Marine alkaloids containing 2-aminoamidazoles provide targets of opportunity for not only the development of novel synthetic chemistry, but also for the generation of novel therapeutic agents or biological probes. In this effort, we have chosen to focus on several related natural products from the oroidin family of sponge metabolites that range in complexity and provide a forum to develop new synthetic methods and strategies. Specifically, we propose to develop synthetic approaches to several of anti-bacterial alkaloids known as the nagelamides. Our strategy is centered on the elaboration of simple imidazoles, specifically the functionalization of 4,5-diiodoimidazole derivatives, which provides a straightforward approach for the construction of useful imidazole-containing building blocks. In the first Specific Aim we propose to develop total syntheses of two closely related oroidin dimers, nagelamide B, and C through a fragment coupling strategy. Specifically, we will employ the sequential and position selective elaboration of 4,5-diiodoimidazoles with Grignard reagents to prepare two functionalized vinylimidazoles, which will be coupled to provide the basic frameworks of the target nagelamides. Preliminary studies from our lab have demonstrated the general feasibility of the approach. In the second Specific Aim we propose to complete the total syntheses of nagelamide R and T. These oroidin dimers are unique within the pyrrole-imidazole family as they are the only reported examples to contain an oxazoline moiety. To approach these molecules, we plan on investigating a tandem palladium-catalyzed oxy-arylation reaction to construct the oxazoline heterocycle and incorporate the second imidazole moiety. In the third Specific Aim we propose to examine a 6?-electrocyclization reaction of 4,5-divinylimidazoles to construct the tetrahydrobenzimidazole skeleton found in several oroidin-derived natural products. We plan on utilizing this chemistry to perform total syntheses of ageliferin and nagelamide E using nagelamide C as a precursor. Samples prepared in the course of this investigation will be offered to programs run by the NIH (NCI-DTP and MLSCN) to determine the bioactivities of synthetic natural products and advanced synthetic intermediates.
Compounds derived from marine sponges typically possess a broad range of biological activities, in the present cases the compounds of interest exhibit anti-bacterial activity. In addition, they frequently demand the development of new synthetic methods and strategies for their assembly. The work described in this proposal aims to define and develop methods to provide synthetic access to reasonable quantities of several of these naturally occurring materials originally found in Agelas sp. marine sponges. Once obtained, the biological activity of these materials will be evaluated through NIH-sponsored programs.
| Herath, Apsara K; Bhandari, Manoj R; Gout, Delphine et al. (2017) Thio acid-mediated conversion of azides to amides - exploratory studies en route to oroidin alkaloids. Tetrahedron Lett 58:3913-3918 |
| Ray, Abhisek; Mukherjee, Sabuj; Das, Jayanta et al. (2015) Preparation and Diels-Alder reactions of 1'-heterosubsituted vinylimidazoles. Tetrahedron Lett 56:3518-3522 |
| Sivappa, Rasapalli; Mukherjee, Sabuj; Dias, H V Rasika et al. (2009) Studies toward the total synthesis of the oroidin dimers. Org Biomol Chem 7:3215-8 |
