Aldol reaction
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The '''aldol reaction''' is an important [[carbon-carbon bond]] formation [[chemical reaction|reaction]] in [[organic chemistry]].<ref name=Wade>
{{cite book
| author = Wade, L. G.
| title = Organic Chemistry
| publisher = Prentice Hall
| date = 6th ed. 2005
| location = Upper Saddle River, New Jersey
| pages = 1056–1066
| id = ISBN 0132367319 }} </ref><ref name=March>
{{cite book
| author = Smith, M. B.; March, J.
| title = Advanced Organic Chemistry
| publisher = Wiley Interscience
| date = 5th ed. 2001
| location = New York
| pages = 1218–1223
| id = ISBN 0-471-58589-0}}
</ref><ref name=Mahrwald2004>
{{cite book
| author = Mahrwald, R.
| title = Modern Aldol Reactions, Volumes 1 and 2
| publisher = Wiley-VCH Verlag GmbH & Co. KGaA
| date = 2004
| location = Weinheim, Germany
| pages = 1218–1223
| id = ISBN 3-527-30714-1}}
</ref> In its usual form, it involves the [[Nucleophile|nucleophilic]] addition of a [[ketone]] [[enolate]] to an [[aldehyde]] to form a β-hydroxy ketone, or "'''aldol'''" ('''ald'''ehyde + alcoh'''ol'''), a structural unit found in many naturally occurring molecules and pharmaceuticals.<ref name=Heathcock1991> {{cite book
| author = [[Clayton Heathcock|Heathcock, C. H.]]
| title = Comp. Org. Syn.
| publisher = Pergamon
| date = 1991
| location = Oxford
| pages = 133–179
| id = ISBN 0-08-040593-2}}
</ref><ref name=Mukaiyama1982>
{{cite journal
| title = The Directed Aldol Reaction
| author = Mukaiyama T.
| journal =Org. React.
| year =1982
| volume =28
| pages =203–331
| dou = 10.1002/0471264180.or028.03
| doi = 10.1002/0471264180.or028.03 }}
</ref><ref name=Paterson1988>
{{cite journal
| title = New Asymmetric Aldol Methodology Using Boron Enolates
| author = Paterson, I.
| journal = Chem. Ind.
| year =1988
| volume =12
| pages =390–394}}</ref> Sometimes, the aldol addition product [[Dehydration reaction|loses a molecule of water]] during the reaction to form an [[α,β-unsaturated carbonyl compound|α,β-unsaturated ketone]]. This is called an [[aldol condensation]]. The aldol reaction was discovered independently by [[Charles-Adolphe Wurtz]]<ref name=Wurtz1872>
{{cite journal
| author = [[Charles-Adolphe Wurtz|Wurtz, C. A.]]
| journal = Bull. Soc. Chim. Fr.
| year =1872
| title =
| volume = 17
| pages =436–442}}</ref><ref name=Wurtz1872b>
{{cite journal
| author = [[Charles-Adolphe Wurtz|Wurtz, C. A.]]
| journal = J. Prakt. Chemie
| year = 1872
| title = Ueber einen Aldehyd-Alkohol
| volume = 5
| issue = 1
| pages = 457–464
| doi = 10.1002/prac.18720050148
}}</ref><ref name=Wurtz1872c>
{{cite journal
| author = [[Charles-Adolphe Wurtz|Wurtz, C. A.]]
| journal = [[Comptes rendus de l'Académie des sciences|Comp. Rend.]]
| year = 1872
| title = Sur un aldéhyde-alcool
| volume = 74
| pages =1361
| url = http://gallica.bnf.fr/ark:/12148/bpt6k3031q/f1361.table}}</ref> and by [[Alexander Porfyrevich Borodin]] in 1872. Borodin observed the aldol dimerization of 3-hydroxybutanal from [[acetaldehyde]] under acidic conditions. The aldol reaction is used widely in the large scale production of commodity chemicals such as [[pentaerythritol]]<ref name=mestres>
{{cite journal
| title = A green look at the aldol reaction
| author = Mestres R.
| journal = Green Chemistry
| year = 2004
| volume =12
| pages = 583–603
| doi = 10.1039/b409143b }}</ref>
and in the [[pharmaceutical industry]] for the synthesis of optically pure drugs. For example, Pfizer's initial route to the heart disease drug Lipitor (INN: [[atorvastatin]]), approved in 1996, employed two aldol reactions, allowing access to multigram-scale quantities of the drug.<ref name=Braun5031> {{cite journal
| title = (R) and (S)-2-acetoxy-1,1,2-triphenylethanol - effective synthetic equivalents of a chiral acetate enolate
| author = M. Braun, R. Devant
| journal = Tetrahedron Letters
| year =1984
| volume =25
| pages =5031–4
| dou = 10.1016/S0040-4039(01)91110-4 | doi = 10.1016/S0040-4039(01)91110-4
}}
</ref><ref name=jackli2004> {{cite book
| author = Jie Jack Li ''et al''.
| title = Contemporary Drug Synthesis
| publisher = Wiley-Interscience
| date = 2004
| location =
| pages = 118-
| id = ISBN 0-471-21480-9}}
</ref>
[[Image:typicalaldol2.gif|center]]
The aldol structural motif is especially common in [[polyketide]]s, a class of [[natural product]]s from which many pharmaceuticals are derived, including the potent immunosuppressant [[FK506]], the [[tetracycline]] antibiotics, and the antifungal agent [[amphotericin B]]. Extensive research on the aldol reaction has produced highly efficient methods which enable the otherwise challenging [[total synthesis|synthesis]] of many [[polyketide]]s in the laboratory.<ref name=MahrwaldSchetter2006>
{{cite journal
| title = Modern Aldol Methods for the Total Synthesis of Polyketides
| author = Schetter, B., Mahrwald, R.
| journal =Angew. Chem. Int. Ed.
| year =2006
| volume =45
| pages =7506–7525
| doi = 10.1002/anie.200602780 }}</ref>
This is important because many polyketides, along with other biologically active molecules, occur naturally in quantities impractically small for further investigation. The synthesis of many such compounds, once considered nearly impossible, can now be performed routinely on the laboratory scale, and is approaching economic viability on a larger scale in some cases, such as the highly active anti-tumor agent [[discodermolide]]. In [[biochemistry]], the aldol reaction is one of the key steps of [[glycolysis]], where it is catalyzed by enzymes called [[aldolase]]s.
