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Enantioselective synthesis
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==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.
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