Editing Enantioselective synthesis

{{Short description|Chemical reaction(s) which favor one chiral isomer over another}}
{{Use dmy dates|date=April 2022}}
[[File:Sharpless Dihydroxylation Scheme.png|thumb|500px|In the [[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]]<br /><br />Key: R<sub>L</sub> = Largest substituent; R<sub>M</sub> = Medium-sized substituent; R<sub>S</sub> = Smallest substituent]]
[[File:Chirality with hands.svg|300px|thumb|Two enantiomers of a generic [[alpha amino acid]]
{{legend|black|[[Carbon]] at the [[chiral center]]}}
{{legend|#ff4500|[[Carboxylic acid]] group}}
{{legend|#00dfff|R group}}
{{legend|grey|[[Hydrogen]]}}]]
'''Enantioselective synthesis''', also called '''asymmetric synthesis''',<ref>{{GoldBookRef|title=asymmetric synthesis| file = A00484}}</ref> 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 (chemistry)|chirality]] are formed in a substrate molecule and which produces the [[stereoisomer]]ic ([[enantiomer]]ic or [[diastereomer]]ic) products in [[Enantiomeric excess|unequal amounts]]."<ref>{{GoldBookRef|title=stereoselective synthesis|file = S05990}}</ref>

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]]s or [[diastereomer]]s of a molecule often have different [[biological activity]].

==Overview==
[[File:Energy diagram for enantioselective synthesis.png|300px|thumb|An [[Energy profile (chemistry)|energy profile]] of an enantioselective addition reaction.]]

Many of the building blocks of biological systems such as [[sugar]]s and [[amino acid]]s are produced exclusively as one [[enantiomer]]. As a result, living systems possess a high degree of [[Chirality (chemistry)|chemical chirality]] and will often react differently with the various enantiomers of a given compound. Examples of this selectivity include:
* '''Flavour:''' the [[artificial sweetener]] [[aspartame]] has two enantiomers. <small>L</small>-aspartame tastes sweet whereas <small>D</small>-aspartame is tasteless.<ref>{{cite journal|last=Gal|first=Joseph|title=The Discovery of Stereoselectivity at Biological Receptors: Arnaldo Piutti and the Taste of the Asparagine Enantiomers-History and Analysis on the 125th Anniversary|journal=Chirality|year=2012|volume=24|issue=12|pages=959–976|doi=10.1002/chir.22071|pmid=23034823}}</ref>
* '''Odor:''' ''R''-(–)-[[carvone]] smells like [[spearmint]] whereas ''S''-(+)-carvone smells like [[caraway]].<ref>{{cite journal | doi = 10.1021/jf60176a035 | title=Chemical and sensory data supporting the difference between the odors of the enantiomeric carvones |author1=Theodore J. Leitereg |author2=Dante G. Guadagni |author3=Jean Harris |author4=Thomas R. Mon |author5=Roy Teranishi | journal=[[J. Agric. Food Chem.]] | volume=19 | issue=4 | year=1971 | pages=785–787| bibcode=1971JAFC...19..785L }}</ref>
* '''Drug effectiveness:''' the [[antidepressant]] drug [[Citalopram]] is sold as a [[racemic]] mixture. However, studies have shown that only [[Escitalopram|the (''S'')-(+) enantiomer]] is responsible for the drug's beneficial effects.<ref name="pmid15107657">{{cite journal |vauthors=Lepola U, Wade A, Andersen HF | title = Do equivalent doses of escitalopram and citalopram have similar efficacy? A pooled analysis of two positive placebo-controlled studies in major depressive disorder | journal = Int Clin Psychopharmacol | volume = 19 | issue = 3 | pages = 149–55 |date=May 2004 | pmid = 15107657 | doi = 10.1097/00004850-200405000-00005 | s2cid = 36768144 }}</ref><ref>{{cite journal|last=Hyttel|first=J.|author2=Bøgesø, K. P. |author3=Perregaard, J. |author4= Sánchez, C. |title=The pharmacological effect of citalopram resides in the (''S'')-(+)-enantiomer|journal=Journal of Neural Transmission|year=1992|volume=88|issue=2|pages=157–160|doi=10.1007/BF01244820|pmid=1632943|s2cid=20110906}}</ref>
* '''Drug safety:''' [[Penicillamine|<small>D</small>‑penicillamine]] is used in [[chelation therapy]] and for the treatment of [[rheumatoid arthritis]] whereas <small>L</small>‑penicillamine is toxic as it inhibits the action of [[pyridoxine]], an essential B vitamin.<ref>{{cite journal|last=JAFFE|first=IA|author2=ALTMAN, K |author3=MERRYMAN, P |title=The Antipyridoxine Effect of Penicillamine in Man.|journal=The Journal of Clinical Investigation|date=Oct 1964|volume=43|issue=10|pages=1869–73|pmid=14236210|doi=10.1172/JCI105060|pmc=289631}}</ref><ref>{{cite journal |last1=Smith |first1=Silas W. |title=Chiral Toxicology: It's the Same Thing...Only Different |journal=Toxicological Sciences |date=July 2009 |volume=110 |issue=1 |pages=4–30 |doi=10.1093/toxsci/kfp097 |pmid=19414517 |doi-access=free}}</ref>

