Chemical Sciences: A Manual for CSIR-UGC National Eligibility Test for Lectureship and JRF/Named Reactions/Aldol Reaction

The aldol reaction is a powerful means of forming carbon-carbon bonds in organic chemistry. Wade, L. G. Organic Chemistry Prentice Hall 6th ed. 2005 Upper Saddle River, New Jersey 1056–1066 0132367319 Smith, M. B.; March, J. Advanced Organic Chemistry Wiley Interscience 5th ed. 2001 New York 1218–1223 0-471-58589-0 Mahrwald, R. Modern Aldol Reactions, Volumes 1 and 2 Wiley-VCH Verlag GmbH & Co. KGaA 2004 Weinheim, Germany 1218–1223 3-527-30714-1 Discovered independently by Charles-Adolphe Wurtz Wurtz, C. A. Bull. Soc. Chim. Fr. 1872 17 436–442 Wurtz, C. A. J. Prakt. Chemie 1872 Ueber einen Aldehyd-Alkohol 5 1 457–464 10.1002/prac.18720050148 Wurtz, C. A. Comp. Rend. 1872 Sur un aldéhyde-alcool 74 1361 http://gallica.bnf.fr/ark:/12148/bpt6k3031q/f1361.table 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. Heathcock, C. H. Comp. Org. Syn. Pergamon 1991 Oxford 133–179 0-08-040593-2 The Directed Aldol Reaction Mukaiyama T. Org. React. 1982 28 203–331 10.1002/0471264180.or028.03 10.1002/0471264180.or028.03 New Asymmetric Aldol Methodology Using Boron Enolates Paterson, I. Chem. Ind. 1988 12 390–394 For example, the aldol reaction has been used in the large-scale production of the commodity chemical pentaerythritol A green look at the aldol reaction Mestres R. Green Chemistry 2004 12 583–603 10.1039/b409143b and the synthesis of the heart disease drug Lipitor (INN: atorvastatin). (R) and (S)-2-acetoxy-1,1,2-triphenylethanol - effective synthetic equivalents of a chiral acetate enolate M. Braun, R. Devant Tetrahedron Letters 1984 25 5031–4 10.1016/S0040-4039(01)91110-4 10.1016/S0040-4039(01)91110-4 Jie Jack Li et al. Contemporary Drug Synthesis Wiley-Interscience 2004 118- 0-471-21480-9 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. Modern Aldol Methods for the Total Synthesis of Polyketides Schetter, B., Mahrwald, R. Angew. Chem. Int. Ed. 2006 45 7506–7525 10.1002/anie.200602780 center 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. thumb|right|300px|A typical experimental setup for an aldol reaction. 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. 600px|A generalized view of the Aldol reaction Enol mechanism When an acid catalyst is used, the initial step in the reaction mechanism involves acid-catalyzed 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 500px|Mechanism for acid-catalyzed aldol reaction of an aldehyde with itself Acid catalyzed dehydration 500px|Mechanism for acid-catalyzed dehydration of an aldol Enolate mechanism If the catalyst is a moderate base such as hydroxide ion or an alkoxide, the aldol reaction occurs via nucleophilic attack by the resonance-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) 500px|Simple mechanism for base-catalyzed aldol reaction of an aldehyde with itself Base catalyzed dehydration (frequently written incorrectly as a single step, see E1cB elimination reaction) 500px|Simple mechanism for the dehydration of an aldol product Although only a catalytic amount of base is required in some cases, the more usual procedure is to use a stoichiometric amount of a strong base such as 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." The Stereochemistry of the Ivanov and Reformatsky Reactions. I Zimmerman, H. E.; Traxler, M. D. 10.1021/ja01565a041 J. Am. Chem. Soc. 1957 79 1920–1923 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. Acyclic stereoselection. 7. Stereoselective synthesis of 2-alkyl-3-hydroxy carbonyl compounds by aldol condensation Heathcock C. H., Buse, C. T., Kleschnick W. A., Pirrung M. C., Sohn J. E., Lampe, J. 10.1021/jo01294a030 J. Org. Chem. 1980 45 1066–1081 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. The Zimmerman–Traxler model Control in the Aldol reaction The problem The problem of "control" in the aldol addition is best demonstrated by an example. Consider the outcome of this hypothetical reaction: alt=|center|Hypothetical aldol reaction In this reaction, two unsymmetrical ketones are being condensed using sodium ethoxide. The basicity of sodium ethoxide is such that it cannot fully deprotonate either of the ketones, but can produce small