Enantioselective synthesis, also calledasymmetric synthesis,[1] is a form ofchemical synthesis. It is defined byIUPAC as "achemical reaction (or reaction sequence) in which one or more new elements ofchirality are formed in a substrate molecule and which produces thestereoisomeric (enantiomeric ordiastereomeric) products inunequal amounts."[2]
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 ofpharmaceuticals, as the differentenantiomers ordiastereomers of a molecule often have differentbiological activity.
Many of the building blocks of biological systems such assugars andamino acids are produced exclusively as oneenantiomer. As a result, living systems possess a high degree ofchemical 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 identicalenthalpies andentropies and hence should be produced in equal amounts by an undirected process – leading to aracemic mixture. Enantioselective synthesis can be achieved by using a chiral feature that favors the formation of one enantiomer over another through interactions at thetransition state. This biasing is known asasymmetric induction and can involve chiral features in thesubstrate,reagent,catalyst, or environment[9] and works by making theactivation 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. Therate constant,k, for a reaction is the function of theactivation energy of the reaction, sometimes called theenergy barrier, and is temperature-dependent. Using theGibbs 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 | |||
Enantioselective catalysis (known traditionally as "asymmetric catalysis") is performed using chiralcatalysts, which are typically chiralcoordination complexes. Catalysis is effective for a broader range of transformations than any other method of enantioselective synthesis. The chiral metal catalysts are almost invariably rendered chiral by usingchiral ligands, but it is possible to generate chiral-at-metal complexes composed entirely ofachiral ligands.[11][12][13]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 isasymmetric hydrogenation, which is used to reduce a wide variety offunctional groups.
The design of new catalysts is dominated by the development of new classes ofligands. Certain ligands, often referred to as "privileged ligands", are effective in a wide range of reactions; examples includeBINOL,Salen, andBOX. Most catalysts are effective for only one type of asymmetric reaction. For example,Noyori asymmetric hydrogenation with BINAP/Ru requires a β-ketone, although another catalyst, BINAP/diamine-Ru, widens the scope to α,β-alkenes andaromatic chemicals.
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 causeracemization of the product.[19] It is typically then recovered for future use.
Chiral auxiliaries must be used instoichiometric amounts to be effective and require additional synthetic steps to append and remove the auxiliary. However, in some cases the only available stereoselective methodology relies on chiral auxiliaries and these reactions tend to be versatile and very well-studied, allowing the most time-efficient access to enantiomerically pure products.[18] Additionally, the products of auxiliary-directed reactions arediastereomers, which enables their facile separation by methods such ascolumn chromatography or crystallization.
Biocatalysis makes use of biological compounds, ranging from isolatedenzymes to living cells, to perform chemical transformations.[20][21]The advantages of these reagents include very highe.e.s and reagent specificity, as well as mild operating conditions andlow environmental impact. Biocatalysts are more commonly used in industry than in academic research;[22] for example in the production ofstatins.[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.
Organocatalysis refers to a form ofcatalysis, where the rate of achemical reaction is increased by anorganic compound consisting ofcarbon,hydrogen,sulfur and other non-metal elements.[24][25]When the organocatalyst ischiral, then enantioselective synthesis can be achieved;[26][27]for example a number of carbon–carbon bond forming reactions become enantioselective in the presence ofproline with thealdol reaction being a prime example.[28]Organocatalysis often employs natural compounds andsecondary amines as chiral catalysts;[29] these are inexpensive andenvironmentally friendly, as no metals are involved.
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 anSN2 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 oramino acid. However, the number of possible reactions the molecule can undergo is restricted and tortuous synthetic routes may be required (e.g.Oseltamivir total synthesis). This approach also requires astoichiometric amount of theenantiopure starting material, which can be expensive if it is not naturally occurring.
The two enantiomers of a molecule possess many of the same physical properties (e.g.melting point,boiling point,polarity etc.) and so behave identically to each other. As a result, they will migrate with an identical Rf inthin layer chromatography and have identical retention times inHPLC andGC. TheirNMR andIR 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 asquartz or standard media that has been chirally modified. This forms the basis ofchiral column chromatography, which can be used on a small scale to allow analysis viaGC andHPLC, or on a large scale to separate chirally impure materials. However this process can require large amount of chiral packing material which can be expensive. A common alternative is to use achiral derivatizing agent to convert the enantiomers into a diastereomers, in much the same way as chiral auxiliaries. These have different physical properties and hence can be separated and analysed using conventional methods. Special chiral derivitizing agents known as 'chiral resolution agents' are used in theNMR spectroscopy of stereoisomers, these typically involve coordination to chiraleuropium complexes such asEu(fod)3 and Eu(hfc)3.
The separation and analysis of component enantiomers of a racemic drugs or pharmaceutical substances are referred to aschiral analysis.[30] orenantioselective analysis. The most frequently employed technique to carry out chiral analysis involves separation science procedures, specifically chiral chromatographic methods.[31]
Theenantiomeric excess of a substance can also be determined using certain optical methods. The oldest method for doing this is to use apolarimeter to compare the level ofoptical rotation in the product against a 'standard' of known composition. It is also possible to performultraviolet-visible spectroscopy of stereoisomers by exploiting theCotton effect.
