Alpha carbon aldol reactions

The biologically active form of vitamin Bg is pyridoxal-5-phosphate (PEP), a coenzyme that exists under physiological conditions in two tautomeric forms (Figure 18.25). PLP participates in the catalysis of a wide variety of reactions involving amino acids, including transaminations, a- and /3-decarboxylations, /3- and ") eliminations, racemizations, and aldol reactions (Figure 18.26). Note that these reactions include cleavage of any of the bonds to the amino acid alpha carbon, as well as several bonds in the side chain. The remarkably versatile chemistry of PLP is due to its ability to... 

The carbon alpha to the carbonyl of aldehydes and ketones can act as a nucleophile in reactions with other electrophilic compounds or intermolecu-larly with itself. The nucleophilic character is imparted via the keto-enol tau-tomerism. A classic example of this reactivity is seen in the aldol condensation (41), as shown in Figure 23. Note that the aldol condensation is potentially reversible (retro-aldol), and compounds containing a carbonyl with a hydroxyl at the (3-position will often undergo the retro-aldol reaction. The aldol condensation reaction is catalyzed by both acids and bases. Aldol products undergo a reversible dehydration reaction (Fig. 23) that is acid or base catalyzed. The dehydration proceeds through an enol intermediate to form the a,(3-unsaturated carbonyl containing compound. 

Condensation reactions involving the carbonyl group are illustrated by the aldol condensation. Under the influence of small amounts of hydroxyl ion two molecules of aldehyde unite to give a more complex molecule. The union occurs between the carbonyl group of one with the alpha carbon atom of another molecule ... 

Aldehydes that do not have hydrogen atoms on the alpha carbon atom do not undergo the aldol condensation. Such aldehydes undergo the Cannizzaro reaction when treated with strong alkali. For example, formaldehyde with strong sodium hydroxide gives sodium formate and methyl alcohol ... 

The phospho-aldol reaction has been known for many years within the phosphorus-chemistry community, under many names (including the Abramov and Pudovik reactions) and is one of the most valuable and powerful synthetic processes for the construction of phosphorus-carbon bonds [1]. The reaction, illustrated in its usual form, is outlined in Scheme 1 a. It involves an addition reaction between a hydrogen-phosphonate ester and a carbonyl substrate to afford an alpha-(a)-functionalised phosphonate ester. Whilst alternative methods or activation have been explored [2], the phospho-aldol reaction is most commonly performed under conditions of base catalysis [3]. 

Consequently, chemists must have at their disposal simple, effective, efficient, and stereoselective synthetic methods to construct the necessary frameworks. Development of catalytic asymmetric variants of the phospho-aldol reaction provides, arguably, the most versatile such process for the simultaneous construction of the [P-C] bond and associated a-carbon functionality with control over the stereochemistry at the newly generated alpha-carbon site. 

The second chapter highlights the past, present and future of the asymmetric phospho-aldol reaction, one of the most powerful method to control the stereochemistry at the alpha-carbon of alpha-functionalized phosphonic systems (T.P. Kee and T.D. Nixon). Attention focused for the future to the design of new catalysts, improved processing and to medicinal chemistry and disease targets. 

The two-carbon acetyl group of acetyl coenzyme A enters the cycle by an enzyme-catalyzed aldol reaction (Section 15.2) between the alpha carbon of acetyl-CoA and the ketone group of oxaloacetate. The product of this reaction is citrate, the tricarboxylic acid from which... 

The enolate ion is nucleophilic at the alpha carbon. Enolates prepared from aldehydes are difficult to control, since aldehydes are also very good electrophiles and a dimerization reaction often occurs (self-aldol condensation). However, the enolate of a ketone is a versatile synthetic tool since it can react with a wide variety of electrophiles. For example, when treated with an unhindered alkyl halide (RX), an enolate will act as a nucleophile in an Sn2 mechanism that adds an alkyl group to the alpha carbon. This two-step a-alkylation process begins by deprotonation of a ketone with a strong base, such as lithium diisopropylamide (LDA) at -78°C, followed by the addition of an alkyl halide. Since the enolate nucleophile is also strongly basic, the alkyl halide must be unhindered to avoid the competing E2 elimination (ideal RX for Sn2 = 1°, ally lie, benzylic). 

The aldol reaction of aldehydes and ketones involves the attack of an enolate (or enol) nucleophile on a carbonyl electrophile. When the alpha (a) carbon of one compound bonds with the carbonyl carbon of another compound, a P-hydroxy carbonyl product is initially formed this product can undergo a further reaction to give an a,P-unsaturated carbonyl product. When either of these patterns is present in a target molecule, it is an indication that the TM might be the product of an aldol reaction, and an aldol disconnection will be one option for retrosynthesis. 

A base-catalyzed aldol reaction begins with deprotonation of the weakly acidic proton next to the carbonyl, on the alpha carbon. The reversible reaction with a mild base such as hydroxide ensures that only a small amount of the ketone will be deprotonated to give a small amount of an enolate intermediate. 

Ultimately, a complete retrosynthesis of a P-amino ketone leads to the three components needed in a Mannich reaction a ketone, an aldehyde, and an amine. The retrosynthesis of a P-amino ketone begins with making a disconnection between the alpha carbon and the carbon bearing the amino group (the beta carbon). This aldol-like disconnection leads to a nucleophilic alpha carbon (enol) and an electrophilic imine carbon (C=N). Further disconnection of the imine affords the two necessary building blocks for its formation an aldehyde and an amine. 

