Stereoselective synthesis of biaryl compounds catalysed by artificial metalloenzymes
Lead Research Organisation:
CARDIFF UNIVERSITY
Department Name: Chemistry
Abstract
Chemical reactions are essential to life. Through the process of evolution, all organisms have developed a set of enzymes that facilitate chemical reactions. Some enzymes are incredibly useful because they can be used to catalyse reactions outside of the original organism to produce important molecules. Biochemical reactions using enzymes can be sustainable and more environmentally friendly than using chemical synthesis. This is because enzymes can minimise the creation of undesired molecules (e.g. high selectivity), can be produced using renewable feedstocks, and can conduct reactions in less toxic solvents and at lower temperatures. Despite the variety of known biochemical reactions, it seems that there are no enzymes that perform many chemical reactions that are useful for the creation of new molecules.
In this proposal we aim to create new enzymes to catalyse a class of reactions that a rarely observed in nature. This will be achieved by combining knowledge from several different disciplines to create new enzymes called artificial metalloenzymes (ArMs). These enzymes are designed to bind transition-metal atoms, allowing them to catalyse a diverse range of reactions. We will focus on designing enzymes that bind first-row transition metals, because they are more earth abundant making their use more sustainable than rarer metals.
In more detail, we will chemically synthesise new transition-metal cofactors. These are small molecules that will contain a transition metal atom. We will then use computational protein design to select amino acid sequences (proteins) that bind these cofactors. We will validate the proteins and their ability to bind the cofactors in the lab using a range of techniques. Finally, we will optimise the new metal-containing proteins into ArMs using well-established directed-evolution techniques. These ArMs will catalyse a type of reaction called a biaryl cross-coupling and can control the formation of two opposite chiral molecules.
These new enzymes have the potential to replace existing chemical reactions to produce small molecules in a more sustainable way. They also provide fine control of reactions, with the potential to produce new chiral molecules that are currently inaccessible with small-molecule catalysis.
In this proposal we aim to create new enzymes to catalyse a class of reactions that a rarely observed in nature. This will be achieved by combining knowledge from several different disciplines to create new enzymes called artificial metalloenzymes (ArMs). These enzymes are designed to bind transition-metal atoms, allowing them to catalyse a diverse range of reactions. We will focus on designing enzymes that bind first-row transition metals, because they are more earth abundant making their use more sustainable than rarer metals.
In more detail, we will chemically synthesise new transition-metal cofactors. These are small molecules that will contain a transition metal atom. We will then use computational protein design to select amino acid sequences (proteins) that bind these cofactors. We will validate the proteins and their ability to bind the cofactors in the lab using a range of techniques. Finally, we will optimise the new metal-containing proteins into ArMs using well-established directed-evolution techniques. These ArMs will catalyse a type of reaction called a biaryl cross-coupling and can control the formation of two opposite chiral molecules.
These new enzymes have the potential to replace existing chemical reactions to produce small molecules in a more sustainable way. They also provide fine control of reactions, with the potential to produce new chiral molecules that are currently inaccessible with small-molecule catalysis.