The aldol reaction is particularly valuable in [[organic synthesis]] because it produces products with ''two'' new [[stereogenic center]]s (on the [[Alpha carbon|α- and β-carbon]] of the aldol adduct, marked with asterisks in the scheme above). Modern methods, described below, now allow the relative and absolute configuration of these centers to be controlled. This is of particular importance when synthesizing pharmaceuticals, since molecules with the same structural connectivity but different stereochemistry often have vastly different chemical and biological properties.
A variety of nucleophiles may be employed in the aldol reaction, including the [[enol]]s, [[enolate]]s, and enol [[ether]]s of ketones, aldehydes, and many other [[carbonyl]] compounds. The [[electrophile|electrophilic]] partner is usually an aldehyde, although many variations, such as the [[Mannich reaction]], exist. When the nucleophile and electrophile are different (the usual case), the reaction is called a '''crossed aldol reaction''' (as opposed to [[dimer]]s formed in an '''aldol dimerization''').
[[Image:aldolrxnpic.jpg|thumb|right|300px|A typical experimental setup for an aldol reaction.<br /> A solution of [[lithium diisopropylamide]] (LDA) in [[tetrahydrofuran]] (THF) (in the flask on the right) is being added to a solution of ''tert''-butyl propionate in the flask on the left, forming its lithium enolate. An aldehyde can then be added to initiate an aldol addition reaction.<br /> Both flasks are submerged in a dry ice/acetone [[cooling bath]] (-78 °C) the temperature of which is being monitored by a thermocouple (the wire on the left).]]
==Mechanisms==
The aldol reaction may proceed via two fundamentally different mechanisms. Carbonyl compounds, such as aldehydes and ketones, can be converted to enols or enol ethers. These compounds, being nucleophilic at the [[Alpha-carbon|α-carbon]], can attack especially reactive protonated carbonyls such as protonated aldehydes. This is the "enol mechanism". Carbonyl compounds, being [[carbon acid]]s, can also be deprotonated to form enolates, which are much more nucleophilic than enols or enol ethers and can attack electrophiles directly. The usual electrophile is an aldehyde, since ketones are much less reactive. This is the "enolate mechanism".
If the conditions are particularly harsh (e.g., NaOMe, MeOH, reflux), condensation may occur, but this can usually be avoided with mild reagents and low temperatures (e.g., LDA (a strong base), THF, -78 °C). Although the aldol addition usually proceeds to near completion, the reaction is not irreversible, since the treatment of aldol adducts with strong bases usually induces retro-aldol cleavage (gives the starting materials). Aldol condensations are irreversible.
:[[Image:Simple aldol reaction.png|600px|A generalized view of the Aldol reaction]]
===Enol mechanism===
When an acid catalyst is used, the initial step in the [[reaction mechanism]] involves acid-catalyzed [[tautomer]]ization of the carbonyl compound to the enol. The acid also serves to activate the carbonyl group of ''another molecule'' by protonation, rendering it highly [[electrophile|electrophilic]]. The enol is [[nucleophile|nucleophilic]] at the α-carbon, allowing it to attack the protonated carbonyl compound, leading to the aldol after [[deprotonation]]. This usually [[Dehydration reaction|dehydrates]] to give the unsaturated carbonyl compound. The scheme shows a typical acid-catalyzed self-condensation of an aldehyde.
'''Acid catalyzed aldol mechanism'''
:[[Image:Enol aldol formation mechanism.png|500px|Mechanism for acid-catalyzed aldol reaction of an aldehyde with itself]]
'''Acid catalyzed dehydration'''
:[[Image:Enol aldol dehydration mechanism.png|500px|Mechanism for acid-catalyzed dehydration of an aldol]]
===Enolate mechanism===
If the [[catalyst]] is a moderate base such as [[hydroxide]] ion or an [[alkoxide]], the aldol reaction occurs via nucleophilic attack by the [[Resonance (chemistry)|resonance-stabilized]] enolate on the carbonyl group of another molecule. The product is the [[alkoxide]] salt of the aldol product. The aldol itself is then formed, and it may then undergo dehydration to give the unsaturated carbonyl compound. The scheme shows a simple mechanism for the base catalyzed aldol reaction of an aldehyde with itself.
'''Base catalyzed aldol reaction''' (shown using [[methoxide|<sup>−</sup>OCH<sub>3</sub>]] as base)
:[[Image:Enolate aldol formation mechanism.png|500px|Simple mechanism for base-catalyzed aldol reaction of an aldehyde with itself]]
'''Base catalyzed dehydration''' (sometimes written as a single step)
:[[Image:Enolate aldol dehydration mechanism.png|500px|Simple mechanism for the dehydration of an aldol product]]
Although only a catalytic amount of base is required in some cases, the more usual procedure is to use a [[stoichiometric]] amount of a strong base such as [[Lithium diisopropylamide|LDA]] or [[Sodium hexamethyldisilazide|NaHMDS]]. In this case, enolate formation is irreversible, and the aldol product is not formed until the metal alkoxide of the aldol product is protonated in a separate workup step.
