Chemical Sciences: A Manual for CSIR-UGC National Eligibility Test for Lectureship and JRF/Named Reactions/Aldol Reaction: Difference between revisions
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[[Image:aldolrxnpic.jpg|thumb|right|300px|A typical experimental setup for an aldol reaction.<br> A solution of lithium diisopropylamide (LDA) in THF (in the flask on the right) is being added to a solution of ''tert''-butyl propionate in the flask on the left, forming the lithium enolate of tert-butyl propionate. An aldehyde will then be added.<br> Both flasks are submerged in a dry ice/acetone bath (-78 °C) the temperature of which is being monitored by a thermocouple (the wire on the left).]]The '''aldol reaction''' is an important [[carbon-carbon bond]] forming [[organic reaction|reaction]] in [[organic chemistry]]{{Ref|Wade}}{{Ref|March}}{{Ref|Mahrwald2004}}. In its usual form, it involves the nucleophilic addition of a [[ketone]] [[enolate]] to an [[aldehyde]].{{Ref|Heathcock1991}}{{Ref|Mukaiyama1982}}{{Ref|Paterson1988}} The initial reaction product is a β-hydroxy [[ketone]] , or "'''aldol'''" ('''ald'''ehyde + alcoh'''ol'''). When the reaction stops at the aldol stage, it is known as an '''aldol addition'''. If the aldol subsequently [[Dehydration reaction|loses a molecule of water]], it forms an [[α,β-unsaturated carbonyl compound|α,β-unsaturated ketone]]. This is called '''[[aldol condensation]]'''. |
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The '''aldol reaction''' is a powerful means of forming [[carbon-carbon bond]]s in [[organic chemistry]].<ref name=Wade> |
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{{cite book |
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A wide variety of nucleophiles may be employed in the aldol reaction, including the enols, enolates, and enol ethers of ketones, aldehydes, and many other carbonyl compounds. The electrophilic partner is usually an aldehyde, although many variations exist. When the nucleophile and electrophile are different (the usual case), the reaction is called a '''crossed aldol reaction''' (as opposed to an '''aldol dimerization'''). In [[1872]], the aldol reaction was discovered independently by [[Charles-Adolphe Wurtz]]{{Ref|Wurtz1872}} and by [[Alexander Porfyrevich Borodin]]. Borodin observed the aldol dimerization of 3-hydroxybutanal from [[acetaldehyde]] under acidic conditions. |
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| author = Wade, L. G. |
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| title = Organic Chemistry |
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| publisher = Prentice Hall |
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| date = 6th ed. 2005 |
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| location = Upper Saddle River, New Jersey |
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| pages = 1056–1066 |
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| isbn = 0132367319 }}</ref><ref name=March> |
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{{cite book |
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| author = Smith, M. B.; March, J. |
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| title = Advanced Organic Chemistry |
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| publisher = Wiley Interscience |
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| date = 5th ed. 2001 |
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| location = New York |
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| pages = 1218–1223 |
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| isbn = 0-471-58589-0}} |
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</ref><ref name=Mahrwald2004> |
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{{cite book |
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| author = Mahrwald, R. |
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| title = Modern Aldol Reactions, Volumes 1 and 2 |
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| publisher = Wiley-VCH Verlag GmbH & Co. KGaA |
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| year = 2004 |
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| location = Weinheim, Germany |
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| pages = 1218–1223 |
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| isbn = 3-527-30714-1}} |
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</ref> |
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Discovered independently by [[Charles-Adolphe Wurtz]]<ref name=Wurtz1872> |
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{{cite journal |
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| author = [[Charles-Adolphe Wurtz|Wurtz, C. A.]] |
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| journal = Bull. Soc. Chim. Fr. |
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| year =1872 |
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| title = |
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| volume = 17 |
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| pages =436–442}}</ref><ref name=Wurtz1872b> |
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{{cite journal |
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| author = [[Charles-Adolphe Wurtz|Wurtz, C. A.]] |
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| journal = J. Prakt. Chemie |
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| year = 1872 |
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| title = Ueber einen Aldehyd-Alkohol |
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| volume = 5 |
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| issue = 1 |
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| pages = 457–464 |
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| doi = 10.1002/prac.18720050148 |
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}}</ref><ref name=Wurtz1872c> |
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{{cite journal |
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| author = [[Charles-Adolphe Wurtz|Wurtz, C. A.]] |
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| journal = [[Comptes rendus de l'Académie des sciences|Comp. Rend.]] |
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| year = 1872 |
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| title = Sur un aldéhyde-alcool |
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| volume = 74 |
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| pages =1361 |
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| url = http://gallica.bnf.fr/ark:/12148/bpt6k3031q/f1361.table}}</ref> and [[Alexander Porfyrevich Borodin]] in 1872, the reaction combines two [[carbonyl]] compounds to form a new [[Hydroxy ketone|β-hydroxy carbonyl compound]]; Borodin observed the dimerization of [[acetaldehyde]] to 3-hydroxybutanal under acidic conditions. These [[Hydroxy ketone|β-hydroxy carbonyl]] products are known as "'''aldols'''" ('''ald'''ehyde + alcoh'''ol'''). Aldol structural units are found in many important molecules, whether naturally occurring or synthetic.<ref name=Heathcock1991>{{cite book |
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| author = [[Clayton Heathcock|Heathcock, C. H.]] |
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| title = Comp. Org. Syn. |
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| publisher = Pergamon |
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| year = 1991 |
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| location = Oxford |
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| pages = 133–179 |
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| isbn = 0-08-040593-2}} |
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</ref><ref name=Mukaiyama1982> |
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{{cite journal |
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| title = The Directed Aldol Reaction |
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| author = Mukaiyama T. |
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| journal =Org. React. |
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| year =1982 |
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| volume =28 |
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| pages =203–331 |
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| dou = 10.1002/0471264180.or028.03 |
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| doi = 10.1002/0471264180.or028.03 }} |
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</ref><ref name=Paterson1988> |
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{{cite journal |
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| title = New Asymmetric Aldol Methodology Using Boron Enolates |
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| author = Paterson, I. |
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| journal = Chem. Ind. |
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| year =1988 |
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| volume =12 |
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| pages =390–394}}</ref> |
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For example, the aldol reaction has been used in the large-scale production of the commodity chemical [[pentaerythritol]]<ref name=mestres> |
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{{cite journal |
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| title = A green look at the aldol reaction |
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| author = Mestres R. |
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| journal = Green Chemistry |
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| year = 2004 |
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| volume =12 |
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| pages = 583–603 |
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| doi = 10.1039/b409143b }}</ref> |
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and the synthesis of the heart disease drug Lipitor (INN: [[atorvastatin]]).<ref name=Braun5031>{{cite journal |
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| title = (R) and (S)-2-acetoxy-1,1,2-triphenylethanol - effective synthetic equivalents of a chiral acetate enolate |
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| author = M. Braun, R. Devant |
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| journal = Tetrahedron Letters |
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| year =1984 |
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| volume =25 |
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| pages =5031–4 |
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| dou = 10.1016/S0040-4039(01)91110-4 | doi = 10.1016/S0040-4039(01)91110-4 |
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}} |
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</ref><ref name=jackli2004>{{cite book |
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| author = Jie Jack Li ''et al.'' |
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| title = Contemporary Drug Synthesis |
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| publisher = Wiley-Interscience |
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| year = 2004 |
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| location = |
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| pages = 118- |
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| isbn = 0-471-21480-9}} |
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</ref> |
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The aldol reaction is powerful because it unites two relatively simple molecules into a more complex one. Increased complexity arises because up to two new [[stereogenic center]]s (on the [[Alpha carbon|α- and β-carbon]] of the aldol adduct, marked with asterisks in the scheme below) are formed. Modern methodology is not only capable of allowing aldol reactions to proceed in high yield, but also controlling both the relative and absolute stereochemical configuration of these stereocenters. This ability to selectively synthesize a particular [[stereoisomer]] is significant because different stereoisomers can have very different chemical or biological properties. |
