Enantioselective C-H Alkylation by Photo-Organocatalysis

Organic chemistry is largely concerned with the chemistry of molecules with a skeleton made up of carbon atoms. The main task of organic synthesis is therefore to create new connections between carbon atoms (but also to other atoms) in order to produce new molecules or to improve existing synthetic routes to known compounds. These molecules can ultimately be used as pesticides or medicinal products. A particular challenge in the production of molecules is the so-called enantioselective synthesis. Just like the hands on your own body, some molecules behave like an image and a mirror image and are therefore not non-superposable. Although these two so-called enantiomers consist of the same atoms, they can have very different (also undesirable) effects on the human body. Therefore, in terms of atom economy, it is a particular challenge to selectively produce only one of these two enantiomers, which can usually be achieved using chemical catalysts. Paolo Melchiorre`s group at the Institut Català d`Investigaci Qumica (ICIQ) in Tarragona (Spain) is a leading global research group in the field of enantioselective catalysis. The Melchiorre group`s approach to catalysis is very innovative and sustainable, as mostly organic catalysts and visible light are used for this task instead of the more common transition metal catalysts. Another very current research focus in the field of organic synthesis is currently the so-called activation of C-H bonds. For this purpose, methods are being developed to split particularly inert carbon-hydrogen bonds and then to link these carbons with other atoms. This is, of course, a huge advancement in the field as it can be used to make a wide variety of new molecules. But here, too, enantiomers can arise again and the development of enantioselective variants is now a great challenge. The aim of this project is to activate particularly inert carbons and to link them with other carbon atoms of other molecules and, ideally, only one of the two possible enantiomers will be obtained.

Summary J4603-N In this project, new methods for the stereoselective synthesis of organic molecules have been developed. Central to this chemistry is the absorbance of visible light, which raises the participating catalyst or reaction intermediates (such as an iminium ion) upon absorbance to a photo-excited state. This allows the generation of highly reactive radicals, which can undergo reactions that are inaccessible for the same molecules in the non-excited ground state. Since it is of high importance in the field of chemical catalysis to produce only one of two (or more) possible stereoisomers of the desired product, a chiral amino catalyst or an enzyme is used in this case to control the sterical outcome of the transformations. More specifically, a new photocatalytic system could be developed for the single electron reduction of chiral iminium ions, which are formed between an organocatalyst and an ,-unsaturated aldehyde in the reaction mixture. Since this approach allows the generation of a highly reactive and chiral radical, this species can be trapped with suitable reaction partners to allow the formation of stereo-enriched products. By use of a cyano source, this process could be successfully employed to the conjugate cyanation of ,-unsaturated aldehydes. The resulting cyano-aldehyde products are particularly interesting compounds, since they can be converted to biologically interesting amino acids by redox manipulations. Furthermore, the capture of the chiral radical with acrylates allowed the synthesis of 1,6-dicarbonyl compounds, which are difficult to obtain otherwise. In addition, another reaction has been realized based on the direct excitation of iminium ions by the absorbance of visible light. Instead of a small molecule amino catalyst however, we could employ an enzyme containing an amine functionality. This allows the utilization of aqueous reaction conditions and the unprecedented use of simple carboxylic acids as reaction partners. The confined space of the active site of the enzyme also allowed the control of two stereocenters, which means the production of only one out of four possible stereoisomers. While one stereocenter is controlled by the enzyme, the other stereocenter can be controlled by the chirality of the starting material used. This is remarkable, since the enzyme assists in the transfer of chiral information from the starting material to the product and prevents the loss of the latter.