===Zimmerman-Traxler model===
More refined forms of the mechanism are known. In 1957, Zimmerman and Traxler proposed that some aldol reactions have "six-membered transition state[[s]] having a [[chair conformation]]."<ref name=Zimmerman1920>{{cite journal
| title = The Stereochemistry of the Ivanov and Reformatsky Reactions. I
| author = Zimmerman, H. E.; Traxler, M. D.|doi = 10.1021/ja01565a041
| journal =[[J. Am. Chem. Soc.]]
| year =1957
| volume =79
| pages =1920–1923}} </ref> This is now known as the '''Zimmerman-Traxler model'''. E-enolates give rise to [[anti isomer|anti products]], whereas Z-enolates give rise to [[syn addition|syn products]]. The factors which control selectivity are the preference for placing substituents equatorially in six-membered transition states and the avoidance of [[pentane interference|syn-pentane interactions]], respectively.<ref name=Heathcock1980>{{cite journal
|title = Acyclic stereoselection. 7. Stereoselective synthesis of 2-alkyl-3-hydroxy carbonyl compounds by aldol condensation
| author = Heathcock C. H., Buse, C. T., Kleschnick W. A., Pirrung M. C., Sohn J. E., Lampe, J.
| doi = 10.1021/jo01294a030
| journal =[[J. Org. Chem.]]
| year = 1980
| volume =45
| pages = 1066–1081}} </ref> E and Z refer to the [[cis-trans isomerism|cis-trans stereochemical relationship]] between the enolate oxygen bearing the positive counterion and the highest priority group on the alpha carbon. In reality, only some metals such as lithium and boron reliably follow the Zimmerman-Traxler model. Thus, in some cases, the [[stereochemistry|stereochemical]] outcome of the reaction may be unpredictable.
:[[Image:scheme2.gif|The Zimmerman-Traxler Model]]
==Control in the Aldol reaction==
===The problem===
The problem of "control" in the aldol addition is best demonstrated by an example. Consider the outcome of this hypothetical reaction:
[[Image:Aldolcontrol1.gif|center|Hypothetical aldol reaction]]
In this reaction, two unsymmetrical ketones are being condensed using [[sodium ethoxide]]. The basicity of sodium ethoxide is such that it cannot fully deprotonate either of the ketones, but can produce small amounts of the sodium enolate of both ketones. Effectively, this means that in addition to being potential aldol electrophiles, both ketones may also act as nucleophiles via their sodium enolate. Two electrophiles and two nucleophiles then potentially results in four possible products:
[[Image:Aldolcontrol2.gif|center|Four possible aldol reaction products]]
Thus, if one wishes to obtain only one of the cross-products, then one must "control" the aldol addition.
===Acidity===
If one partner is considerably more acidic than the other, then control may be automatic. The most acidic proton is abstracted by the base and an enolate is formed. This type of control only works if the difference in acidity is large enough and no excess of base is used for the reaction. The simplest control is if only one of the reactants has acidic protons and only this molecule forms the enolate. For example, the addition of diethyl malonate into benzaldehyde would only produce one product:
[[Image:Aldolcontrol3.gif|center|Acidic control of the aldol reaction]]
In this case, the doubly activated [[methylene]] protons of the [[malonate]] would be preferentially deprotonated by sodium ethoxide and quantitatively form the sodium enolate. Since [[benzaldehyde]] has no acidic alpha-protons, there is only one possible nucleophile-electrophile combination; hence, control has been achieved. Note that this approach combines two elements of control: increased acidity of the alpha protons on the nucleophile and the lack of alpha protons on the electrophile.
===Order of addition===
One common solution is to form the enolate of one partner first, and then add the other partner under [[kinetic reaction control|kinetic control]].<ref name=OS1985>Bal, B.; Buse, C. T.; Smith, K.; Heathcock, C. H. ''[[Org. Syn.]]'', Coll. Vol. 7, p.185 (1990); Vol. 63, p.89 (1985). ([http://www.orgsyn.org/orgsyn/prep.asp?prep=cv7p0185 Article]) </ref> Kinetic control means that the forward aldol addition reaction must be significantly faster than the reverse retro-aldol reaction. For this approach to succeed, two other conditions must also be satisfied; namely, it must be possible to quantitatively form the enolate of one partner and the forward aldol reaction must be significantly faster than the transfer of the enolate from one partner to another. Common kinetic control conditions involve the formation of the enolate of a ketone with [[LDA]] at -78 °C, followed by the slow addition of an aldehyde.
==Enolates==
===Formation===
The enolate may be formed by using a strong base ("hard conditions") or using a [[Lewis acid]] and a weak base ("soft conditions"):
[[Image:scheme3a.gif]]
For [[deprotonation]] to occur, the stereoelectronic requirement is that the alpha-C-H [[sigma bond]] must be able to overlap with the pi* orbital of the [[carbonyl]]:
[[Image:scheme3c.gif|center|Stereoelectronic deprotonation requirements]]
===Geometry===
Extensive studies have been performed on the formation of enolates under many different conditions. It is now possible to generate, in most cases, the desired enolate geometry:<ref name=Brown1989> {{cite journal
| title = Major effect of the leaving group in dialkylboron chlorides and triflates in controlling the stereospecific conversion of ketones into either [[E]]- or [[Z]]-enol borinates
| author = [[Herbert C. Brown|Brown H. C.]], Dhar R. K., Bakshi R. K., Pandiarajan P. K., Singaram B.
| doi = 10.1021/ja00191a058
| journal =[[J. Am. Chem. Soc.]]
| year =1989
| volume =111
| pages =3441–3442}}</ref>
[[Image:scheme3.gif|center|Stereoselective enolate generation]]
(-- In the above image, the second reaction scheme should say >99% E-enolate, not Z --)
For ketones, most enolization conditions give Z enolates. For [[ester]]s, most enolization conditions give E enolates. The addition of [[Hexamethylphosphoramide|HMPA]] is known to reverse the [[stereoselectivity]] of deprotonation.