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For example, stereogenic aldol units are especially common in [[polyketide]]s, a class of [[natural products|molecules found in biological organisms]]. In nature, polyketides are synthesized by enzymes which effect iterative [[Claisen condensation]]s. The 1,3-dicarbonyl products of these reactions can then be variously derivatized to produce a wide variety of interesting structures. Often, such derivitization involves the reduction of one of the carbonyl groups, producing the aldol subunit. Some of these structures have potent biological properties: the potent immunosuppressant [[FK506]], the anti-tumor agent [[discodermolide]], or the antifungal agent [[amphotericin B]], for example. Although the synthesis of many such compounds was once considered nearly impossible, aldol methodology has allowed their efficient [[total synthesis|synthesis]] in many cases.<ref name=MahrwaldSchetter2006> |
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{{cite journal |
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| title = Modern Aldol Methods for the Total Synthesis of Polyketides |
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| author = Schetter, B., Mahrwald, R. |
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| journal =Angew. Chem. Int. Ed. |
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| year =2006 |
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| volume =45 |
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| pages =7506–7525 |
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| doi = 10.1002/anie.200602780 }}</ref> |
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[[Image:typicalaldol2.gif|center]] |
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A typical modern '''aldol addition reaction''', shown above, might involve the [[nucleophilic addition]] of a [[ketone]] [[enolate]] to an [[aldehyde]]. Once formed, the aldol product can sometimes [[Dehydration reaction|lose a molecule of water]] to form an [[α,β-unsaturated carbonyl compound]]. This is called '''[[aldol condensation]]'''. 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 or ketone (many variations, such as the [[Mannich reaction]], exist). When the nucleophile and electrophile are different, the reaction is called a '''crossed aldol reaction'''; conversely, when the nucleophile and electrophile are the same, the reaction is called '''aldol dimerization'''. |
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[[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) will be transferred into a solution of ''tert''-butyl propionate in the flask on the left, forming the lithium enolate of ''tert''-butyl propionate. 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).]] |
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==Mechanisms== |
==Mechanisms== |
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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." |
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If an aldehyde or ketone is converted to an enol or enolate, it becomes [[nucleophile|nucleophilic]] at the [[Alpha-carbon|α-carbon]]. [[carbonyl|α,β-unsaturated aldehydes or ketones]] can also be [[deprotonation|deprotonated]] to form [[vinyl|vinylogous]] enolates.{{Ref|Casiraghi2000}} This allows it to attack an [[electrophile|electrophilic]] component (a carbonyl or protonated carbonyl) to form the aldol. The aldol reaction may proceed under [[acid (chemistry)|acidic]] or [[base (chemistry)|basic]] conditions, as shown above. If [[specific acid catalysis]] is used, the reaction involves a weak nucleophile (an enol) attacking a strong electrophile (the [[protonation|protonated]] carbonyl). Under basic conditions, a nucleophile (the enolate) is formed which is strong enough to react with the unprotonated carbonyl. If the conditions are particularly harsh (e.g., NaOMe, MeOH, reflux), dehydration may occur, but is usually (e.g., LDA, THF, -78 °C) avoided. 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. |
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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. |
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:[[Image:Simple aldol reaction.png|600px|A generalized view of the Aldol reaction]] |
:[[Image:Simple aldol reaction.png|600px|A generalized view of the Aldol reaction]] |
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===Enol mechanism=== |
===Enol mechanism=== |
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When an acid catalyst is used, the initial step in the [[reaction mechanism]] involves acid-catalyzed [[tautomer |
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. |
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:[[Image:Enol aldol mechanism.png|450px|Mechanism for acid-catalyzed aldol reaction of an aldehyde with itself]] |
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'''Acid catalyzed aldol mechanism''' |
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:[[Image:Enol aldol formation mechanism.png|500px|Mechanism for acid-catalyzed aldol reaction of an aldehyde with itself]] |
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'''Acid catalyzed dehydration''' |
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:[[Image:Enol aldol dehydration mechanism.png|500px|Mechanism for acid-catalyzed dehydration of an aldol]] |
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===Enolate mechanism=== |
===Enolate mechanism=== |
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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. |
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. |
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'''Base catalyzed aldol reaction''' (shown using [[methoxide|<sup>−</sup>OCH<sub>3</sub>]] as base) |
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:[[Image:Enolate aldol mechanism.png|450px|Simple mechanism for base-catalyzed aldol reaction of an aldehyde with itself]] |
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:[[Image:Enolate aldol formation mechanism.png|500px|Simple mechanism for base-catalyzed aldol reaction of an aldehyde with itself]] |
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'''Base catalyzed dehydration''' (frequently written incorrectly as a single step, see [[E1cB elimination reaction]]) |
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If a stronger base such as [[Lithium diisopropylamide|LDA]] or [[Sodium hexamethyldisilazide|NaHMDS]] is used in [[stoichiometric]] amounts, the formation of the enolate becomes irreversible, and this helps to drive the reaction forward. In such cases the aldol product is not formed until a separate protonation step is performed. Otherwise, the mechanism can be regarded as the same. |
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:[[Image:Enolate aldol dehydration mechanism.png|500px|Simple mechanism for the dehydration of an aldol product]] |
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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. |
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===Zimmerman-Traxler model=== |
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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|Zimmerman1920}} This has become 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]] based on [[pentane interference]].{{Ref|Heathcock1980}} 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, with the result that the [[stereochemistry|stereochemical]] outcome of the reaction may be unpredictable. |
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===Zimmerman–Traxler model=== |
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:[[Image:scheme2.gif|The Zimmerman-Traxler Model]] |
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More refined forms of the mechanism are known. In 1957, [[Howard Zimmerman|Zimmerman]] and Traxler proposed that some aldol reactions have "six-membered transition states having a [[chair conformation]]."<ref name=Zimmerman1920>{{cite journal |
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| title = The Stereochemistry of the Ivanov and Reformatsky Reactions. I |
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| author = Zimmerman, H. E.; Traxler, M. D.|doi = 10.1021/ja01565a041 |
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| journal =[[J. Am. Chem. Soc.]] |
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| year =1957 |
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| volume =79 |
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| 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 |
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|title = Acyclic stereoselection. 7. Stereoselective synthesis of 2-alkyl-3-hydroxy carbonyl compounds by aldol condensation |
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| author = Heathcock C. H., Buse, C. T., Kleschnick W. A., Pirrung M. C., Sohn J. E., Lampe, J. |
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| doi = 10.1021/jo01294a030 |
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| journal =[[J. Org. Chem.]] |
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| year = 1980 |
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| volume =45 |
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| 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. |
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:[[Image:scheme2.gif|The Zimmerman–Traxler model]] |
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==Control in the Aldol reaction== |
==Control in the Aldol reaction== |
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===The problem=== |
===The problem=== |
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The problem of "control" in the aldol addition is best demonstrated by an example. |
The problem of "control" in the aldol addition is best demonstrated by an example. Consider the outcome of this hypothetical reaction: |
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[[Image:Aldolcontrol1.gif|center|Hypothetical aldol reaction]] |
[[Image:Aldolcontrol1.gif|center|Hypothetical aldol reaction]] |
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In this reaction, two unsymmetrical ketones are being condensed using [[sodium ethoxide]]. |
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: |
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[[Image:Aldolcontrol2.gif|center|Four possible aldol reaction products]] |
[[Image:Aldolcontrol2.gif|center|Four possible aldol reaction products]] |
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Thus, if one wishes to obtain only one of the cross-products, |
Thus, if one wishes to obtain only one of the cross-products, one must "control" the aldol addition. |
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===Acidity=== |
===Acidity=== |
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If one partner is considerably more acidic than the other, then control may be automatic. For example, the addition of diethyl malonate into benzaldehyde would |
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: |
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[[Image:Aldolcontrol3.gif|center|Acidic control of the aldol reaction]] |
[[Image:Aldolcontrol3.gif|center|Acidic control of the aldol reaction]] |
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In this case, the doubly activated [[methylene]] protons of the [[malonate]] would be preferentially deprotonated by sodium ethoxide and quantitatively form the sodium enolate. |
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. |
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===Order of addition=== |
===Order of addition=== |
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One common solution is to form the enolate of one partner first, and then add the other partner under [[kinetic reaction control|kinetic control]] |
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 [[Lithium diisopropylamide|LDA]] at −78 °C, followed by the slow addition of an aldehyde. |
