Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - ELICOS (Enantioselective Light-induced Catalysis for Organic Synthesis)

Teaser

Chirality is one of the most fascinating and important properties of matter. The interaction of small molecules with biological systems is determined by the orientation of its atoms in three-dimensional space. As a consequence, enantiomeric molecules may have completely...

Summary

Chirality is one of the most fascinating and important properties of matter. The interaction of small molecules with biological systems is determined by the orientation of its atoms in three-dimensional space. As a consequence, enantiomeric molecules may have completely different pharmacological properties and this fact has stimulated extensive research efforts towards the synthesis of enantiomerically pure compounds. With regard to organic compounds, the key issue is to install the first stereogenic carbon atom with high enantioselectivity as the creation of consecutive stereogenic centers will lead to diastereoisomers. Although chiral compounds available from Nature still play an important role as starting materials in organic synthesis, the most important and effective way to create enantiomerically pure compounds de novo is based on enantioselective (asymmetric) catalysis. The Nobel Prize in Chemistry 2001 recognized the pioneering efforts of W. S. Knowles, R. Noyori and K. B. Sharpless towards the development of enantioselective catalytic oxidation and hydrogenation reactions. Modern pharmaceutical drug production, a market of almost one trillion €, relies heavily on enantioselective catalytic methods.
Given the continuing success, which enantioselective catalysis has encountered over the last decades, it is striking that it has – until very recently – not played a role in the photochemical synthesis of chiral molecules (for more information, see: Angew. Chem. Int. Ed. 2015, 54, 3872). The fact, that photochemistry lags behind the development in enantioselective catalysis, is critical since there is a large number of biologically relevant molecular scaffolds that are only accessible by photochemical but not by thermal reactions. Major reasons for this lack in progress towards enantioselective light-induced catalysis are intrinsic difficulties encountered when designing potential catalysts for such a process. By definition, photochemical reactions occur upon absorption of light, which in turn involves a significant change in the electronic structure of the photoexcited molecule. The molecule is promoted to a higher energy level, from which successive reactions compete with decay pathways to the ground state (fluorescence, internal conversion). Efficient photochemical reactions consequently have relatively low activation barriers and product formation is rapid while many thermal reactions have significant activation barriers and proceed with very low reaction rates even at elevated temperature. A catalyst of a thermal reaction lowers the activation barrier by interacting with the substrate and can be favorably used to eventually create a new stereogenic center. In a photochemical reaction, the situation is different because catalysis is not necessarily required to drive the reaction forward. The critical issue is to find chiral catalysts that interact with a photochemical substrate while it is excited from the ground state to the excited state. Reaction pathways have to be devised which avoid uncatalyzed racemic background reactions.
The goal of the ELICOS project is to develop catalytic methods that allow for the enantioselective synthesis of a broad variety of compound classes by light-induced reactions. The mode of action of potential catalysts is based on energy transfer or on wavelength-selective excitation. If successful, a widespread application of enantioselective photochemical reactions in organic synthesis will be secured and a multitude of structurally diverse products will become available in enantiomerically form for high-tech applications.
For more information, see also: http://portal.mytum.de/pressestelle/faszination-forschung/2016nr18/05_Millions_at_my_Beck.pdf

Work performed

A notable achievement in the first half of the funding period is the fact that several four-membered carbocycles (cyclobutanes) are now available in enantiopure form by a generally applicable intermolecular [2+2] photocycloaddition. A suitable chiral Lewis acid catalyst was developed which is capable to process cyclic enones without the necessity of any further functionalization. The method has been applied to the enantioslective total synthesis of grandisol, a terpenoid natural product. The results were disclosed in the Journal of the American Chemical Society (DOI: 10.1021/jacs.8b01011).
Two new concepts for the activation of photochemical substrates in a catalytic fashion have been discovered. The first concept relies on the temporary formation of cations which show a long-wavelength (bathochromic) shift relative to their precursors. They can thus be excited by visible light and react in a reaction that is unprecedented for this substrate class. The second concept is based on the reversible formation of iminium ions from carbonyl compounds. It was shown that the triplet energy of the ions is lower than the triplet energy of the carbonyl compounds. When employing a suitable sensitizer with a triplet energy that is sufficient to excite the iminium ion but not the carbonyl compound a selective photoreaction becomes possible. The two concepts were disclosed in publications which appeared in the journal Angewandte Chemie (DOI: 10.1002/anie.201700837; DOI: 10.1002/anie.201710441).
In the same journal, the conceptual approaches towards enantioselective photochemical reactions based on chromophore activation have been recently summarized (DOI: 10.1002/anie.201804006).

Final results

The goal of this project is to provide new catalytic methods for the photochemical production of enantiopure compounds. We strive to find manifold generally applicable ways to achieve this goal either by chromophore activation or by triplet sensitization. At the end of the project we hope to provide the scientific community with as many solutions as possible to convert a given substrate enantioselectively to a given product in a photochemical reaction. The most significant challenge of the project is to tame reactions which do not take place on the ground state hypersurface but several hundreds of kJ per mole above. Any reaction which we are able to modulate in an enantioselective fashion is consequently a significant progress beyond the state of the art.
Science-based Impact: It has been shown in several examples that previously known racemic photochemical reactions can be modified to prepare enantiopure compounds. In addition, new catalytic photochemical reactions have been discovered which now wait to be exploited in an enantioselective fashion. It is noted that the area of photochemistry receives increasing interest form the scientific community which in part is due to the activities of the project (see also the Editorial which was written on the occasion of the year of light: DOI:10.1002/anie.201507439).
Socio-economic Impact: The power of photochemical reactions rests on the fact that they do not require any external energy but the energy of photons. They are in this regard optimal transformations which allow to harvest the energy of solar photons and to convert it into unique structures. The impact of the project on society rests on the efficient use of energy and on the construction of molecular structures which promise applications in medicine and technology.