[[Image:scheme3b.gif|center|Effect of HMPA addition]]
The stereoselective formation of enolates has been rationalized with the so-called '''Ireland model''',<ref name= Ireland1975> {{cite journal
|title = The stereoselective generation of ester enolates
| author = Ireland, R. E.; Willard, A. K.
| doi = 10.1016/S0040-4039(00)91213-9
| journal =[[Tetrahedron Lett.]]
| year = 1975
| volume =16
| issue =46
| pages = 3975–3978}}</ref><ref name=Narula1981> {{cite journal
|title = An analysis of the diastereomeric transition state interactions for the kinetic deprotonation of acyclic carbonyl derivatives with lithium diisopropylamide
| author = Narula, A. S.
| doi = 10.1016/S0040-4039(01)82081-5
| journal =[[Tetrahedron Lett.]]
| year = 1981
| volume =22
| issue =41
| pages = 4119–4122}}</ref><ref name=Ireland1991> {{cite journal
|title = Stereochemical control in the ester enolate Claisen rearrangement. 1. Stereoselectivity in silyl ketene acetal formation
| author = Ireland, R. E.; Wipf, P.; Armstrong, J. D.
| doi = 10.1021/jo00002a030
| journal =[[J. Org. Chem.]]
| year = 1991
| volume =56
| pages = 650–657}}</ref><ref name=Xie1997> {{cite journal
|title = Highly Stereoselective Kinetic Enolate Formation: Steric vs Electronic Effects
| author = Xie L., Isenberger K. M., Held G., Dahl, L. M.
| doi = 10.1021/jo971260a
| journal =[[J. Org. Chem.]]
| year = 1997
| volume =62
| pages = 7516–7519}}</ref> although its validity is somewhat questionable. In most cases, it is not known which, if any, intermediates are [[monomer]]ic or [[oligomer]]ic in nature; nonetheless, the Ireland model remains a useful tool for understanding enolates.
[[Image:scheme3d.gif|center|The Ireland model]]
In the Ireland model, the deprotonation is assumed to proceed by a six-membered monomeric transition state. The larger of the two substituents on the electrophile (in the case above, methyl is larger than proton) adopts an equatorial disposition in the favored transition state, leading to a preference for E enolates. The model clearly fails in many cases; for example, if the solvent mixture is changed from THF to 23% HMPA-THF (as seen above), the enolate geometry is inexplicably reversed.
===Kinetic vs. thermodynamic enolates===
If an unsymmetrical ketone is subjected to base, it has the potential to form two regioisomeric enolates (ignoring enolate geometry). For example:
[[Image:Enolateregio1.gif|center|Kinetic and thermodynamic enolates]]
The trisubstituted enolate is considered the [[thermodynamic reaction control|kinetic]] enolate while the tetrasubstituted enolate is considered the thermodynamic enolate. The alpha hydrogen deprotonated to form the kinetic enolate is less hindered, and therefore deprotonated more quickly. In general, tetrasubstituted olefins are more stable than trisubstituted olefins due to hyperconjugative stabilization. The ratio of enolate regioisomers is heavily influenced by the choice of base. For the above example, kinetic control may be established with LDA at -78 °C, giving 99:1 selectivity of kinetic: thermodynamic enolate, while thermodynamic control may be established with [[organolithium reagent|triphenylmethyllithium]] at [[room temperature]], giving 10:90 selectivity.
In general, kinetic enolates are favored by cold temperatures, relatively ionic metal-oxygen bonds, and rapid deprotonation using a slight excess of a strong, hindered base while thermodynamic enolates are favored by higher temperatures, relatively covalent metal-oxygen bonds, and longer equilibration times for deprotonation using a slight sub-stoichiometric amount of strong base. Use of a sub-stoichiometric amount of base allows some small fraction of unenolized carbonyl compound to equilibrate the enolate to the thermodynamic regioisomer by acting as a proton shuttle.
==Stereoselectivity==
The aldol reaction is particularly useful because two new stereogenic centers are generated in one reaction. Extensive research has been performed to understand the reaction mechanism and improve the selectivity observed under many different conditions. The ''syn''/''anti'' convention is commonly used to denote the relative stereochemistry at the α- and β-carbon.
[[Image:aldolsynanti.png|500px|Syn and anti products from an aldol reaction]]
The convention applies when propionate (or higher order) nucleophiles are added to aldehydes. The ''R'' group of the ketone and the ''R''' group of the aldehyde are aligned in a "zig zag" pattern in the plane of the paper, and the disposition of the formed stereocenters is deemed ''syn'' or ''anti'', depending if they are on the same or opposite sides of the main chain.
Older papers use the ''[[Erythrose|erythro]]''-''[[Threose|threo]]'' nomenclature familiar from carbohydrate chemistry.
===E vs. Z enolates===
There is no significant difference between the level of [[stereoinduction]] observed with E and Z enolates:<ref name=Brown1989 />
[[Image:EvsZstereoselectivity.gif|center|Anti-aldol formation via Z-enolate]]
[[Image:EvsZstereoselectivity2.gif|center|Syn-aldol formation via E-enolate]]
===Metal ion===
The enolate metal cation may play a large role in determining the level of stereoselectivity in the aldol reaction. [[Boron]] is often used because its [[bond length]]s are significantly shorter than that of other metals such as [[lithium]], [[aluminium]], or [[magnesium]]. For example, boron-carbon and boron-oxygen bonds are 1.4–1.5 [[Ångstrom|Å]] and 1.5–1.6 Å in length, respectively, whereas typical metal-carbon and metal-oxygen bonds are typically 1.9–2.2 Å and 2.0–2.2 Å in length, respectively. This has the effect of "tightening" the [[transition state]]:<ref name=JACS1981_3099> {{cite journal
| title = Stereoselective aldol condensations via boron enolates
| author = Evans D. A., Nelson J. V., Vogel E., Taber T. R.|doi = 10.1021/ja00401a031
| journal =[[J. Am. Chem. Soc.]]
| year =1981
| volume =103
| pages =3099–3111}}</ref>
[[Image:Metalion.gif|center]]
===Stereoselectivity: Alpha stereocenter on the enolate===
The aldol reaction may exhibit "substrate-based stereocontrol", in which existing [[Chirality (chemistry)|chirality]] on either reactant influences the stereochemical outcome of the reaction. This has been extensively studied, and in many cases, one can predict the sense of [[asymmetric induction]], if not the absolute level of [[diastereoselectivity]]. If the enolate contains a [[stereocenter]] in the alpha position, excellent stereocontrol may be realized.
