Aldol condensation retro-reaction

Originally, the term aldol condensation referred specifically to the reaction of an aldehyde (having an a-hydrogen) with an aldehyde/ketone to form a j8-hydroxy aldehyde (the aldol). The reverse reaction is often referred to as a retrograde aldol reaction, a retro-aldol condensation (or reaction), or an aldol cleavage. March categorizes aldol condensations into five classes. The first is condensation between two identical aldehydes... 

According to Scheme 6.27, GLA/DH A can he obtained from C6 sugars (glucose and fructose) via retro-aldol condensation. This reaction can he catalyzed hy a hase as well as Lewis acid. A Br0nsted hase HT catalyst has also heen shown to produce lactic acid from glucose in basic aqueous solution [138]. 

The first step in the nonreversible degradation reactions is the formation of a reactive a-dicarbonyl species through the p-elimination of a hydroxide ion. The subsequent reaction pathways to all degradation products can be described by just five reaction types, namely, p-elimination, benzilic acid rearrangement, a-dicarbonyl cleavage, aldol condensation, and retro-aldol condensation (see Fig. 7).31 Retro-aldol condensation and a-dicarbonyl cleavage involve C-C bond... 

Three-cmbon ring expansionThe cyclic p-keto esters 1 with a 4-oxopentyl group at the a-position do not undergo the expected aldol condensation on treatment with KOC(CH3)3 in DMSO, but undergo ring expansion to medium-size ketones (2). The reaction may involve aldol and retro-aldol condensation. A similar... 

Figure 1. Kinetic parameters for the selection of antibody-catalyzed aldol and retro-aldol reactions, reflecting the biocatalyst s ability to accept substrates that differ clearly with respect to their molecular geometry. No background reaction was observed for the self-condensation of cyclopentanone. The indicated value for cyclopentanone addition to pentanal was estimated using the published kuncat value of 2.28 X 10 M s for the aldol addition of acetone to an aldehyde. Reproduced with permission of the authors and the American Association for the Advancement of Science.

An Oppenauer reaction produces the selective oxidation of a secondary alcohol, leading to a (3-hydroxyketone that suffers a retro-aldol condensation under the basic reaction conditions, resulting in the evolution of formaldehyde. 

The synthetic method (a) is the regioselective reduction of an a,/ -unsaturated aldehyde or ketone (Section 5.18.2, p. 798), which is most conveniently effected by the Meerwein-Ponndorf-Verley procedure (Section 5.4.1, p. 520). The further disconnection shown of the a, -carbonyl compound is a retro-aldol condensation (Section 5.18.2, p. 799) however it should be emphasised that other routes to the unsaturated carbonyl compound, such as the Horner-Emmons reaction (Section 5.18.2, p. 799), may also be feasible. 

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. 

Although attempts to catalyze bimolecular aldol condensations without resorting to enamine chemistry have not yet been successful, the Schultz group92 has prepared an antibody against the phosphinate hapten 115 that catalyzes the retro aldol reaction of 116 (kcJKm = 125 M-1 s l). The equilibrium in this case strongly disfavors the condensation product, and a histidine induced in response to the phosphinate may be involved in catalysis. Interestingly and in contrast to the previous examples, the stereoselectivity of the antibody is modest. The syn diastereomer of 116 was found to be the better substrate for the antibody by 2 1 over the anti diastereomer, but no evidence of enantioselectivity was observed. 

B as an ester- or lactone-substituted aldehyde enolate. Such enolates undergo condensations with all kinds of aldehydes, including paraformaldehyde. An adduct E is formed initially, acy-lating itself as soon as it is heated. The reaction could proceed intramolecularly via the tetrahedral intermediate D or intermolecularly as a retro-Claisen condensation. In both cases, the result is an acyloxy-substituted ester enolate. In the example given in Figure 13.50, this is the formyloxy-substituted lactone enolate C. As in the second step of an Elcb elimination, C eliminates the sodium salt of a carboxylic acid. The a,/)-unsaturated ester (in Figure 13.50 the 0J,/3-unsaturated lactone) remains as the aldol condensation product derived from the initial ester (here, a lactone) and the added aldehyde (here, paraformaldehyde). 