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==Enolates== |
==Enolates== |
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===Geometry=== |
===Geometry=== |
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Extensive studies have been performed on the formation of enolates under many different conditions. |
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 |
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| 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 |
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| author = [[Herbert C. Brown|Brown H. C.]], Dhar R. K., Bakshi R. K., Pandiarajan P. K., Singaram B. |
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| doi = 10.1021/ja00191a058 |
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| journal =[[J. Am. Chem. Soc.]] |
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| year =1989 |
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| volume =111 |
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| pages =3441–3442}}</ref> |
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[[Image:scheme3.gif|center|Stereoselective enolate generation]] |
[[Image:scheme3.gif|center|Stereoselective enolate generation]] |
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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. |
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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. |
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[[Image:scheme3b.gif|center|Effect of HMPA addition]] |
[[Image:scheme3b.gif|center|Effect of HMPA addition]] |
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The stereoselective formation of enolates has been rationalized with the |
The stereoselective formation of enolates has been rationalized with the '''Ireland model''',<ref name= Ireland1975>{{cite journal |
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|title = The stereoselective generation of ester enolates |
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| author = Ireland, R. E.; Willard, A. K. |
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| doi = 10.1016/S0040-4039(00)91213-9 |
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| journal =[[Tetrahedron Lett.]] |
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| year = 1975 |
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| volume =16 |
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| issue =46 |
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| pages = 3975–3978}}</ref><ref name=Narula1981>{{cite journal |
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|title = An analysis of the diastereomeric transition state interactions for the kinetic deprotonation of acyclic carbonyl derivatives with lithium diisopropylamide |
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| author = Narula, A. S. |
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| doi = 10.1016/S0040-4039(01)82081-5 |
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| journal =[[Tetrahedron Lett.]] |
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| year = 1981 |
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| volume =22 |
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| issue =41 |
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| pages = 4119–4122}}</ref><ref name=Ireland1991>{{cite journal |
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|title = Stereochemical control in the ester enolate Claisen rearrangement. 1. Stereoselectivity in silyl ketene acetal formation |
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| author = Ireland, R. E.; Wipf, P.; Armstrong, J. D. |
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| doi = 10.1021/jo00002a030 |
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| journal =[[J. Org. Chem.]] |
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| year = 1991 |
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| volume =56 |
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| pages = 650–657}}</ref><ref name=Xie1997>{{cite journal |
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|title = Highly Stereoselective Kinetic Enolate Formation: Steric vs Electronic Effects |
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| author = Xie L., Isenberger K. M., Held G., Dahl, L. M. |
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| doi = 10.1021/jo971260a |
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| journal =[[J. Org. Chem.]] |
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| year = 1997 |
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| volume =62 |
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| 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. |
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[[Image:scheme3d.gif|center|The Ireland model]] |
[[Image:scheme3d.gif|center|The Ireland model]] |
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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. |
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===Kinetic vs. thermodynamic enolates=== |
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If an unsymmetrical ketone is subjected to base, it has the potential to form two regioisomeric enolates (ignoring enolate geometry). For example: |
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===Kinetic versus thermodynamic enolates=== |
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If an unsymmetrical ketone is subjected to base, it has the potential to form two regioisomeric enolates (ignoring enolate geometry). For example: |
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[[Image:Enolateregio1.gif|center|Kinetic and thermodynamic enolates]] |
[[Image:Enolateregio1.gif|center|Kinetic and thermodynamic enolates]] |
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The trisubstituted enolate is considered the [[thermodynamic reaction control|kinetic]] enolate while the |
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. |
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. |
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==Stereoselectivity== |
==Stereoselectivity== |
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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. |
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===E vs. Z enolates=== |
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There is no significant difference between the level of [[stereoinduction]] observed with E and Z enolates:{{Ref|JACS1989_3441}} |
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[[Image:aldolsynanti.png|500px|Syn and anti products from an aldol reaction]] |
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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 (or screen), 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. |
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Older papers use the ''[[Erythrose|erythro]]''-''[[Threose|threo]]'' nomenclature familiar from carbohydrate chemistry. |
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===E versus Z enolates=== |
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There is no significant difference between the level of [[stereoinduction]] observed with ''E'' and ''Z'' enolates:<ref name=Brown1989 /> |
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[[Image:EvsZstereoselectivity.gif|center|Anti-aldol formation via Z-enolate]] |
[[Image:EvsZstereoselectivity.gif|center|Anti-aldol formation via Z-enolate]] |
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Line 87: | Line 276: | ||
===Metal ion=== |
===Metal ion=== |
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The enolate metal cation may play a large role in determining the level of stereoselectivity in the aldol reaction. |
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 |
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| journal =[[J. Am. Chem. Soc.]] |
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| year =1981 |
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| volume =103 |
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| pages =3099–3111}}</ref> |
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[[Image:Metalion.gif]] |
[[Image:Metalion.gif|center]] |
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===Stereoselectivity: Alpha stereocenter on the enolate=== |
===Stereoselectivity: Alpha stereocenter on the enolate=== |
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The aldol reaction may exhibit "substrate-based stereocontrol", in which existing [[Chirality (chemistry)|chirality]] on either reactant influences the |
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]] |
[[Image:enolatealphacenter.gif|center|Aldol reaction with enolate-based stereocontrol]] |
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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. |
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]] |
[[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 |
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. |
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| doi = 10.1021/ja00003a051 |
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| journal =[[J. Am. Chem. Soc.]] |
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| year =1991|volume =113 |
|||
| pages =1047–1049}}</ref> |
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[[Image:enolatealphacentereg.gif|center|Aldol reaction with enolate-based stereocontrol]] |
[[Image:enolatealphacentereg.gif|center|Aldol reaction with enolate-based stereocontrol]] |
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===Stereoselectivity: Alpha stereocenter on the electrophile=== |
===Stereoselectivity: Alpha stereocenter on the electrophile=== |
||
When enolates attacks aldehydes with an alpha stereocenter, excellent stereocontrol is also possible. |
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 |
| title = Concerning the diastereofacial selectivity of the aldol reactions of .alpha.-methyl chiral aldehydes and lithium and boron propionate enolates |
||
| author = Roush W. R. |
| author = Roush W. R. |
||
| journal = [[J. Org. Chem.]] |
| journal = [[J. Org. Chem.]] |
||
| year = 1991 |
| year = 1991 |
||
| volume = 56 |
| volume = 56 |
||
| pages = |
| pages = 4151–4157 |
||
| doi = 10.1021/jo00013a015}}</ref |
| doi = 10.1021/jo00013a015}}</ref> is presented below: |
||
[[Image:Aldehydealphamodel.gif|center|The general model of the aldol reaction with carbonyl-based stereocontrol]] |
[[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. |
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 |
| title = Aldol strategy: coordination of the lithium cation with an alkoxy substituent |
||
| author = Masamune S., Ellingboe J. W., Choy W. |
| author = Masamune S., Ellingboe J. W., Choy W. |
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Line 123: | Line 324: | ||
| year =1982 |
| year =1982 |
||
| volume =104 |
| volume =104 |
||
| pages = |
| 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 |
|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. |
| author = Evans D. A., Dart M. J., Duffy J. L., Rieger D. L. |
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Line 129: | Line 330: | ||
| year =1995 |
| year =1995 |
||
| volume =117 |
| volume =117 |
||
| pages = |
| pages =9073–9074}}</ref> |
||
[[Image:aldehydealphaeg.gif|center|Examples of the aldol reaction with carbonyl-based stereocontrol]] |
[[Image:aldehydealphaeg.gif|center|Examples of the aldol reaction with carbonyl-based stereocontrol]] |
||
===Stereoselectivity: Merged model for stereoinduction=== |
===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.{{ |
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. |
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| doi = 10.1002/anie.198500013 |
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| journal =[[Angew. Chem. Int. Ed. Engl.]] |
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| year =1985 |
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| volume =24 |
|||