[[Image:enolatealphacenter.gif|center|Aldol reaction with enolate-based stereocontrol]]
In the case of an E enolate, the dominant control element is [[allylic strain|allylic 1,3-strain]] whereas in the case of a Z enolate, the dominant control element is the avoidance of 1,3-diaxial interactions. The general model is presented below:
[[Image:enolatealphacentermodel.gif|center|General model of the aldol reaction with enolate-based stereocontrol]]
For clarity, the stereocenter on the enolate has been [[epimer]]ized; in reality, the opposite diastereoface of the aldehyde would have been attacked. In both cases, the 1,3-syn diastereomer is favored. There are many examples of this type of stereocontrol:<ref name=JACS1991_1047>{{cite journal
| title = Stereoselective aldol reactions of chlorotitanium enolates. An efficient method for the assemblage of polypropionate-related synthons
| author = Evans D. A., Rieger D. L., Bilodeau M. T., Urpi F.
| doi = 10.1021/ja00003a051
| journal =[[J. Am. Chem. Soc.]]
| year =1991|volume =113
| pages =1047–1049}} </ref>
[[Image:enolatealphacentereg.gif|center|Aldol reaction with enolate-based stereocontrol]]
===Stereoselectivity: Alpha stereocenter on the electrophile===
When enolates attacks aldehydes with an alpha stereocenter, excellent stereocontrol is also possible. The general observation is that E enolates exhibit [[Felkin model|Felkin]] diastereoface selection, while Z enolates exhibit anti-Felkin selectivity. The general model<ref name=Evans1982TS>Evans, D. A. ''et al.'' ''Top. Stereochem.'' '''1982''', ''13'', 1–115. (Review)</ref><ref name=Roush1991>{{cite journal
| title = Concerning the diastereofacial selectivity of the aldol reactions of .alpha.-methyl chiral aldehydes and lithium and boron propionate enolates
| author = Roush W. R.
| journal = [[J. Org. Chem.]]
| year = 1991
| volume = 56
| pages = 4151–4157
| doi = 10.1021/jo00013a015}}</ref> is presented below:
[[Image:Aldehydealphamodel.gif|center|The general model of the aldol reaction with carbonyl-based stereocontrol]]
Since Z enolates must react through a [[transition state]] which either contains a destabilizing syn-pentane interaction or anti-Felkin [[rotamer]], Z-enolates exhibit lower levels of diastereoselectivity in this case. Some examples are presented below:<ref name=JACS1982_5526>{{cite journal
| title = Aldol strategy: coordination of the lithium cation with an alkoxy substituent
| author = Masamune S., Ellingboe J. W., Choy W.
| doi = 10.1021/ja00384a062
| journal =[[J. Am. Chem. Soc.]]
| year =1982
| volume =104
| pages = 1047–1049}} </ref><ref name=JACS1995_9073>{{cite journal
|title = Double Stereodifferentiating Aldol Reactions. The Documentation of "Partially Matched" Aldol Bond Constructions in the Assemblage of Polypropionate Systems
| author = Evans D. A., Dart M. J., Duffy J. L., Rieger D. L.
| doi = 10.1021/ja00140a027| journal =[[J. Am. Chem. Soc.]]
| year =1995
| volume =117
| pages =9073–9074}}</ref>
[[Image:aldehydealphaeg.gif|center|Examples of the aldol reaction with carbonyl-based stereocontrol]]
===Stereoselectivity: Merged model for stereoinduction===
If both the enolate and the aldehyde both contain pre-existing chirality, then the outcome of the "double stereodifferentiating" aldol reaction may be predicted using a merged stereochemical model that takes into account the enolate facial bias, enolate geometry, and aldehyde facial bias.<ref name=Masamune1985>{{cite journal
| title = Double Asymmetric Synthesis and a New Strategy for Stereochemical Control in Organic Synthesis
| author = Masamune S., Choy W., Petersen J. S., Sita L. R.
| doi = 10.1002/anie.198500013
| journal =[[Angew. Chem. Int. Ed. Engl.]]
| year =1985
| volume =24
| pages =1–30}} </ref> Several examples of the application of this model are given below:<ref name=JACS1995_9073 />
[[Image:Mergedmodel.gif]]
==Evans' oxazolidinone chemistry==
Modern organic syntheses now require the synthesis of compounds in [[enantiopure]] form. Since the aldol addition reaction creates two new stereocenters, up to four stereoisomers may result.
[[Image:Evansaldol1.gif|center|Aldol reaction creates stereoisomers]]
Many methods which control both relative stereochemistry (i.e., syn or anti, as discussed above) and absolute [[stereochemistry]] (i.e., R or S) have been developed.