In the case of (11), retrosynthetic functional group interconversion into the aldol followed by disconnection of the a, /J-bond gives the dipolar synthon (15), of which the reagent equivalent is the 1,4-dicarbonyl compound, hexane-2,5-dione (i.e. a retro-aldol condensation). The action of base on this diketone effects the forward aldol reaction followed by spontaneous dehydration (see Expt 7.4 for formulation). 

The mechanism of Step 4 involves a retro-aldol condensation reaction on the open-chain form of D-fructose 1,6-bisphosphate. This reaction, and the origin of the carbon atoms in the products, is shown below. 

By analyzing an input molecule, substructures are found which point to chapters in the reaction library. There, descriptions of changes in these substructures are contained which will occur in the course of a certain reaction. Implementing these changes leads to synthetic precursors. Thus, the recognition of the substructure of a /3-hydroxy-carbonyl group would point to the chapter aldol condensation in the reaction library. There the structural changes of a retro-aldol condensation are contained and result in the two carbonyl compounds as precursors (see Fig. 1). As the reac-... 

In an alternative approach to molecules of this type, Dauben and Hart examined the base-catalyzed rearrangement of vinylogous 0-hydroxy ketones such as 305 and 308 (Scheme 48).321 Their conversion to 306 and 309 can be accounted for in terms of a vinylogous retro-aldol condensation followed by intramolecular 1,4 addition of an intermediate dienolate to the resulting enone moiety. Subsequent to this reaction, conjugation of the double bond away from the ring juncture followed by a transannular vinylogous aldol condensation produces the observed products. 

Aldol condensation. The final step in a synthesis of the tricyclic taxane ring system involves an intramolecular aldol condensation of 2. Treatment with the usual bases results in a retro Michael reaction, but the desired cyclization to 3 can be effected in 90% yield by use of bromomagnesium diisopropylamide (1) or isopropylcyclohexylamide. The hydroxy ketone undergoes retroaldolization in the presence of mild acids or bases, but can be reduced and stored as the corresponding stable diol. 

Retro-aldol condensations are also known to take place during pyrolysis. The mechanism of these reactions can be written as follows ... 

In order to confirm the structures of solanapyrones, chemical synthesis of these phytotoxins were attempted based on biogenetic consideration [55], The retro synthesis envisaged intramolecular Diels-Alder reaction of the achiral polyketide triene (a), a key intermediate, which is further divided into a pyrone moiety (b) and a diene moiety (c). The moieties a and b were prepared from dehydroacetic acid and hexadienyl acetate, respectively. Aldol condensation of the aldehyde (72) with the dithioacetal (73) gave a dienol, which was further converted to a triene (74). The intramolecular Diels-Alder reaction of 74 in toluene at 170-190 °C for 1 hr in a sealed tube yielded a mixture of the adducts (75) and (76) in a ratio of 1 2. This product ratio depends on the solvents, i.e. in water (1 7), and should be useful in differentiating between artificial and enzymatic reactions in biosynthetic studies. Removal of the thioacetal groups in 75 and 76 yielded solanapyrone A (67) and D (70) in a ratio of 3 5. Though solanapyrone D (70) had not been isolated from the natural resources at this stage, the structure and stereochemistry were confirmed by H NMR spectrum. 

Butlerov found out that in alkaline medium (calcium hydroxide), formaldehyde HCHO polymerizes to form about 20 different sugars as racemic mixtures, Butlerov 1861. The reaction requires a divalent metal ion. Breslow found a detailed mechanism of reaction that explains the reaction products, (Breslow 1959). He found that glycol-aldehyde is the first product that is subsequently converted into glyceral-dehyde (a triose), di-hydroxy-acetone, and then into various other sugars, tetrose, pentose, and hexose. The formose reaction advances in an autocatalytic way in which the reaction product is itself the catalyst for that reaction with a long induction period. The intermediary steps proceed via aldol and retro-aldol condensations and, in addition, keto-enol tautomerizations. It remains unexplained how the phosphorylation of 3-glyceraldehyde leads to glycral-3-phosphate (Fig. 3.6). Future work should study whether or not ribozymes exist that can carry out this reaction in a stereo-specific way. 

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