Aldol reaction

The aldol reaction is a means of forming carbon–carbon bonds in organic chemistry.[1][2][3] Discovered independently by the Russian chemist Alexander Borodin in 1869[4] and by the French chemist Charles-Adolphe Wurtz in 1872,[5][6][7] the reaction combines two carbonyl compounds (the original experiments used aldehydes) to form a new β-hydroxy carbonyl compound. These products are known as aldols, from the aldehyde + alcohol, a structural motif seen in many of the products. Aldol structural units are found in many important molecules, whether naturally occurring or synthetic.[8][9][10] For example, the aldol reaction has been used in the large-scale production of the commodity chemical pentaerythritol[11] and the synthesis of the heart disease drug Lipitor (atorvastatin, calcium salt).[12][13]

The aldol reaction 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 capable of not only allowing aldol reactions to proceed in high yield but also controlling both the relative and absolute configuration of these stereocenters.[14] This ability to selectively synthesize a particular stereoisomer is significant because different stereoisomers can have very different chemical and 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 that 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 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.[15]

Typical aldol-en

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; on the converse, when the nucleophile and electrophile are the same, the reaction is called an aldol dimerization.

Aldolrxnpic
A typical experimental setup for an aldol reaction.
The flask on the right is a solution of lithium diisopropylamide (LDA) in tetrahydrofuran (THF). The flask on the left is a solution of the lithium enolate of tert-butyl propionate (formed by addition of LDA to tert-butyl propionate). An aldehyde can then be added to the enolate flask 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).
Aldol reaction
Reaction type Coupling reaction
Identifiers
Organic Chemistry Portal aldol-addition
RSC ontology ID RXNO:0000016

Mechanisms

The aldol reaction may proceed by two fundamentally different mechanisms. Carbonyl compounds, such as aldehydes and ketones, can be converted to enols or enol ethers. These species, 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 under irreversible conditions, the isolated aldol adducts are sensitive to base-induced retro-aldol cleavage to return starting materials. In contrast, retro-aldol condensations are rare, but possible.[16]

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

Mechanism for acid-catalyzed aldol reaction of an aldehyde with itself

Acid-catalyzed dehydration

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)

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)

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, Howard Zimmerman and M.D. Traxler proposed that some aldol reactions have "six-membered transition states having a chair conformation."[17] 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 that control selectivity are the preference for placing substituents equatorially in six-membered transition states and the avoidance of syn-pentane interactions, respectively.[18] 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 reliably follow the Zimmerman–Traxler model. Thus, in some cases, the stereochemical outcome of the reaction may be unpredictable.

The Zimmerman–Traxler model

Crossed-aldol reactant control

The problem of "control" in the aldol addition is best demonstrated by an example. Consider the outcome of this hypothetical reaction:

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. 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, have potential to result in four possible products:

Four possible aldol reaction products

Thus, if one wishes to obtain only one of the cross-products, one must control which carbonyl becomes the nucleophilic enol/enolate and which remains in its electrophilic carbonyl form.

Acidity

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 produce only one product. Only the malonate has α hydrogens, so it is the nucleophilic partner, whereas the non-enolizeable benzaldehyde can only be the electrophile:

Acidic control of the aldol reaction

The malonate is particularly easy to deprotonate because the α position is flanked by more than one carbonyl. Double-activation makes the enolate more stable, so not as strong a base is required to form it. An extension of this effect can allow control over which of the two carbonyl reactants becomes the enolate even if both do have α hydrogens. If one partner is considerably more acidic than the other, the most acidic proton is abstracted by the base and an enolate is formed at that carbonyl while the carbonyl that is less acidic is not affected by the base. This type of control works only if the difference in acidity is large enough and no excess of base is used for the reaction. A typical substrate for this situation is when the deprotonatable position is activated by more than one carbonyl-like group. Common examples include a CH2 group flanked by two carbonyls or nitriles (see for example the Knoevenagel condensation and the first steps of the Malonic ester synthesis).

Order of addition

One common solution is to form the enolate of one partner first, and then add the other partner under kinetic control.[19] 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; 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"):

Aldol scheme 3a

In this diagram, B: represents the base which takes the proton. The dibutylboron triflate actually becomes attached to the oxygen only during the reaction. The second product on the right (formed from the N,N-diisopropylethylamine) should be i-Pr2EtNH+ OTf.

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:

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:[20]

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.

Effect of HMPA addition

The stereoselective formation of enolates has been rationalized with the Ireland model,[21][22][23][24] 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.

The Ireland model

In the Ireland model, the deprotonation is assumed to proceed by a six-membered or cyclic[25] 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 reversed, which is inconsistent with this model and its cyclic transition state.

Regiochemistry

If an unsymmetrical ketone is subjected to base, it has the potential to form two regioisomeric enolates (ignoring enolate geometry). For example:

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, conditions that give relatively ionic metal–oxygen bonding, and rapid deprotonation using a slight excess of a strong, sterically hindered base. The large base only deprotonates the more accessible hydrogen, and the low temperatures and excess base help avoid equilibration to the more stable alternate enolate after initial enolate formation. Thermodynamic enolates are favored by longer equilibration times at higher temperatures, conditions that give relatively covalent metal–oxygen bonding, and use of a slight sub-stoichiometric amount of strong base. By using insufficient base to deprotonate all of the carbonyl molecules, the enolates and carbonyls can exchange protons with each other and equilibrate to their more stable isomer. Using various metals and solvents can provide control over the amount of ionic character in the metal–oxygen bond.

