Research is directed toward the laboratory synthesis of the type A streptogramin antibiotics. These compounds include the virginiamycins M1 and M2, griseoviridin, the madumycins, and A 17002 C. These antibiotics are used extensively in agriculture but also have a number of important applications in treating human diseases. The streptogramin A antibiotics act synergistically with the type B streptogramins. Their mode of action is the inhibition of peptide synthesis in prokaryotic cells. Eukaryotic cells are not affected. The laboratory syntheses will be accomplished through use of new methodology for the preparation of (1) 4-carboxy-1,3-oxazoles, (2) functionalized 1,3-dienes, (3) Alpha-carboalkoxy vinyl sulfides, and (4) macrocyclic lactams andmacrolides. In addition, extensive use is made of optically active intermediates derived from sugar derivatives. Most of the new methodology is based upon the use of transition metal reagents. Complexes of palladium, rhodium, molybdenum, and tungsten are included in this work. Many applications of this new methodology beyond the synthesis of the streptogramin antibiotics are described. The final products of the syntheses will be tested for antibacterial activity, ribosomal binding, and other types of biological activity. Emphasis will be placed upon gaining a greater understanding of the mechanism of action of the streptogramin antibiotics at the molecular level. Synthetic analogs will be of major importance in these studies.
