Marine sponges belonging to the Calcarea family have been studied for some time and have yielded a wide variety of structurally unique secondary metabolites. In particular, these sponges have produced a large number of bioactive alkaloids containing an imidazole heterocycle, typically substituted with two benzylic fragments at various locations around the azole nucleus and at various oxidation states. This review will describe the isolation, structural determination and synthetic studies towards this growing class of natural products.

The first total synthesis of the Leucetta alkaloid calcaridine A is described based on a biosynthetic postulate. Application of an oxidative rearrangement of a 4,5-disubstituted imidazole leads to the formation of both calcaridine A and epi-calcaridine A. An X-ray crystal structure determination on the latter has allowed the assignment of the relative configuration of the epimeric natural product and calcaridine A by extrapolation.2-Aminoimidazole-containing alkaloids isolated from marine sponges have recently captured the attention of a number of synthetic groups, in particular several members of the oroidin family. 1-6 Other families of imidazole-containing alkaloids, including examples isolated from Leucetta sponges, have similarly attracted the attention of several groups. 7-9 Recently Crews and coworkers reported a series of structurally novel natural products 1-4 isolated from a Fijian marine sponge, Leucetta sp., some of which have modest anti-bacterial activity. 10, 11 Some concerns have been raised based on synthetic studies directed towards spiroleucettadine (2) with respect to the accuracy of the assigned structure. 12-14 This structural ambiguity notwithstanding, within each of these compounds a 2-aminoimidazole moiety and two benzyl moieties can be identified, although there are differences in the position of oxidation. There are obvious, if experimentally undefined, biosynthetic relationships between these molecules, and thus an approach to one may provide intermediates that can be used en route to other family members. In both the Crews reports ,11 and in a subsequent report by Watson and co-workers of an approach to the assigned structure of spiroleucettadine (2), 12 it is suggested that calcaridine A (1) and the other congeners 2-4 are derived from rearrangement and/or oxidation chemistry of naamine A 15-17 (14-desmethoxy 6) or a closely related derivative. 10-12 This particular postulate led us to speculate that calcaridine A, at least, is formed by an oxidative rearrangement of an intermediate that we term 14-methoxynaamine A (6). Although 6 appears to be unknown in the literature at the present time, several years ago the N-substituted derivative, 14-methoxynaamidine A (5) was isolated from a Leucetta sp. sponge, and therefore it is tempting to speculate that 6 is a biosynthetic precursor to both (1) and (5). 18 In this communication, we describe the successful execution of a "biomimetically-inspired" approach to (±)-calcaridine A (1) which employs our recently discovered oxidative rearrangement of 4,5-disubstituted imidazoles to the corresponding 4,4-disubstituted-5-imidazolone. 19-21 Although calcaridine A may not be considered a complex and challenging natural product per se, it contains two vicinal stereocenters for which neither the absolute nor the relative lovely@uta.edu. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript stereochemistry were reported (our synthetic studies have led to the assignment of the relative stereochemistry). In...

Short total syntheses of the Leucetta-derived alkaloids, kealiinines A-C, have been accomplished using an intramolecular Friedel-Crafts-dehydration sequence of a bis benzylic diol. The precursor diol was obtained through a series of position specific Grignard reactions from 1-methyl-4,5-diiodoimidazole. C2-Azidation and hydrogenation of the azide then provided the reported structures of kealiinines A-C. While the 1H NMR data did not completely match for these materials, the HPLC data were consistent with the assigned structure of these materials.

An investigation of the utility of N-sulfonyloxaziridines to effect the oxidative rearrangement of tetrahydrobenzimidazoles to spiro fused 5-imidazolones is reported. In addition to the anticipated rearrangement manifold, it was found that 2-amino substituted derivatives afford products resulting from rearrangement, or alternatively from addition of methanol or water depending on the nature of the N-substituents and reaction conditions.

Simple total syntheses of two Leucetta-derived marine alkaloids have been developed using position specific halogen-metal exchange of polyhaloimidazoles to introduce the benzyl substituted sidechains. Introduction of the C2 amine group by lithiation and trapping with tosyl azide provides amines on catalytic hydrogenation, which can be converted to naamidine G and 14-methoxynaamidine G using a procedure described in the literature.2-Aminoimidazole alkaloids have recently attracted the attention of the synthetic community, in particular several members of the oroidin family of alkaloids.