We propose the first enantioselective total synthesis of brasilicardin A, a potent cytotoxic and immunosuppressive agent recently isolated from the fermentation broth of the pathogenic antinomycete Nocardia brasiliensis. Brasilicardin A displayed potent cytotoxicity against a number of cell lines and produced a pattern of differential cytotoxicity in an NCI human tumor screen unlike any known antitumor compound, suggesting a novel mode of action. However, further biological evaluation is hindered by poor bioavailability (15 L of fermentation broth provide only 3.6 mg of brasilicardin A). Total synthesis is thus required for further biological testing. Toward our goal of total synthesis, we propose three methods for the construction of the rare anti/syn/anti- perhydrophenanthrene core of the molecule, two of which represent novel enantioselective methodologies amenable to construction of thermodynamically disfavored trans-fused bicyclic compounds containing an angular methyl group. Additionally, we outline a strategy for generating combinatorial brasilicardin libraries by utilizing the developing field of combinatorial oligosaccharide synthesis. Our endeavor promises to deliver sufficient quantities of brasilicardin A to allow further biological evaluation and, in connection with the proposed combinatorial approach to the disaccharide moiety, possibly identify novel compounds with increased potential for the treatment of human cancers.
| Siu, Tony; Cox, Christopher D; Danishefsky, Samuel J (2003) Total synthesis of lactonamycinone. Angew Chem Int Ed Engl 42:5629-34 |
| Cox, C; Danishefsky, S J (2001) Concise synthesis of a lactonamycin model system by diastereoselective dihydroxylation of a highly functionalized naphthoquinone. Org Lett 3:2899-902 |
| Cox, C; Danishefsky, S J (2000) Synthesis of the functionalized tricyclic core of lactonamycin by oxidative dearomatization. Org Lett 2:3493-6 |