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.

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 saccharide chemistry.

Enolate geometry

There is no significant difference between the level of stereoinduction observed with E and Z enolates. Each alkene geometry leads primarily to one specific relative stereochemistry in the product, E giving anti and Z giving syn:[20]

Anti-aldol formation through E-enolate
Syn-aldol formation through Z-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[26][27] because its bond lengths are significantly shorter than that of metals such as lithium, aluminium, or magnesium.

Enolate metal ion

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 1.9–2.2 Å and 2.0–2.2 Å in length, respectively. The use of boron rather than a metal "tightens" the transition state and gives greater stereoselectivity in the reaction.[28] Thus the above reaction gives a syn:anti ratio of 80:20 using a lithium enolate compared to 97:3 using a bibutylboron enolate.

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.

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:

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:[29]

Aldol reaction with enolate-based stereocontrol

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[30][31] is presented below:

The general model of the aldol reaction with carbonyl-based stereocontrol

Since Z enolates must react through a transition state that contains either a destabilizing syn-pentane interaction or an anti-Felkin rotamer, Z-enolates exhibit lower levels of diastereoselectivity in this case. Some examples are presented below:[32][33]

Examples of the aldol reaction with carbonyl-based stereocontrol

Unified model of stereoinduction

If both the enolate and the aldehyde 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.[34] Several examples of the application of this model are given below:[33]

Mergedmodel

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.

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.

Four possible stereoisomers of the aldol reaction

A widely used method is the Evans' acyl oxazolidinone method.[35][36] 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.

Evansaldol3

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. However, enantiopure oxazolidinones are derived in 2 synthetic steps from comparatively inexpensive amino acids, which means that large-scale syntheses can be made more economical by in-house preparation. This usually involves borohydride mediated reduction of the acid moiety, followed by condensation/cyclisation of the resulting amino alcohol with a simple carbonate ester such as diethylcarbonate.

Evansaldol4

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:[37]

Evansaldol5

Often, a single diastereomer may be obtained by one crystallization of the aldol adduct. However, 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:[38]

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:[39] and anti selective:[40]

Evans aldol 7

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 that often feature the aldol retron.

Intramolecular reaction

Intramolecular aldol reaction example
Fig. 1: Mechanism of an exemplary intramolecular aldol reaction in basic conditions.

Intramolecular aldol reaction is the condensation reaction of two aldehyde groups or ketone groups in the same molecule. Five- or six-membered α, β-unsaturated ketone or aldehydes are formed as products. This reaction is an important approach to the formation of carbon-carbon bonds in organic molecules containing ring systems. As an example, under strong basic conditions (e.g. sodium hydroxide), hexane-2,5-dione (compound A in Figure 1) can cyclize via intramolecular aldol reaction to form the 3-methylcyclopent-2-en-1-one (compound B).

The mechanism of the intramolecular aldol reaction involves formation of a key enolate intermediate followed by an intramolecular nucleophilic addition process. First, hydroxide abstracts the α-hydrogen on a terminal carbon to form the enolate. Next, a nucleophilic attack of the enolate on the other keto group forms a new carbon-carbon bond (red) between carbons 2 and 6. At last, usually under heating conditions, the elimination of water molecule yields the cyclized α,β-unsaturated ketone.

Intramolecular aldol reaction in the total synthesis of Wortmannin
Fig. 2: Intramolecular aldol reaction in the total synthesis of (+)-Wortmannin.

Intramolecular aldol reactions have been widely used in total syntheses of various natural products, especially alkaloids and steroids. An example is the application of an intramolecular aldol reaction in the ring closure step for total synthesis of (+)-Wortmannin by Shigehisa, et al.[41] (Figure 2).

Modern variations and methods

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:[38][42]

Acetatealdol1

Mukaiyama aldol reaction

The Mukaiyama aldol reaction[43] is the nucleophilic addition of silyl enol ethers to aldehydes catalyzed by a Lewis acid such as boron trifluoride (as boron trifluoride etherate) or titanium tetrachloride.[44][45] 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.[46]

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.

Acetatealdol2

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.[47][48]

Acetatealdol3

Crimmins thiazolidinethione aldol

A more recent version of the Evans' auxiliary is the Crimmins thiazolidinethione.[49][50] The yields, diastereoselectivities, and enantioselectivities of the reaction are, in general, 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.

Crimminsaldol1

Organocatalysis

A more recent development is the use of chiral secondary amine catalysts. These secondary amines form transient enamines when exposed to ketones, which may react enantioselectively[51] with suitable aldehyde electrophiles. The amine reacts with the carbonyl to form an enamine, the enamine acts as an enol-like nucleophile, and then the amine is released from the product all—the amine itself is a catalyst. This enamine catalysis method is 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:

Organocatalytic1

This reaction is known as the Hajos-Parrish reaction[52][53] (also known as the Hajos-Parrish-Eder-Sauer-Wiechert reaction, referring to a contemporaneous report from Schering of the reaction under harsher conditions).[54] 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 offers a simple way of generating enantioselectivity in reactions without using transition metals, which have the possible disadvantages of being toxic or expensive.

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:[55]

Organocatalytic2

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:[56]

Organocatalytic3

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.