One of the most accurate ways of determining the chirality of compound is to determine itsabsolute configuration byX-ray crystallography. However this is a labour-intensive process which requires that a suitablesingle crystal be grown.
In 1815 the French physicistJean-Baptiste Biot showed that certain chemicals could rotate the plane of a beam of polarised light, a property calledoptical activity.[32]The nature of this property remained a mystery until 1848, whenLouis Pasteur proposed that it had a molecular basis originating from some form ofdissymmetry,[33][34]with the termchirality being coined byLord Kelvin a year later.[35]The origin of chirality itself was finally described in 1874, whenJacobus Henricus van 't Hoff andJoseph Le Bel independently proposed thetetrahedral geometry of carbon.[36][37] Structural models prior to this work had been two-dimensional, and van 't Hoff and Le Bel theorized that the arrangement of groups around this tetrahedron could dictate the optical activity of the resulting compound through what became known as theLe Bel–van 't Hoff rule.
In 1894Hermann Emil Fischer outlined the concept ofasymmetric induction;[39] in which he correctly ascribed selective the formation ofD-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 theKiliani–Fischer synthesis.[40]
The first enantioselective chemical synthesis is most often attributed toWilly Marckwald,Universität zu Berlin, for abrucine-catalyzed enantioselectivedecarboxylation of 2-ethyl-2-methylmalonic acid reported in 1904.[38][41] A slight excess of the levorotary form of the product of the reaction, 2-methylbutyric acid, was produced; as this product is also anatural product—e.g., as a side chain oflovastatin formed by its diketide synthase (LovF) during itsbiosynthesis[42]—this result constitutes the first recorded total synthesis with enantioselectivity, as well other firsts (as Koskinen notes, first "example ofasymmetric catalysis,enantiotopic selection, andorganocatalysis").[38] This observation is also of historical significance, as at the time enantioselective synthesis could only be understood in terms ofvitalism. At the time many prominent chemists such asJöns 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]
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 byspontaneous resolution (where enantiomers separate upon crystallisation) orkinetic resolution (where one enantiomer is selectively destroyed). The only tool for analysing enantiomers wasoptical activity using apolarimeter, a method which provides no structural data.
It was not until the 1950s that major progress really began. Driven in part by chemists such asR. B. Woodward andVladimir Prelog but also by the development of new techniques.The first of these wasX-ray crystallography, which was used to determine theabsolute configuration of an organic compound byJohannes Bijvoet in 1951.[46]Chiral chromatography was introduced a year later by Dalgliesh, who usedpaper 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 chiralHPLC separation.[48]
While it was known that the different enantiomers of a drug could have different activities, with significant early work being done byArthur Robertson Cushny,[49][50] this was not accounted for in early drug design and testing. However, following thethalidomide 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 seriouslyteratogenic,[51] eventually causing birth defects in more than 10,000 babies. The disaster prompted many countries to introduce tougher rules for the testing and licensing of drugs, such as theKefauver-Harris Amendment (US) andDirective 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.
The Cahn–Ingold–Prelog priority rules (often abbreviated as theCIP 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 bygas chromatography[55] an important development as the technology was in common use at the time.
Metal-catalysed enantioselective synthesis was pioneered byWilliam S. Knowles,Ryōji Noyori andK. Barry Sharpless; for which they would receive the 2001Nobel Prize in Chemistry. Knowles and Noyori began with the development ofasymmetric hydrogenation, which they developed independently in 1968. Knowles replaced the achiraltriphenylphosphine ligands inWilkinson's catalyst with chiralphosphine ligands. This experimental catalyst was employed in an asymmetric hydrogenation with a modest 15%enantiomeric excess. Knowles was also the first to apply enantioselective metal catalysis to industrial-scale synthesis; while working for theMonsanto Company he developed an enantioselective hydrogenation step for the production ofL-DOPA, utilising theDIPAMP ligand.[56][57][58]
 |  | |
| Knowles: Asymmetric hydrogenation (1968) | Noyori: Enantioselective cyclopropanation (1968) |
|---|
Noyori devised a copper complex using a chiralSchiff base ligand, which he used for themetal–carbenoid cyclopropanation ofstyrene.[59] 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 theNoyori asymmetric hydrogenation reaction.
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, usingosmium tetroxide, being the earliest.
During the same period, methods were developed to allow the analysis of chiral compounds byNMR; either using chiral derivatizing agents, such asMosher's acid,[63]oreuropium based shift reagents, of which Eu(DPM)3 was the earliest.[64]
Chiral auxiliaries were introduced byE.J. Corey in 1978[65] and featured prominently in the work ofDieter Enders. Around the same time enantioselective organocatalysis was developed, with pioneering work including theHajos–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 includingasymmetric ester hydrolysis with pig-liver esterase. The emerging technology ofgenetic engineering has allowed the tailoring of enzymes to specific processes, permitting an increased range of selective transformations. For example, in the asymmetric hydrogenation ofstatin precursors.[23]
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