| pages =1–30}}</ref> Several examples of the application of this model are given below:<ref name=JACS1995_9073 /> |
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[[Image:Mergedmodel.gif]] |
[[Image:Mergedmodel.gif]] |
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==Evans' oxazolidinone chemistry== |
==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. |
|||
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. |
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[[Image:Evansaldol1.gif|center|Aldol reaction creates stereoisomers]] |
[[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. |
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. |
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[[Image:Evansaldol2.gif|center|Four possible stereoisomers of the aldol reaction]] |
[[Image:Evansaldol2.gif|center|Four possible stereoisomers of the aldol reaction]] |
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A widely used method is the Evans' [[acyl]] [[oxazolidinone]] method. |
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. |
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[[Image:Evansaldol3.gif|center]] |
[[Image:Evansaldol3.gif|center]] |
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In the case of the Evans' method, the chiral auxiliary appended is an [[oxazolidinone]], and the resulting carbonyl compound is an [[imide]]. |
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. |
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[[Image:Evansaldol4.gif|center]] |
[[Image:Evansaldol4.gif|center]] |
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The [[acylation]] of an oxazolidinone is a convenient procedure, and is informally referred to as "loading done". |
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 |
| title = Enantioselective aldol condensations. 2. Erythro-selective chiral aldol condensations via boron enolates |
||
| author = Evans D. A., Bartroli J., Shih T. L. |
| author = Evans D. A., Bartroli J., Shih T. L. |
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Line 163: | Line 369: | ||
| year =1981 |
| year =1981 |
||
| volume =103 |
| volume =103 |
||
| pages = |
| pages =2127–2129}}</ref> |
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[[Image:Evansaldol5.gif|center]] |
[[Image:Evansaldol5.gif|center]] |
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Often, a single [[diastereomer]] may be obtained by one [[crystallization]] of the aldol adduct. |
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 |
| title = The total synthesis of the polyether antibiotic X-206 |
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| author = Evans D. A., Bender S. L., Morris J. |
| author = Evans D. A., Bender S. L., Morris J. |
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Line 174: | Line 380: | ||
| year =1988 |
| year =1988 |
||
| volume =110 |
| volume =110 |
||
| pages = |
| pages =2506–2526}}</ref> |
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[[Image:Evansaldol6.gif|center|Evans' chiral oxazolidinone cleavage]] |
[[Image:Evansaldol6.gif|center|Evans' chiral oxazolidinone cleavage]] |
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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: |
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 |
| 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. |
| author = Evans D.A., Clark J.S., Metternich R., Sheppard G.S. |
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Line 185: | Line 391: | ||
| year =1990 |
| year =1990 |
||
| volume =112 |
| volume =112 |
||
| pages = |
| pages =866–868}}</ref> and anti selective:<ref name=JACS922127>{{cite journal |
||
|title = Diastereoselective anti aldol reactions of chiral |
|title = Diastereoselective anti aldol reactions of chiral ethyl ketones. Enantioselective processes for the synthesis of polypropionate natural products |
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| author = Evans D.A., Ng, H.P., Clark J.S., |
| author = Evans D.A., Ng, H.P., Clark J.S., Rieger D.L. |
||
| journal = Tetrahedron |
| journal = Tetrahedron |
||
| year = 1992|volume = 48 |
| year = 1992|volume = 48 |
||
| pages = |
| pages = 2127–2142 |
||
| doi =10.1016/S0040-4020(01)88879-7}}</ref |
| doi =10.1016/S0040-4020(01)88879-7}}</ref> |
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[[Image:Evansaldol7.gif|center]] |
[[Image:Evansaldol7.gif|center]] |
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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. |
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. |
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==Modern |
==Modern aldol chemistry== |
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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. |
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===Acetate aldol reactions=== |
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Recent methodology now allows a much wider variety of aldol reactions to be conducted, often with a catalytic amount of chiral ligand. When reactions employ small amounts of enantiomerically pure ligands to induce the formation of enantiomerically pure products, the reactions are typically termed "catalytic, asymmetric"; for example, many different catalytic, asymmetric aldol reactions are now available. |
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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> |
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===Acetate Aldol Reactions=== |
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A key limitation to the chiral auxiliary approach described previously is the failure of N-acetyl imides to react selectively. An early approach was to use a temporary thioether group{{Ref|JACS882506}}: |
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[[Image:Acetatealdol1.gif|center]] |
[[Image:Acetatealdol1.gif|center]] |
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===Mukaiyama aldol reaction=== |
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A more modern approach is the catalytic, asymmetric addition of silyl ketene acetals to aldehydes ("Mukaiyama aldol reaction"). Carreira has described particularly useful methodology, noteworthy for its high levels of enantioselectivity and wide substrate scope. |
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{{main|Mukaiyama aldol reaction}} |
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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 tetrachloride]].<ref> |
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{{cite journal |
|||
| title = Reactions of silyl enol ethers with carbonyl compounds activated by titanium tetrachloride |
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| author = Teruaki Mukaiyama, Kazuo Banno, and Koichi Narasaka |
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| journal = [[J. Am. Chem. Soc.]] |
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| volume = 96 |
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| issue = 24 |
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| pages = 7503–7509 |
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| year = 1974 |
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| url = |
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| 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 |
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| title = Catalytic, enantioselective aldol additions with methyl and ethyl acetate ''O''-silyl enolates — a chira; tridentate chelate as a ligand for titanium(IV) |
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| author = Carreira E.M., Singer R.A., Lee W.S. |
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| doi = 10.1021/ja00098a065 |
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| journal =[[J. Am. Chem. Soc.]] |
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| year =1994 |
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| volume =116 |
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| pages =8837–8}}</ref> |
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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. |
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ref: Carreira, E.M. et al. JACS 1994, 116, 8837-8838. |
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The method works on unbranched aliphatic aldehydes, which are often poor electrophiles for catalytic, asymmetric processes. This may be due to poor electronic and steric differentiation between their enantiofaces. |
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[[Image:Acetatealdol2.gif|center]] |
[[Image:Acetatealdol2.gif|center]] |
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The analogous vinylogous Mukaiyama aldol process can also be rendered catalytic and asymmetric. |
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 |
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| author = Kruger J., Carreira E.M. |
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ref: Carreira, E.M. et al. JACS 1998, 120, 837-838. ACIE, 1998, 37, 3124-3126. |
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| doi = 10.1021/ja973331t |
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| journal =[[J. Am. Chem. Soc.]] |
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| year =1998 |
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| volume =120 |
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| pages =837–8}}</ref><ref name=Carreira1998-2>{{cite journal |
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| title = Mechanistic insights into Cu-catalyzed asymmetric aldol reactions: Chemical and spectroscopic evidence for a metalloenolate intermediate |
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| 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 |
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| journal = Angew. Chem. Intl. Ed. |
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| year =1998 |
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| volume =37 |
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| pages =3124–6 |
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}}</ref> |
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[[Image:Acetatealdol3.gif|center]] |
[[Image:Acetatealdol3.gif|center]] |
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===Crimmins thiazolidinethione aldol=== |
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===Acyloxazolidinethiones=== |
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A more recent version of the Evans' auxiliary is the '''Crimmins thiazolidinethione'''.<ref name=Crimmins1997>{{cite journal |
|||
| title = Asymmetric Aldol Additions with Titanium Enolates of Acyloxazolidinethiones: Dependence of Selectivity on Amine Base and Lewis Acid Stoichiometry |
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| author = Crimmins M. T., King B. W., Tabet A. E. |
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| doi = 10.1021/ja9716721 |
|||
| journal = Journal of the American Chemical Society |
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| year = 1997 |
|||
| volume =119 |
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| issue = 33 |
|||
| pages =7883–7884}}</ref><ref name=Crimmins2000>{{cite journal |
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| title = Titanium enolates of thiazolidinethione chiral auxiliaries: Versatile tools for asymmetric aldol additions |
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| author = Crimmins M. T., Chaudhary K. |
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| doi = 10.1021/ol9913901 |
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| journal = Organic Letters |
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| year = 2000 |
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| volume =2 |
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| issue = 6 |
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| pages =775–777 |
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| pmid = 10754681}}</ref> |
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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. NOTE: the structure of sparteine shown below is missing a N atom. |