As such enantioselective synthesis is of great importance but it can also be difficult to achieve. Enantiomers possess identical [[Enthalpy of formation|enthalpies]] and [[Entropy|entropies]] and hence should be produced in equal amounts by an undirected process – leading to a [[racemic]] 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]]. This biasing is known as [[asymmetric induction]] and can involve chiral features in the [[Substrate (chemistry)|substrate]], [[reagent]], [[catalyst]], or environment<ref>{{GoldBookRef|title=asymmetric induction|file = A00483}}</ref> and works by making the [[activation energy]] required to form one enantiomer lower than that of the opposing enantiomer.<ref>{{Clayden}}Page 1226</ref>

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 the 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, Δ''G''*, means that the relative rates for opposing stereochemical outcomes at a given temperature, ''T'', is:

:<math>\frac{k_1}{k_2} = 10^\frac{\Delta \Delta G^*}{T \times 1.98 \times 2.3}</math>

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.

:{| class="wikitable"
|-
! ΔΔ''G''* (kcal)
!colspan=2 |{{sfrac|''k''<sub>1</sub>|''k''<sub>2</sub>}} at 273&nbsp;K
!colspan=2 |{{sfrac|''k''<sub>1</sub>|''k''<sub>2</sub>}} at 298&nbsp;K
!colspan=2 |{{sfrac|''k''<sub>1</sub>|''k''<sub>2</sub>}} at 323&nbsp;K)
|-
| style="text-align:center;" | 1.0
| {{decimal cell|6.37}}
| {{decimal cell|5.46}}
| {{decimal cell|4.78}}
|-
| style="text-align:center;" | 2.0
| {{decimal cell|40.6}}
| {{decimal cell|29.8}}
| {{decimal cell|22.9}}
|-
| style="text-align:center;" | 3.0
| {{decimal cell|259}}
| {{decimal cell|162}}
| {{decimal cell|109}}
|-
| style="text-align:center;" | 4.0
| {{decimal cell|1650}}
| {{decimal cell|886}}
| {{decimal cell|524}}
|-
| style="text-align:center;" | 5.0
| {{decimal cell|10500}}
| {{decimal cell|4830}}
| {{decimal cell|2510}}
|}

==Approaches==
===Enantioselective catalysis===
Enantioselective catalysis (known traditionally as "asymmetric catalysis") is performed using chiral [[catalysts]], which are typically chiral [[coordination complex]]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]]s, but it is possible to generate chiral-at-metal complexes composed entirely of [[achiral]] ligands.<ref>{{cite journal|last=Bauer|first=Eike B.|title=Chiral-at-metal complexes and their catalytic applications in organic synthesis|journal=Chemical Society Reviews|year=2012|volume=41|issue=8|pages=3153–67|doi=10.1039/C2CS15234G|pmid=22306968}}</ref><ref>{{Cite journal|last1=Zhang|first1=Lilu|last2=Meggers|first2=Eric|date=2017-02-21|title=Steering Asymmetric Lewis Acid Catalysis Exclusively with Octahedral Metal-Centered Chirality|url=https://doi.org/10.1021/acs.accounts.6b00586|journal=Accounts of Chemical Research|volume=50|issue=2|pages=320–330|doi=10.1021/acs.accounts.6b00586|pmid=28128920|issn=0001-4842|url-access=subscription}}</ref><ref>{{Cite journal|last1=Huang|first1=Xiaoqiang|last2=Meggers|first2=Eric|date=2019-03-19|title=Asymmetric Photocatalysis with Bis-cyclometalated Rhodium Complexes|url=https://pubs.acs.org/doi/10.1021/acs.accounts.9b00028|journal=Accounts of Chemical Research|language=en|volume=52|issue=3|pages=833–847|doi=10.1021/acs.accounts.9b00028|pmid=30840435|s2cid=73503362 |issn=0001-4842|url-access=subscription}}</ref>
Most enantioselective catalysts are effective at low substrate/catalyst ratios.<ref>{{cite book|last1=N. Jacobsen|first1=Eric|last2=Pfaltz|first2=Andreas|last3=Yamamoto|first3=Hisashi|title=Comprehensive asymmetric catalysis 1-3|date=1999|publisher=Springer|location=Berlin|isbn=978-3-540-64337-1}}</ref><ref>{{cite journal |author1=M. Heitbaum |author2=F. Glorius |author3=I. Escher | title = Asymmetric Heterogeneous Catalysis | year = 2006 | journal = [[Angewandte Chemie International Edition]] | volume = 45 | issue = 29 | pages = 4732–4762 | doi = 10.1002/anie.200504212 | pmid = 16802397}}</ref> Given their high efficiencies, they are often suitable for industrial scale synthesis, even with expensive catalysts.<ref>Asymmetric Catalysis on Industrial Scale, (Blaser, Schmidt), Wiley-VCH, 2004.</ref> A versatile example of enantioselective synthesis is [[asymmetric hydrogenation]], which is used to reduce a wide variety of [[functional group]]s.