[[Image:Evansaldol2.gif|center|Four possible stereoisomers of the aldol reaction]]
A widely used method is the Evans' [[acyl]] [[oxazolidinone]] method.<ref name=Evans1982AldrichActa>Evans, D. A. ''[[Aldrichimica Acta]]'' '''1982''', ''15'', 23. (Review)</ref><ref name=OS1990> Gage, J. R.; Evans, D. A. [[Organic Syntheses]], Coll. Vol. 8, p.339 (1993); Vol. 68, p.83 (1990). ([http://www.orgsyn.org/orgsyn/prep.asp?prep=cv8p0339 Article])</ref> Developed in the late 1970s and 1980s by [[David A. Evans]] and coworkers, the method works by temporarily creating a chiral enolate by appending a [[chiral auxiliary]]. The pre-existing chirality from the auxiliary is then transferred to the aldol adduct by performing a diastereoselective aldol reaction. Upon subsequent removal of the auxiliary, the desired aldol stereoisomer is revealed.
[[Image:Evansaldol3.gif|center]]
In the case of the Evans' method, the chiral auxiliary appended is an [[oxazolidinone]], and the resulting carbonyl compound is an [[imide]]. A number of oxazolidinones are now readily available in both enantiomeric forms. These may cost roughly $10-$20 US dollars per gram, rendering them relatively expensive.
[[Image:Evansaldol4.gif|center]]
The [[acylation]] of an oxazolidinone is a convenient procedure, and is informally referred to as "loading done". Z-enolates, leading to syn-aldol adducts, can be reliably formed using boron-mediated soft enolization:<ref name=Bartroli1981> {{cite journal
| title = Enantioselective aldol condensations. 2. Erythro-selective chiral aldol condensations via boron enolates
| author = Evans D. A., Bartroli J., Shih T. L.
| doi = 10.1021/ja00398a058
| journal =[[J. Am. Chem. Soc.]]
| year =1981
| volume =103
| pages =2127–2129}}</ref>
[[Image:Evansaldol5.gif|center]]
Often, a single [[diastereomer]] may be obtained by one [[crystallization]] of the aldol adduct. Unfortunately, anti-aldol adducts cannot be obtained reliably with the Evans method. Despite the cost and the limitation to give only ''syn'' adducts, the method's superior reliability, ease of use, and versatility render it the method of choice in many situations. Many methods are available for the cleavage of the auxiliary:<ref name=JACS882506>{{cite journal
| title = The total synthesis of the polyether antibiotic X-206
| author = Evans D. A., Bender S. L., Morris J.
| doi = 10.1021/ja00216a026
| journal =[[J. Am. Chem. Soc.]]
| year =1988
| volume =110
| pages =2506–2526}}</ref>
[[Image:Evansaldol6.gif|center|Evans' chiral oxazolidinone cleavage]]
Upon construction of the imide, both syn and anti-selective aldol addition reactions may be performed, allowing the assemblage of three of the four possible stereoarrays: syn selective:<ref name=JACS90866>{{cite journal
| title = Diastereoselective aldol reactions using .beta.-keto imide derived enolates. A versatile approach to the assemblage of polypropionate systems
| author = Evans D.A., Clark J.S., Metternich R., Sheppard G.S.
| doi = 10.1021/ja00158a056
| journal =[[J. Am. Chem. Soc.]]
| year =1990
| volume =112
| pages =866–868}}</ref> and anti selective:<ref name=JACS922127>{{cite journal
|title = Diastereoselective anti aldol reactions of chiral ethyl ketones. Enantioselective processes for the synthesis of polypropionate natural products
| author = Evans D.A., Ng, H.P., Clark J.S., Rieger D.L.
| journal = Tetrahedron
| year = 1992|volume = 48
| pages = 2127–2142
| doi =10.1016/S0040-4020(01)88879-7}}</ref>
[[Image:Evansaldol7.gif|center]]
In the syn-selective reactions, both enolization methods give the Z enolate, as expected; however, the stereochemical outcome of the reaction is controlled by the methyl stereocenter, rather than the chirality of the oxazolidinone. The methods described allow the stereoselective assembly of [[polyketide]]s, a class of natural products which often feature the aldol retron.
==Modern Aldol Chemistry==
Recent methodology now allows a much wider variety of aldol reactions to be conducted, often with a catalytic amount of [[Chiral reagent|chiral ligand]]. When reactions employ small amounts of [[enantiopure|enantiomerically]] pure ligands to induce the formation of enantiomerically pure products, the reactions are typically termed "catalytic, asymmetric"; for example, many different catalytic, [[asymmetric synthesis|asymmetric]] aldol reactions are now available.
===Acetate Aldol Reactions===
A key limitation to the [[chiral auxiliary]] approach described previously is the failure of N-acetyl [[imide]]s to react selectively. An early approach was to use a temporary [[thioether]] group:<ref name=JACS882506 /><ref>In this reaction the nucleophile is a boron enolate derived from reaction with [[dibutylboron triflate]] (nBu<sub>2</sub>BOTf), the base is [[N,N-Diisopropylethylamine]]. The thioether is removed in step 2 by [[Raney Nickel]] / hydrogen [[organic reduction|reduction]]</ref>
[[Image:Acetatealdol1.gif|center]]
===Mukaiyama aldol reaction===
{{main|Mukaiyama aldol reaction}}
The [[Mukaiyama aldol reaction]] is the [[nucleophilic addition]] of [[silyl enol ether]]s to [[aldehyde]]s catalyzed by a [[Lewis acid]] such as [[boron trifluoride]] or [[titanium chloride]].<ref>
{{cite journal
| title = Reactions of silyl enol ethers with carbonyl compounds activated by titanium tetrachloride
| author = Teruaki Mukaiyama, Kazuo Banno, and Koichi Narasaka
| journal = [[J. Am. Chem. Soc.]]