amounts of the sodium enolate of both ketones. Effectively, this means that in addition to being potential aldol electrophiles, both ketones may also act as nucleophiles via their sodium enolate. Two electrophiles and two nucleophiles then potentially results in four possible products: alt=|center|Four possible aldol reaction 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: alt=|center|Acidic control of the aldol reaction In this case, the doubly activated methylene protons of the malonate would be preferentially deprotonated by sodium ethoxide and quantitatively form the sodium enolate. Since benzaldehyde has no acidic alpha-protons, there is only one possible nucleophile-electrophile combination; hence, control has been achieved. Note that this approach combines two elements of control: increased acidity of the alpha protons on the nucleophile and the lack of alpha protons on the electrophile. Order of addition One common solution is to form the enolate of one partner first, and then add the other partner under kinetic control.Bal, B.; Buse, C. T.; Smith, K.; Heathcock, C. H. Org. Syn., Coll. Vol. 7, p.185 (1990); Vol. 63, p.89 (1985). (Article) Kinetic control means that the forward aldol addition reaction must be significantly faster than the reverse retro-aldol reaction. For this approach to succeed, two other conditions must also be satisfied; namely, it must be possible to quantitatively form the enolate of one partner and the forward aldol reaction must be significantly faster than the transfer of the enolate from one partner to another. Common kinetic control conditions involve the formation of the enolate of a ketone with LDA at −78 °C, followed by the slow addition of an aldehyde. Enolates Formation The enolate may be formed by using a strong base ("hard conditions") or using a Lewis acid and a weak base ("soft conditions"): Image:scheme3a.gif For deprotonation to occur, the stereoelectronic requirement is that the alpha-C-H sigma bond must be able to overlap with the pi* orbital of the carbonyl: center|Stereoelectronic deprotonation requirements Geometry Extensive studies have been performed on the formation of enolates under many different conditions. It is now possible to generate, in most cases, the desired enolate geometry: 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 Brown H. C., Dhar R. K., Bakshi R. K., Pandiarajan P. K., Singaram B. 10.1021/ja00191a058 J. Am. Chem. Soc. 1989 111 3441–3442 center|Stereoselective enolate generation 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. center|Effect of HMPA addition The stereoselective formation of enolates has been rationalized with the Ireland model, The stereoselective generation of ester enolates Ireland, R. E.; Willard, A. K. 10.1016/S0040-4039(00)91213-9 Tetrahedron Lett. 1975 16 46 3975–3978 An analysis of the diastereomeric transition state interactions for the kinetic deprotonation of acyclic carbonyl derivatives with lithium diisopropylamide Narula, A. S. 10.1016/S0040-4039(01)82081-5 Tetrahedron Lett. 1981 22 41 4119–4122 Stereochemical control in the ester enolate Claisen rearrangement. 1. Stereoselectivity in silyl ketene acetal formation Ireland, R. E.; Wipf, P.; Armstrong, J. D. 10.1021/jo00002a030 J. Org. Chem. 1991 56 650–657 Highly Stereoselective Kinetic Enolate Formation: Steric vs Electronic Effects Xie L., Isenberger K. M., Held G., Dahl, L. M. 10.1021/jo971260a J. Org. Chem. 1997 62 7516–7519 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. center|The Ireland model In the Ireland model, the deprotonation is assumed to proceed by a six-membered monomeric transition state. The larger of the two substituents on the electrophile (in the case above, methyl is larger than proton) adopts an equatorial disposition in the favored transition state, leading to a preference for E enolates. The model clearly fails in many cases; for example, if the solvent mixture is changed from THF to 23% HMPA-THF (as seen above), the enolate geometry is inexplicably reversed. Kinetic 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: center|Kinetic and thermodynamic enolates 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. 