Asymmetric synthesis

(¦ā·sə¦me·trik ′sin·thə·səs)

(organic chemistry) Chemical synthesis of a pure enantiomer, or of an enantiomorphic mixture in which one enantiomer predominates, without the use of resolution.

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A reaction or series of reactions leading to predominant or exclusive formation of a single enantiomer, that is, a stereoisomer that is not superimposable on its mirror image. Among the organic compounds that are usually the target of asymmetric synthesis, the most common structural element that makes one exist as an enantiomer is a carbon atom with a single bond to four different atoms or groups (a stereogenic center), as the two enantiomers of 3-methylhexane, (R)-3-methylhexane (1) and (S)-3-methylhexane (2).

Enantiomers are said to be chiral. They are asymmetric; symmetric molecules, possessing a plane or point of symmetry, are superimposable on their mirror images. Not all molecules exist as enantiomers. See also Prochirality.

Other structural elements can give rise to asymmetry, for example substituted allene functional groups, as in (S)-2,3-pentadiene (3) and (R)-2,3-pentadiene (4), and binaphthyl systems,

as in (R)-1,1′-binaphthyl (5) and (S)-1,1′-binaphthyl (6), which are said to have axial chirality. Rules exist for unambiguously designating the three-dimensional orientations (configurations) of the atoms attached to such structural elements; these designations are the R versus S terms. See also Stereochemistry.

Asymmetry in molecules is very important to the biological activity of the molecule. Because almost all of the molecules in an organism, such as occur in cell membranes, enzymes, receptors, and nucleic acids (which mediate all life processes) are asymmetric, they interact differently with different enantiomers. For example, the S enantiomer of asparagine (7; a common amino acid) has a bitter flavor, while the R enantiomer (8) has a sweet

flavor, due to the fact that each of the two enantiomers binds differently to chemoreceptors in the tongue. Thalidomide, a drug once prescribed to counteract pregnancy-related morning sickness, is an effective sedative as the R enantiomer (9), but the S enantiomer (10) is a potent teratogen (it causes birth defects). In general, only one enantiomer of a drug, agrochemical (herbicide, pesticide), flavoring agent, or other molecule (when asymmetric) has the desired biological effect, while the other enantiomer has very different effects or, at least, places a metabolic burden on the body. For this reason, asymmetric synthesis to produce only one enantiomer of a molecule for such uses is extremely important. See also Amino acids; Chemoreception; Protein.

The two enantiomers of an asymmetric molecule have identical physical properties, except that they rotate plane-polarized light in opposite directions. The ability to rotate plane-polarized light (referred to as optical activity) is a property that only asymmetric molecules possess: one pure enantiomer will rotate the plane of polarization in one direction [clockwise, thus behaving as a d (dextrorotatory) or + enantiomer], and the opposite enantiomer will rotate the plane of polarization the same number of degrees but in the opposite direction [counterclockwise, thus an l (levorotatory) or − enantiomer]. A 50:50 mixture of two enantiomers of a molecule is called a racemic mixture (designated dl or ±); it will not rotate the plane of plane-polarized light. By knowing the specific rotation of a pure enantiomer, it is possible to calculate the relative amounts of each enantiomer (the so-called optical purity) in an unequal mixture. See also Optical activity; Racemization.

Another distinguishing property of two enantiomers is that each will react with a single enantiomer of another chiral molecule at a different rate. This process is related to the existence of diastereomers, which are stereoisomers that are not enantiomers. Diastereomers can occur in many forms. One common manifestation is the case where a molecule possesses two (or more) stereogenic carbon centers. Diastereomers, unlike enantiomers, possess different physical and chemical properties; they have different free energies while enantiomers are identical in energy. Therefore, if a reaction is designed so that it passes through two possible pathways, each involving transition states which are diastereomeric, to produce two possible stereoisomers of the product, then the pathway which involves the lower-energy transition state will proceed faster; thus one stereoisomer of the product will predominate in the product mixture. The greater the difference between the energies of the transition states, the greater the predominance of one product stereoisomer. This is the basis of asymmetric synthesis. See also Free energy.

A common strategy to achieve asymmetric synthesis is to place a chiral center in proximity to the location where the new stereogenic center is to be introduced. When the reaction proceeds, the configuration of the new stereogenic centers being formed are influenced by the chirality of the chiral reactant; the chiral reactant “induces” chirality at the newly formed stereogenic centers.

In some cases, a chiral solvent or a chiral catalyst is used to induce chirality. In all cases, the existing chiral entity in the reaction (reactant or solvent or catalyst) is involved in the transition state, resulting in diastereomeric transition states of which the lower-energy one is favored.

Another strategy for synthesizing predominantly one enantiomer of a product is to react a racemic mixture of a starting material with a chiral reagent or catalyst that reacts faster with one of the enantiomers of the starting material than the other so that one enantiomer is consumed and the other is not. Such processes are known as kinetic resolutions. A kinetic resolution strategy for asymmetric synthesis is not as desirable as an asymmetric reaction strategy, because half of the starting material is left behind as the unwanted stereoisomer. See also Enzyme; Molecular isomerism.

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