Ljubisa Jovanovic

• Neolignans, dehydrodimers of phenylpropenes, are natural products that exhibit different biological activities. 8,5’-Neolignans containing a trans- dihydrobenzofuran skeleton are the most abundant neolignans in nature. The published syntheses of trans-dihydrobenzofurans are multistep procedures that are time consuming and provide the product in low yield. Furthermore, all dimerisation reactions either in the presence of enzymes or mediated by metal salts are yielding dimers consisting of two units of the same phenylpropene compound, narrowing substantially the substitution pattern. Two different general synthetic approaches were examined. The first strategy was the enantioselective deprotonation at the α-carbon of the ο-alkyl phenols in the presence of a chiral diamine and sBuLi. Synthesis of several new phosphorous-based directed ortho-metalation groups was studied. The examined compounds having these new groups decomposed even under very mild reaction conditions and are not suitable for the application in the synthesis. The secondNeolignans, dehydrodimers of phenylpropenes, are natural products that exhibit different biological activities. 8,5’-Neolignans containing a trans- dihydrobenzofuran skeleton are the most abundant neolignans in nature. The published syntheses of trans-dihydrobenzofurans are multistep procedures that are time consuming and provide the product in low yield. Furthermore, all dimerisation reactions either in the presence of enzymes or mediated by metal salts are yielding dimers consisting of two units of the same phenylpropene compound, narrowing substantially the substitution pattern. Two different general synthetic approaches were examined. The first strategy was the enantioselective deprotonation at the α-carbon of the ο-alkyl phenols in the presence of a chiral diamine and sBuLi. Synthesis of several new phosphorous-based directed ortho-metalation groups was studied. The examined compounds having these new groups decomposed even under very mild reaction conditions and are not suitable for the application in the synthesis. The second strategy was to examine one [3+2] cycloaddition reaction, transition metal catalysed Heck oxyarylation reaction, in the synthetic approach to compounds having trans-dihydrobenzofuran skeleton. Palladium catalysed Heck oxyarylation reaction with halogenophenols or ortho-diazonium phenols as the starting material allowed the trans-dihydrobenzofuran compounds as the major products in acceptable yield and in one step. The products were formed under ligand free condition, as well as in the presence of some strong coordinating ligands (Ph3P). The experiments with several chiral ligands, showed that the obtained trans-dihydrobenzofurans were racemic mixtures. This result suggests formation of an achiral intermediate along the reaction pathway, which causes the lack of stereoselectivity in the products. Initially formed trans-dihydrobenzofuran compounds are the key precursors of many naturally occurring neolignans, and can be easily converted to 8,5’-neolignan derivatives.…
• 8,5’-Neolignane sind Naturstoffe die verschiedene biologische Aktivitäten ausüben. 8,5’-Neolignane mit Dihydrobenzofuran-Kernstruktur haben antioxidative Wirkung und sind als ACAT- und PAF-Inhibitoren bekannt. Zwar gibt es einige stereoselektive Synthesen von 8,5’-Neolignanen, diese sind aber kompliziert und/oder lassen nur ein eingeschränktes Substitutionsmuster zu. In der vorliegenden Dissertation wurden zwei neue Synthesewege, nämlich die Palladium-katalysierte Cycloaddition von o-Halogenphenolen und Phenylpropenen, und die α-Alkylierung, präsentiert. Diese Synthesewege führen diastereoselektiv, in ein bis drei Schritten, zu trans-Dihydrobenzofuranen, den gewünschten, potentiell bioaktiven Zielverbindungen. Ferner wurde gezeigt, dass sich ausdiesen Verbindungen verschiedene 8,5’-Neolignane schnell und einfach herstellen lassen.