Enantioselective synthesis

Enantioselective Synthesis

Chirality is a key concept in enantioselective synthesis.

Enantioselective synthesis, also known as asymmetric synthesis, is a form of chemical synthesis that aims to produce a specific enantiomer of a chiral molecule. This process is crucial in the production of pharmaceuticals, agrochemicals, and other substances where the stereochemistry of the product is important for its biological activity.

Principles of Enantioselective Synthesis

Enantioselective synthesis relies on the use of chiral reagents, catalysts, or auxiliaries to favor the formation of one enantiomer over the other. The goal is to achieve high enantioselectivity, which is often quantified by the enantiomeric excess (ee) of the product.

Chirality and Stereochemistry

Chirality is a property of a molecule that makes it non-superimposable on its mirror image. This is analogous to the way left and right hands are mirror images but cannot be perfectly aligned. In chemistry, chiral molecules have at least one stereocenter, typically a carbon atom with four different substituents.

Energy Considerations

Energy diagram illustrating the difference in activation energy for the formation of two enantiomers.

The success of enantioselective synthesis often depends on the difference in activation energy between the pathways leading to each enantiomer. A chiral catalyst or auxiliary can lower the activation energy for the formation of one enantiomer, thus favoring its production.

Methods of Enantioselective Synthesis

Several strategies are employed in enantioselective synthesis, including the use of chiral catalysts, chiral auxiliaries, and chiral pool synthesis.

Chiral Catalysts

Chiral catalysts are often used to induce asymmetry in a reaction. These catalysts can be metal-based or organic in nature.

Sharpless Dihydroxylation

The Sharpless dihydroxylation reaction.

The Sharpless dihydroxylation is a well-known example of enantioselective synthesis using a chiral catalyst. It involves the addition of two hydroxyl groups to an alkene to form a vicinal diol.

Noyori Asymmetric Hydrogenation

Noyori's asymmetric hydrogenation.

The Noyori asymmetric hydrogenation is another example, where a chiral ruthenium or rhodium catalyst is used to hydrogenate ketones or imines to produce chiral alcohols or amines.

Chiral Auxiliaries

General scheme of a reaction using a chiral auxiliary.

Chiral auxiliaries are temporary chiral groups that are attached to a substrate to control the stereochemistry of a reaction. After the reaction, the auxiliary is removed to yield the desired enantiomer.

Chiral Pool Synthesis

Chiral pool synthesis involves the use of naturally occurring chiral compounds as starting materials. These compounds, such as amino acids or sugars, are used to build more complex chiral molecules.

Historical Context

Marckwald's early example of asymmetric synthesis.

The concept of asymmetric synthesis dates back to the late 19th century. One of the earliest examples was reported by Paul Walden and Rudolf Fittig. Later, Hermann Emil Fischer and Julius von Marckwald made significant contributions to the field.

Applications

Enantioselective synthesis is crucial in the pharmaceutical industry, where the biological activity of a drug can be highly dependent on its stereochemistry. Many drugs are marketed as single enantiomers to maximize efficacy and minimize side effects.

Related Pages

• Chirality (chemistry)
• Stereochemistry
• Catalysis
• Asymmetric induction