Asymmetric Synthesis
   HOME

TheInfoList



OR:

Enantioselective synthesis, also called asymmetric synthesis, is a form of
chemical synthesis As a topic of chemistry, chemical synthesis (or combination) is the artificial execution of chemical reactions to obtain one or several products. This occurs by physical and chemical manipulations usually involving one or more reactions. In mo ...
. It is defined by
IUPAC The International Union of Pure and Applied Chemistry (IUPAC ) is an international federation of National Adhering Organizations working for the advancement of the chemical sciences, especially by developing nomenclature and terminology. It is ...
as "a
chemical reaction A chemical reaction is a process that leads to the chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the positions of electrons in the forming and break ...
(or reaction sequence) in which one or more new elements of chirality are formed in a substrate molecule and which produces the
stereoisomer In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms i ...
ic (
enantiomer In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...
ic or diastereomeric) products in unequal amounts." 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
enantiomer In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...
s or diastereomers of a molecule often have different
biological activity In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or ...
.


Overview

Many of the building blocks of biological systems such as sugars and
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
s are produced exclusively as one
enantiomer In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...
. 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
artificial sweetener A sugar substitute is a food additive that provides a sweetness like that of sugar while containing significantly less food energy than sugar-based sweeteners, making it a zero-calorie () or low-calorie sweetener. Artificial sweeteners may ...
aspartame has two enantiomers. L-aspartame tastes sweet whereas D-aspartame is tasteless. * Odor: ''R''-(–)- carvone smells like spearmint whereas ''S''-(+)-carvone smells like caraway. * Drug effectiveness: the
antidepressant Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness ...
drug Citalopram is sold as a
racemic In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...
mixture. However, studies have shown that only the (''S'')-(+) enantiomer is responsible for the drug's beneficial effects. * Drug safety: D‑penicillamine is used in
chelation therapy Chelation therapy is a medical procedure that involves the administration of chelating agents to remove heavy metals from the body. Chelation therapy has a long history of use in clinical toxicology and remains in use for some very specific medi ...
and for the treatment of
rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and ...
whereas L‑penicillamine is toxic as it inhibits the action of pyridoxine, an essential B vitamin. As such enantioselective synthesis is of great importance but it can also be difficult to achieve. Enantiomers possess identical enthalpies and entropies and hence should be produced in equal amounts by an undirected process – leading to a
racemic In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...
mixture. Enantioselective synthesis can be achieved by using a chiral feature that favors the formation of one enantiomer over another through interactions at the
transition state In chemistry, the transition state of a chemical reaction is a particular configuration along the reaction coordinate. It is defined as the state corresponding to the highest potential energy along this reaction coordinate. It is often marked ...
. This biasing is known as asymmetric induction and can involve chiral features in the
substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (locomotion), the surface over which an organism lo ...
, reagent,
catalyst Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
, or environment and works by making the
activation energy In chemistry and physics, activation energy is the minimum amount of energy that must be provided for compounds to result in a chemical reaction. The activation energy (''E''a) of a reaction is measured in joules per mole (J/mol), kilojoules p ...
required to form one enantiomer lower than that of the opposing enantiomer. 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 In chemical kinetics a reaction rate constant or reaction rate coefficient, ''k'', quantifies the rate and direction of a chemical reaction. For a reaction between reactants A and B to form product C the reaction rate is often found to have the f ...
, ''k'', for a reaction is function of the
activation energy In chemistry and physics, activation energy is the minimum amount of energy that must be provided for compounds to result in a chemical reaction. The activation energy (''E''a) of a reaction is measured in joules per mole (J/mol), kilojoules p ...
of the reaction, sometimes called the ''energy barrier'', and is temperature-dependent. Using the
Gibbs free energy In thermodynamics, the Gibbs free energy (or Gibbs energy; symbol G) is a thermodynamic potential that can be used to calculate the maximum amount of work (physics), work that may be performed by a closed system, thermodynamically closed system a ...
of the energy barrier, Δ''G''*, means that the relative rates for opposing stereochemical outcomes at a given temperature, ''T'', is: :\frac = 10^\frac 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. :