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[[Image:crimminsaldol1.gif|center]] |
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===Organocatalytic aldol reactions=== |
===Organocatalytic aldol reactions=== |
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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: |
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An exciting new development is the use of chiral secondary amine catalysts. These secondary amines form transient enamines when exposed to ketones, which may react enantioselectively with suitable aldehyde electrophiles. This is known as "enamine catalysis" which is a kind of "organocatalysis", since the catalyst is entirely based on a small organic molecule. In the well-known first report, proline efficiently catalyzed the cyclization of a triketone (ref: Eder, U.; Sauer, G.; Wiechert, R.; ACIE 1971, 10, 496): |
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[[Image:organocatalytic1.gif|center]] |
[[Image:organocatalytic1.gif|center]] |
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This reaction is known as the [[Hajos-Parrish reaction]]<ref>Z. G. Hajos, D. R. Parrish, German Patent DE 2102623 '''1971'''</ref><ref>{{cite journal |
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This is commonly referred to as the "Hajos-Parrish-Eder-Sauer-Wiechert reaction". The secondary amines can be used in catalytic amounts because the transient enamines are much more nucleophilic than the parent ketones, precluding any achiral background reaction. This strategy is particularly powerful because it offers a simple and effective way to induce highly organized chiral transition states. Interestingly, proline-catalyzed aldol reactions do not show any non-linear effects. Combined with isotopic labelling evidence and computational studies, the proposed mechanism for proline-catalyzed aldol reactions is as follows (ref: List, B. Chem. Commun. 2006, 819-824.): |
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| title = Asymmetric synthesis of bicyclic intermediates of natural product chemistry |
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| first = Zoltan G. | last = Hajos |
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| coauthor = Parrish, David R. |
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| journal = [[Journal of Organic Chemistry]] |
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| year =1974 |
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| volume =39 |
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| issue = 12 |
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| pages =1615–1621 |
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| 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>{{cite journal |
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| title = New Type of Asymmetric Cyclization to Optically Active Steroid CD Partial Structures |
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| first = Ulrich | last = Eder |
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| coauthor = Sauer, Gerhard; Wiechert, Rudolf |
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| journal =[[Angewandte Chemie International Edition in English]] |
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| year =1971 |
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| volume =10 |
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| issue = 7 |
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| pages =1615–1621 |
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| 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. |
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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>{{cite journal |
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| title = The ying and yang of asymmetric aminocatalysis |
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| first = Benjamin | last = List |
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| coauthor = |
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| journal = [[Chemical Communications]] |
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| year =2006 |
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| volume = |
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| issue = 8 |
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| pages =819–824 |
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| doi = 10.1039/b514296m }}</ref> |
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[[Image:organocatalytic2.gif|center]] |
[[Image:organocatalytic2.gif|center]] |
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This strategy allows the otherwise challenging cross-aldol reaction between two aldehydes. |
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>{{cite journal |
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| title = The First Direct and Enantioselective Cross-Aldol Reaction of Aldehydes |
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| first = Alan B. | last = Northrup |
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| coauthor = MacMillan David W. C. |
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| journal = [[Journal of the American Chemical Society]] |
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| year =2002 |
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| volume = 124 |
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| issue = 24 |
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| pages =6798–6799 |
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| doi = 10.1021/ja0262378 }}</ref> |
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[[Image:organocatalytic3.gif|center]] |
[[Image:organocatalytic3.gif|center]] |
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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. |
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An elegant demonstration of the power of |
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. |
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[[Image:organocatalytic4.gif|center]] |
[[Image:organocatalytic4.gif|center]] |
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The aldol dimerization of alpha-oxyaldehydes requires that the aldol adduct, itself an aldehyde, be inert to further aldol reactions.<ref>{{cite journal |
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The aldol dimerization of alpha-oxyaldehydes (ref: MacMillan et al. ACIE, 2004, 43, 2152-2154) requires that the aldol adduct, itself an aldehyde, be inert to further aldol reactions. Earlier studies revealed that aldehydes bearing alpha-alkyloxy or alpha-silyloxy substitutents were suitable for this reaction, while aldehydes bearing electron-withdrawing substituents 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 silyloxycarbenium ion to preferentially cyclize, rather than undergo further aldol reaction. In the end, glucose, mannose, and allose were synthesized: |
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| author = Northrup A. B., Mangion I. K., Hettche F., MacMillan D. W. C. |
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| title = Enantioselective Organocatalytic Direct Aldol Reactions of -Oxyaldehydes: Step One in a Two-Step Synthesis of Carbohydrates |
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| journal = Angewandte Chemie International Edition in English |
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| volume = 43 |
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| issue = 16 |
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| pages = 2152–2154 |
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| year = 2004 |
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| doi = 10.1002/anie.200453716}} |
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</ref> |
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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: |
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[[Image:organocatalytic5.gif|center]] |
[[Image:organocatalytic5.gif|center]] |
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==="Direct" aldol additions=== |
==="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: |
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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: |
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[[Image:directaldol1.gif|center]] |
[[Image:directaldol1.gif|center]] |
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One approach, recently demonstrated by Evans, is to silylate the aldol adduct |
One approach, recently demonstrated by Evans, is to silylate the aldol adduct:<ref>{{cite journal |
||
| last = Evans |
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| first = D. A. |
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| coauthor = Tedrow, J. S.; Shaw, J. T.; Downey, C. W. |
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| title = Diastereoselective Magnesium Halide-Catalyzed anti-Aldol Reactions of Chiral N-Acyloxazolidinones |
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| journal = [[J. Am. Chem. Soc.]] |
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| volume = 124 |
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| issue = 3 |
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| pages = 392–393 |
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| year = 2002 |
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| doi = 10.1021/ja0119548}}</ref><ref>{{cite journal |
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| last = Evans |
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| first = David A. |
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| coauthor = Downey, C. Wade; Shaw, Jared T.; Tedrow, Jason S. |
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| title = Magnesium Halide-Catalyzed Anti-Aldol Reactions of Chiral N-Acylthiazolidinethiones |
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| journal = [[Organic Letters]] |
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| volume = 4 |
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| issue = 7 |
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| pages = 1127–1130 |
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| year = 2002 |
|||
| doi = 10.1021/ol025553o}}</ref> |
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[[Image:directaldol2.gif|center]] |
[[Image:directaldol2.gif|center]] |
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This method is more cost effective and industrially useful than the more typical enolate-based procedures. |
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>{{cite journal |
||
| last = Magdziak |
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| first = D. |
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| coauthor = Lalic, G.; Lee, H. M.; Fortner, K. C.; Aloise, A. D.; Shair, M. D. |
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| title = Catalytic Enantioselective Thioester Aldol Reactions That Are Compatible with Protic Functional Groups |
|||
| journal = [[J. Am. Chem. Soc.]] |
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| volume = 127 |
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| issue = 20 |
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| pages = 7284–7285 |
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| year = 2005 |
|||
| 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. |
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[[Image:directaldol3.gif|center]] |
[[Image:directaldol3.gif|center]] |
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==Biological aldol reactions== |
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==References== |
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Examples of aldol reactions in biochemistry include the splitting of [[fructose-1,6-bisphosphate]] into [[dihydroxyacetone]] and [[glyceraldehyde-3-phosphate]] in the second stage of [[glycolysis]] which is an example of a reverse aldol reaction catalysed by the enzyme [[aldolase A]]. |