[[File:Noyori Asymmetric Hydrogenation Scheme.png|center|400px]]

The design of new catalysts is dominated by the development of new classes of [[ligand]]s. Certain ligands, often referred to as "[[privileged ligand]]s", are effective in a wide range of reactions; examples include [[BINOL]], [[Salen ligand|Salen]], and [[Bisoxazoline ligand|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]] and [[aromatic chemical]]s.

===Chiral auxiliaries===
{{Main|Chiral auxiliary}}
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.<ref>{{cite book|last1=Roos|first1=Gregory|title=Compendium of chiral auxiliary applications.|date=2002|publisher=Acad. Press|location=San Diego, CA|isbn=978-0-12-595344-3}}</ref><ref name = "Glorius review">{{cite journal | author = Glorius, F. |author2=Gnas, Y. | title = Chiral Auxiliaries – Principles and Recent Applications | year = 2006 | journal = [[Synthesis (journal)|Synthesis]] | volume = 2006 | pages = 1899–1930 | doi = 10.1055/s-2006-942399 | issue = 12}}</ref> At the end of the reaction the auxiliary is removed, under conditions that will not cause [[racemization]] of the product.<ref name="Evans review">{{cite book |last1=Evans |first1=D. A. | last2=Helmchen | first2=G. | last3= Rüping | first3=M. | editor-first=M. |editor-last=Christmann |title=Asymmetric Synthesis – The Essentials |publisher=Wiley-VCH Verlag GmbH & Co. |year=2007 |pages=3–9 |chapter=Chiral Auxiliaries in Asymmetric Synthesis |isbn=978-3-527-31399-0}}</ref> It is typically then recovered for future use.

[[File:Auxiliary general scheme.png|center|500px]]

Chiral auxiliaries must be used in [[stoichiometric]] 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.<ref name = "Glorius review" /> Additionally, the products of auxiliary-directed reactions are [[diastereomers]], which enables their facile separation by methods such as [[column chromatography]] or crystallization.