Approaches


Enantioselective catalysis

Enantioselective catalysis (known traditionally as "asymmetric catalysis") is performed using chiral catalysts, which are typically chiral
coordination complex A coordination complex consists of a central atom or ion, which is usually metallic and is called the ''coordination centre'', and a surrounding array of bound molecules or ions, that are in turn known as ''ligands'' or complexing agents. Many ...
es. 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 using
chiral ligand Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as "a chemical reaction (or reaction sequence) in which one or more new elements of chirality are formed in a substrate molec ...
s, but it is possible to generate chiral-at-metal complexes composed entirely of achiral ligands. Most enantioselective catalysts are effective at low substrate/catalyst ratios. Given their high efficiencies, they are often suitable for industrial scale synthesis, even with expensive catalysts. A versatile example of enantioselective synthesis is asymmetric hydrogenation, which is used to reduce a wide variety of
functional group In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the res ...
s. The design of new catalysts is dominated by the development of new classes of
ligand In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ele ...
s. Certain ligands, often referred to as "
privileged ligand In homogeneous catalysis, ''C''2-symmetric ligands refer to ligands that lack mirror symmetry but have ''C''2 symmetry (two-fold rotational symmetry). Such ligands are usually bidentate and are valuable in catalysis. The ''C''2 symmetry of ligan ...
s", are effective in a wide range of reactions; examples include BINOL, Salen, and BOX. 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 In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond. Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic, an ...
and 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. At the end of the reaction the auxiliary is removed, under conditions that will not cause racemization of the product. It is typically then recovered for future use. Chiral auxiliaries must be used in
stoichiometric Stoichiometry refers to the relationship between the quantities of reactants and products before, during, and following chemical reactions. Stoichiometry is founded on the law of conservation of mass where the total mass of the reactants equ ...
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. Additionally, the products of auxiliary-directed reactions are diastereomers, which enables their facile separation by methods such as column chromatography or crystallization.