Organocatalytic4

The aldol dimerization of alpha-oxyaldehydes requires that the aldol adduct, itself an aldehyde, be inert to further aldol reactions.[57] 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:

Organocatalytic5

"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 requirement for a multistep sequence in favor of a "direct" reaction that could be done in a single process step. One idea is to generate the enolate using a metal catalyst that is released after the aldol addition mechanism. The general problem is that the addition generates an alkoxide, which is much more basic than the starting materials. This product binds tightly to the metal, preventing it from reacting with additional carbonyl reactants.

Aldol alkoxide product

One approach, demonstrated by Evans, is to silylate the aldol adduct.[58][59] A silicon reagent such as TMSCl is added in the reaction, which replaces the metal on the alkoxide, allowing turnover of the metal catalyst. Minimizing the number of reaction steps and amount of reactive chemicals used leads to a cost-effective and industrially useful reaction.

Directaldol2

A more recent biomimetic approach by Shair uses beta-thioketoacids as the nucleophile.[60] The ketoacid moiety is decarboxylated in situ. The process is similar to the way malonyl-CoA is used by Polyketide synthases. The chiral ligand is case is a bisoxazoline. Aromatic and branched aliphatic aldehydes are typically poor substrates.

Directaldol3

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 fourth stage of glycolysis, which is an example of a reverse ("retro") aldol reaction catalyzed by the enzyme aldolase A (also known as fructose-1,6-bisphosphate aldolase).

In the glyoxylate cycle of plants and some prokaryotes, isocitrate lyase produces glyoxylate and succinate from isocitrate. Following deprotonation of the OH group, isocitrate lyase cleaves isocitrate into the four-carbon succinate and the two-carbon glyoxylate by an aldol cleavage reaction. This cleavage is very similar mechanistically to the aldolase A reaction of glycolysis.

