Enantiomerenreine Synthesen von Antibiotika der Nargenicingruppe

The increasing resistance of bacterial pathogens against antibiotics necessitates new antibiotics. Synthesis of antibiotics plays an important role in defining their chemistry and improving their activity. As synthetic targets we have chosen a group of recently isolated antibiotics with new and complex structures, activity against resistant bacteria and oral applicability. After preparing the substructures of our first target, nodusmicin, combining the substructures to the ten membered lactone, the most difficult part of our convergent synthesis, was intended. The knowledge gained by these synthetic efforts were used for syntheses of structurally related antibiotics. Towards an EPC Synthesis of Nodusmicin Two strategies were chosen to look for the most effective sequence to combine the enantiomerically pure substructures. The attachment of the propionic ester was afforded by oxymercuration yielding the oxygen bridged cis-decalin which was added to acrylic ester. The attack from the less hindered convex face required epimerization, which failed. Thus attachment to the concave face was secured by intramolecular cyclization with a shortened side chain. Radical as well as polar cyclization were successful and sequential elongation of the side chain has been achieved. Two variants led to the successful construction of the sterically hindered trisubstituted double bond with a slightly simplified model. Transfer of these methods to the fully substituted cis-decalin derivative failed. Reckoning with smaller sterical hindrance, the attachment of the highly substituted pentyl side chain was placed prior to fragmentation. Thus the fragmentation reaction has been improved. Attempts to optimize the addition reaction are under way. Synthesis of the Decalin Subunit of Coloradocin The cis-decalin subunit of coloradocin, the structurally most complex antibiotic of the nargenicin antibiotics, was synthesized starting with an intermediate of our synthetic attempts towards nodusmicin. After transforming the functionalities of this tetracyclic ß-diketal reductive cleavage with SmI2 led to a tricyclic diketone. Selective partial reduction was followed by acidic fragmentation to the desired cis-decalin derivative. The very mild conditions of this fragmentation led us to examine a synthetic variant that should allow easy connection with other subunits of the projected convergent EPC-synthesis of coloradocin. Synthesis of the Hydrinden Part of the Cochleamycins and the Macquarimicins Cycloaddition of 5,5-dimethoxy-1,2,3,4-tetrachlorocyclopentadiene to cyclopent-2-enone yielded the common intermediate of both syntheses. To continue the synthesis of the cochleamycins stereoselective methylation was followed by selective reduction of the ketone. Then treatment with sodium in ethanol led to the tetracyclic compound which was fragmented to hydrindanone carboxylic acid. Transformation of the functionalities led to the hydrindene derivative of the cochleamycins. To gain the respective hydrindene derivative of the macquarimicins the common intermediate was transformed by Claisen condensation with formate ester and hydrogenation led to the epimeric methylated ketone. After forming the respective tetracycle and fragmentation to the hydrindanone carboxylic acid transforming the functionalities completed the synthesis. The enantiomerically pure common intermediate of both syntheses was afforded by photochemical conversion of cyclopentadiene to cyclopent-2-en- 1,4-diol. The corresponding diacetate was partially saponified by Lipase catalysis. Protection of the hydroxy group was followed by cycloaddition to 5,5-dimethoxy-1,2,3,4-tetrachlorocyclopentadiene. Functionality transform led to the enantiomerically pure common intermediate of both syntheses. Thus formal EPC-syntheses of both hydrindene derivatives were achieved.