Since the target molecule is an a,P-unsaturated carbonyl, one possible approach would be an aldol reaction. A disconnection can be made directly through the C=C double bond, or a stepwise approach can be taken by first imagining the TM as a P-hydroxy structure that can then be disconnected between the alpha and beta carbons. Either approach leads to the same aldol starting materials a nucleophilic alpha carbon (enolate) and an electrophilic carbonyl carbon (benzaldehyde). 

Like the aldol and the Claisen, the Michael reaction also involves an enolate, so the mechanism begins with the deprotonation of an alpha carbon. In the Michael reaction, however, the electrophile is not an ordinary carbonyl, but an a,P-unsaturated carbonyl. Attack of the stable enolate nucleophile occurs at the beta carbon of the a,P-unsaturated carbonyl (called a 1,4-addition or conjugate addition or even Michael addition) to give an enolate intermediate. Protonation at the alpha carbon of the enolate gives the final product, a 1,5-dicarbonyl compound. 

The aldol reaction, the reaction of an enolate nucleophile with a carbonyl electrophile to give a P-hydroxy carbonyl product, has the potential to form two new chirality centers. It is possible to both predict and control the stereochemical relationship between a group on the alpha carbon and the newly formed hydroxyl group on the beta carbon. Since this relationship depends on the stereochemistry of the enolate involved, formation of the enolate must first be discussed. 

A carbon atom alpha to a carbonyl function may become nucleophilic either by forming an etiolate (Eq. 18.3) or an enol (Eq. 18.4). In the crossed-aldol reaction described in the previous section (Scheme 18.4), the nucleophilic character of the carbon atom alpha to a ketone function was provided by enolate formation. However, in the experiment that follows, nucleophilicity at the a-carbon atom is promoted by enol formation. The overall reaction is the acid-catalyzed conversion of 2-methylpropanal (26) and 3-buten-2-one (27) into 4,4-dimethyl-2-cyclohexen-1-one (29), as shown in Equation 18.12. For the first stage of the reaction, the enol form of 26 serves as the nucleophile in the 1,4- or conjugate addition to the a,3-unsaturated ketone 27 to give 28. In the second stage, an enol is the nucleophile in the cyclization of 28 by an intramolecular aldol condensation that is acid-catalyzed. The conjugate addition to give 28 is an example of a... 

This will always be the case whenever an enolate attacks a carbonyl group, regardless of the structure of the starting ketone and the structure of the enolate. The alpha carbon of the enolate is directly attacking the carbonyl group of the ketone. That wiU always place the OH group in the beta position. Always. This product is called a jS-hydroxy ketone, and the reaction is called an aldol addition. 

Aldol Addition and Related Reactions. Procedures that involve the formation and subsequent reaction of anions derived from active methylene compounds constitute a very important and synthetically useful class of organic reactions. Perhaps the most common are those reactions in which the anion, usually called an enolate, is formed by removal of a proton from the carbon atom alpha to the carbonyl group. Addition of this enolate to another carbonyl of an aldehyde or ketone, followed by protonation, constitutes aldol addition, for example... 

Exercise 17-21 a. A useful modification of aldol addition to methanal, known as the Mannich reaction, uses a secondary amine (usually as its hydrochloride salt) to selectively introduce one carbon atom at the alpha position of an aldehyde or ketone. The actual product is the salt of an amino ketone. For example,... 

One exception to the general application of these ketone syntheses was failure of compounds having an alpha-substituted carbon atom such as isobutyl alcohol or 2-ethylhexanol to undergo the dehydrogenation (7) condensation reaction. This failure of alpha-substituted reactants to undergo the ketone synthesis was unexpected as the aldol condensation of alpha-substituted aldehydes with one labile hydrogen atom occurs readily. 

Base-catalyzed hydration of conjugated carbonyls, followed by retro-aldol fragmentation has been a common strategy for studying the reaction cascade (1-4). The kinetically important step in the base-catalyzed hydration of an alpha/beta unsaturated carbonyl is similar to a nucleophilic substitution reaction at carbon 3. The reaction cascade proceeds rapidly from the conjugated carbonyl through its hydration and subsequent fragmentation. 

The aldol condensation involves the reaction of two molecules of an aldehyde or ketone that has alpha hydrogens. Abstraction of an alpha hydrogen by base produces a carbanion which attacks the carbonyl carbon of the other molecule by base-initiated nucleophilic addition an alcohol group is formed. Often the alcohol dehydrates to form the final product, an unsaturated aldehyde or ketone. In a crossed aldol condensation, a carbonyl compound with alpha hydrogens reacts with one without alpha hydrogens. 

Identify all the alpha hydrogens in the molecule, and for each one, form an enolate anion. Then decide which enolate anion would form the more stable ring upon reaction with the other carbonyl in the molecule. It often helps to number the atoms in the ketone or aldehyde.The product of dehydration of any aldol product is always an a,j3-unsaturated carbonyl compound. The C — C double bond always forms between the a-carbon and the carbon that was once bonded to the —OH group. 

The product of this reaction is a P-hydroxy carbonyl that contains a newly formed carbon-carbon bond between the alpha and beta carbons. This is the key bond to be identified in a P-hydroxy carbonyl TM a disconnection at this bond will lead to an aldol retrosynthesis. 

The classic aldol condensation involves generation of an enolate by removal of an acidic proton from a carbon alpha to the carbonyl group of an aldehyde or ketone, and subsequent nucleophilic addition of this enolate to the carbonyl carbon of an aldehyde or ketone. This reaction is base catalyzed and involves the following mechanistic steps ... 

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