Biocatalysis

Biocatalysis makes use of biological compounds, ranging from isolated
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
s to living cells, to perform chemical transformations. 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; for example in the production of
statin Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs. L ...
s. 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 Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recycl ...
, where the rate of a
chemical reaction A chemical reaction is a process that leads to the chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the positions of electrons in the forming and break ...
is increased by an
organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon- hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. Th ...
consisting of
carbon Carbon () is a chemical element with the symbol C and atomic number 6. It is nonmetallic and tetravalent—its atom making four electrons available to form covalent chemical bonds. It belongs to group 14 of the periodic table. Carbon makes ...
,
hydrogen Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-toxic ...
,
sulfur Sulfur (or sulphur in British English) is a chemical element with the symbol S and atomic number 16. It is abundant, multivalent and nonmetallic. Under normal conditions, sulfur atoms form cyclic octatomic molecules with a chemical formul ...
and other non-metal elements.Special Issue: When the organocatalyst is
chiral Chirality is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is distinguishable from i ...
, then enantioselective synthesis can be achieved; for example a number of carbon–carbon bond forming reactions become enantioselective in the presence of proline with the
aldol reaction The aldol reaction is a means of forming carbon–carbon bonds in organic chemistry. Discovered independently by the Russian chemist Alexander Borodin in 1869 and by the French chemist Charles-Adolphe Wurtz in 1872, the reaction combines two c ...
being a prime example. Organocatalysis often employs natural compounds and secondary amines as chiral catalysts; these are inexpensive and
environmentally friendly Environment friendly processes, or environmental-friendly processes (also referred to as eco-friendly, nature-friendly, and green), are sustainability and marketing terms referring to goods and services, laws, guidelines and policies that cl ...
, 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
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
. 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 a
stoichiometric Stoichiometry refers to the relationship between the quantities of reactants and products before, during, and following chemical reactions. Stoichiometry is founded on the law of conservation of mass where the total mass of the reactants equ ...
amount of the 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 the same physical properties (e.g.
melting point The melting point (or, rarely, liquefaction point) of a substance is the temperature at which it changes state from solid to liquid. At the melting point the solid and liquid phase exist in equilibrium. The melting point of a substance depends ...
, boiling point,
polarity Polarity may refer to: Science * Electrical polarity, direction of electrical current * Polarity (mutual inductance), the relationship between components such as transformer windings * Polarity (projective geometry), in mathematics, a duality of o ...
etc.) and so behave identically to each other. As a result, they will migrate with an identical Rf in thin layer chromatography and have identical retention times in
HPLC High-performance liquid chromatography (HPLC), formerly referred to as high-pressure liquid chromatography, is a technique in analytical chemistry used to separate, identify, and quantify each component in a mixture. It relies on pumps to pa ...
and GC. Their 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
quartz Quartz is a hard, crystalline mineral composed of silica ( silicon dioxide). The atoms are linked in a continuous framework of SiO4 silicon-oxygen tetrahedra, with each oxygen being shared between two tetrahedra, giving an overall chemical ...
or standard media that has been chirally modified. This forms the basis of chiral column chromatography, which can be used on a small scale to allow analysis via GC and
HPLC High-performance liquid chromatography (HPLC), formerly referred to as high-pressure liquid chromatography, is a technique in analytical chemistry used to separate, identify, and quantify each component in a mixture. It relies on pumps to pa ...
, 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 a chiral 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 the
NMR spectroscopy of stereoisomers Nuclear magnetic resonance spectroscopy of stereoisomers most commonly known as NMR spectroscopy of stereoisomers is a chemical analysis method that uses NMR spectroscopy to determine the absolute configuration of stereoisomers. For example, the '' ...
, 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 chiral analysis. or
enantioselective analysis Chiral analysis refers to the quantification of component enantiomers of racemic drug substances or pharmaceutical compounds. Other synonyms commonly used include enantiomer analysis, enantiomeric analysis, and enantioselective analysis. Chiral ...
. The most frequently employed technique to carryout chiral analysis involves separation science procedures, specifically chiral chromatographic methods. The
enantiomeric excess In stereochemistry, enantiomeric excess (ee) is a measurement of purity used for chiral substances. It reflects the degree to which a sample contains one enantiomer in greater amounts than the other. A racemic mixture has an ee of 0%, while a s ...
of a substance can also be determined using certain optical methods. The oldest method for doing this is to use a
polarimeter A polarimeter is a scientific instrument used to measure the angle of rotation caused by passing polarized light through an optically active substance.optical rotation Optical rotation, also known as polarization rotation or circular birefringence, is the rotation of the orientation of the plane of polarization about the optical axis of linearly polarized light as it travels through certain materials. Circular ...
in the product against a 'standard' of known composition. It is also possible to perform ultraviolet-visible spectroscopy of stereoisomers by exploiting the Cotton effect. One of the most accurate ways of determining the chirality of compound is to determine its absolute configuration by
X-ray crystallography X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angle ...
. However this is a labour-intensive process which requires that a suitable
single crystal In materials science, a single crystal (or single-crystal solid or monocrystalline solid) is a material in which the crystal lattice of the entire sample is continuous and unbroken to the edges of the sample, with no grain boundaries.RIWD. "R ...
be grown.


History


Inception (1815–1905)

In 1815 the French physicist Jean-Baptiste Biot showed that certain chemicals could rotate the plane of a beam of polarised light, a property called
optical activity Optical rotation, also known as polarization rotation or circular birefringence, is the rotation of the orientation of the plane of polarization about the optical axis of linearly polarized light as it travels through certain materials. Circular ...
. 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'', with the term ''chirality'' being coined by
Lord Kelvin William Thomson, 1st Baron Kelvin, (26 June 182417 December 1907) was a British mathematician, mathematical physicist and engineer born in Belfast. Professor of Natural Philosophy at the University of Glasgow for 53 years, he did important ...
a year later. The origin of chirality itself was finally described in 1874, when
Jacobus Henricus van 't Hoff Jacobus Henricus "Henry" van 't Hoff Jr. (; 30 August 1852 – 1 March 1911) was a Dutch physical chemist. A highly influential theoretical chemist of his time, van 't Hoff was the first winner of the Nobel Prize in Chemistry. His pioneer ...
and
Joseph Le Bel Joseph Achille Le Bel (21 January 1847 in Pechelbronn – 6 August 1930, in Paris, France) was a French chemist. He is best known for his work in stereochemistry. Le Bel was educated at the École Polytechnique in Paris. In 1874 he announced ...
independently proposed the tetrahedral geometry of carbon. 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 the Le Bel–van 't Hoff rule. In 1894 Hermann Emil Fischer outlined the concept of asymmetric induction; 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. The first enantioselective chemical synthesis is most often attributed to Willy Marckwald, Universität zu Berlin, for a brucine-catalyzed enantioselective
decarboxylation Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is ...
of 2-ethyl-2-methyl malonic acid reported in 1904. A slight excess of the levorotary form of the product of the reaction, 2-methylbutyric acid, was produced; as this product is also a
natural product A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical sy ...
—e.g., as a side chain of lovastatin formed by its diketide synthase (LovF) during its biosynthesis—this result constitutes the first recorded total synthesis with enantioselectivity, as well other firsts (as Koskinen notes, first "example of asymmetric catalysis, enantiotopic selection, and
organocatalysis In organic chemistry, organocatalysis is a form of catalysis in which the rate of a chemical reaction is increased by an organic catalyst. This "organocatalyst" consists of carbon, hydrogen, sulfur and other nonmetal elements found in organic com ...
"). This observation is also of historical significance, as at the time enantioselective synthesis could only be understood in terms of
vitalism Vitalism is a belief that starts from the premise that "living organisms are fundamentally different from non-living entities because they contain some non-physical element or are governed by different principles than are inanimate things." Wher ...
. At the time many prominent chemists such as
Jöns Jacob Berzelius Baron Jöns Jacob Berzelius (; by himself and his contemporaries named only Jacob Berzelius, 20 August 1779 – 7 August 1848) was a Swedish chemist. Berzelius is considered, along with Robert Boyle, John Dalton, and Antoine Lavoisier, to be ...
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. 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).


