Progress toward the total synthesis of brasilicardin A

Brasilicardin A (BraA) is an active metabolite from the fermentation broth of the pathogenic actinomycete Norcardia brasiliensis IFM 0406. Brasilicardin A is a potent immunosuppressive agent (IC50 0.057 mug/mL) comparable in activity to the known immunosuppressant cyclosporin A (IC50 0.15 mug/mL) in a mouse mixed lymphocyte assay. The structurally intriguing molecule consists of a disaccharide moiety, a tricyclic terpenoid core possessing a B ring in a twist boat conformation, and an amino acid sidechain. Based on previous results from our lab, we pursued a facially selective Diels-Alder cycloaddition route to synthesize the C ring. The A and B rings were both derived from the classic starting material, the Wieland-Miescher ketone. During the synthesis of the diene starting material for the Diels-Alder reaction we synthesized a novel vinyl boronate (E)-2-(2-(Phenylmethoxy)etheny1)-4,4,5,5-tetramethy1-1,3,2-dioxaborolane via a highly regio- and stereoselective hydroboration of benzyloxyacetylene. This methodology should be useful for synthesizing 1-alkoxy dienes. A novel ethylene equivalent dienophile, Se-phenyl prop-2-eneselenoate, was discovered and used in the Diels-Alder reaction for the construction of the C ring. The B ring twist boat conformation was imposed using a hydroxyl directed cyclopropanation. A reductive ring opening and anti selective trapping of a lithium enolate installed the last of the five contiguous stereocenters of the terpenoid core. The relative stereochemistry was proven via an x-ray diffraction experiment. These experiments coupled with previous experiments in our lab with the A ring stereochemistry formally provides the seven stereocenters of the core. The experiments described in this thesis outline the most advanced intermediates yet toward the total synthesis of brasilicardin A.