Approaches to heterocyclic rich anti-microbial natural products

About This Grant

Abstract Natural products continue to provide inspiration for the development of small molecules (new chemical entities) for use in medicine. Nitrogen heterocycles are found in many FDA-approved drugs and therefore are considered privileged structures. Thus, the investigation of natural products containing nitrogen heterocycles appears to provide high synergy and a high likelihood of discovering new and useful bioactive molecules. This proposal is divided into three aims, each of which involves the construction and elaboration of nitrogen containing heterocycles. Aim 1 is directed towards the total synthesis of ceratinadin B, a member of the bromotyrosine- derived natural product family. Isolated through bioactivity-guided fractionation, this molecules possess activity as an inhibitor of mycothiol S-conjugate amidase a part of the biosynthetic pathway for the assembly of mycothiol. Inhibition of mycothiol biosynthetic enzymes may be useful in anti-tubercular therapy. Ceratinadin B contains two distinct structural domains, a relatively common chiral spiro isoxazoline and an unusual imidazolyl-quinolone fragment for which no synthetic studies have been reported. A general solution for the asymmetric construction of the spirocylic fragment is proposed based on a Wacker inspired Pd/Cu-co- catalyzed dearomatizing spirocyclization reaction to assemble the spiro isoxazoline. It is proposed to use de novo construction of the bis heterocycle through a novel variant of the Gould-Jacobs reaction to assemble the 3-hydroxyquinolone and a classical Hantzsch-like synthesis of the aminoimidazole. Preliminary studies suggest that this sequence of events is feasible. Condensation of the two heterocyclic building blocks will afford ceratinadin B. The synthetic natural product and advanced precursors will be evaluated as anti-tuberucular agents in cellular assays (M. smegmatis/M. marinum) through collaborators. Aim 2 seeks to investigate a recently discovered tandem reaction sequence that generates quite complex polycyclic azacycles from readily available building blocks. The optimization, scope, and limitations of this sequence as well of the evaluation of post-cyclization transformation. Potential application to the total synthesis of “-izidine natura; products are outlined. Aim 3 focuses on the development of an asymmetric total synthesis of terrazoanthines A-B which were recently isolated from an Ecuadorian invertebrate. It is planned to employ a desymmetrizing α-fuctionalization of a 4- substituted cyclohexanone to permit the asymmetric annulation of the guanidine moiety through a Hantzsch azole synthesis.