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Simple sugars are cyclic aldol trimers of acetaldehyde that can be prepared synthetically. |
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5) Multiple footnotes to the same reference: see [[Wikipedia:Footnotes]] for a how-to, if you don't succeed by simply following the pattern. |
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<div class="references-small"> |
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| title = Stereoselective aldol condensations via boron enolates |
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| title = Stereoselective aldol reactions of chlorotitanium enolates. An efficient method for the assemblage of polypropionate-related synthons |
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# {{Note|Evans1982TS}} Evans, D. A. ''et al.'' ''Top. Stereochem.'' '''1982''', ''13'', 1-115. (Review) |
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# {{Note|Evans1982AldrichActa}} Evans, D. A. ''Aldrichimica Acta'' '''1982''', ''15'', 23. (Review) |
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| title = Enantioselective aldol condensations. 2. Erythro-selective chiral aldol condensations via boron enolates |
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| title = Diastereoselective aldol reactions using .beta.-keto imide derived enolates. A versatile approach to the assemblage of polypropionate systems |
|||
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|||
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</div> |
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==See also== |
==See also== |
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{{portal|Chemistry|Nuvola apps edu science.svg}} |
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* [[Aldol-Tishchenko reaction]] |
* [[Aldol-Tishchenko reaction]] |
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* [[Aldonic acid]] |
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* [[Baylis-Hillman reaction]] |
* [[Baylis-Hillman reaction]] |
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* [[Cannizzaro reaction]] |
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* [[Ivanov reaction]] |
* [[Ivanov reaction]] |
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* [[Knoevenagel condensation]] |
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* [[Reformatsky reaction]] |
* [[Reformatsky reaction]] |
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* [[Cannizzaro reaction]] |
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==References== |
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[[Category:Addition reactions]] |
[[Category:Addition reactions]] |
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[[Category:Carbon-carbon bond forming reactions]] |
[[Category:Carbon-carbon bond forming reactions]] |
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[[ar:تفاعل آلدول]] |
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Revision as of 20:28, 20 May 2010
Template:Featured article The aldol reaction is a powerful means of forming carbon-carbon bonds in organic chemistry.[1][2][3] Discovered independently by Charles-Adolphe Wurtz[4][5][6] and Alexander Porfyrevich Borodin in 1872, the reaction combines two carbonyl compounds to form a new β-hydroxy carbonyl compound; Borodin observed the dimerization of acetaldehyde to 3-hydroxybutanal under acidic conditions. These β-hydroxy carbonyl products are known as "aldols" (aldehyde + alcohol). Aldol structural units are found in many important molecules, whether naturally occurring or synthetic.[7][8][9] For example, the aldol reaction has been used in the large-scale production of the commodity chemical pentaerythritol[10] and the synthesis of the heart disease drug Lipitor (INN: atorvastatin).[11][12]
The aldol reaction is powerful because it unites two relatively simple molecules into a more complex one. Increased complexity arises because up to two new stereogenic centers (on the α- and β-carbon of the aldol adduct, marked with asterisks in the scheme below) are formed. Modern methodology is not only capable of allowing aldol reactions to proceed in high yield, but also controlling both the relative and absolute stereochemical configuration of these stereocenters. This ability to selectively synthesize a particular stereoisomer is significant because different stereoisomers can have very different chemical or biological properties.
For example, stereogenic aldol units are especially common in polyketides, a class of molecules found in biological organisms. In nature, polyketides are synthesized by enzymes which effect iterative Claisen condensations. The 1,3-dicarbonyl products of these reactions can then be variously derivatized to produce a wide variety of interesting structures. Often, such derivitization involves the reduction of one of the carbonyl groups, producing the aldol subunit. Some of these structures have potent biological properties: the potent immunosuppressant FK506, the anti-tumor agent discodermolide, or the antifungal agent amphotericin B, for example. Although the synthesis of many such compounds was once considered nearly impossible, aldol methodology has allowed their efficient synthesis in many cases.[13]
A typical modern aldol addition reaction, shown above, might involve the nucleophilic addition of a ketone enolate to an aldehyde. Once formed, the aldol product can sometimes lose a molecule of water to form an α,β-unsaturated carbonyl compound. This is called aldol condensation. A variety of nucleophiles may be employed in the aldol reaction, including the enols, enolates, and enol ethers of ketones, aldehydes, and many other carbonyl compounds. The electrophilic partner is usually an aldehyde or ketone (many variations, such as the Mannich reaction, exist). When the nucleophile and electrophile are different, the reaction is called a crossed aldol reaction; conversely, when the nucleophile and electrophile are the same, the reaction is called aldol dimerization.
A solution of lithium diisopropylamide (LDA) in tetrahydrofuran (THF) (in the flask on the right) will be transferred into a solution of tert-butyl propionate in the flask on the left, forming the lithium enolate of tert-butyl propionate. An aldehyde can then be added to initiate an aldol addition reaction.
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 α-carbon, can attack especially reactive protonated carbonyls such as protonated aldehydes. This is the "enol mechanism." Carbonyl compounds, being carbon acids, 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.
Enol mechanism
When an acid catalyst is used, the initial step in the reaction mechanism involves acid-catalyzed tautomerization of the carbonyl compound to the enol. The acid also serves to activate the carbonyl group of another molecule by protonation, rendering it highly electrophilic. The enol is nucleophilic at the α-carbon, allowing it to attack the protonated carbonyl compound, leading to the aldol after deprotonation. This usually dehydrates to give the unsaturated carbonyl compound. The scheme shows a typical acid-catalyzed self-condensation of an aldehyde.
Acid catalyzed aldol mechanism
Acid catalyzed dehydration
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-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 −OCH3 as base)
Base catalyzed dehydration (frequently written incorrectly as a single step, see E1cB elimination reaction)
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 LDA or 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 states having a chair conformation."[14] This is now known as the Zimmerman–Traxler model. E-enolates give rise to anti products, whereas Z-enolates give rise to syn products. The factors which control selectivity are the preference for placing substituents equatorially in six-membered transition states and the avoidance of syn-pentane interactions, respectively.[15] E and Z refer to the 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 stereochemical outcome of the reaction may be unpredictable.
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:
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:
Thus, if one wishes to obtain only one of the cross-products, 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:
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 control.[16] 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"):
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:
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:[17]
For ketones, most enolization conditions give Z enolates. For esters, most enolization conditions give E enolates. The addition of HMPA is known to reverse the stereoselectivity of deprotonation.
The stereoselective formation of enolates has been rationalized with the Ireland model,[18][19][20][21] although its validity is somewhat questionable. In most cases, it is not known which, if any, intermediates are monomeric or oligomeric in nature; nonetheless, the Ireland model remains a useful tool for understanding enolates.
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 versus thermodynamic enolates
If an unsymmetrical ketone is subjected to base, it has the potential to form two regioisomeric enolates (ignoring enolate geometry). For example:
The trisubstituted enolate is considered the 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 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.
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 (or screen), 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 erythro-threo nomenclature familiar from carbohydrate chemistry.
E versus Z enolates
There is no significant difference between the level of stereoinduction observed with E and Z enolates:[17]
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 lengths 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 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:[22]
Stereoselectivity: Alpha stereocenter on the enolate
The aldol reaction may exhibit "substrate-based stereocontrol", in which existing 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.
In the case of an E enolate, the dominant control element is 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:
For clarity, the stereocenter on the enolate has been epimerized; 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:[23]
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 diastereoface selection, while Z enolates exhibit anti-Felkin selectivity. The general model[24][25] is presented below:
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:[26][27]
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.[28] Several examples of the application of this model are given below:[27]
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.
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.
A widely used method is the Evans' acyl oxazolidinone method.[29][30] 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.
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.
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:[31]
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:[32]
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:[33] and anti selective:[34]
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 polyketides, 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 ligand. When reactions employ small amounts of enantiomerically pure ligands to induce the formation of enantiomerically pure products, the reactions are typically termed "catalytic, asymmetric"; for example, many different catalytic, 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 imides to react selectively. An early approach was to use a temporary thioether group:[32][35]
Mukaiyama aldol reaction
The Mukaiyama aldol reaction is the nucleophilic addition of silyl enol ethers to aldehydes catalyzed by a Lewis acid such as boron trifluoride or titanium tetrachloride.[36][37] 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.[38]
The method works on unbranched aliphatic aldehydes, which are often poor electrophiles for catalytic, asymmetric processes. This may be due to poor electronic and steric differentiation between their enantiofaces.