===Biocatalysis===
{{Main|Biocatalysis}}
Biocatalysis makes use of biological compounds, ranging from isolated [[enzyme]]s to living cells, to perform chemical transformations.<ref>{{GoldBookRef|title=Biocatalysis| file = B00652}}</ref><ref>{{cite book|last1=Faber|first1=Kurt|title=Biotransformations in organic chemistry a textbook|date=2011|publisher=Springer-Verlag|location=Berlin|isbn=978-3-642-17393-6|edition=6th rev. and corr.}}</ref>
The advantages of these reagents include very high [[Enantiomeric excess|e.e.s]] and reagent specificity, as well as mild operating conditions and [[Green chemistry|low environmental impact]]. Biocatalysts are more commonly used in industry than in academic research;<ref>{{cite journal|last=Schmid|first=A.|author2=Dordick, J. S. |author3=Hauer, B. |author4=Kiener, A. |author5=Wubbolts, M. |author6= Witholt, B. |journal=Nature|year=2001|volume=409|issue=6817|pages=258–268|doi=10.1038/35051736|pmid=11196655|title=Industrial biocatalysis today and tomorrow|bibcode=2001Natur.409..258S|s2cid=4340563}}</ref> for example in the production of [[statin]]s.<ref name="statin">{{cite journal|last=Müller|first=Michael|title=Chemoenzymatic Synthesis of Building Blocks for Statin Side Chains|journal=Angewandte Chemie International Edition|date=7 January 2005|volume=44|issue=3|pages=362–365|doi=10.1002/anie.200460852|pmid=15593081|doi-access=free}}</ref>
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===
{{Main|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.<ref>{{cite book | title=Asymmetric Organocatalysis|author1=Berkessel, A. |author2=Groeger, H. | year=2005| publisher=Wiley-VCH| location=Weinheim| isbn=3-527-30517-3}}</ref><ref name="Special_Issue_Chem_Rev">Special Issue: {{Cite journal | volume = 107 | issue = 12 | pages = 5413–5883 | first = Benjamin| last = List | title = Organocatalysis | journal = Chem. Rev. | year = 2007 | doi = 10.1021/cr078412e| doi-access = free }}</ref>
When the organocatalyst is [[Chirality (chemistry)|chiral]], then enantioselective synthesis can be achieved;<ref>{{cite book|last=Gröger|first=Albrecht Berkessel; Harald|title=Asymmetric organocatalysis – from biomimetic concepts to applications in asymmetric synthesis|year=2005|publisher=Wiley-VCH|location=Weinheim|isbn=3-527-30517-3|edition=1. ed., 2. reprint.}}</ref><ref>{{cite journal|last=Dalko|first=Peter I.|author2=Moisan, Lionel|title=Enantioselective Organocatalysis|journal=Angewandte Chemie International Edition|date=15 October 2001|volume=40|issue=20|pages=3726–3748|doi=10.1002/1521-3773(20011015)40:20<3726::AID-ANIE3726>3.0.CO;2-D|pmid=11668532}}</ref>
for example a number of carbon–carbon bond forming reactions become enantioselective in the presence of [[proline]] with the [[Aldol reaction#Organocatalysis|aldol reaction]] being a prime example.<ref>{{cite journal|last=Notz|first=Wolfgang|author2=Tanaka, Fujie |author3=Barbas, Carlos F. |title=Enamine-Based Organocatalysis with Proline and Diamines: The Development of Direct Catalytic Asymmetric Aldol, Mannich, Michael, and Diels−Alder Reactions|journal=Accounts of Chemical Research|date=1 August 2004|volume=37|issue=8|pages=580–591|doi=10.1021/ar0300468|pmid=15311957}}</ref>
Organocatalysis often employs natural compounds and [[secondary amine]]s as chiral catalysts;<ref>{{cite journal|last1=Bertelsen|first1=Søren|last2=Jørgensen|first2=Karl Anker|title=Organocatalysis—after the gold rush|journal=Chemical Society Reviews|date=2009|volume=38|issue=8|pages=2178–89|doi=10.1039/b903816g|pmid=19623342}}</ref> these are inexpensive and [[green chemistry|environmentally friendly]], as no metals are involved.

===Chiral pool synthesis===
{{Main|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|S<sub>N</sub>2 reaction]].

[[File:SN2 reaction mechanism.png|center|450px]]

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]]. 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]] 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 many of the same physical properties (e.g. [[melting point]], [[boiling point]], [[Chemical polarity|polarity]] etc.) and so behave identically to each other. As a result, they will migrate with an identical R<sub>f</sub> in [[thin layer chromatography]] and have identical retention times in [[High-performance liquid chromatography|HPLC]] and [[gas chromatography|GC]]. Their [[NMR]] and [[Infrared spectroscopy|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]] 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 [[gas chromatography|GC]] and [[High-performance liquid chromatography|HPLC]], 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]], these typically involve coordination to chiral [[europium]] complexes such as [[EuFOD|Eu(fod)<sub>3</sub>]] and Eu(hfc)<sub>3</sub>.

The separation and analysis of component enantiomers of a racemic drugs or pharmaceutical substances are referred to as [[chiral analysis]].<ref>{{Cite book|last=Allenmark|first=Stig G.|title=Chromatographic enantioseparation : methods and applications|publisher=E. Horwood|year=1988|isbn=0-85312-988-6|location=Chichester, West Sussex, England|pages=64–66}}</ref> or [[enantioselective analysis]]. The most frequently employed technique to carry out chiral analysis involves separation science procedures, specifically chiral chromatographic methods.<ref>{{Cite book|last1=Snyder|first1=Lloyd R.|last2=Kirkland|first2=Joseph J.|last3=Glajch|first3=Joseph L.|date=1997-02-28|title=Practical HPLC Method Development|url=http://dx.doi.org/10.1002/9781118592014|doi=10.1002/9781118592014|isbn=978-1-118-59201-4}}</ref>