| volume = 96
| issue = 24
| pages = 7503–7509
| year = 1974
| url =
| doi = 10.1021/ja00831a019 }}</ref><ref>3-Hydroxy-3-Methyl-1-Phenyl-1-Butanone by Crossed Aldol Reaction Teruaki Mukaiyama and Koichi Narasaka [[Organic Syntheses]], Coll. Vol. 8, p.323 ('''1993'''); Vol. 65, p.6 ('''1987''') [http://www.orgsynth.org/orgsyn/pdfs/CV8P0323.pdf Link]</ref> The Mukaiyama aldol reaction does not follow the Zimmerman-Traxler model. Carreira has described particularly useful asymmetric methodology with silyl ketene acetals, noteworthy for its high levels of enantioselectivity and wide substrate scope.<ref name=carreira1994> {{cite journal
| title = Catalytic, enantioselective aldol additions with methyl and ethyl acetate ''O''-silyl enolates - a chira; tridentate chelate as a ligand for titanium(IV)
| author = Carreira E.M., Singer R.A., Lee W.S.
| doi = 10.1021/ja00098a065
| journal =[[J. Am. Chem. Soc.]]
| year =1994
| volume =116
| pages =8837–8}} </ref>
The method works on [[Branching (chemistry)|unbranched]] aliphatic aldehydes, which are often poor [[electrophile]]s for catalytic, asymmetric processes. This may be due to poor electronic and steric differentiation between their [[enantioface]]s.
[[Image:Acetatealdol2.gif|center]]
The analogous [[vinylogous]] Mukaiyama aldol process can also be rendered catalytic and asymmetric. The example shown below works efficiently for aromatic (but not aliphatic) aldehydes and the mechanism is believed to involve a chiral, metal-bound dienolate.<ref name=Carreira1998>{{cite journal
| title = Apparent catalytic generation of chiral metal enolates: Enantioselective dienolate additions to aldehydes mediated by Tol-BINAP center Cu(II) fluoride complexes
| author = Kruger J., Carreira E.M.
| doi = 10.1021/ja973331t
| journal =[[J. Am. Chem. Soc.]]
| year =1998
| volume =120
| pages =837–8}}</ref><ref name=Carreira1998-2>{{cite journal
| title = Mechanistic insights into Cu-catalyzed asymmetric aldol reactions: Chemical and spectroscopic evidence for a metalloenolate intermediate
| author = Pagenkopf B.L., Kruger J., Stojanovic A., Carreira E.M.| doi = 10.1002/(SICI)1521-3773(19981204)37:22<3124::AID-ANIE3124>3.0.CO;2-1
| journal = Angew. Chem. Intl. Ed.
| year =1998
| volume =37
| pages =3124–6
}}</ref>
[[Image:Acetatealdol3.gif|center]]
===Crimmins thiazoldinethione aldol===
A more recent version of the Evans' auxiliary is the '''Crimmins thiazoldinethione'''.<ref name=Crimmins1997>{{cite journal
| title = Asymmetric Aldol Additions with Titanium Enolates of Acyloxazolidinethiones: Dependence of Selectivity on Amine Base and Lewis Acid Stoichiometry
| author = Crimmins M. T., King B. W., Tabet A. E.
| doi = 10.1021/ja9716721
| journal = Journal of the American Chemical Society
| year = 1997
| volume =119
| issue = 33
| pages =7883–7884}}</ref><ref name=Crimmins2000>{{cite journal
| title = Titanium enolates of thiazolidinethione chiral auxiliaries: Versatile tools for asymmetric aldol additions
| author = Crimmins M. T., Chaudhary K.
| doi = 10.1021/ol9913901
| journal = Organic Letters
| year = 2000
| volume =2
| issue = 6
| pages =775–777}}</ref>
The [[chemical yield|yields]], [[diastereoselectivity|diastereoselectivities]], and enantioselectivities of the reaction are generally high, although not as high as in comparable Evans cases. Unlike the Evans auxiliary, however, the thiazoldinethione can perform acetate aldol reactions (ref: Crimmins, Org. Lett. 2007, 9(1), 149–152.) and can produce the "Evans syn" or "non-Evans syn" adducts by simply varying the amount of [[sparteine|(-)-sparteine]]. The reaction is believed to proceed via six-membered, titanium-bound [[transition state]]s, analogous to the proposed transition states for the Evans auxiliary.
[[Image:crimminsaldol1.gif|center]]
===Organocatalytic aldol reactions===
An exciting new development is the use of chiral secondary [[amine]] catalysts. These secondary amines form transient [[enamine]]s when exposed to ketones, which may react enantioselectively with suitable aldehyde electrophiles. This is known as '''enamine catalysis''', a type of [[organocatalysis]], since the catalyst is entirely based on a small organic molecule. In a seminal example, [[proline]] efficiently catalyzed the cyclization of a triketone:
[[Image:organocatalytic1.gif|center]]
This reaction is known as the [[Hajos-Parrish reaction]]<ref>Z. G. Hajos, D. R. Parrish, German Patent DE 2102623 '''1971'''</ref> <ref>''Asymmetric synthesis of bicyclic intermediates of natural product chemistry'' Zoltan G. Hajos, David R. Parrish [[J. Org. Chem.]]; '''1974'''; 39(12); 1615-1621. {{DOI|10.1021/jo00925a003}}</ref> (also known as the Hajos-Parrish-Eder-Sauer-Wiechert reaction, referring to a contemporaneous report from Schering of the reaction under harsher conditions)<ref>''New Type of Asymmetric Cyclization to Optically Active Steroid CD Partial Structures'' [[Angewandte Chemie International Edition in English]] Volume 10, Issue 7, Date: July '''1971''', Pages: 496-497 Ulrich Eder, Gerhard Sauer, Rudolf Wiechert {{DOI|10.1002/anie.197104961}}</ref>. Under the Hajos-Parrish conditions only a catalytic amount of proline is necessary (3 mol%). There is no danger of an achiral background reaction because the transient enamine intermediates are much more nucleophilic than their parent ketone enols. This strategy is particularly powerful because it offers a simple way of generating enantioselectivity in reactions without using transition metals, which have the possible disadvantages of being toxic or expensive.