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 spontaneous resolution (where enantiomers separate upon crystallisation) or kinetic resolution (where one enantiomer is selectively destroyed). The only tool for analysing enantiomers was
optical activity Optical rotation, also known as polarization rotation or circular birefringence, is the rotation of the orientation of the plane of polarization about the optical axis of linearly polarized light as it travels through certain materials. Circular ...
using a
polarimeter A polarimeter is a scientific instrument used to measure the angle of rotation caused by passing polarized light through an optically active substance.R. B. Woodward Robert Burns Woodward (April 10, 1917 – July 8, 1979) was an American organic chemist. He is considered by many to be the most preeminent synthetic organic chemist of the twentieth century, having made many key contributions to the subject, ...
and Vladimir Prelog but also by the development of new techniques. The first of these was
X-ray crystallography X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angle ...
, which was used to determine the absolute configuration of an organic compound by Johannes Bijvoet in 1951. Chiral chromatography was introduced a year later by Dalgliesh, who used
paper chromatography Paper chromatography is an analytical method used to separate coloured chemicals or substances. It is now primarily used as a teaching tool, having been replaced in the laboratory by other chromatography methods such as thin-layer chromatograph ...
to separate chiral amino acids. 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 High-performance liquid chromatography (HPLC), formerly referred to as high-pressure liquid chromatography, is a technique in analytical chemistry used to separate, identify, and quantify each component in a mixture. It relies on pumps to pa ...
separation.


