The aldol structural motif is especially common in polyketides, a class of natural products from which many pharmaceuticals are derived, including the potent immunosuppressant FK506, the tetracycline antibiotics, and the antifungal agent amphotericin B. Extensive research on the aldol reaction has produced highly efficient methods which enable the otherwise challenging synthesis of many polyketides in the laboratory. This is important because many polyketides, along with other biologically active molecules, occur naturally in quantities impractically small for further investigation. The synthesis of many such compounds, once considered nearly impossible, can now be performed routinely on the laboratory scale, and is approaching economic viability on a larger scale in some cases, such as the highly active anti-tumor agent discodermolide. In biochemistry, the aldol reaction is one of the key steps of glycolysis, where it is catalyzed by enzymes called aldolases.
The aldol reaction is particularly valuable in organic synthesis because it produces products with two new stereogenic centers (on the α- and β-carbon of the aldol adduct, marked with asterisks in the scheme above). Modern methods, described below, now allow the relative and absolute configuration of these centers to be controlled. This is of particular importance when synthesizing pharmaceuticals, since molecules with the same structural connectivity but different stereochemistry often have vastly different chemical and biological properties.
A variety of nucleophiles may be employed in the aldol reaction, including the enols, enolates, and enol ethers of ketones, aldehydes, and many other carbonyl compounds. The electrophilic partner is usually an aldehyde, although many variations, such as the Mannich reaction, exist. When the nucleophile and electrophile are different (the usual case), the reaction is called a crossed aldol reaction (as opposed to dimers formed in an aldol dimerization).
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.
Acid catalyzed aldol mechanism
Acid catalyzed dehydration
Base catalyzed aldol reaction (shown using −OCH3 as base)
Base catalyzed dehydration (sometimes written as a single step)
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.
In this reaction, two unsymmetrical ketones are being condensed using sodium ethoxide. The basicity of sodium ethoxide is such that it cannot fully deprotonate either of the ketones, but can produce small amounts of the sodium enolate of both ketones. Effectively, this means that in addition to being potential aldol electrophiles, both ketones may also act as nucleophiles via their sodium enolate. Two electrophiles and two nucleophiles then potentially results in four possible products:
Thus, if one wishes to obtain only one of the cross-products, then one must "control" the aldol addition.
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.
(-- In the above image, the second reaction scheme should say >99% E-enolate, not Z --) For ketones, most enolization conditions give Z enolates. For esters, most enolization conditions give E enolates. The addition of HMPA is known to reverse the stereoselectivity of deprotonation.
The stereoselective formation of enolates has been rationalized with the so-called Ireland model, although its validity is somewhat questionable. In most cases, it is not known which, if any, intermediates are monomeric or oligomeric in nature; nonetheless, the Ireland model remains a useful tool for understanding enolates.
In the Ireland model, the deprotonation is assumed to proceed by a six-membered monomeric transition state. The larger of the two substituents on the electrophile (in the case above, methyl is larger than proton) adopts an equatorial disposition in the favored transition state, leading to a preference for E enolates. The model clearly fails in many cases; for example, if the solvent mixture is changed from THF to 23% HMPA-THF (as seen above), the enolate geometry is inexplicably reversed.
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.
The convention applies when propionate (or higher order) nucleophiles are added to aldehydes. The R group of the ketone and the R' group of the aldehyde are aligned in a "zig zag" pattern in the plane of the paper, and the disposition of the formed stereocenters is deemed syn or anti, depending if they are on the same or opposite sides of the main chain.
In the case of an E enolate, the dominant control element is allylic 1,3-strain whereas in the case of a Z enolate, the dominant control element is the avoidance of 1,3-diaxial interactions. The general model is presented below:
For clarity, the stereocenter on the enolate has been epimerized; in reality, the opposite diastereoface of the aldehyde would have been attacked. In both cases, the 1,3-syn diastereomer is favored. There are many examples of this type of stereocontrol:
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:
Many methods which control both relative stereochemistry (i.e., syn or anti, as discussed above) and absolute stereochemistry (i.e., R or S) have been developed.
A widely used method is the Evans' acyl oxazolidinone method. Developed in the late 1970s and 1980s by David A. Evans and coworkers, the method works by temporarily creating a chiral enolate by appending a chiral auxiliary. The pre-existing chirality from the auxiliary is then transferred to the aldol adduct by performing a diastereoselective aldol reaction. Upon subsequent removal of the auxiliary, the desired aldol stereoisomer is revealed.
In the case of the Evans' method, the chiral auxiliary appended is an oxazolidinone, and the resulting carbonyl compound is an imide. A number of oxazolidinones are now readily available in both enantiomeric forms. These may cost roughly $10-$20 US dollars per gram, rendering them relatively expensive.
The acylation of an oxazolidinone is a convenient procedure, and is informally referred to as "loading done". Z-enolates, leading to syn-aldol adducts, can be reliably formed using boron-mediated soft enolization:
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:
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: and anti selective:
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.
The method works on unbranched aliphatic aldehydes, which are often poor electrophiles for catalytic, asymmetric processes. This may be due to poor electronic and steric differentiation between their enantiofaces.
The analogous vinylogous Mukaiyama aldol process can also be rendered catalytic and asymmetric. The example shown below works efficiently for aromatic (but not aliphatic) aldehydes and the mechanism is believed to involve a chiral, metal-bound dienolate.
This reaction is known as the Hajos-Parrish reaction (also known as the Hajos-Parrish-Eder-Sauer-Wiechert reaction, referring to a contemporaneous report from Schering of the reaction under harsher conditions). 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:
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:
In contrast to the preference for syn adducts typically observed in enolate-based aldol additions, these organocatalyzed aldol additions are anti-selective. In many cases, the organocatalytic conditions are mild enough to avoid polymerization. However, selectivity requires the slow syringe-pump controlled addition of the desired electrophilic partner because both reacting partners typically have enolizable protons. If one aldehyde has no enolizable protons or alpha- or beta-branching, additional control can be achieved.
An elegant demonstration of the power of asymmetric organocatalytic aldol reactions was disclosed by MacMillan and coworkers in 2004 in their synthesis of differentially protected carbohydrates. While traditional synthetic methods accomplish the synthesis of hexoses using variations of iterative protection-deprotection strategies, requiring 8–14 steps, organocatalysis can access many of the same substrates using an efficient two-step protocol involving the proline-catalyzed dimerization of alpha-oxyaldehydes followed by tandem Mukaiyama aldol cyclization.
The aldol dimerization of alpha-oxyaldehydes requires that the aldol adduct, itself an aldehyde, be inert to further aldol reactions. 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:
One approach, recently demonstrated by Evans, is to silylate the aldol adduct:
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. The ketoacid moiety is decarboxylated in situ (the chiral ligand is a bisoxazoline). Interestingly, aromatic and branched aliphatic aldehydes are typically poor substrates.
Agency Reviews Patent Application Approval Request for "Method of Carbon Chain Extension Using Novel Aldol Reaction"
Dec 04, 2012; By a News Reporter-Staff News Editor at Life Science Weekly -- A patent application by the inventors Silks, Louis A. (Los Alamos,...
WIPO ASSIGNS PATENT TO LOS ALAMOS NATIONAL SECURITY FOR "METHOD OF CARBON CHAIN EXTENSION USING NOVEL ALDOL REACTION" (AMERICAN INVENTORS)
Feb 25, 2011; GENEVA, Feb. 25 -- Publication No. WO/2011/022041 was published on Feb. 24. Title of the invention: "METHOD OF CARBON CHAIN...