled chemodivergent access to the target molecules. C(2)-acetoxylation and global deprotection afforded (−)-trichodermaketone E and its C(2)-epimer in 10 steps. Alternatively, C(4)-deprotonation, γ-hydroxylation, and deprotection provided (−)-trichodermaketone A in 10 steps. C(4)-hydroxylation using SeO2 generated (−)-trichodermaketone A and its epimer, initially assigned as (−)-trichodermaketone B. Comparison of spectroscopic data with reported values revealed that the published stereochemical configuration of trichodermaketone B is incorrect. Overall, this report represents the first example of the use of the Garcia Gonzalez reaction for complex natural product synthesis.