See also

References

  1. ^ Wade, L. G. (2005). Organic Chemistry (6th ed.). Upper Saddle River, New Jersey: Prentice Hall. pp. 1056–66. ISBN 978-0-13-236731-8.
  2. ^ Smith, M. B.; March, J. (2001). Advanced Organic Chemistry (5th ed.). New York: Wiley Interscience. pp. 1218–23. ISBN 978-0-471-58589-3.
  3. ^ Mahrwald, R. (2004). Modern Aldol Reactions, Volumes 1 and 2. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co. KGaA. pp. 1218–23. ISBN 978-3-527-30714-2.
  4. ^ See:
  5. ^ Wurtz, C. A. (1872). "Sur un aldéhyde-alcool" [On an aldehyde alcohol]. Bulletin de la Société Chimique de Paris. 2nd series (in French). 17: 436–442.
  6. ^ Wurtz, C. A. (1872). "Ueber einen Aldehyd-Alkohol" [About an aldehyde alcohol]. Journal für Praktische Chemie (in German). 5 (1): 457–464. doi:10.1002/prac.18720050148.
  7. ^ Wurtz, C. A. (1872). "Sur un aldéhyde-alcool" [On an aldehyde alcohol]. Comptes rendus de l'Académie des sciences (in French). 74: 1361.
  8. ^ Heathcock, C. H. (1991). "The Aldol Reaction: Acid and General Base Catalysis". In Trost, B. M.; Fleming, I. Comprehensive Organic Synthesis. 2. Elsevier Science. pp. 133–179. doi:10.1016/B978-0-08-052349-1.00027-5. ISBN 978-0-08-052349-1.
  9. ^ Mukaiyama T. (1982). The Directed Aldol Reaction. Org. React. 28. pp. 203–331. doi:10.1002/0471264180.or028.03. ISBN 978-0471264187.
  10. ^ Paterson, I. (1988). "New Asymmetric Aldol Methodology Using Boron Enolates". Chem. Ind. 12: 390–394.
  11. ^ Mestres R. (2004). "A green look at the aldol reaction". Green Chemistry. 6 (12): 583–603. doi:10.1039/b409143b.
  12. ^ 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 (44): 5031–4. doi:10.1016/S0040-4039(01)91110-4.
  13. ^ Jie Jack Li; et al. (2004). Contemporary Drug Synthesis. Wiley-Interscience. pp. 118–. ISBN 978-0-471-21480-9.
  14. ^ Wulff W. D.; Andersson B. A (1994). "Stereoselective aldol addition reactions of Fischer carbene complexes via electronic tuning of the metal center for enolate reactivity". Inorganica Chimica Acta. 220 (1–2): 215–231. doi:10.1016/0020-1693(94)03874-0.
  15. ^ Schetter, B.; Mahrwald, R. (2006). "Modern Aldol Methods for the Total Synthesis of Polyketides". Angew. Chem. Int. Ed. 45 (45): 7506–7525. doi:10.1002/anie.200602780. PMID 17103481.
  16. ^ Guthrie, J.P.; Cooper, K.J.; Cossar, J.; Dawson, B.A.; Taylor, K.F. (1984). "The retroaldol reaction of cinnamaldehyde". Can. J. Chem. 62 (8): 1441–1445. doi:10.1139/v84-243.
  17. ^ Zimmerman, H. E.; Traxler, M. D. (1957). "The Stereochemistry of the Ivanov and Reformatsky Reactions. I". Journal of the American Chemical Society. 79 (8): 1920–1923. doi:10.1021/ja01565a041.
  18. ^ 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". Journal of Organic Chemistry. 45 (6): 1066–1081. doi:10.1021/jo01294a030.
  19. ^ Bal, B.; Buse, C. T.; Smith, K.; Heathcock, C. H., (2SR,3RS)-2,4-Dimethyl-3-Hydroxypentanoic Acid, Org. Synth., Coll. Vol. 7, p.185 (1990); Vol. 63, p.89 (1985).
  20. ^ 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". Journal of the American Chemical Society. 111 (9): 3441–3442. doi:10.1021/ja00191a058.
  21. ^ Ireland, R. E.; Willard, A. K. (1975). "The stereoselective generation of ester enolates". Tetrahedron Letters. 16 (46): 3975–3978. doi:10.1016/S0040-4039(00)91213-9.
  22. ^ Narula, A. S. (1981). "An analysis of the diastereomeric transition state interactions for the kinetic deprotonation of acyclic carbonyl derivatives with lithium diisopropylamide". Tetrahedron Letters. 22 (41): 4119–4122. doi:10.1016/S0040-4039(01)82081-5.
  23. ^ Ireland, RE; Wipf, P; Armstrong, JD (1991). "Stereochemical control in the ester enolate Claisen rearrangement. 1. Stereoselectivity in silyl ketene acetal formation". Journal of Organic Chemistry. 56 (2): 650–657. doi:10.1021/jo00002a030.
  24. ^ Xie, L; Isenberger, KM; Held, G; Dahl, LM (October 1997). "Highly Stereoselective Kinetic Enolate Formation: Steric vs Electronic Effects". Journal of Organic Chemistry. 62 (21): 7516–7519. doi:10.1021/jo971260a. PMID 11671880.
  25. ^ Directed Aldol Synthesis – Formation of E-enolate and Z-enolate
  26. ^ Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1.
  27. ^ Cowden, C. J.; Paterson, I. (2004). Asymmetric Aldol Reactions Using Boron Enolates. Organic Reactions. pp. 1–200. doi:10.1002/0471264180.or051.01. ISBN 978-0471264187.
  28. ^ Evans, D. A.; Nelson J. V.; Vogel E.; Taber T. R. (1981). "Stereoselective aldol condensations via boron enolates". Journal of the American Chemical Society. 103 (11): 3099–3111. doi:10.1021/ja00401a031.
  29. ^ 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". Journal of the American Chemical Society. 113 (3): 1047–1049. doi:10.1021/ja00003a051.
  30. ^ Evans D. A. et al. Top. Stereochem. 1982, 13, 1–115. (Review)
  31. ^ Roush W. R. (1991). "Concerning the diastereofacial selectivity of the aldol reactions of .alpha.-methyl chiral aldehydes and lithium and boron propionate enolates". Journal of Organic Chemistry. 56 (13): 4151–4157. doi:10.1021/jo00013a015.
  32. ^ Masamune S.; Ellingboe J. W.; Choy W. (1982). "Aldol strategy: coordination of the lithium cation with an alkoxy substituent". Journal of the American Chemical Society. 104 (20): 1047–1049. doi:10.1021/ja00384a062.
  33. ^ 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". Journal of the American Chemical Society. 117 (35): 9073–9074. doi:10.1021/ja00140a027.
  34. ^ 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.
  35. ^ Evans D. A. Aldrichimica Acta 1982, 15, 23. (Review)
  36. ^ Gage J. R.; Evans D. A., Diastereoselective Aldol Condensation Using A Chiral Oxazolidinone Auxiliary: (2S*,3S*)-3-Hydroxy-3-Phenyl-2-Methylpropanoic Acid, Organic Syntheses, Coll. Vol. 8, p.339 (1993); Vol. 68, p.83 (1990).
  37. ^ Evans, D. A.; Bartroli J.; Shih T. L. (1981). "Enantioselective aldol condensations. 2. Erythro-selective chiral aldol condensations via boron enolates". Journal of the American Chemical Society. 103 (8): 2127–2129. doi:10.1021/ja00398a058.
  38. ^ a b Evans, D. A.; Bender S. L.; Morris J. (1988). "The total synthesis of the polyether antibiotic X-206". Journal of the American Chemical Society. 110 (8): 2506–2526. doi:10.1021/ja00216a026.
  39. ^ 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". Journal of the American Chemical Society. 112 (2): 866–868. doi:10.1021/ja00158a056.
  40. ^ 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 (11): 2127–2142. doi:10.1016/S0040-4020(01)88879-7.
  41. ^ Shigehisa, H.; Mizutani, T.; Tosaki, S. Y.; Ohshima, T.; Shibasaki, M, Tetrahedron 2005, 61, 5057-5065.
  42. ^ 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
  43. ^ S. B. Jennifer Kan; Kenneth K.-H. Ng; Ian Paterson (2013). "The Impact of the Mukaiyama Aldol Reaction in Total Synthesis". Angewandte Chemie International Edition. 52 (35): 9097–9108. doi:10.1002/anie.201303914. PMID 23893491.
  44. ^ Teruaki Mukaiyama; Kazuo Banno; Koichi Narasaka (1974). "Reactions of silyl enol ethers with carbonyl compounds activated by titanium tetrachloride". Journal of the American Chemical Society. 96 (24): 7503–7509. doi:10.1021/ja00831a019.
  45. ^ 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)
  46. ^ 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)". Journal of the American Chemical Society. 116 (19): 8837–8. doi:10.1021/ja00098a065.
  47. ^ 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". Journal of the American Chemical Society. 120 (4): 837–8. doi:10.1021/ja973331t.
  48. ^ 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. Int. Ed. 37 (22): 3124–6. doi:10.1002/(SICI)1521-3773(19981204)37:22<3124::AID-ANIE3124>3.0.CO;2-1.
  49. ^ 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.
  50. ^ 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.
  51. ^ Carreira, E. M.; Fettes, A.; Martl, C. (2006). Catalytic Enantioselective Aldol Addition Reactions. Org. React. 67. pp. 1–216. doi:10.1002/0471264180.or067.01. ISBN 978-0471264187.
  52. ^ Z. G. Hajos, D. R. Parrish, German Patent DE 2102623 1971
  53. ^ Hajos, Zoltan G.; Parrish, David R. (1974). "Asymmetric synthesis of bicyclic intermediates of natural product chemistry". Journal of Organic Chemistry. 39 (12): 1615–1621. doi:10.1021/jo00925a003.
  54. ^ Eder, Ulrich; Sauer, Gerhard; Wiechert, Rudolf (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.
  55. ^ List, Benjamin (2006). "The ying and yang of asymmetric aminocatalysis". Chemical Communications (8): 819–824. doi:10.1039/b514296m. PMID 16479280.
  56. ^ Northrup, Alan B.; MacMillan David W. C. (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. PMID 12059180.
  57. ^ 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. PMID 15083470.
  58. ^ Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. (2002). "Diastereoselective Magnesium Halide-Catalyzed anti-Aldol Reactions of Chiral N-Acyloxazolidinones". Journal of the American Chemical Society. 124 (3): 392–393. doi:10.1021/ja0119548. PMID 11792206.
  59. ^ Evans, David A.; Downey, C. Wade; Shaw, Jared T.; Tedrow, Jason S. (2002). "Magnesium Halide-Catalyzed Anti-Aldol Reactions of Chiral N-Acylthiazolidinethiones". Organic Letters. 4 (7): 1127–1130. doi:10.1021/ol025553o. PMID 11922799.
  60. ^ Magdziak, D.; Lalic, G.; Lee, H. M.; Fortner, K. C.; Aloise, A. D.; Shair, M. D. (2005). "Catalytic Enantioselective Thioester Aldol Reactions That Are Compatible with Protic Functional Groups". Journal of the American Chemical Society. 127 (20): 7284–7285. doi:10.1021/ja051759j. PMID 15898756.