The [[enantiomeric excess]] of a substance can also be determined using certain optical methods. The oldest method for doing this is to use a [[polarimeter]] to compare the level of [[optical rotation]] 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]]. 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 [[Jean-Baptiste Biot]] showed that certain chemicals could rotate the plane of a beam of polarised light, a property called [[optical activity]].<ref>{{cite book | editor= Lakhtakia, A. | title=Selected Papers on Natural Optical Activity (SPIE Milestone Volume 15) |publisher=SPIE | year=1990}}</ref>
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'',<ref>{{cite journal|last1=Gal|first1=Joseph|title=Louis Pasteur, language, and molecular chirality. I. Background and Dissymmetry|journal=Chirality|date=January 2011|volume=23|issue=1|pages=1–16|doi=10.1002/chir.20866|pmid=20589938}}</ref><ref>{{cite book | author= Pasteur, L. | title=Researches on the molecular asymmetry of natural organic products, English translation of French original, published by Alembic Club Reprints (Vol. 14, pp. 1–46) in 1905, facsimile reproduction by SPIE in a 1990 book | year=1848}}</ref>
with the term ''chirality'' being coined by [[Lord Kelvin]] a year later.<ref>{{cite journal |title=Tracing the Origins and Evolution of Chirality and Handedness in Chemical Language |author=Pedro Cintas |journal=Angewandte Chemie International Edition |volume=46 |issue=22 |pages=4016–4024 |doi=10.1002/anie.200603714 |year=2007 |pmid=17328087}}</ref>
The origin of chirality itself was finally described in 1874, when [[Jacobus Henricus van 't Hoff|Jacobus Henricus van&nbsp;'t Hoff]] and [[Joseph Le Bel]] independently proposed the [[tetrahedral]] geometry of carbon.<ref>{{cite journal|last1=Le Bel|first1=Joseph|title=Sur les relations qui existent entre les formules atomiques des corps organiques et le pouvoir rotatoire de leurs dissolutions|journal=Bull. Soc. Chim. Fr.|date=1874|volume=22|pages=337–347|url=http://gallica.bnf.fr/ark:/12148/bpt6k2819715/f341.image|trans-title=On the relations which exist between the atomic formulas of organic compounds and the rotatory power of their solutions}}</ref><ref>van 't Hoff, J.H. (1874) [https://babel.hathitrust.org/cgi/pt?id=hvd.32044106337231;view=1up;seq=479 "Sur les formules de structure dans l'espace"] (On structural formulas in space),  ''Archives Néerlandaises des Sciences Exactes et Naturelles'', '''9''' :  445–454.</ref> Structural models prior to this work had been two-dimensional, and van&nbsp;'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]].
[[File:MarckwaldAsymmetricSynthesis.svg|thumb|right|600px|Marckwald's brucine-catalyzed enantioselective decarboxylation of 2-ethyl-2-methyl[[malonic acid]], resulting in a slight excess of the [[levorotary]] form of the 2-methylbutyric acid product.<ref name=Koskinen2012>{{cite book|last1=Koskinen|first1=Ari M.P.|title=Asymmetric synthesis of natural products|date=2013|publisher=Wiley|location=Hoboken, N.J.|isbn=978-1-118-34733-1|pages=17, 28–29|edition=Second}}</ref>]]

In 1894 [[Hermann Emil Fischer]] outlined the concept of [[asymmetric induction]];<ref>{{cite journal|last=Fischer|first=Emil|title=Synthesen in der Zuckergruppe II|journal=Berichte der Deutschen Chemischen Gesellschaft|date=1 October 1894|volume=27|issue=3|pages=3189–3232|doi=10.1002/cber.189402703109|url=https://zenodo.org/record/1425760}}</ref> in which he correctly ascribed selective the formation of <small>D</small>-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]].<ref>{{cite journal|last=Fischer|first=Emil|author2=Hirschberger, Josef|title=Ueber Mannose. II|journal=Berichte der Deutschen Chemischen Gesellschaft|date=1 January 1889|volume=22|issue=1|pages=365–376|doi=10.1002/cber.18890220183|url=https://zenodo.org/record/1425553}}</ref>
[[Image:Brucine2.svg|thumb|right|200px|Brucine, an [[alkaloid]] [[natural product]] related to [[strychnine]], used successfully as an [[organocatalyst]] by Marckwald in 1904.<ref name=Koskinen2012/>]]

