EPC-Synthesen der Cochleamycine und der Macquarimicine

Research project P 14608 EPC-Syntheses of Cochleamycins and of Macquarimicins Edda GÖSSINGER 08.05.2000 The increasing resistance of bacterial pathogens and tumor cells necessitates the development of new and efficient drugs. Total synthesis can play an important role in defining the chemistry of such drugs. Therefore we have chosen the recently discovered structurally unique antibiotics cochleamycins and macquarimicins, which have not been synthesized sofar as synthetic targets. These penta-respectively hexacyclic polyketide macrolides are active against Gram positive and Gram negative bacteria as well as against tumor cells. Due to their unusual structures crossresistance with known antibiotica, is unlikely. The unusual structures of these antibiotics require a highly flexible synthetic plan due to the incomplete knowledge of steric and stereoelectronic effects in very complex compounds. Therefore we have decided on convergent syntheses, which permit to synthesize two substructures independently. In preliminary experiments the construction of the two subunits were established. Further improvements and variants are demonstrated. To assemble the two chiral subunits we have devised several pathways. Within the most short and therefore most preferable of these synthetic routes the ß-ketolactone derivative and the hydrindane system are connected either by Knoevenagel condensation or by substitution. Consequently the double cyclization is achieved either by radical tandem reaction or by selenium reagent mediated tandem cyclization to the hexacyclic antibiotics of the cochleamycin/macquarimicin type. Due to our faulty knowledge of steric and stereoelectronic effects we have devised alternative stepwise cyclizations. The stepwise ionic cyclization offers the advantage that the construction of the pentacyclic antibiotics is feasible too. In this case our attention is focussed on the cyclization to the ten membered ring, because construction of medium sized rings is still a partially unsolved problem in organic chemistry. For this reason we have looked for a further synthetic route, where the cyclization to the ten membered ring proceeds along a pathway referring to the last steps in the hypothetical biosynthesis of the pentacyclic antibiotics. Here too the same chiral hydrindane derivative as in all previous synthetic routes can be utilized. However matching the biosynthetic pathway the synthesis is now a linear one. We also plan to investigate the conversion of the thus obtained pentacyclic antibiotics to the hexacyclic antibiotics as provided for by the biosynthetic pathway.