Enantioselective synthesis

Source: Wikipedia, the free encyclopedia.

Sharpless dihydroxylation reaction the chirality of the product can be controlled by the "AD-mix" used. This is an example of enantioselective synthesis using asymmetric induction


Key: RL = Largest substituent; RM = Medium-sized substituent; RS = Smallest substituent
  Carboxylic acid group
  R group

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

pharmaceuticals, as the different enantiomers or diastereomers of a molecule often have different biological activity
.

Overview

An energy profile of an enantioselective addition reaction.

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. Enantiomers possess identical

catalyst, or environment[9] and works by making the activation energy required to form one enantiomer lower than that of the opposing enantiomer.[10]

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

rate constant, k, for a reaction is function of the activation energy of the reaction, sometimes called the energy barrier, and is temperature-dependent. Using the Gibbs free energy
of the energy barrier, ΔG*, means that the relative rates for opposing stereochemical outcomes at a given temperature, T, is:

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

aromatic chemicals
.

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

diastereomers, which enables their facile separation by methods such as column chromatography
or crystallization.

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

secondary amines as chiral catalysts;[29] these are inexpensive and environmentally friendly
, as no metals are involved.

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

enantiopure
starting material, which can be expensive if it is not naturally occurring.

Separation and analysis of enantiomers

The two enantiomers of a molecule possess many of the same physical properties (e.g.

NMR and IR
spectra are identical.

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

NMR spectroscopy of stereoisomers, these typically involve coordination to chiral europium complexes such as Eu(fod)3
and Eu(hfc)3.

The separation and analysis of component enantiomers of a racemic drugs or pharmaceutical substances are referred to as

enantioselective analysis. The most frequently employed technique to carry out chiral analysis involves separation science procedures, specifically chiral chromatographic methods.[31]

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

optical activity.[32]
The nature of this property remained a mystery until 1848, when Louis Pasteur proposed that it had a molecular basis originating from some form of dissymmetry,[33][34] with the term chirality being coined by Lord Kelvin a year later.[35] The origin of chirality itself was finally described in 1874, when
Le Bel–van 't Hoff rule
.

levorotary form of the 2-methylbutyric acid product.[38]

In 1894

Hermann Emil Fischer outlined the concept of asymmetric induction;[39] in which he correctly ascribed selective the formation of D-glucose by plants to be due to the influence of optically active substances within chlorophyll. Fischer also successfully performed what would now be regarded as the first example of enantioselective synthesis, by enantioselectively elongating sugars via a process which would eventually become the Kiliani–Fischer synthesis.[40]

organocatalyst by Marckwald in 1904.[38]

The first enantioselective chemical synthesis is most often attributed to

enantiotopic selection, and organocatalysis").[38] This observation is also of historical significance, as at the time enantioselective synthesis could only be understood in terms of vitalism. At the time many prominent chemists such as Jöns Jacob Berzelius argued that natural and artificial compounds were fundamentally different and that chirality was simply a manifestation of the 'vital force' which could only exist in natural compounds.[43] Unlike Fischer, Marckwald had performed an enantioselective reaction upon an achiral, un-natural starting material, albeit with a chiral organocatalyst (as we now understand this chemistry).[38][44][45]

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

, a method which provides no structural data.

It was not until the 1950s that major progress really began. Driven in part by chemists such as

but also by the development of new techniques. The first of these was X-ray crystallography, which was used to determine the absolute configuration of an organic compound by Johannes Bijvoet in 1951.[46] Chiral chromatography was introduced a year later by Dalgliesh, who used paper chromatography to separate chiral amino acids.[47] Although Dalgliesh was not the first to observe such separations, he correctly attributed the separation of enantiomers to differential retention by the chiral cellulose. This was expanded upon in 1960, when Klem and Reed first reported the use of chirally-modified silica gel for chiral
HPLC separation.[48]

The two enantiomers of thalidomide:
Left: (S)-thalidomide
Right: (R)-thalidomide

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

Directive 65/65/EEC1
(EU).

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

CIP system) were first published in 1966; allowing enantiomers to be more easily and accurately described.[53][54]
The same year saw first successful enantiomeric separation by gas chromatography[55] an important development as the technology was in common use at the time.

Metal-catalysed enantioselective synthesis was pioneered by

Monsanto Company he developed an enantioselective hydrogenation step for the production of L-DOPA, utilising the DIPAMP ligand.[56][57][58]

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 the
Noyori asymmetric hydrogenation
reaction.

The Sharpless oxyamination

Sharpless 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

NMR; either using chiral derivatizing agents, such as Mosher's acid,[63]
or europium based shift reagents, of which Eu(DPM)3 was the earliest.[64]

Chiral auxiliaries were introduced by

Hajos–Parrish–Eder–Sauer–Wiechert reaction
. Enzyme-catalyzed enantioselective reactions became more and more common during the 1980s,[66] particularly in industry,[67] with their applications including asymmetric ester hydrolysis with pig-liver esterase. The emerging technology of genetic engineering has allowed the tailoring of enzymes to specific processes, permitting an increased range of selective transformations. For example, in the asymmetric hydrogenation of statin precursors.[23]

See also

References

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