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.[39][40]
Crimmins thiazolidinethione aldol
A more recent version of the Evans' auxiliary is the Crimmins thiazolidinethione.[41][42] The yields, 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. The reaction is believed to proceed via six-membered, titanium-bound transition states, analogous to the proposed transition states for the Evans auxiliary. NOTE: the structure of sparteine shown below is missing a N atom.
Organocatalytic aldol reactions
An exciting new development is the use of chiral secondary amine catalysts. These secondary amines form transient enamines 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:
This reaction is known as the Hajos-Parrish reaction[43][44] (also known as the Hajos-Parrish-Eder-Sauer-Wiechert reaction, referring to a contemporaneous report from Schering of the reaction under harsher conditions).[45] 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 studies, the proposed reaction mechanism for proline-catalyzed aldol reactions is as follows:[46]
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 polymerize easily or react unselectively to give a statistical mixture of products. The first example is shown below:[47]
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 carbohydrates. While traditional synthetic methods accomplish the synthesis of hexoses using variations of iterative 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.
The aldol dimerization of alpha-oxyaldehydes requires that the aldol adduct, itself an aldehyde, be inert to further aldol reactions.[48] Earlier studies revealed that aldehydes bearing alpha-alkyloxy or alpha-silyloxy substituents were suitable for this reaction, while aldehydes bearing Electron-withdrawing groups 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 silyloxycarbenium ion to preferentially cyclize, rather than undergo further aldol reaction. In the end, glucose, mannose, and allose were synthesized:
"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:
One approach, recently demonstrated by Evans, is to silylate the aldol adduct:[49][50]
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.[51] The ketoacid moiety is decarboxylated in situ (the chiral ligand is a bisoxazoline). Interestingly, aromatic and branched aliphatic aldehydes are typically poor substrates.
Biological aldol reactions
Examples of aldol reactions in biochemistry include the splitting of fructose-1,6-bisphosphate into dihydroxyacetone and glyceraldehyde-3-phosphate in the second stage of glycolysis which is an example of a reverse aldol reaction catalysed by the enzyme aldolase A.
Simple sugars are cyclic aldol trimers of acetaldehyde that can be prepared synthetically.
See also
- Aldol-Tishchenko reaction
- Aldonic acid
- Baylis-Hillman reaction
- Cannizzaro reaction
- Ivanov reaction
- Knoevenagel condensation
- Reformatsky reaction
References
- ↑
Wade, L. G. (6th ed. 2005). Organic Chemistry. Upper Saddle River, New Jersey: Prentice Hall. pp. 1056–1066. ISBN 0132367319.
{{cite book}}
: Check date values in:|date=
(help) - ↑
Smith, M. B.; March, J. (5th ed. 2001). Advanced Organic Chemistry. New York: Wiley Interscience. pp. 1218–1223. ISBN 0-471-58589-0.
{{cite book}}
: Check date values in:|date=
(help)CS1 maint: multiple names: authors list (link) - ↑ Mahrwald, R. (2004). Modern Aldol Reactions, Volumes 1 and 2. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co. KGaA. pp. 1218–1223. ISBN 3-527-30714-1.
- ↑
Wurtz, C. A. (1872). Bull. Soc. Chim. Fr. 17: 436–442.
{{cite journal}}
: Missing or empty|title=
(help) - ↑ Wurtz, C. A. (1872). "Ueber einen Aldehyd-Alkohol". J. Prakt. Chemie. 5 (1): 457–464. doi:10.1002/prac.18720050148.
- ↑ Wurtz, C. A. (1872). "Sur un aldéhyde-alcool". Comp. Rend. 74: 1361.
- ↑ Heathcock, C. H. (1991). Comp. Org. Syn. Oxford: Pergamon. pp. 133–179. ISBN 0-08-040593-2.
- ↑
Mukaiyama T. (1982). "The Directed Aldol Reaction". Org. React. 28: 203–331. doi:10.1002/0471264180.or028.03.
{{cite journal}}
: Unknown parameter|dou=
ignored (help) - ↑ Paterson, I. (1988). "New Asymmetric Aldol Methodology Using Boron Enolates". Chem. Ind. 12: 390–394.
- ↑ Mestres R. (2004). "A green look at the aldol reaction". Green Chemistry. 12: 583–603. doi:10.1039/b409143b.
- ↑ M. Braun, R. Devant (1984). "(R) and (S)-2-acetoxy-1,1,2-triphenylethanol - effective synthetic equivalents of a chiral acetate enolate". Tetrahedron Letters. 25: 5031–4. doi:10.1016/S0040-4039(01)91110-4.
{{cite journal}}
: Unknown parameter|dou=
ignored (help) - ↑ Jie Jack Li; et al. (2004). Contemporary Drug Synthesis. Wiley-Interscience. pp. 118-. ISBN 0-471-21480-9.
{{cite book}}
: Explicit use of et al. in:|author=
(help) - ↑
Schetter, B., Mahrwald, R. (2006). "Modern Aldol Methods for the Total Synthesis of Polyketides". Angew. Chem. Int. Ed. 45: 7506–7525. doi:10.1002/anie.200602780.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ↑ Zimmerman, H. E.; Traxler, M. D. (1957). "The Stereochemistry of the Ivanov and Reformatsky Reactions. I". J. Am. Chem. Soc. 79: 1920–1923. doi:10.1021/ja01565a041.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ↑ Heathcock C. H., Buse, C. T., Kleschnick W. A., Pirrung M. C., Sohn J. E., Lampe, J. (1980). "Acyclic stereoselection. 7. Stereoselective synthesis of 2-alkyl-3-hydroxy carbonyl compounds by aldol condensation". J. Org. Chem. 45: 1066–1081. doi:10.1021/jo01294a030.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ↑ Bal, B.; Buse, C. T.; Smith, K.; Heathcock, C. H. Org. Syn., Coll. Vol. 7, p.185 (1990); Vol. 63, p.89 (1985). (Article)
- ↑ a b Brown H. C., Dhar R. K., Bakshi R. K., Pandiarajan P. K., Singaram B. (1989). "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". J. Am. Chem. Soc. 111: 3441–3442. doi:10.1021/ja00191a058.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ↑ Ireland, R. E.; Willard, A. K. (1975). "The stereoselective generation of ester enolates". Tetrahedron Lett. 16 (46): 3975–3978. doi:10.1016/S0040-4039(00)91213-9.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ↑ Narula, A. S. (1981). "An analysis of the diastereomeric transition state interactions for the kinetic deprotonation of acyclic carbonyl derivatives with lithium diisopropylamide". Tetrahedron Lett. 22 (41): 4119–4122. doi:10.1016/S0040-4039(01)82081-5.
- ↑ Ireland, R. E.; Wipf, P.; Armstrong, J. D. (1991). "Stereochemical control in the ester enolate Claisen rearrangement. 1. Stereoselectivity in silyl ketene acetal formation". J. Org. Chem. 56: 650–657. doi:10.1021/jo00002a030.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ↑ Xie L., Isenberger K. M., Held G., Dahl, L. M. (1997). "Highly Stereoselective Kinetic Enolate Formation: Steric vs Electronic Effects". J. Org. Chem. 62: 7516–7519. doi:10.1021/jo971260a.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ↑ Evans D. A., Nelson J. V., Vogel E., Taber T. R. (1981). "Stereoselective aldol condensations via boron enolates". J. Am. Chem. Soc. 103: 3099–3111. doi:10.1021/ja00401a031.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ↑ Evans D. A., Rieger D. L., Bilodeau M. T., Urpi F. (1991). "Stereoselective aldol reactions of chlorotitanium enolates. An efficient method for the assemblage of polypropionate-related synthons". J. Am. Chem. Soc. 113: 1047–1049. doi:10.1021/ja00003a051.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ↑ Evans, D. A. et al. Top. Stereochem. 1982, 13, 1–115. (Review)
- ↑ Roush W. R. (1991). "Concerning the diastereofacial selectivity of the aldol reactions of .alpha.-methyl chiral aldehydes and lithium and boron propionate enolates". J. Org. Chem. 56: 4151–4157. doi:10.1021/jo00013a015.