Interestingly, proline-catalyzed aldol reactions do not show any non-linear effects (the enantioselectivity of the products is directly proportional to the enantiopurity of the catalyst). Combined with [[isotopic labelling]] evidence and [[computational chemistry|computational studies]], the proposed [[reaction mechanism]] for proline-catalyzed aldol reactions is as follows:<ref>''The ying and yang of asymmetric aminocatalysis'' Benjamin List [[Chem. Commun.]], '''2006''', 819–824, {{DOI|10.1039/b514296m}}</ref>
[[Image:organocatalytic2.gif|center]]
This strategy allows the otherwise challenging cross-aldol reaction between two aldehydes. In general, cross-aldol reactions between aldehydes are typically challenging because they can [[polymerization|polymerize]] easily or react unselectively to give a statistical mixture of products. The first example is shown below:<ref>''The First Direct and Enantioselective Cross-Aldol Reaction of Aldehydes'' Alan B. Northrup and David W. C. MacMillan [[J. Am. Chem. Soc.]]; '''2002'''; 124(24) pp 6798–6799; (Communication) {{DOI|10.1021/ja0262378}}</ref>
[[Image:organocatalytic3.gif|center]]
In contrast to the preference for syn adducts typically observed in enolate-based aldol additions, these organocatalyzed aldol additions are anti-selective. In many cases, the organocatalytic conditions are mild enough to avoid polymerization. However, selectivity requires the slow syringe-pump controlled addition of the desired electrophilic partner because both reacting partners typically have enolizable protons. If one aldehyde has no enolizable protons or alpha- or beta-branching, additional control can be achieved.
An elegant demonstration of the power of asymmetric organocatalytic aldol reactions was disclosed by MacMillan and coworkers in 2004 in their synthesis of differentially protected [[carbohydrate]]s. While traditional synthetic methods accomplish the synthesis of [[hexose]]s using variations of iterative [[protective group|protection-deprotection]] strategies, requiring 8–14 steps, organocatalysis can access many of the same substrates using an efficient two-step protocol involving the proline-catalyzed dimerization of alpha-oxyaldehydes followed by tandem Mukaiyama aldol cyclization.
[[Image:organocatalytic4.gif|center]]
The aldol dimerization of alpha-oxyaldehydes requires that the aldol adduct, itself an aldehyde, be inert to further aldol reactions.<ref>{{cite journal
| author = Northrup A. B., Mangion I. K., Hettche F., MacMillan D. W. C.
| title = Enantioselective Organocatalytic Direct Aldol Reactions of -Oxyaldehydes: Step One in a Two-Step Synthesis of Carbohydrates
| journal = Angewandte Chemie International Edition in English
| volume = 43
| issue = 16
| pages = 2152–2154
| year = 2004
| doi = 10.1002/anie.200453716}}
</ref>
Earlier studies revealed that aldehydes bearing alpha-alkyloxy or alpha-[[silyloxy]] [[substituent]]s were suitable for this reaction, while aldehydes bearing [[Electron-withdrawing group]]s such as [[acetoxy]] were unreactive. The protected [[erythrose]] product could then be converted to four possible sugars via Mukaiyama aldol addition followed by [[lactol]] formation. This requires appropriate diastereocontrol in the Mukaiyama aldol addition and the product [[carbenium ion|silyloxycarbenium ion]] to preferentially cyclize, rather than undergo further aldol reaction. In the end, [[glucose]], [[mannose]], and [[allose]] were synthesized:
[[Image:organocatalytic5.gif|center]]
==="Direct" aldol additions===
In the usual aldol addition, a carbonyl compound is deprotonated to form the enolate. The enolate is added to an aldehyde or ketone, which forms an alkoxide, which is then protonated on workup. A superior method, in principle, would avoid the deprotonation-aldol-protonation sequence in favor of a "direct aldol addition". The major issue in such a process is that the aldol addition generates an alkoxide, which is much more basic than the starting materials, precluding catalyst turnover:
[[Image:directaldol1.gif|center]]
One approach, recently demonstrated by Evans, is to silylate the aldol adduct:<ref>''Diastereoselective Magnesium Halide-Catalyzed anti-Aldol Reactions of Chiral N-Acyloxazolidinones '' Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. [[J. Am. Chem. Soc.]]; (Communication); '''2002'''; 124(3); 392–393. {{DOI| 10.1021/ja0119548}}; OL 2002, 4, 1127</ref>
[[Image:directaldol2.gif|center]]
This method is more cost effective and industrially useful than the more typical enolate-based procedures. A more recent, biomimetic approach by Shair uses beta-thioketoacids as the nucleophile.<ref>''Catalytic Enantioselective Thioester Aldol Reactions That Are Compatible with Protic Functional Groups'' Magdziak, D.; Lalic, G.; Lee, H. M.; Fortner, K. C.; Aloise, A. D.; Shair, M. D. [[J. Am. Chem. Soc.]]; (Communication); '''2005'''; 127(20); 7284–7285. {{DOI|10.1021/ja051759j}} </ref> The ketoacid moiety is [[decarboxylation|decarboxylated]] [[in situ]] (the [[chiral ligand]] is a [[bisoxazoline ligand|bisoxazoline]]). Interestingly, aromatic and branched aliphatic aldehydes are typically poor substrates.
[[Image:directaldol3.gif|center]]
==See also==
* [[Aldol-Tishchenko reaction]]
* [[Baylis-Hillman reaction]]
* [[Ivanov reaction]]
* [[Reformatsky reaction]]
* [[Cannizzaro reaction]]
* [[Aldonic acid]]
* [[Knoevenagel condensation]]
==References==
{{reflist|2}}
[[Category:Addition reactions]]
[[Category:Carbon-carbon bond forming reactions]]
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