500px|Syn and anti products from an aldol reaction The convention applies when propionate (or higher order) nucleophiles are added to aldehydes. The R group of the ketone and the R group of the aldehyde are aligned in a "zig zag" pattern in the plane of the paper (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: center|Anti-aldol formation via Z-enolate center|Syn-aldol formation via E-enolate Metal ion The enolate metal cation may play a large role in determining the level of stereoselectivity in the aldol reaction. Boron is often used because its bond 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: Stereoselective aldol condensations via boron enolates Evans D. A., Nelson J. V., Vogel E., Taber T. R. 10.1021/ja00401a031 J. Am. Chem. Soc. 1981 103 3099–3111 center 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. center|Aldol reaction with enolate-based stereocontrol 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: center|General model of the aldol reaction with enolate-based stereocontrol 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: Stereoselective aldol reactions of chlorotitanium enolates. An efficient method for the assemblage of polypropionate-related synthons Evans D. A., Rieger D. L., Bilodeau M. T., Urpi F. 10.1021/ja00003a051 J. Am. Chem. Soc. 1991 113 1047–1049 center|Aldol reaction with enolate-based stereocontrol Stereoselectivity: Alpha stereocenter on the electrophile When enolates attacks aldehydes with an alpha stereocenter, excellent stereocontrol is also possible. The general observation is that E enolates exhibit Felkin diastereoface selection, while Z enolates exhibit anti-Felkin selectivity. The general modelEvans, D. A. et al. Top. Stereochem. 1982, 13, 1–115. (Review) Concerning the diastereofacial selectivity of the aldol reactions of .alpha.-methyl chiral aldehydes and lithium and boron propionate enolates Roush W. R. J. Org. Chem. 1991 56 4151–4157 10.1021/jo00013a015 is presented below: center|The general model of the aldol reaction with carbonyl-based stereocontrol Since Z enolates must react through a transition state which either contains a destabilizing syn-pentane interaction or anti-Felkin rotamer, Z-enolates exhibit lower levels of diastereoselectivity in this case. Some examples are presented below: Aldol strategy: coordination of the lithium cation with an alkoxy substituent Masamune S., Ellingboe J. W., Choy W. 10.1021/ja00384a062 J. Am. Chem. Soc. 1982 104 1047–1049 Double Stereodifferentiating Aldol Reactions. The Documentation of "Partially Matched" Aldol Bond Constructions in the Assemblage of Polypropionate Systems Evans D. A., Dart M. J., Duffy J. L., Rieger D. L. 10.1021/ja00140a027 J. Am. Chem. Soc. 1995 117 9073–9074 center|Examples of the aldol reaction with carbonyl-based stereocontrol Stereoselectivity: Merged model for stereoinduction If both the enolate and the aldehyde both contain pre-existing chirality, then the outcome of the "double stereodifferentiating" aldol reaction may be predicted using a merged stereochemical model that takes into account the enolate facial bias, enolate geometry, and aldehyde facial bias. Double Asymmetric Synthesis and a New Strategy for Stereochemical Control in Organic Synthesis Masamune S., Choy W., Petersen J. S., Sita L. R. 10.1002/anie.198500013 Angew. Chem. Int. Ed. Engl. 1985 24 1–30 Several examples of the application of this model are given below: Image:Mergedmodel.gif Evans' oxazolidinone chemistry Modern organic syntheses now require the synthesis of compounds in enantiopure form. Since the aldol addition reaction creates two new stereocenters, up to four stereoisomers may result. 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. center|Four possible stereoisomers of the aldol reaction A widely used method is the Evans' acyl oxazolidinone method.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) 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. center In the case of the Evans' method, the chiral auxiliary appended is an oxazolidinone, and the resulting carbonyl compound is an imide. A number of oxazolidinones are now readily available in both enantiomeric forms. These may cost roughly $10–$20 US dollars per gram, rendering them relatively expensive. center The acylation of an oxazolidinone is a convenient procedure, and is informally referred to as "loading done". Z-enolates, leading to syn-aldol adducts, can be reliably formed using boron-mediated soft enolization: Enantioselective aldol condensations. 