The Chemistry of Metal Enolates [Part 1]

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Chemistry of the Alkaline Earth Metal Enolates

Check for new and used marketplace copies. Metal enolates form a class of compounds that have recently received much attention because of their part in the selective formation of carbon-carbon bonds via the aldol reaction. Other applications for metal enolates, such as their use in forming metal coatings, are also discussed. This volume extends and complements the previous volume 1, which was published in Skip Navigation and go to main content Bestsellers Books.

Print this page. The Chemistry of Metal Enolates. Used from other sellers Check for new and used marketplace copies. Organic Chemistry Jonathan Clayden, Nick Molecular Model Set for Organic A Guidebook to Mechanism in Org 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. 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.

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The convention applies when propionate or higher order nucleophiles are added to aldehydes. The R group of the ketone and the R' group of the aldehyde are aligned in a "zig zag" pattern in the plane of the paper or screen , and the disposition of the formed stereocenters is deemed syn or anti , depending if they are on the same or opposite sides of the main chain. 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].

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. For example, boron—carbon and boron—oxygen bonds are 1. The use of boron rather than a metal "tightens" the transition state and gives greater stereoselectivity in the reaction. The aldol reaction may exhibit "substrate-based stereocontrol", in which existing chirality on either reactant influences the stereochemical outcome of the reaction.

This has been extensively studied, and in many cases, one can predict the sense of asymmetric induction , if not the absolute level of diastereoselectivity. If the enolate contains a stereocenter in the alpha position, excellent stereocontrol may be realized. In the case of an E enolate, the dominant control element is allylic 1,3-strain whereas in the case of a Z enolate, the dominant control element is the avoidance of 1,3-diaxial interactions.

The Chemistry of Metal Enolates, 2 Volume Set - Google книги

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: [29]. 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:. 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]. 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.

Modern organic syntheses now require the synthesis of compounds in enantiopure form.

Since the aldol addition reaction creates two new stereocenters, up to four stereoisomers may result. Many methods which control both relative stereochemistry i. A widely used method is the Evans' acyl oxazolidinone method. 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. 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.

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

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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]. 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].

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.

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Intramolecular aldol reaction is the condensation reaction of two aldehyde groups or ketone groups in the same molecule. 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. The mechanism of the intramolecular aldol reaction involves formation of a key enolate intermediate followed by an intramolecular nucleophilic addition process.

Next, a nucleophilic attack of the enolate on the other keto group forms a new carbon-carbon bond red between carbons 2 and 6. Intramolecular aldol reactions have been widely used in total syntheses of various natural products, especially alkaloids and steroids. Recent [ when? 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. 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]. 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. Carreira has described particularly useful asymmetric methodology with silyl ketene acetals, noteworthy for its high levels of enantioselectivity and wide substrate scope. 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.

A more recent [ when? Unlike the Evans auxiliary, however, the thiazoldinethione can perform acetate aldol reactions ref: Crimmins, Org. 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. 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:. 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.

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]. 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]. 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 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. 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:. 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.

One approach, demonstrated by Evans, is to silylate the aldol adduct. Minimizing the number of reaction steps and amount of reactive chemicals used leads to a cost-effective and industrially useful reaction. 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. Examples of aldol reactions in biochemistry include the splitting of fructose-1,6-bisphosphate into dihydroxyacetone and glyceraldehydephosphate 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. From Wikipedia, the free encyclopedia. Main article: Mukaiyama aldol reaction. Chemistry portal. Organic Chemistry 6th ed.

Advanced Organic Chemistry 5th ed. New York: Wiley Interscience. Modern Aldol Reactions, Volumes 1 and 2. Petersburg am October " V. Petersburg on Garner, Susan Amy "Hydrogen-mediated carbon-carbon bond formations: Applied to reductive aldol and Mannich reactions," Ph.

The Chemistry of Metal Enolates [Part 1] The Chemistry of Metal Enolates [Part 1]
The Chemistry of Metal Enolates [Part 1] The Chemistry of Metal Enolates [Part 1]
The Chemistry of Metal Enolates [Part 1] The Chemistry of Metal Enolates [Part 1]
The Chemistry of Metal Enolates [Part 1] The Chemistry of Metal Enolates [Part 1]
The Chemistry of Metal Enolates [Part 1] The Chemistry of Metal Enolates [Part 1]
The Chemistry of Metal Enolates [Part 1] The Chemistry of Metal Enolates [Part 1]
The Chemistry of Metal Enolates [Part 1] The Chemistry of Metal Enolates [Part 1]
The Chemistry of Metal Enolates [Part 1] The Chemistry of Metal Enolates [Part 1]

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