External links

Aldol

An aldol or aldol adduct (from "Aldehyde alcohol") is a hydroxy ketone or aldehyde, and is the product of aldol addition (as opposed to aldol condensation, which produces an α,β-unsaturated carbonyl moiety).

When used alone, the term "aldol" may also refer specifically to the compound 3-hydroxybutanal.

Aldol condensation

An aldol condensation is a condensation reaction in organic chemistry in which an enol or an enolate ion reacts with a carbonyl compound to form a β-hydroxyaldehyde or β-hydroxyketone (an aldol reaction), followed by dehydration to give a conjugated enone.

Aldol condensations are important in organic synthesis, because they provide a good way to form carbon–carbon bonds. For example, the Robinson annulation reaction sequence features an aldol condensation; the Wieland–Miescher ketone product is an important starting material for many organic syntheses. Aldol condensations are also commonly discussed in university level organic chemistry classes as a good bond-forming reaction that demonstrates important reaction mechanisms.

In its usual form, it involves the nucleophilic addition of a ketone enolate to an aldehyde to form a β-hydroxy ketone, or "aldol" (aldehyde + alcohol), a structural unit found in many naturally occurring molecules and pharmaceuticals.

The name aldol condensation is also commonly used, especially in biochemistry, to refer to just the first (addition) stage of the process—the aldol reaction itself—as catalyzed by aldolases. However, the aldol reaction is not formally a condensation reaction because it does not involve the loss of a small molecule.

The reaction between an aldehyde or ketone having an alpha-hydrogen with an aromatic carbonyl compound lacking an alpha hydrogen is called the Claisen–Schmidt condensation. This reaction is named after two of its pioneering investigators Rainer Ludwig Claisen and J. G. Schmidt, who independently published on this topic in 1880 and 1881. An example is the synthesis of dibenzylideneacetone. Quantitative yields in Claisen–Schmidt reactions have been reported in the absence of solvent using sodium hydroxide as the base and plus benzaldehydes. Because the enolizeable nucleophilic carbonyl compound and the electrophilic carbonyl compound are two different chemicals, the Claisen–Schmidt reaction is an example of a crossed aldol process.

Aldol–Tishchenko reaction

The Aldol–Tishchenko reaction is a tandem reaction involving an aldol reaction and a Tishchenko reaction. In organic synthesis it is a method to convert aldehydes and ketones into 1,3-hydroxyl compounds. The reaction sequence in many examples starts from conversion of a ketone into an enolate by action of lithium diisopropylamide (LDA), to which a suitable aldehyde is added. The resulting mono-ester diol is then converted into the diol by a hydrolysis step. With both the acetyl trimethylsilane and propiophenone as reactants, the diol is obtained as a pure diastereoisomer.

