Catalytic asymmetric Stetter reaction

• Applicant: Professor Dr. Michael Müller
• Subject Area: Biological and Biomimetic Chemistry
• Term: from 2010 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 128900243

A demanding task for chemo- as well as for biocatalysis represents the development of methods forming regio- and stereoselective bonds between two carbons. With the elucidation of the PigD-catalyzed Stetter reaction, we identified a method for the synthesis of enantiomerically pure 1,4-dicarbonylic compounds. The aim of this project is to analyze, optimize and establish this extraordinary asymmetnc reaction catalyzed by a ThDP-dependent enzyme, opening the door for a possible application on a preparative scale. Thereby we expand the potential of the Stetter reaction to an intermolecular asymmetric opportunity that has, so far, several limitations with the means of organocatalysis. The generated 1,4-dicarbonyl compounds can subsequently be used as chiral building blocks in (biomimetic) syntheses. A detailed biochemical and structural analysis of the ThDP-dependent enzyme PigD and its homologues is essential for the characterization of the parameters determining the enzymatic Stetter reaction. The understanding of the activity of these unusual ThPD-dependent enzymes, the so-called Stetterases, is an important contribution for the goals of the proposed Research Unit and for even the whole field of thiamine catalysis. In particular because of their decarboxylation activity with specific substrates, these Stetterases build a link between the classical ThDP-dependent decarboxylases and the so far unique enzyme MenD that is known to catalyze a Stetter-like 1,4- addition to an a,ß-unsaturated carboxylic acid. An in-depth characterization of these enzymes, including their structure-function relationships, substrate range, reaction mechanism and parameters determining chemo- and stereoselectivity, is a prerequisite for the directed use in the chemo-enzymatic syntheses of chiral compounds.

• DFG Programme: Research Units
• Subproject of: FOR 1296: Diversity of Asymmetric Thiamine Catalysis