Enantioselective synthesis
Enantioselective synthesis, also called asymmetric synthesis,
Put more simply: it is the synthesis of a compound by a method that favors the formation of a specific enantiomer or diastereomer. Enantiomers are stereoisomers that have opposite configurations at every chiral center. Diastereomers are stereoisomers that differ at one or more chiral centers.
Enantioselective synthesis is a key process in modern chemistry and is particularly important in the field of
Overview
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:
- Flavour: the
- Odor: R-(–)-carvone smells like spearmint whereas S-(+)-carvone smells like caraway.[4]
- Drug effectiveness: the
- Drug safety: D‑penicillamine is used in chelation therapy and for the treatment of rheumatoid arthritis whereas L‑penicillamine is toxic as it inhibits the action of pyridoxine, an essential B vitamin.[7][8]
As such enantioselective synthesis is of great importance but it can also be difficult to achieve. Enantiomers possess identical
Enantioselectivity is usually determined by the relative rates of an enantiodifferentiating step—the point at which one reactant can become either of two enantiomeric products. The
This temperature dependence means the rate difference, and therefore the enantioselectivity, is greater at lower temperatures. As a result, even small energy-barrier differences can lead to a noticeable effect.
ΔΔG* (kcal) k1/k2 at 273 K k1/k2 at 298 K k1/k2 at 323 K) 1.0 6
.37 5
.46 4
.78 2.0 40
.6 29
.8 22
.9 3.0 259 162 109 4.0 1650 886 524 5.0 10500 4830 2510
Approaches
Enantioselective catalysis
Enantioselective catalysis (known traditionally as "asymmetric catalysis") is performed using chiral
Most enantioselective catalysts are effective at low substrate/catalyst ratios.[14][15] Given their high efficiencies, they are often suitable for industrial scale synthesis, even with expensive catalysts.[16] A versatile example of enantioselective synthesis is asymmetric hydrogenation, which is used to reduce a wide variety of functional groups.The design of new catalysts is dominated by the development of new classes of
Chiral auxiliaries
A chiral auxiliary is an organic compound which couples to the starting material to form a new compound which can then undergo diastereoselective reactions via intramolecular asymmetric induction.[17][18] At the end of the reaction the auxiliary is removed, under conditions that will not cause racemization of the product.[19] It is typically then recovered for future use.
Chiral auxiliaries must be used in
Biocatalysis
Biocatalysis makes use of biological compounds, ranging from isolated enzymes to living cells, to perform chemical transformations.[20][21] The advantages of these reagents include very high e.e.s and reagent specificity, as well as mild operating conditions and low environmental impact. Biocatalysts are more commonly used in industry than in academic research;[22] for example in the production of statins.[23] The high reagent specificity can be a problem, however, as it often requires that a wide range of biocatalysts be screened before an effective reagent is found.
Enantioselective organocatalysis
Organocatalysis refers to a form of catalysis, where the rate of a chemical reaction is increased by an organic compound consisting of carbon, hydrogen, sulfur and other non-metal elements.[24][25] When the organocatalyst is chiral, then enantioselective synthesis can be achieved;[26][27] for example a number of carbon–carbon bond forming reactions become enantioselective in the presence of proline with the aldol reaction being a prime example.[28] Organocatalysis often employs natural compounds and
Chiral pool synthesis
Chiral pool synthesis is one of the simplest and oldest approaches for enantioselective synthesis. A readily available chiral starting material is manipulated through successive reactions, often using achiral reagents, to obtain the desired target molecule. This can meet the criteria for enantioselective synthesis when a new chiral species is created, such as in an SN2 reaction.
Chiral pool synthesis is especially attractive for target molecules having similar chirality to a relatively inexpensive naturally occurring building-block such as a sugar or
Separation and analysis of enantiomers
The two enantiomers of a molecule possess many of the same physical properties (e.g.
This can make it very difficult to determine whether a process has produced a single enantiomer (and crucially which enantiomer it is) as well as making it hard to separate enantiomers from a reaction which has not been 100% enantioselective. Fortunately, enantiomers behave differently in the presence of other chiral materials and this can be exploited to allow their separation and analysis.
Enantiomers do not migrate identically on chiral chromatographic media, such as
The separation and analysis of component enantiomers of a racemic drugs or pharmaceutical substances are referred to as
The
One of the most accurate ways of determining the chirality of compound is to determine its absolute configuration by X-ray crystallography. However this is a labour-intensive process which requires that a suitable single crystal be grown.
History
Inception (1815–1905)
In 1815 the French physicist
In 1894
The first enantioselective chemical synthesis is most often attributed to
Early work (1905–1965)
The development of enantioselective synthesis was initially slow, largely due to the limited range of techniques available for their separation and analysis. Diastereomers possess different physical properties, allowing separation by conventional means, however at the time enantiomers could only be separated by
It was not until the 1950s that major progress really began. Driven in part by chemists such as
Thalidomide
While it was known that the different enantiomers of a drug could have different activities, with significant early work being done by Arthur Robertson Cushny,[49][50] this was not accounted for in early drug design and testing. However, following the thalidomide disaster the development and licensing of drugs changed dramatically.
First synthesized in 1953, thalidomide was widely prescribed for morning sickness from 1957 to 1962, but was soon found to be seriously
Early research into the teratogenic mechanism, using mice, suggested that one enantiomer of thalidomide was teratogenic while the other possessed all the therapeutic activity. This theory was later shown to be incorrect and has now been superseded by a body of research.[52] However it raised the importance of chirality in drug design, leading to increased research into enantioselective synthesis.
Modern age (since 1965)
The Cahn–Ingold–Prelog priority rules (often abbreviated as the
Metal-catalysed enantioselective synthesis was pioneered by
Knowles: Asymmetric hydrogenation (1968) | Noyori: Enantioselective cyclopropanation (1968) |
---|
Noyori devised a copper complex using a chiral
In common with Knowles' findings, Noyori's results for the enantiomeric excess for this first-generation ligand were disappointingly low: 6%. However continued research eventually led to the development of theSharpless complemented these reduction reactions by developing a range of asymmetric oxidations (Sharpless epoxidation,[60] Sharpless asymmetric dihydroxylation,[61] Sharpless oxyamination[62]) during the 1970s and 1980s. With the asymmetric oxyamination reaction, using osmium tetroxide, being the earliest.
During the same period, methods were developed to allow the analysis of chiral compounds by
Chiral auxiliaries were introduced by
See also
- Aza-Baylis–Hillman reaction, for the use of a chiral ionic liquid in enantioselective synthesis
- Kelliphite, a chiral ligand widely used in asymmetric synthesis
- Spontaneous absolute asymmetric synthesis, the synthesis of chiral products from achiral precursors and without the use of optically active catalysts or auxiliaries. It is relevant to the discussion homochirality in nature.
- Tacticity, a property of polymers which originates from enantioselective synthesis
- Chiral analysis
- Enantioselective analysis
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