Alexander Borodin

Alexander Porfiryevich Borodin (Russian: Алекса́ндр Порфи́рьевич Бороди́н, IPA: [ɐlʲɪkˈsandr pɐrˈfʲi rʲjɪvʲɪtɕ bərɐˈdʲin] (listen); 12 November 1833 – 27 February 1887) was a Russian chemist and Romantic musical composer of Georgian ancestry. He was one of the prominent 19th-century composers known as "The Mighty Handful", a group dedicated to producing a uniquely Russian kind of classical music, rather than imitating earlier Western European models. Borodin is known best for his symphonies, his two string quartets, the symphonic poem In the Steppes of Central Asia and his opera Prince Igor. Music from Prince Igor and his string quartets was later adapted for the US musical Kismet.

A doctor and chemist by profession, Borodin made important early contributions to organic chemistry. Although he is presently known better as a composer, during his lifetime, he regarded medicine and science as his primary occupations, only practising music and composition in his spare time or when he was ill. As a chemist, Borodin is known best for his work concerning organic synthesis, including being among the first chemists to demonstrate nucleophilic substitution, as well as being the co-discoverer of the aldol reaction. Borodin was a promoter of education in Russia and founded the School of Medicine for Women in Saint Petersburg, where he taught until 1885.

Allylic strain

Allylic strain (also known as A1,3 strain, 1,3-allylic strain, or A-strain) in organic chemistry is a type of strain energy resulting from the interaction between a substituent on one end of an olefin with an allylic substituent on the other end. If the substituents (R and R') are large enough in size, they can sterically interfere with each other such that one conformer is greatly favored over the other. Allyic strain was first recognized in the literature in 1965 by Johnson and Malhotra. The authors were investigating cyclohexane conformations including endocyclic and exocylic double bonds when they noticed certain conformations were disfavored due to the geometry constraints caused by the double bond. Organic chemists capitalize on the rigidity resulting from allylic strain for use in asymmetric reactions.

Charles Adolphe Wurtz

Charles Adolphe Wurtz (French: [vyʁts]; 26 November 1817 – 10 May 1884) was an Alsatian French chemist. He is best remembered for his decades-long advocacy for the atomic theory and for ideas about the structures of chemical compounds, against the skeptical opinions of chemists such as Marcellin Berthelot and Etienne Henri Sainte-Claire Deville. He is well known by organic chemists for the Wurtz reaction, to form carbon-carbon bonds by reacting alkyl halides with sodium, and for his discoveries of ethylamine, ethylene glycol, and the aldol reaction. Wurtz was also an influential writer and educator.

Chiral Lewis acid

Chiral Lewis acids (CLAs) are a type of Lewis acid catalyst that effects the chirality of the substrate as it reacts with it. In such reactions the synthesis favors the formation of a specific enantiomer or diastereomer. The method then is an enantioselective asymmetric synthesis reaction. Since they affect chirality, they produce optically active products from optically inactive or mixed starting materials. This type of preferential formation of one enantiomer or diastereomer over the other is formally known as an asymmetric induction. In this kind of Lewis acid. the electron-accepting atom is typically a metal, such as indium, zinc, lithium, aluminium, titanium, or boron. The chiral-altering ligands employed for synthesizing these acids most often have multiple Lewis basic sites (often a diol or a dinitrogen structure) that allow the formation of a ring structure involving the metal atom.Achiral Lewis acids have been used for decades to promote the synthesis of racemic mixtures in a myriad different reactions. Starting in the 1960s chemists have use the chiral acids to induce the enantioselective reactions. Common reaction types include Diels-Alder reactions, the ene reaction, [2+2] cycloaddition reactions, hydrocyanation of aldehydes, and most notably, Sharpless expoxidations.

David A. Evans

David A. Evans (born 1941) is the Abbott and James Lawrence Professor Emeritus in the Department of Chemistry and Chemical Biology at Harvard University. He is a prominent figure in the field of organic chemistry and his research focuses on synthetic chemistry and total synthesis, particularly of large biologically active molecules. Among his best-known work is the development of aldol reaction methodology (for example, Evans' acyl oxazolidinone method).

DeMayo reaction

The DeMayo reaction is a photochemical reaction in which the enol of a 1,3-diketone reacts with an alkene (or another species with a C=C bond) and the resulting cyclobutane ring undergoes a retro-aldol reaction to yield a 1,5-diketone:

The net effect is to add the two carbon atoms in the C=C double bond between the two carbonyl groups of the diketone. It is thus useful in syntheses both as a relatively selective way to join two parts of a molecule and as a way to apply the more developed chemistry of 1,3-diketone synthesis to 1,5-diketones. The first part is a [2+2] cycloaddition. The ensuing retro-aldol cleavage is favored by the relative instability of the cyclobutane ring.

Dibutylboron trifluoromethanesulfonate

Dibutylboron trifluoromethanesulfonate (also called dibutylboron triflate or DBBT) is a reagent in organic chemistry. Its chemical formula is C9H18BF3O3S. It is used in asymmetric synthesis for example in the formation of boron enolates in the aldol reaction.

Hajos–Parrish–Eder–Sauer–Wiechert reaction

The Hajos–Parrish–Eder–Sauer–Wiechert reaction in organic chemistry is a proline catalysed asymmetric aldol reaction. The reaction is named after its principal investigators, Zoltan Hajos others, from Hoffmann-La Roche and Schering AG. Discovered in the 1970s the original Hajos-Parrish catalytic procedure - shown in the reaction equation - leading to the optically active bicyclic ketol as well as the Eder-Sauer-Wiechert modification leading to the optically active enedione through the loss of water from the ketol paved the way of asymmetric organocatalysis. It has been used extensively as a tool in the synthesis of steroids and other enantiomerically pure molecules.

