Target-Oriented Synthesis of the Prostacyclin Derivative Beraprost
Final Report Abstract
The described research project is centered around the synthetic investigations of prostanoids especially the construction of the tricyclic backbone of beraprost as well as the synthetic investigations towards the synthesis of other prostanoids. The construction of the tricyclic core starts with the literature known synthesis of the enal published by Aggarwal and co-workers starting from 1,5-dimethoxytetrahydrofurane, which is hydrolyzed to the relatively unstable succinaldehyde, which can undergo a domino-aldol reaction under catalysis of L-proline and dibenzylammonium trifluoroacetate. For a better understanding of the process, as well as for the establishment of reproducible results, NMR studies has been investigated. After optimisation of the process the reaction can be carried out giving reproducible results and also the overall costs of the process was minimized due to cheaper purification materials. After elimination of the hemiacetal to the enolether it was possible to construct this tricyclic backbone via an inverse-demand Diels-Alder reaction with subsequent decarboxylation. Aromatisation of the received enolether to the aromatic ring did not give any desired product so far. Furthermore, the synthesized methyl acetal was used in a Heck reaction with a vinyl bromide in moderate yields. Subsequent decarbonylation with a Palladium source instead of Rhodium based catalysts gave the decarbonylated compound, which will further investigated in the synthesis of PGA2, a prostaglandin. Another possible synthetic target using the methyl acetal as starting point is thromboxane B2, which belongs to the class of thromboxanes. Also the ketone has been synthesized within the funded period to start investigations for the selective Baeyer-Villiger oxidation in presence of the double bond.
