One of a number of intriguing new alkaloids isolated from the Leucetta sp. sponge in 2004, spiroleucettadine displayed unique structural features on a restricted scaffold: a trans-fused 5,5-bicyclic ring system together with an amino hemiketal moiety. Attempts to synthesize the initially proposed structure failed, raising questions as to its veracity, and structure revision ensued in 2008; no successful synthetic approach has been reported to date. Herein, we describe the enantiospecific total synthesis of (-)-spiroleucettadine by a highly efficient biomimetic approach starting from l-tyrosine. One of two key hypervalent-iodine-mediated oxidation reactions forged the spirocyclic center, and the other enabled the installation of the methylamine side chain in the penultimate step. Our approach provides synthetic access to a new class of spiroannulated natural products and will enable future studies of the structure-biological-activity relationships of these antibacterial compounds.

The interesting history of (–)-spiroleucettadine, a marine natural product, is discussed along with some of our original unsuccessful synthetic strategies. Finally, we briefly discuss our reported enantiospecific synthesis of spiroleucettadine, and how we plan to use this as a platform for further studies around this interesting class of molecules.

Various strategies toward the synthesis of the marine natural product (-)-spiroleucettadine are described. In the original strategy, a biomimetic inspired oxidation of a 2-imidazoline scaffold uncovered unexpected reactivity, where benzylic oxidation followed by a Baeyer-Villiger reaction was observed. The second generation approach examined oxidative dearomatization of the phenol ring system first, where a competing spirocyclization process was uncovered. Efforts to forge the scaffold via a carbocation mediated benzyl migration were unsuccessful. Highlights of the successful synthesis include two consecutive hypervalent iodine reactions: the first formed the spirocyclic center and the second facilitated installation of an acetate group at the C-5 position to allow for subsequent introduction of the methyl amine side chain.

The synthesis of anithiactin A has been achieved in four steps. Several closely related analogues were synthesised and their biological activity against colon and breast cancer cell lines evaluated. Anithiactin A was found not to be cytotoxic even at a high concentration (100 μM); however, two 4-substituted phenyl thiazoles were found to be moderately cytotoxic at 10 μM. Based on these results, 4-substitution on the phenyl group appears to be critical for cytotoxicity. However, the exact electronic and structural requirements are unclear.

One of anumber of intriguing new alkaloids isolated from the Leucetta sp.s ponge in 2004, spiroleucettadine displayed unique structural features on ar estricted scaffold: at rans-fused 5,5-bicyclic ring system together with an amino hemiketal moiety.Attempts to synthesize the initially proposed structure failed, raising questions as to its veracity,a nd structure revision ensued in 2008;n os uccessful synthetic approach has been reported to date.H erein, we describe the enantiospecific total synthesis of (À)-spiroleucettadine by ah ighly efficient biomimetic approach starting from l-tyrosine.O ne of two key hypervalent-iodine-mediated oxidation reactions forged the spirocyclic center,a nd the other enabled the installation of the methylamine side chain in the penultimate step.O ur approach provides synthetic access to anew class of spiroannulated natural products and will enable future studies of the structure-biological-activity relationships of these antibacterial compounds. Conflict of interestTheauthors declare no conflict of interest.