2. Erythro-selective chiral aldol condensations via boron enolates Evans D. A., Bartroli J., Shih T. L. 10.1021/ja00398a058 J. Am. Chem. Soc. 1981 103 2127–2129 center Often, a single diastereomer may be obtained by one crystallization of the aldol adduct. Unfortunately, anti-aldol adducts cannot be obtained reliably with the Evans method. Despite the cost and the limitation to give only syn adducts, the method's superior reliability, ease of use, and versatility render it the method of choice in many situations. Many methods are available for the cleavage of the auxiliary: The total synthesis of the polyether antibiotic X-206 Evans D. A., Bender S. L., Morris J. 10.1021/ja00216a026 J. Am. Chem. Soc. 1988 110 2506–2526 center|Evans' chiral oxazolidinone cleavage Upon construction of the imide, both syn and anti-selective aldol addition reactions may be performed, allowing the assemblage of three of the four possible stereoarrays: syn selective: Diastereoselective aldol reactions using .beta.-keto imide derived enolates. A versatile approach to the assemblage of polypropionate systems Evans D.A., Clark J.S., Metternich R., Sheppard G.S. 10.1021/ja00158a056 J. Am. Chem. Soc. 1990 112 866–868 and anti selective: Diastereoselective anti aldol reactions of chiral ethyl ketones. Enantioselective processes for the synthesis of polypropionate natural products Evans D.A., Ng, H.P., Clark J.S., Rieger D.L. Tetrahedron 1992 48 2127–2142 10.1016/S0040-4020(01)88879-7 center In the syn-selective reactions, both enolization methods give the Z enolate, as expected; however, the stereochemical outcome of the reaction is controlled by the methyl stereocenter, rather than the chirality of the oxazolidinone. The methods described allow the stereoselective assembly of 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: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 center Mukaiyama aldol reaction 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. Reactions of silyl enol ethers with carbonyl compounds activated by titanium tetrachloride Teruaki Mukaiyama, Kazuo Banno, and Koichi Narasaka J. Am. Chem. Soc. 96 24 7503–7509 1974 10.1021/ja00831a019 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 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. Catalytic, enantioselective aldol additions with methyl and ethyl acetate O-silyl enolates — a chira; tridentate chelate as a ligand for titanium(IV) Carreira E.M., Singer R.A., Lee W.S. 10.1021/ja00098a065 J. Am. Chem. Soc. 1994 116 8837–8 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. center The analogous vinylogous Mukaiyama aldol process can also be rendered catalytic and asymmetric. The example shown below works efficiently for aromatic (but not aliphatic) aldehydes and the mechanism is believed to involve a chiral, metal-bound dienolate. Apparent catalytic generation of chiral metal enolates: Enantioselective dienolate additions to aldehydes mediated by Tol-BINAP center Cu(II) fluoride complexes Kruger J., Carreira E.M. 10.1021/ja973331t J. Am. Chem. Soc. 1998 120 837–8 Mechanistic insights into Cu-catalyzed asymmetric aldol reactions: Chemical and spectroscopic evidence for a metalloenolate intermediate Pagenkopf B.L., Kruger J., Stojanovic A., Carreira E.M. 10.1002/(SICI)1521-3773(19981204)37:22<3124::AID-ANIE3124>3.0.CO;2-1 Angew. Chem. Intl. Ed. 1998 37 3124–6 center Crimmins thiazolidinethione aldol A more recent version of the Evans' auxiliary is the Crimmins thiazolidinethione. Asymmetric Aldol Additions with Titanium Enolates of Acyloxazolidinethiones: Dependence of Selectivity on Amine Base and Lewis Acid Stoichiometry Crimmins M. T., King B. W., Tabet A. E. 10.1021/ja9716721 Journal of the American Chemical Society 1997 119 33 7883–7884 Titanium enolates of thiazolidinethione chiral auxiliaries: Versatile tools for asymmetric aldol additions Crimmins M. T., Chaudhary K. 10.1021/ol9913901 Organic Letters 2000 2 6 775–777 10754681 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. center 