Editing Enantioselective synthesis (section)

==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"
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|[[File:Hydrogenation-Knowles1968.png|350px]]
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|[[File:AsymmetricSynthesisNoyori.png|350px]]
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!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" />