Figure 1.

In the original reaction shown in Figure 1. naturally occurring chiral proline is the chiral catalyst in an Aldol reaction. The starting material is an achiral triketone and it requires just 3% of proline to obtain the reaction product, a ketol in 93% enantiomeric excess. As shown above, Hajos and Parrish worked at ambient temperature in dimethylformamide (DMF) solvent using a catalytic amount (3% molar equiv.) of (S)-(−)-proline enabling them to isolate the optically active intermediate bicyclic ketol. Thus, they described the first use of proline in a catalytic asymmetric aldol reaction.

The Schering group worked under non biological conditions using (S)-Proline (47 mol%), 1N perchloric acid, in acetonitrile at 80 °C. Hence, they could not isolate the Hajos, Parrish intermediate bicyclic ketol but instead the condensation product (S)-7a-methyl-2,3,7,7a-tetrahydro-1H-indene-1,5(6H)-dione through the loss of water. Thirty-seven years later a new group at Schering AG published the continuation of the earlier Schering work . Instead of the aforementioned non biological conditions the new group used the Hajos-Parrish catalytic procedure. Thus, they could isolate the optically active 6,5-bicyclic ketol described so far only in the Hajos-Parrish publications .

Hajos and Parrish investigated further the exact configuration of the above cis-fused-7a-methyl- 6,5-bicyclic-ketol by circular dichroism, and these results were confirmed by a single-crystal X-ray diffraction study. The centro symmetrical crystal of the corresponding racemic ketol without a heavy atom label has been obtained by the use of racemic proline. It showed by X-ray diffraction an axial orientation of the angular methyl group and an equatorial orientation of the hydroxyl group in the chair conformer of the six-membered ring. This is in good agreement with the crystal structure of the CD-ring of digitoxigenin. The structure of this ketol and its ethyl homologue are shown as follows.

Similar studies of the 7a-ethyl-homologue showed that the ethyl bicycic ketol existed in a cis conformation in which the 7a-ethyl group is equatorially oriented and the hydroxyl group is axially oriented in the chair form of the six-membered ring as shown above. The reason for a preference for this conformation could be enhanced 1,3-diaxial interaction in the other cis conformer between the angular ethyl group and the axial hydrogens at C-4 and C-6 in the six membered ring.

In a 2000 study the Barbas group found that intermolecular aldol additions (those between ketones and aldehydes) are also possible albeit with use of considerably more proline:

The authors noted the similarity of proline, the aldolase antibodies they had created and natural aldolase enzymes aldolase A all of which operate through an enamine intermediate. In this reaction the large concentration of acetone (one of the two reactants) suppresses various possible side-reactions: reaction of the ketone with proline to an oxazolidinone and reaction of the aldehyde with proline to an azomethine ylide.

Notz and List went on to expand the utility of this reaction to the synthesis of 1,2-diols:

In their full account of their 2000 Communication, the group revealed that proline together with the thiazolium salt 5,5-dimethyl thiazolidinium-4-carboxylate were found to be the most effective catalysts among a large group of amines, while catalysis with (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine salts formed the basis for the development of diamine organocatalysts that have proven effective in a wide variety or organocatalytic reactions.The asymmetric synthesis of the Wieland-Miescher ketone (1985) is another intramolecular reaction also based on proline, that was explored by the Barbas group in 2000. In this study the Barbas group demonstrated for the first time that proline can catalyze the cascade Michael-aldol reaction through combined iminium-enamine catalysis. This work is significant because despite the 30-year history and application of the Hajos-Parrish reaction in industry, the triketone substrate for this reaction had always been synthesized in a discrete independent step, demonstrating that there was a fundamental lack of understanding of the chemical mechanism of this reaction. The Barbas group had reported the aldolase antibody catalyzed iminium-enamine Robinson annulation in their 1997 study that marked the beginning of their studies in the area now called organocatalysis. In a report published in 2002 Carlos F. Barbas III said: "Work in the 1970s on proline-catalyzed intramolecular aldol addition reactions by synthetic organic chemists Zoltan G. Hajos and David R. Parrish of the chemical research department at Hoffmann-La Roche, Nutley, N.J., inspired us to look more closely at parallels between small-molecule catalysts and enzymes".In 2002 the Macmillan group was the first to demonstrate the proline catalyzed Aldol reaction between different aldehydes. This reaction is unusual because in general aldehydes will self-condense.

The organocatalytic intermolecular aldol reaction is now known as the Barbas-List Aldol reaction.

Modified aldol tandem reaction

Modified aldol tandem reaction is a sequential chemical transformation that combines aldol reaction with other chemical reactions that generate enolates. Enolates are a common building block in chemical syntheses and are typically formed by the addition of base to a ketone or aldehyde. Modified Aldol tandem reactions allow similar reactivity to be produced without the need for a base which may have adverse effects in a given chemical synthesis. A representative example is the decarboxylative aldol reaction (Figure "Modified aldol tandem reaction, decarboxylative aldol reaction as an example"), where the enolate is generated via decarboxylation reaction mediated by either transition metals or organocatalysts. Key advantage of this reaction over other types of aldol reaction is the selective generation of an enolate in the presence of aldehydes. This allows for the directed aldol reaction to produce a desired cross aldol.