The first enantioselective chemical synthesis is most often attributed to [[Willy Marckwald]], [[Humboldt-Universität zu Berlin|Universität zu Berlin]], for a [[brucine]]-catalyzed enantioselective [[decarboxylation]] of 2-ethyl-2-methyl[[malonic acid]] reported in 1904.<ref name=Koskinen2012/><ref>{{cite journal | doi = 10.1002/cber.19040370165 | title = Ueber asymmetrische Synthese | year = 1904 | author = Marckwald, W. | journal = Berichte der Deutschen Chemischen Gesellschaft | volume = 37 | pages = 349–354| url = https://zenodo.org/record/1426100 }}</ref> 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]]—e.g., as a side chain of [[lovastatin]] formed by its diketide synthase (LovF) during its [[biosynthesis]]<ref>{{cite journal|last1=Campbell|first1=Chantel D.|last2=Vederas|first2=John C.|title=Biosynthesis of lovastatin and related metabolites formed by fungal iterative PKS enzymes|journal=Biopolymers|date=23 June 2010|volume=93|issue=9|pages=755–763|doi=10.1002/bip.21428|pmid=20577995|doi-access=free}}</ref>—this result constitutes the first recorded total synthesis with enantioselectivity, as well other firsts (as Koskinen notes, first "example of [[asymmetric catalysis]], [[enantioselectivity|enantiotopic selection]], and [[organocatalysis]]").<ref name=Koskinen2012/> 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.<ref>{{citation | editor-last = Cornish-Bawden | editor-first= Athel | title = New Beer in an Old Bottle. Eduard Buchner and the Growth of Biochemical Knowledge | publisher = Universitat de València | year = 1997 | pages = 72–73 | url = https://books.google.com/books?id=HFrBP8S7my4C&q=Berzelius+vitalism+1815&pg=PA73| isbn= 978-84-370-3328-0}}</ref> 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).<ref name=Koskinen2012/><ref>Much of this early work was published in German, however contemporary English accounts can be found in the papers of [[Alexander McKenzie (chemist)|Alexander McKenzie]], with continuing analysis and commentary in modern reviews such as Koskinen (2012).</ref><ref>{{cite journal|last=McKenzie|first=Alexander|title=CXXVII.Studies in asymmetric synthesis. I. Reduction of menthyl benzoylformate. II. Action of magnesium alkyl haloids on menthyl benzoylformate|journal=J. Chem. Soc. Trans.|date=1 January 1904|volume=85|pages=1249–1262|doi=10.1039/CT9048501249|url=https://zenodo.org/record/1567059}}</ref>

===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]] using a [[polarimeter]], 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 [[R. B. Woodward]] and [[Vladimir Prelog]] 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 Martin Bijvoet|Johannes Bijvoet]] in 1951.<ref>{{cite journal|last=Bijvoet|first=J. M. |author2=Peerdeman, A. F. |author3=van Bommel, A. J.|title=Determination of the Absolute Configuration of Optically Active Compounds by Means of X-Rays|journal=Nature|year=1951|volume=168|issue=4268|pages=271–272|doi=10.1038/168271a0|bibcode=1951Natur.168..271B|s2cid=4264310 }}</ref>
Chiral chromatography was introduced a year later by Dalgliesh, who used [[paper chromatography]] to separate chiral amino acids.<ref>{{cite journal|last=Dalgliesh|first=C. E.|title=756. The optical resolution of aromatic amino-acids on paper chromatograms|journal=Journal of the Chemical Society (Resumed)|year=1952|pages=3940|doi=10.1039/JR9520003940}}</ref>
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.<ref>{{cite journal|last=Klemm|first=L.H.|author2=Reed, David|title=Optical resolution by molecular complexation chromatography|journal=Journal of Chromatography A|year=1960|volume=3|pages=364–368|doi=10.1016/S0021-9673(01)97011-6}}</ref>

