Asymmetric synthesis

Introduction

Asymmetric synthesis, also known as chiral synthesis or enantioselective synthesis, is a key concept in the field of organic chemistry. It refers to a process where chemically identical but mirror-image molecules, known as enantiomers, are produced in unequal amounts. This is significant because the physical properties of enantiomers are identical, but their biological or chemical reactivity can differ dramatically.

History and Development

The concept of asymmetric synthesis has its roots in the 19th century, when Louis Pasteur observed that tartaric acid, a compound derived from wine production, could rotate plane-polarized light. Pasteur's work laid the foundation for the concept of chirality and the development of stereochemistry, a sub-discipline of chemistry that deals with the spatial arrangement of atoms in molecules.

The first successful asymmetric synthesis was carried out by Emil Fischer and Arthur Speier in 1894. They synthesized fructose from glucose using a process now known as the Fischer-Speier esterification. This marked the beginning of a new era in synthetic chemistry, where the focus shifted from merely creating compounds to controlling the stereochemistry of the synthesis.

The field of asymmetric synthesis has grown exponentially since the 20th century, with the development of various methods and catalysts that can selectively produce one enantiomer over the other. The development of these methods has been recognized with several Nobel Prizes in Chemistry, including those awarded to William S. Knowles and Ryōji Noyori in 2001, and to K. Barry Sharpless in 2002.

Principles of Asymmetric Synthesis

The key to asymmetric synthesis is the creation of a chiral environment that can influence the outcome of a reaction. This can be achieved through the use of chiral auxiliaries, chiral catalysts, or chiral substrates.

Chiral Auxiliaries

Chiral auxiliaries are chiral compounds that are temporarily attached to the substrate to control the stereochemistry of the reaction. They are designed to favor the formation of one enantiomer over the other. After the reaction, the chiral auxiliary can be removed and recycled. Examples of chiral auxiliaries include the Evans auxiliary and the Davis oxaziridine.

Chiral Catalysts

Chiral catalysts are compounds that can influence the stereochemistry of a reaction without being consumed. They work by binding to the substrate in a way that favors the formation of one enantiomer. Examples of chiral catalysts include the BINAP ligand used in the Noyori asymmetric hydrogenation and the salen ligand used in the Jacobsen epoxidation.

Chiral Substrates

Chiral substrates are compounds that already possess a chiral center. The existing chirality can be used to control the stereochemistry of the reaction. This method is often used in conjunction with chiral auxiliaries or chiral catalysts to enhance the enantioselectivity of the reaction.

Techniques in Asymmetric Synthesis

There are several techniques in asymmetric synthesis, each with its own advantages and disadvantages. These include asymmetric induction, chiral pool synthesis, and biocatalysis.

Asymmetric Induction

Asymmetric induction is a technique where a chiral auxiliary or a chiral catalyst is used to control the stereochemistry of a reaction. The chiral auxiliary or catalyst influences the transition state of the reaction, favoring the formation of one enantiomer.

Chiral Pool Synthesis

Chiral pool synthesis is a technique where a chiral substrate is used as the starting material. The existing chirality of the substrate is used to control the stereochemistry of the reaction. This method is often used when the desired product is a derivative of a naturally occurring chiral compound.

Biocatalysis

Biocatalysis is a technique where biological catalysts, such as enzymes or whole cells, are used to carry out asymmetric synthesis. Biocatalysis is particularly useful for producing chiral compounds because many biological reactions are inherently chiral.

Applications of Asymmetric Synthesis

Asymmetric synthesis has wide-ranging applications in various fields, including pharmaceuticals, agrochemicals, and materials science.

In the pharmaceutical industry, asymmetric synthesis is used to produce chiral drugs, which can have different therapeutic effects depending on their chirality. For example, the drug thalidomide has one enantiomer that is effective against morning sickness, while the other enantiomer is teratogenic.

In the agrochemical industry, asymmetric synthesis is used to produce chiral pesticides and herbicides, which can have different effects on pests and crops depending on their chirality.

In materials science, asymmetric synthesis is used to produce chiral materials, such as chiral polymers and chiral nanoparticles, which can have unique optical, electronic, and mechanical properties.