Total Synthesis of the Resveratrol-based Oligomer Family

This Erwin-Schrödinger-Auslandsstipendium research proposal aims for the first total synthesis of the most complex members of the resveratrol-based oligomer family in a generalized way. These secondary metabolites are prepared by Nature through uncontrolled oligomerization of the simple stilbenoid resveratrol and possess unique arrays of promising biological properties. Since the selective synthesis of oligomeric natural products is an unsolved synthetic problem we want to develop a new strategy to access this important class of molecules. We want to generate all the carbogenic complexity through the identification of common, non obvious building blocks different from Natures starting material and their transformation into complex key intermediates. Building on the successful synthesis of resveratrol dimers we want to aim for the next step and challenge the highly complex and structurally unique trimers and tetramers. Almost every member of higher complexity in this class of molecules bears a dihydrobenzofuran unit, so we will first focus on this problem and develop suitable approaches. In our proposal we present several promising strategies for this motive using the resveratrol dimer ampelopsin B as a test system. This includes approaches based on C-H insertion reactions, enantioselective iridium-catalyzed allylic arylation or quinone methide intermediates. After finding appropriate solutions, they will be applied to challenge complex target molecules like nepalensinol B, ampelopsin H or vaticanol C. For the synthesis of tetramers like hopeaphenol or dibalanocarpol we have to develop dimerisation strategies for advanced precursors, therefore we propose a SmI2 mediated radical based pinacol coupling and other methods. The dimerisation reactions to these molecules would be among the most complex ever achieved. Finally we want to develop an approach to achieve the synthesis of molecules of highest complexity like paucifloral A and B. We believe that this work will lead to the first total syntheses of a number of compounds with a promising multitude of biological properties in a minimum number of steps. Therefore new synthetic strategies and methods will be developed to contribute a part of the solution of how to prepare highly complex oligomeric natural products in a selective way.