[[File:Thalidomide-structures.png|thumb|300px|right|The two enantiomers of thalidomide:<br />Left: (''S'')-thalidomide<br />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]],<ref>{{cite journal|last=Cushny|first=AR|title=Atropine and the hyoscyamines-a study of the action of optical isomers|journal=The Journal of Physiology|date=2 November 1903|volume=30|issue=2|pages=176–94|pmid=16992694|pmc=1540678|doi=10.1113/jphysiol.1903.sp000988}}</ref><ref>{{cite journal|last=Cushny|first=AR|author2=Peebles, AR|title=The action of optical isomers: II. Hyoscines|journal=The Journal of Physiology|date=13 July 1905|volume=32|issue=5–6|pages=501–10|pmid=16992790|pmc=1465734|doi=10.1113/jphysiol.1905.sp001097}}</ref> 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 [[teratogenic]],<ref>{{cite journal|last=McBride|first=W. G.| title=Thalidomide and Congenital Abnormalities |journal=The Lancet|year=1961|volume=278|issue=7216|pages=1358|doi=10.1016/S0140-6736(61)90927-8}}</ref> 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.<ref>{{cite journal |last1=Ito |first1=Takumi |last2=Ando |first2=Hideki |last3=Handa |first3=Hiroshi |title=Teratogenic effects of thalidomide: molecular mechanisms |journal=Cellular and Molecular Life Sciences |date=May 2011 |volume=68 |issue=9 |pages=1569–1579 |doi=10.1007/s00018-010-0619-9|pmid=21207098 |s2cid=12391084 |pmc=11114848 }}</ref> 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.<ref>{{Cite journal |author1= Robert Sidney Cahn |author2-link=Christopher Kelk Ingold |author2=Christopher Kelk Ingold |author3-link=Vladimir Prelog |author3=Vladimir Prelog | title = Specification of Molecular Chirality | journal = [[Angewandte Chemie International Edition]] | volume = 5 | issue = 4 | pages = 385–415 | year = 1966 | doi = 10.1002/anie.196603851|author1-link=Robert Sidney Cahn }}</ref><ref>{{cite journal |author1= Vladimir Prelog |author2=Günter Helmchen  | title = Basic Principles of the CIP-System and Proposals for a Revision | journal = [[Angewandte Chemie International Edition]] | volume = 21 | issue = 8 | pages = 567–583 | year = 1982 | doi = 10.1002/anie.198205671|author1-link=Vladimir Prelog }}</ref>
The same year saw first successful enantiomeric separation by [[gas chromatography]]<ref>{{cite journal|last=Gil-Av|first=Emanuel|author2=Feibush, Binyamin |author3=Charles-Sigler, Rosita |title=Separation of enantiomers by gas liquid chromatography with an optically active stationary phase|journal=Tetrahedron Letters|year=1966|volume=7|issue=10|pages=1009–1015|doi=10.1016/S0040-4039(00)70231-0}}</ref> an important development as the technology was in common use at the time.

Metal-catalysed enantioselective synthesis was pioneered by [[William S. Knowles]], [[Ryōji Noyori]] and [[K. Barry Sharpless]]; for which they would receive the 2001 [[Nobel Prize in Chemistry]]. Knowles and Noyori began with the development of [[asymmetric hydrogenation]], which they developed independently in 1968. Knowles replaced the achiral [[triphenylphosphine]] ligands in [[Wilkinson's catalyst]] with chiral [[phosphine ligand]]s. 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 the [[Monsanto Company]] he developed an enantioselective hydrogenation step for the production of [[L-DOPA]], utilising the [[DIPAMP]] ligand.<ref>{{cite journal|last=Vineyard|first=B. D.|author2=Knowles, W. S. |author3=Sabacky, M. J. |author4=Bachman, G. L. |author5= Weinkauff, D. J. |title=Asymmetric hydrogenation. Rhodium chiral bisphosphine catalyst|journal=Journal of the American Chemical Society|year=1977|volume=99|issue=18|pages=5946–5952|doi=10.1021/ja00460a018|bibcode=1977JAChS..99.5946V }}</ref><ref>{{cite journal|last=Knowles|first=William S.|title=Asymmetric Hydrogenations (Nobel Lecture) |journal=Angewandte Chemie International Edition|year=2002|volume=41|issue=12|pages=1999–2007|doi=10.1002/1521-3773(20020617)41:12<1998::AID-ANIE1998>3.0.CO;2-8|pmid=19746594}}</ref><ref>{{cite journal|last1=Knowles|first1=W. S.|title=Application of organometallic catalysis to the commercial production of L-DOPA|journal=Journal of Chemical Education|date=March 1986|volume=63|issue=3|pages=222|doi=10.1021/ed063p222|bibcode=1986JChEd..63..222K}}</ref>

{| align="center"
|- 
|[[File:Hydrogenation-Knowles1968.png|350px]]
|width="100px"|
|[[File:AsymmetricSynthesisNoyori.png|350px]]
|-
!align="center"|Knowles: Asymmetric hydrogenation (1968)
|width="100px"|
!align="center"|Noyori: Enantioselective cyclopropanation (1968)
|}

Noyori devised a copper complex using a chiral [[Schiff base]] ligand, which he used for the [[Intermolecular metal-catalyzed carbenoid cyclopropanations|metal–carbenoid cyclopropanation]] of [[styrene]].<ref>{{cite journal | title = Homogeneous catalysis in the decomposition of diazo compounds by copper chelates: Asymmetric carbenoid reactions | journal = [[Tetrahedron (journal)|Tetrahedron]] | volume = 24 | issue = 9 | year = 1968 | pages = 3655–3669 |author1=H. Nozaki |author2=H. Takaya |author3=S. Moriuti |author4=R. Noyori | doi = 10.1016/S0040-4020(01)91998-2}}</ref>  
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.

