ABSTRACT
Platensilin, platensimycin, and platencin are potent inhibitors of ß-ketoacyl-acyl carrier protein synthase (FabF) in the bacterial and mammalian fatty acid synthesis system, presenting promising drug leads for both antibacterial and antidiabetic therapies. Herein, a bioinspired skeleton reconstruction approach is reported, which enables the unified synthesis of these three natural FabF inhibitors and their skeletally diverse analogs, all stemming from a common ent-pimarane core. The synthesis features a diastereoselective biocatalytic reduction and an intermolecular Diels-Alder reaction to prepare the common ent-pimarane core. From this intermediate, stereoselective Mn-catalyzed hydrogen atom-transfer hydrogenation and subsequent Cu-catalyzed carbenoid C-H insertion afford platensilin. Furthermore, the intramolecular Diels-Alder reaction succeeded by regioselective ring opening of the newly formed cyclopropane enables the construction of the bicyclo[3.2.1]-octane and bicyclo[2.2.2]-octane ring systems of platensimycin and platencin, respectively. This skeletal reconstruction approach of the ent-pimarane core facilitates the preparation of analogs bearing different polycyclic scaffolds. Among these analogs, the previously unexplored cyclopropyl analog 47 exhibits improved antibacterial activity (MIC80 = 0.0625 µg/mL) against S. aureus compared to platensimycin.
Subject(s)
Adamantane , Aminobenzoates , Aminophenols , Anilides , Polycyclic Compounds , Aminophenols/chemistry , Aminophenols/pharmacology , Aminophenols/chemical synthesis , Polycyclic Compounds/chemistry , Polycyclic Compounds/pharmacology , Polycyclic Compounds/chemical synthesis , Adamantane/chemistry , Adamantane/pharmacology , Adamantane/chemical synthesis , Adamantane/analogs & derivatives , Anilides/pharmacology , Anilides/chemistry , Anilides/chemical synthesis , Aminobenzoates/pharmacology , Aminobenzoates/chemistry , Aminobenzoates/chemical synthesis , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Staphylococcus aureus/drug effects , Molecular Structure , Cycloaddition Reaction , Microbial Sensitivity Tests , Stereoisomerism , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistryABSTRACT
An enantioselective synthetic approach for preparing manginoids and guignardones, two types of biogenetically related meroterpenoids, is reported. This bioinspired and divergent synthesis employs an oxidative 1,3-dicarbonyl radical-initiated cyclization and cyclodehydration of the common precursor to forge the central ring of the manginoids and guignardones, respectively, at a late stage. Key synthetic steps include silica-gel-promoted semipinacol rearrangement to form the 6-oxabicyclo[3.2.1]octane skeleton and the Suzuki-Miyaura reaction of vinyl bromide to achieve fragment coupling. This synthesis protocol enables the asymmetric syntheses of four fungal meroterpenoids from commercially available materials.