Abstract
ConspectusBiological systems have often served as inspiration for the design of synthetic catalysts. The lock and key analogy put forward by Emil Fischer in 1894 to explain the high substrate specificity of enzymes has been used as a general guiding principle aimed at enhancing the selectivity of chemical processes by optimizing attractive and repulsive interactions in molecular recognition events. However, although a perfect fit of a substrate to a catalytic site may enhance the selectivity of a specific catalytic reaction, it inevitably leads to a narrow substrate scope, excluding substrates with different sizes and shapes from efficient binding. An ideal catalyst should instead be able to accommodate a wide range of substrates—it has indeed been recognized that enzymes also are often highly promiscuous as a result of their ability to change their conformation and shape in response to a substrate—and preferentially be useful in various types of processes. In biological adaptation, the process by which species become fitted to new environments is crucial for their ability to cope with changing environmental conditions. With this in mind, we have been exploring catalytic systems that can adapt their size and shape to the environment with the goal of developing synthetic catalysts with wide scope.In this Account, we describe our studies aimed at elucidating how metal catalysts with flexible structural units adapt their binding pockets to the reacting substrate. Throughout our studies, ligands equipped with tropos biaryl units have been explored, and the palladium-catalyzed allylic alkylation reaction has been used as a suitable probe to study the adaptability of the catalytic systems. The conformations of catalytically active metal complexes under different conditions have been studied by both experimental and theoretical methods. By the design of ligands incorporating two flexible units, the symmetry properties of metal complexes could be used to facilitate conformational analysis and thereby provide valuable insight into the structures of complexes involved in the catalytic cycle. The importance of flexibility was convincingly demonstrated when a phosphine group in a privileged ligand that is well-known for its versatility in a number of processes was exchanged for a tropos biaryl phosphite unit: the result was a truly self-adaptive ligand with dramatically increased scope.
Highlights
Enantioselective transition metal catalysis is an enabling technology for the preparation of enantiomerically enriched chiral compounds, and extensive efforts during the last decades have resulted in metal catalysts with impressive performances
An attractive alternative to those ligands classified as privileged consists of ligands with stereochemical flexibility.[11]. The authors of this Account are interested in flexible ligands that are capable of adapting their structure to a reacting substrate
Enantioselectivities of up to 99% ee were reached in the allylic substitution of linear pubs.acs.org/accounts
Summary
Enantioselective transition metal catalysis is an enabling technology for the preparation of enantiomerically enriched chiral compounds, and extensive efforts during the last decades have resulted in metal catalysts with impressive performances. Efficient ligands have commonly been identified using empirical methods, ranging from trialand-error approaches to more or less rational design.[5] For the efficient evaluation of catalyst performance, a variety of procedures have been developed, including high-throughput screening technologies, today increasingly by the use of highefficiency robotics.[6]. Such empirical methods are supplemented or even being replaced by computationally guided methods. The authors of this Account are interested in flexible ligands that are capable of adapting their structure to a reacting substrate
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