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: center This reaction is known as the Hajos-Parrish reactionZ. G. Hajos, D. R. Parrish, German Patent DE 2102623 1971 Asymmetric synthesis of bicyclic intermediates of natural product chemistry Zoltan G. Hajos Parrish, David R. Journal of Organic Chemistry 1974 39 12 1615–1621 10.1021/jo00925a003 (also known as the Hajos-Parrish-Eder-Sauer-Wiechert reaction, referring to a contemporaneous report from Schering of the reaction under harsher conditions). New Type of Asymmetric Cyclization to Optically Active Steroid CD Partial Structures Ulrich Eder Sauer, Gerhard; Wiechert, Rudolf Angewandte Chemie International Edition in English 1971 10 7 1615–1621 10.1002/anie.197104961 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: The ying and yang of asymmetric aminocatalysis Benjamin List Chemical Communications 2006 8 819–824 10.1039/b514296m center This strategy allows the otherwise challenging cross-aldol reaction between two aldehydes. In general, cross-aldol reactions between aldehydes are typically challenging because they can polymerize easily or react unselectively to give a statistical mixture of products. The first example is shown below: The First Direct and Enantioselective Cross-Aldol Reaction of Aldehydes Alan B. Northrup MacMillan David W. C. Journal of the American Chemical Society 2002 124 24 6798–6799 10.1021/ja0262378 center In contrast to the preference for syn adducts typically observed in enolate-based aldol additions, these organocatalyzed aldol additions are anti-selective. In many cases, the organocatalytic conditions are mild enough to avoid polymerization. However, selectivity requires the slow syringe-pump controlled addition of the desired electrophilic partner because both reacting partners typically have enolizable protons. If one aldehyde has no enolizable protons or alpha- or beta-branching, additional control can be achieved. An elegant demonstration of the power of asymmetric organocatalytic aldol reactions was disclosed by MacMillan and coworkers in 2004 in their synthesis of differentially protected 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. center The aldol dimerization of alpha-oxyaldehydes requires that the aldol adduct, itself an aldehyde, be inert to further aldol reactions. Northrup A. B., Mangion I. K., Hettche F., MacMillan D. W. C. 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 2004 10.1002/anie.200453716 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: center "Direct" aldol additions In the usual aldol addition, a carbonyl compound is deprotonated to form the enolate. The enolate is added to an aldehyde or ketone, which forms an alkoxide, which is then protonated on workup. A superior method, in principle, would avoid the deprotonation-aldol-protonation sequence in favor of a "direct aldol addition". The major issue in such a process is that the aldol addition generates an alkoxide, which is much more basic than the starting materials, precluding catalyst turnover: center One approach, recently demonstrated by Evans, is to silylate the aldol adduct: Evans D. A. Tedrow, J. S.; Shaw, J. T.; Downey, C. W. Diastereoselective Magnesium Halide-Catalyzed anti-Aldol Reactions of Chiral N-Acyloxazolidinones J. Am. Chem. Soc. 124 3 392–393 2002 10.1021/ja0119548 Evans David A. Downey, C. Wade; Shaw, Jared T.; Tedrow, Jason S. Magnesium Halide-Catalyzed Anti-Aldol Reactions of Chiral N-Acylthiazolidinethiones Organic Letters 4 7 1127–1130 2002 10.1021/ol025553o center This method is more cost effective and industrially useful than the more typical enolate-based procedures. A more recent, biomimetic approach by Shair uses beta-thioketoacids as the nucleophile. Magdziak D. Lalic, G.; Lee, H. M.; Fortner, K. C.; Aloise, A. D.; Shair, M. D. Catalytic Enantioselective Thioester Aldol Reactions That Are Compatible with Protic Functional Groups J. Am. Chem. Soc. 127 20 7284–7285 2005 10.1021/ja051759j The ketoacid moiety is decarboxylated in situ (the chiral ligand is a bisoxazoline). Interestingly, aromatic and branched aliphatic aldehydes are typically poor substrates. center 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. References 30em