Synthesis of Antimicrobial Natural Products Targeting FtsZ: (+)-Totarol and Related Totarane Diterpenes

Abstract

An efficient, convergent synthesis of totarol by a diastereoselective epoxide/alkene/arene bicyclization is described. The reported synthesis enables the preparation of related diterpenes totaradiol and totarolone as well as previously unavailable derivatives that exhibit comparable inhibition of the bacterial cell division protein FtsZ.Bacterial cell division is a novel target for the development of new antibiotics to fight infections that are resistant to current therapies.1 FtsZ is the central protein of bacterial cell division that forms the Z-ring at mid-cell and enables septation.2 This GTPase is structurally related to eukaryotic tubulin, which has been successfully targeted as a treatment for cancer. Although tubulin is targeted by many small molecules, and several are in clinical use as drugs, inhibitors of FtsZ are significantly lower in number and in vitro potency. More significantly, three separate allosteric sites of inhibition on tubulin have been identified for taxol, colchicine, and the Vinca alkaloids. Similar knowledge regarding FtsZ is lacking, and no direct evidence for inactivation outside the GTP binding site has been reported.3 Our group is interested in developing efficient syntheses of natural products that target FtsZ with the long-term goal of using synthesis to elucidate the mechanism by which these compounds act on this protein. 4 , 5 Totarol is a diterpene produced in the sap of Podocarpus totara, a conifer native to New Zealand. The wood from the tree is prized for its resistance to rot and the antimicrobial properties of the secondary metabolites in the sap are well-established.6 Totarol is approved for use as an antimicrobial additive in several consumer products, including toothpaste and acne treatments.7 Although several previous studies have probed the origin of totarol's antimicrobial activity,8 FtsZ was only recently identified as a discrete molecular target.9We have undertaken the synthesis of totarol and related diterpenes as part of a broader research program aimed at discerning the mechanism by which FtsZ can be inactivated by shaw@chem.ucdavis.edu. Supporting Information Available Experimental procedures for the preparation of all new compounds. This information is available free of charge via the internet at http://pubs.acs.org. NIH Public Access Author ManuscriptOrg Lett. Author manuscript; available in PMC 2011 August 6. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript small molecules. Previous syntheses of totarol include routes to racemic material10 and semi-syntheses11 from chiral terpenoid precursors. Recent routes to related tricyclic systems have focused on electrophile-induced cyclization of polyene-derived precursors. Efficient syntheses of analogous ticyclic compounds have been reported using enantioselective protonation12 and halogenation13 of alkenes to effect polycyclization reactions. None of these efforts to date has resulted in the synthesis of the related diterpenoids totaradiol and totarolone. As a result, medicin...

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