Molecular receptor which mimic oxyanion holesmolecular recognition and catalysis

Resumen

The general objective of this Thesis is the design and synthesis of small organic molecules which mimic the oxyanion-hole scaffold found in hydrolytic enzymes. They employ this structural motif to associate anions and electronegative groups such as carbonyls from esters and amides and reduce the activation energy of many reactions in which a negatively-charged transition state is generated. These artificial oxyanion-hole mimic will be used to associate the carboxylic acid group of amino acids in order to carry out the chiral resolution of racemic mixtures of amino acids. In addition, they will be employed to catalyse the transesterification of non-activated esters by mimicking the mechanism of natural hydrolases. Chapter 1 Catalytic properties of enzymes are basically sustained by their ability in the association of a substrate and keeping it close to the active centre. A preorganized tertiary structure allows them to play as catalysts, setting up the space where the substrate interacts with the enzyme and the reaction takes place. For example, the active centre of proteases, such as chymotrypsin, is formed by a catalytic triad, an hydrophobic pocket, and an oxyanion hole. The last two moieties bind the aromatic unit and the amide carbonyl, respectively. The oxyanion hole contains hydrogen bond donor groups which stabilise the carbonyl group and the negatively charged oxygen atom of the tetrahedral intermediate in the hydrolysis reaction. Backbone amides usually act as hydrogen bond donor groups. As the oxyanion hole can bind anions, the development of supramolecular receptors with an oxyanion-hole geometry is a good starting point for anion binding. Amino acids are the building blocks in protein synthesis and are essential in human nutrition. There are several industrial syntheses of amino acids which include an enzymatic step and generate enantiomerically pure L-amino acids, the enantiomer required for human diet. Organic syntheses of amino acids are usually cheaper and do not require the specific conditions of enzymatic synthesis, however they generally afford the amino acids racemic mixture. Racemic synthesis combined with chiral supramolecular receptors could improve and reduce costs in the industrial obtention of amino acids. Chapter 2 Enzymes are the most efficient catalysts in Nature. The configuration of their active centre, established by the three-dimensional structure of the protein, allows them to increase the rate of reactions that otherwise would be very slow or even could not take place. Supramolecular interactions, such as hydrogen bonding, - stacking or hydrophobic interactions, among others, are essential to set up and maintain the three-dimensional structure of enzymes, and they also play an important role for the enzyme-substrate association. All these concepts explain the catalytic activity of the enzymes and are essential to understand how to improve artificial enzymes designs. Hydrolases enzymes catalyses the cleavage of many different bonds, such as amide or ester bonds. These compounds are widely employed in food and pharmacy industries, even though their use is conditioned by the strict enzyme stability requirements (pH, ionic strength or temperature affect the enzyme structure); they usually are more expensive than synthetic catalysts. Most hydrolases have an active center formed by a hydrophobic pocket, a catalytic triad and an oxyanion hole. The catalytic triad is in charge of the nucleophilic attack on the substrates while the oxyanion hole stabilises both the substrate and the negatively-charged intermediate. These two features are the main responsible for the reaction rate acceleration. Thus, mimicking the catalytic triad and the oxyanion hole with a small organic molecule with a similar geometry should provide comparable reaction rates. The design and synthesis of organocatalysts that are as efficient as enzymes would be ideal to improve many synthetic and industrial processes and is still a challenge in Organic Chemistry.