[[File:Sharpless Oxyamination Scheme.png|thumb|left|250px|The Sharpless oxyamination]]
Sharpless complemented these reduction reactions by developing a range of asymmetric oxidations ([[Sharpless epoxidation]],<ref>{{cite journal|last=Katsuki|first=Tsutomu|author2=Sharpless, K. Barry|title=The first practical method for asymmetric epoxidation|journal=Journal of the American Chemical Society|year=1980|volume=102|issue=18|pages=5974–5976|doi=10.1021/ja00538a077|bibcode=1980JAChS.102.5974K }}</ref> [[Sharpless asymmetric dihydroxylation]],<ref>{{cite journal|last=Jacobsen|first=Eric N.|author2=Marko, Istvan. |author3=Mungall, William S. |author4=Schroeder, Georg. |author5= Sharpless, K. Barry. |title=Asymmetric dihydroxylation via ligand-accelerated catalysis|journal=Journal of the American Chemical Society|year=1988|volume=110|issue=6|pages=1968–1970|doi=10.1021/ja00214a053|bibcode=1988JAChS.110.1968J }}</ref> [[Sharpless oxyamination]]<ref>{{cite journal|last=Sharpless|first=K. Barry|author2=Patrick, Donald W. |author3=Truesdale, Larry K. |author4= Biller, Scott A. |title=New reaction. Stereospecific vicinal oxyamination of olefins by alkyl imido osmium compounds|journal=Journal of the American Chemical Society|year=1975|volume=97|issue=8|pages=2305–2307|doi=10.1021/ja00841a071|bibcode=1975JAChS..97.2305S }}</ref>) 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]],<ref>{{cite journal | author = J. A. Dale, D. L. Dull and [[Harry S. Mosher|H. S. Mosher]] | title =α-Methoxy-α-trifluoromethylphenylacetic acid, a versatile reagent for the determination of enantiomeric composition of alcohols and amines | year = 1969 | journal = [[J. Org. Chem.]] | volume = 34 | issue = 9 | pages = 2543–2549 | doi = 10.1021/jo01261a013}}</ref>
or [[europium]] based shift reagents, of which Eu(DPM)<sub>3</sub> was the earliest.<ref>{{cite journal|last=Hinckley|first=Conrad C.|title=Paramagnetic shifts in solutions of cholesterol and the dipyridine adduct of trisdipivalomethanatoeuropium(III). A shift reagent|journal=Journal of the American Chemical Society|year=1969|volume=91|issue=18|pages=5160–5162|doi=10.1021/ja01046a038|pmid=5798101|bibcode=1969JAChS..91.5160H }}</ref>

Chiral auxiliaries were introduced by [[E.J. Corey]] in 1978<ref>{{cite journal|last=Ensley|first=Harry E.|author2=Parnell, Carol A. |author3=Corey, Elias J. |title=Convenient synthesis of a highly efficient and recyclable chiral director for asymmetric induction|journal=The Journal of Organic Chemistry|year=1978|volume=43|issue=8|pages=1610–1612|doi=10.1021/jo00402a037}}</ref> 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,<ref>{{cite journal|last=Sariaslani|first=F.Sima|author2=Rosazza, John P.N.|title=Biocatalysis in natural products chemistry|journal=Enzyme and Microbial Technology|year=1984|volume=6|issue=6|pages=242–253|doi=10.1016/0141-0229(84)90125-X}}</ref> particularly in industry,<ref>{{cite journal|last=Wandrey|first=Christian|author2=Liese, Andreas |author3=Kihumbu, David |title=Industrial Biocatalysis: Past, Present, and Future|journal=Organic Process Research & Development|year=2000|volume=4|issue=4|pages=286–290|doi=10.1021/op990101l}}</ref> 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.<ref name="statin" />

==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 [[polymer]]s which originates from enantioselective synthesis
* [[Chiral analysis]]
* [[Enantioselective analysis]]

==References==
{{reflist}}

{{chemical synthesis}}
{{Chiral synthesis}}
{{Branches of chemistry}}
{{Authority control}}

[[Category:Chemical synthesis]]
[[Category:Stereochemistry]]
[[Category:Asymmetry]]