Enantioselective synthesis

Enantioselective synthesis, also called chiral synthesis or asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as: a chemical reaction (or reaction sequence) in which one or more new elements of chirality are formed in a substrate molecule and which produces the stereoisomeric (enantiomeric or diastereoisomeric) products in unequal amounts.

Put more simply: it is the synthesis of a compound by a method that favors the formation of a specific enantiomer or diastereomer.

Enantioselective synthesis is a key process in modern chemistry and is particularly important in the field of pharmaceuticals, as the different enantiomers or diastereomers of a molecule often have different biological activity.

Many of the building blocks of biological systems, such as sugars and amino acids, are produced exclusively as one enantiomer. As a result, living systems possess a high degree of chemical chirality and will often react differently with the various enantiomers of a given compound. Examples of this selectivity include:

As such, enantioselective synthesis is of great importance; but it can also be difficult to achieve. Asymmetric induction can occur intramolecularly when given a chiral starting material. This behaviour can be exploited, especially when the goal is to make several consecutive chiral centres to give a specific enantiomer of a specific diastereomer. An aldol reaction, for example, is inherently diastereoselective; if the aldehyde is enantiopure, the resulting aldol adduct is diastereomerically and enantiomerically pure.

Enantioselective catalysis is a widely practiced method for generating chiral compounds.

Enantiomers possess identical enthalpies and entropies and hence should be produced in equal amounts by an undirected process – leading to a racemic mixture. The nonselectivity can be biased using a chiral feature that favors the formation of one enantiomer over another via interactions at the transition state. This biasing is known as asymmetric induction and can involve chiral features in the substrate, reagent, catalyst, or environment and works by making the activation energy required to form one enantiomer lower than that of the opposing enantiomer.

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