- ↑ Masamune S., Ellingboe J. W., Choy W. (1982). "Aldol strategy: coordination of the lithium cation with an alkoxy substituent". J. Am. Chem. Soc. 104: 1047–1049. doi:10.1021/ja00384a062.
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: CS1 maint: multiple names: authors list (link) - ↑ a b Evans D. A., Dart M. J., Duffy J. L., Rieger D. L. (1995). "Double Stereodifferentiating Aldol Reactions. The Documentation of "Partially Matched" Aldol Bond Constructions in the Assemblage of Polypropionate Systems". J. Am. Chem. Soc. 117: 9073–9074. doi:10.1021/ja00140a027.
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: CS1 maint: multiple names: authors list (link) - ↑ Masamune S., Choy W., Petersen J. S., Sita L. R. (1985). "Double Asymmetric Synthesis and a New Strategy for Stereochemical Control in Organic Synthesis". Angew. Chem. Int. Ed. Engl. 24: 1–30. doi:10.1002/anie.198500013.
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: CS1 maint: multiple names: authors list (link) - ↑ Evans, D. A. Aldrichimica Acta 1982, 15, 23. (Review)
- ↑ Gage, J. R.; Evans, D. A. Organic Syntheses, Coll. Vol. 8, p.339 (1993); Vol. 68, p.83 (1990). (Article)
- ↑ Evans D. A., Bartroli J., Shih T. L. (1981). "Enantioselective aldol condensations. 2. Erythro-selective chiral aldol condensations via boron enolates". J. Am. Chem. Soc. 103: 2127–2129. doi:10.1021/ja00398a058.
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: CS1 maint: multiple names: authors list (link) - ↑ a b Evans D. A., Bender S. L., Morris J. (1988). "The total synthesis of the polyether antibiotic X-206". J. Am. Chem. Soc. 110: 2506–2526. doi:10.1021/ja00216a026.
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: CS1 maint: multiple names: authors list (link) - ↑ Evans D.A., Clark J.S., Metternich R., Sheppard G.S. (1990). "Diastereoselective aldol reactions using .beta.-keto imide derived enolates. A versatile approach to the assemblage of polypropionate systems". J. Am. Chem. Soc. 112: 866–868. doi:10.1021/ja00158a056.
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: CS1 maint: multiple names: authors list (link) - ↑ Evans D.A., Ng, H.P., Clark J.S., Rieger D.L. (1992). "Diastereoselective anti aldol reactions of chiral ethyl ketones. Enantioselective processes for the synthesis of polypropionate natural products". Tetrahedron. 48: 2127–2142. doi:10.1016/S0040-4020(01)88879-7.
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: CS1 maint: multiple names: authors list (link) - ↑ In this reaction the nucleophile is a boron enolate derived from reaction with dibutylboron triflate (nBu2BOTf), the base is N,N-Diisopropylethylamine. The thioether is removed in step 2 by Raney Nickel / hydrogen reduction
- ↑
Teruaki Mukaiyama, Kazuo Banno, and Koichi Narasaka (1974). "Reactions of silyl enol ethers with carbonyl compounds activated by titanium tetrachloride". J. Am. Chem. Soc. 96 (24): 7503–7509. doi:10.1021/ja00831a019.
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: CS1 maint: multiple names: authors list (link) - ↑ 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) Link
- ↑ Carreira E.M., Singer R.A., Lee W.S. (1994). "Catalytic, enantioselective aldol additions with methyl and ethyl acetate O-silyl enolates — a chira; tridentate chelate as a ligand for titanium(IV)". J. Am. Chem. Soc. 116: 8837–8. doi:10.1021/ja00098a065.
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: CS1 maint: multiple names: authors list (link) - ↑ Kruger J., Carreira E.M. (1998). "Apparent catalytic generation of chiral metal enolates: Enantioselective dienolate additions to aldehydes mediated by Tol-BINAP center Cu(II) fluoride complexes". J. Am. Chem. Soc. 120: 837–8. doi:10.1021/ja973331t.
- ↑ Pagenkopf B.L., Kruger J., Stojanovic A., Carreira E.M. (1998). "Mechanistic insights into Cu-catalyzed asymmetric aldol reactions: Chemical and spectroscopic evidence for a metalloenolate intermediate". Angew. Chem. Intl. Ed. 37: 3124–6. doi:10.1002/(SICI)1521-3773(19981204)37:22<3124::AID-ANIE3124>3.0.CO;2-1.
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: CS1 maint: multiple names: authors list (link) - ↑ Crimmins M. T., King B. W., Tabet A. E. (1997). "Asymmetric Aldol Additions with Titanium Enolates of Acyloxazolidinethiones: Dependence of Selectivity on Amine Base and Lewis Acid Stoichiometry". Journal of the American Chemical Society. 119 (33): 7883–7884. doi:10.1021/ja9716721.
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: CS1 maint: multiple names: authors list (link) - ↑ Crimmins M. T., Chaudhary K. (2000). "Titanium enolates of thiazolidinethione chiral auxiliaries: Versatile tools for asymmetric aldol additions". Organic Letters. 2 (6): 775–777. doi:10.1021/ol9913901. PMID 10754681.
- ↑ Z. G. Hajos, D. R. Parrish, German Patent DE 2102623 1971
- ↑ Hajos, Zoltan G. (1974). "Asymmetric synthesis of bicyclic intermediates of natural product chemistry". Journal of Organic Chemistry. 39 (12): 1615–1621. doi:10.1021/jo00925a003.
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: Unknown parameter|coauthor=
ignored (|author=
suggested) (help) - ↑ Eder, Ulrich (1971). "New Type of Asymmetric Cyclization to Optically Active Steroid CD Partial Structures". Angewandte Chemie International Edition in English. 10 (7): 1615–1621. doi:10.1002/anie.197104961.
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: Unknown parameter|coauthor=
ignored (|author=
suggested) (help) - ↑ List, Benjamin (2006). "The ying and yang of asymmetric aminocatalysis". Chemical Communications (8): 819–824. doi:10.1039/b514296m.
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: Cite has empty unknown parameter:|coauthor=
(help) - ↑ Northrup, Alan B. (2002). "The First Direct and Enantioselective Cross-Aldol Reaction of Aldehydes". Journal of the American Chemical Society. 124 (24): 6798–6799. doi:10.1021/ja0262378.
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: Unknown parameter|coauthor=
ignored (|author=
suggested) (help) - ↑ Northrup A. B., Mangion I. K., Hettche F., MacMillan D. W. C. (2004). "Enantioselective Organocatalytic Direct Aldol Reactions of -Oxyaldehydes: Step One in a Two-Step Synthesis of Carbohydrates". Angewandte Chemie International Edition in English. 43 (16): 2152–2154. doi:10.1002/anie.200453716.
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: CS1 maint: multiple names: authors list (link) - ↑ Evans, D. A. (2002). "Diastereoselective Magnesium Halide-Catalyzed anti-Aldol Reactions of Chiral N-Acyloxazolidinones". J. Am. Chem. Soc. 124 (3): 392–393. doi:10.1021/ja0119548.
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: Unknown parameter|coauthor=
ignored (|author=
suggested) (help) - ↑ Evans, David A. (2002). "Magnesium Halide-Catalyzed Anti-Aldol Reactions of Chiral N-Acylthiazolidinethiones". Organic Letters. 4 (7): 1127–1130. doi:10.1021/ol025553o.
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: Unknown parameter|coauthor=
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suggested) (help) - ↑ Magdziak, D. (2005). "Catalytic Enantioselective Thioester Aldol Reactions That Are Compatible with Protic Functional Groups". J. Am. Chem. Soc. 127 (20): 7284–7285. doi:10.1021/ja051759j.
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: Unknown parameter|coauthor=
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