Periodic Reporting for period 4 - ELICOS (Enantioselective Light-induced Catalysis for Organic Synthesis)
Okres sprawozdawczy: 2020-07-01 do 2020-12-31
Upon excitation by light, molecules reach states of higher energy, so called excited states. The energy input allows the molecule to access reaction pathways which are not possible in a conventional (thermal) chemical reaction. As a consequence, products are generated which display unique structural features and which can only be formed by light-induced (photochemical) processes. The quintessential reaction is the [2+2] photocycloaddition of alkenes leading to strained cyclobutanes. In the course of many photochemical reactions, stereogenic centers are formed making the products of the reaction chiral. Chirality in chemistry refers to the fact that molecules exist in two configurations which cannot be superimposed despite the fact that their spatial coordinates are identical. Our hands, which is where the name stems from, have the same property; they behave as image and mirror image. The interaction of small molecules within 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 Prizes for Chemistry in 2001 and 2021 recognized pioneering efforts towards the development of thermal enantioselective reactions. Modern pharmaceutical drug production, a market of almost one trillion €, relies heavily on enantioselective catalytic methods.
Given the continuing success that enantioselective catalysis has encountered over the last few decades, it is striking that it has – until very recently – not played a role in the photochemical synthesis of chiral molecules. 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. Efficient photochemical reactions 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. The goal of the ELICOS (Enantioselective Light-Induced Catalysis for Organic Synthesis) project was to develop catalytic methods that would allow for the enantioselective synthesis of a variety of versatile compound classes by light-induced reactions. It was meant to address the intrinsic challenge of modulating excited state reactivity and to advance the field by new concepts and mechanistic insights.
Given the continuing success that enantioselective catalysis has encountered over the last few decades, it is striking that it has – until very recently – not played a role in the photochemical synthesis of chiral molecules. 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. Efficient photochemical reactions 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. The goal of the ELICOS (Enantioselective Light-Induced Catalysis for Organic Synthesis) project was to develop catalytic methods that would allow for the enantioselective synthesis of a variety of versatile compound classes by light-induced reactions. It was meant to address the intrinsic challenge of modulating excited state reactivity and to advance the field by new concepts and mechanistic insights.
A major output of ELICOS was the development of catalytic enantioselective [2+2] photocycloaddition reactions leading to chiral cyclobutanes. The most successful approach is based on the use of chiral Lewis acids as catalyst. Review articles on the topic have appeared in Accounts of Chemical Research (DOI: 10.1021/acs.accounts.0c00379) and Angewandte Chemie (DOI: 10.1002/anie.201804006).* The approach relies on the fact that the Lewis acid changes the electronic properties of a molecule to which it coordinates. Due to this change, it is possible to excite a Lewis acid-bound substrate at a longer wavelength as compared to an unbound substrate. Most notably, a method was found to involve a versatile class of olefin components, so called enones, in an intermolecular [2+2] photocycloaddition reaction with almost any given alkene. The resulting cyclobutanes were formed with high enantioselectivity and the method was applied to the synthesis of a naturally occurring cyclobutane, grandisol, an aggregation pheromone of the cotton boll weevil. Furthermore, enantioselective Lewis acid catalysis was successfully extended to the ortho photocycloaddition, a unique dearomatization reaction, and to the formation of cyclopropanes by an oxadi-π-methane rearrangement. The latter reaction was applied to the enantioselective synthesis of the naturally occurring insecticide trans-chrysanthemic acid. In a second approach towards cyclobutanes, a study of whether the catalytic formation of thionium or iminium ions allows for a catalytic [2+2] photocycloaddition was carried out. It was discovered that an energy transfer to iminium ions is possible and that the reaction can be rendered catalytic upon judicious choice of the sensitizer. A sensitizer is a compound which is excited by light and is capable to transfer the light energy to another molecule. A method was developed for the enantioselective formation of cyclobutanecarboxaldehydes from the respective iminium ions and its mechanism was elucidated in detail. A third pillar of the project aimed at the synthesis of potential catalysts that combine a substrate binding site with a photocatalytic entity. An array of catalysts was prepared with chiral thioureas and chiral phosphoric acids which were considered to bind to a substrate by hydrogen bonding or ion pairing. A chiral phosphoric acid showed a very promising catalytic activity and continues to be studied.
* For a complete list of ELICOS publications, please see: https://www.ch.nat.tum.de/en/oc1/research/elicos/
* For a complete list of ELICOS publications, please see: https://www.ch.nat.tum.de/en/oc1/research/elicos/
In summary, the ELICOS project has enabled the chemical science to take a major step towards catalytic enantioselective photochemical reactions. The most significant challenge of the project was to tame reactions which do not take place on the ground state hypersurface but several hundreds of kJ per mole above. Apart from our own achievements, the concepts emanating from the project have been embraced by the rapidly growing community of synthetic photochemists and continue to be successfully applied to challenging photochemical transformations.
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. The area of photochemistry receives increasing interest form the scientific community which in part is due to the activities of the project.
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.
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. The area of photochemistry receives increasing interest form the scientific community which in part is due to the activities of the project.
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.