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, this was not accounted for in early drug design and testing. However, following the
thalidomide Thalidomide, sold under the brand names Contergan and Thalomid among others, is a medication used to treat a number of cancers (including multiple myeloma), graft-versus-host disease, and a number of skin conditions including complications o ...
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
teratogenic Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology. The relat ...
, 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 the Kefauver-Harris Amendment (US) and 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. 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 CIP may refer to: Business and finance * Commercially Important Person * Construction in progress, a balance sheet assets item * Continual improvement process * "Carriage and Insurance Paid to" Incoterms * Customer Identification Program, in US ...
) were first published in 1966; allowing enantiomers to be more easily and accurately described. The same year saw first successful enantiomeric separation by gas chromatography an important development as the technology was in common use at the time. Metal-catalysed enantioselective synthesis was pioneered by
William S. Knowles William Standish Knowles (June 1, 1917 – June 13, 2012) was an American chemist. He was born in Taunton, Massachusetts. Knowles was one of the recipients of the 2001 Nobel Prize in Chemistry. He split half the prize with Ryōji Noyori for thei ...
, Ryōji Noyori and
K. Barry Sharpless Karl Barry Sharpless (born April 28, 1941) is an American chemist and a two-time Nobel laureate in Chemistry known for his work on stereoselective reactions and click chemistry. Sharpless was awarded half of the 2001 Nobel Prize in Chemistry " ...
; for which they would receive the 2001
Nobel Prize in Chemistry ) , image = Nobel Prize.png , alt = A golden medallion with an embossed image of a bearded man facing left in profile. To the left of the man is the text "ALFR•" then "NOBEL", and on the right, the text (smaller) "NAT•" then "M ...
. Knowles and Noyori began with the development of asymmetric hydrogenation, which they developed independently in 1968. Knowles replaced the achiral
triphenylphosphine Triphenylphosphine (IUPAC name: triphenylphosphane) is a common organophosphorus compound with the formula P(C6H5)3 and often abbreviated to P Ph3 or Ph3P. It is widely used in the synthesis of organic and organometallic compounds. PPh3 exists ...
ligands in Wilkinson's catalyst with chiral phosphine ligands. This experimental catalyst was employed in an asymmetric hydrogenation with a modest 15%
enantiomeric excess In stereochemistry, enantiomeric excess (ee) is a measurement of purity used for chiral substances. It reflects the degree to which a sample contains one enantiomer in greater amounts than the other. A racemic mixture has an ee of 0%, while a s ...
. Knowles was also the first to apply enantioselective metal catalysis to industrial-scale synthesis; while working for the
Monsanto Company The Monsanto Company () was an American agrochemical and agricultural biotechnology corporation founded in 1901 and headquartered in Creve Coeur, Missouri. Monsanto's best known product is Roundup, a glyphosate-based herbicide, developed in the ...
he developed an enantioselective hydrogenation step for the production of
L-DOPA -DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOP ...
, utilising the DIPAMP ligand. Noyori devised a copper complex using a chiral Schiff base ligand, which he used for the metal–carbenoid cyclopropanation of styrene. 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. Sharpless complemented these reduction reactions by developing a range of asymmetric oxidations ( Sharpless epoxidation, Sharpless asymmetric dihydroxylation,
Sharpless oxyamination The Sharpless oxyamination (often known as Sharpless aminohydroxylation) is the chemical reaction that converts an alkene to a vicinal amino alcohol. The reaction is related to the Sharpless dihydroxylation, which converts alkenes to vicinal dio ...
) 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, or europium based shift reagents, of which Eu(DPM)3 was the earliest. Chiral auxiliaries were introduced by E.J. Corey in 1978 and featured prominently in the work of Dieter Enders. Around the same time enantioselective organocatalysis was developed, with pioneering work including the Hajos–Parrish–Eder–Sauer–Wiechert reaction. Enzyme-catalyzed enantioselective reactions became more and more common during the 1980s, particularly in industry, with their applications including asymmetric ester hydrolysis with pig-liver esterase. The emerging technology of
genetic engineering Genetic engineering, also called genetic modification or genetic manipulation, is the modification and manipulation of an organism's genes using technology. It is a set of technologies used to change the genetic makeup of cells, including ...
has allowed the tailoring of enzymes to specific processes, permitting an increased range of selective transformations. For example, in the asymmetric hydrogenation of
statin Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs. L ...
precursors.


See also

*
Aza-Baylis–Hillman reaction The aza-Baylis–Hillman reaction or aza-BH reaction in organic chemistry is a variation of the Baylis–Hillman reaction and describes the reaction of an electron deficient alkene, usually an α,β-unsaturated carbonyl compound, with an imine in ...
, for the use of a chiral ionic liquid in enantioselective synthesis *
Kelliphite Kelliphite is an acronym for the organophosphorus compound 6,6'- 1,1'-Biphenyl-2,2'-diyl)bis(oxy)is ,8-di-tbutyl-1,2,10,11-tetramethylibenzo ,f1,3,2]dioxaphosphepin. This Chiral synthesis, chiral ligand is widely used in asymmetric synthesis. In o ...
, 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
polymer A polymer (; Greek ''poly-'', "many" + '' -mer'', "part") is a substance or material consisting of very large molecules called macromolecules, composed of many repeating subunits. Due to their broad spectrum of properties, both synthetic and ...
s which originates from enantioselective synthesis * Chiral analysis *
Enantioselective analysis Chiral analysis refers to the quantification of component enantiomers of racemic drug substances or pharmaceutical compounds. Other synonyms commonly used include enantiomer analysis, enantiomeric analysis, and enantioselective analysis. Chiral ...


References

{{Branches of chemistry Chemical synthesis Stereochemistry Asymmetry