Transition metals have been used to mediate the modified aldol tandem reaction. Allyl β-keto carboxylates can be used as substrate for palladium-mediated decarboxylative aldol reaction (Figure "Palladium-mediated decarboxylative aldol reaction with allyl β-keto carboxylates"). The allyl group can be removed by palladium, following decarboxylation reaction selectively generates the enolate at the β-keto group, which could further react with aldehyde to generate aldols.

Using decarboxylation reaction to generate enolate is a common strategy in biosynthetic pathways such as polyketide synthesis, where malonic acid half thioester can be converted to the corresponding enolate for Claisen condensation reaction. Inspired by this, a modified tandem aldol reaction has been developed using the malonic acid half thioester as the enolate source. A copper based catalyst system has been developed for efficient aldol generation at mild conditions (Figure "Decarboxylative aldol reaction with malonic acid half thioester").

Mukaiyama aldol addition

The Mukaiyama aldol addition is an organic reaction and a type of aldol reaction between a silyl enol ether and an aldehyde or formate. The reaction was discovered by Teruaki Mukaiyama (1927–2018) in 1973. His choice of reactants allows for a crossed aldol reaction between an aldehyde and a ketone or a different aldehyde without self-condensation of the aldehyde. For this reason the reaction is used extensively in organic synthesis.

Multiple Michael/aldol reaction

Multiple Michael/aldol reaction (or domino Michael/aldol reaction) is a consecutive series of reactions composed of either Michael addition reactions or aldol reactions. More than two steps of reaction are usually involved. This reaction has been used for synthesis of large macrocyclic or polycyclic ring structures.

Gary Posner and co-workers were the first to report using multiple Michael/aldol reactions to construct macrolide structures. Their method utilized a Michael-Michael-Michael-ring closure (MIMI-MIRC) or a Michael-Michael-aldol-ring closure annulation sequences to assemble acrylates and/or aldehydes together to form substituted 9-, 10-, and 11-membered macrolide structures. Besides synthesis of complex ring structures, multiple Michael/aldol reaction can also be used for rapid production of complex compound libraries.

Aldolases have been used to mediate multiple aldol reactions. Chi-Huey Wong and co-workers had shown that 2-deoxyribose-5-phosphate aldolase and fructose-1, 6-diphosphate aldolase could be used together in a one-pot reaction to connect two aldehydes and one ketone together through sequential aldol reacations. This reaction could be used to generate a variety of carbohydrate derivatives.

Nitroaldol reaction

The Henry Reaction (also referred to as the nitro-aldol reaction) is a classic carbon–carbon bond formation reaction in organic chemistry. Discovered in 1895 by the Belgian chemist Louis Henry (1834-1913), it is the combination of a nitroalkane and an aldehyde or ketone in the presence of a base to form β-nitro alcohols. This type of reaction is commonly referred to as a "nitro-aldol" reaction (nitroalkane, aldehyde, and alcohol). It is nearly analogous to the aldol reaction that had been discovered 23 years prior that couples two carbonyl compounds to form β-hydroxy carbonyl compounds known as "aldols" (aldehyde and alcohol). The Henry reaction is a useful technique in the area of organic chemistry due to the synthetic utility of its corresponding products, as they can be easily converted to other useful synthetic intermediates. These conversions include subsequent dehydration to yield nitroalkenes, oxidation of the secondary alcohol to yield α-nitro ketones, or reduction of the nitro group to yield β-amino alcohols.

Many of these uses have been exemplified in the syntheses of various pharmaceuticals including the β-blocker (S)-propranolol, the HIV protease inhibitor Amprenavir (Vertex 478), and construction of the carbohydrate subunit of the anthracycline class of antibiotics, L-Acosamine. The synthetic scheme of the L-Acosamine synthesis can be found in the Examples section of this article.

Selone

In chemistry, a selone is the structural analog of a ketone where selenium replaces oxygen. Selones are used as chiral derivatizing agents for selenium-77 NMR spectroscopy. Chiral oxazolidineselones are excellent partners in the stereospecific aldol reaction, and 77Se NMR can verify the enantiomeric purity of the aldol product.

Vinylogy

Vinylogy is the transmission of electronic effects through a conjugated organic bonding system. The concept was introduced in 1926 by Ludwig Claisen to explain the acidic properties of formylacetone and related ketoaldehydes. Its adjectival form, vinylogous, is used to describe functional groups in which the standard moieties of the group are separated only by a conjugated bonded system. For example, a carbon-carbon double bond (>C=C<, a "vinyl" moiety) between a carbonyl group and a hydroxyl group is referred to as a vinylogous carboxylic acid, analogous electronically to a carboxylic acid, RCOOH.

Zingerone

Zingerone, also called vanillylacetone, is thought by some to be a key component of the pungency of ginger, but imparts the "sweet" flavor of cooked ginger. Zingerone is a crystalline solid that is sparingly soluble in water and soluble in ether. When synthesized and tasted does not have any pungency, suggesting it is more likely that zingerone is a decomposition product of, rather than the direct source of, the pungency of ginger.Zingerone is similar in chemical structure to other flavor chemicals such as vanillin and eugenol. It is used as a flavor additive in spice oils and in perfumery to introduce spicy aromas.

Fresh ginger does not contain zingerone, but it is produced by cooking or drying of the ginger root, which causes a reverse aldol reaction on gingerol.

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