Ketone reversible aldol condensation

In aldol condensation, aldehydes and ketones react to form a larger molecule (Section 14.4). This reaction is a reverse aldol condensation. The large ketone sugar fructose-l,6-bisphosphate is broken down into dihydroxyacetone phosphate (a ketone) and gIyceraldehyde-3-phosphate (an aldehyde). 

The aldol reaction is a carbonyl condensation that occurs between two aldehyde or ketone molecules. Aldol reactions are reversible, leading first to a /3-hydroxy aldehyde or ketone and then to an cr,/6-unsaturated product. Mixed aldol condensations between two different aldehydes or ketones generally give a mixture of all four possible products. A mixed reaction can be successful, however, if one of the two partners is an unusually good donor (ethyl aceto-acetate, for instance) or if it can act only as an acceptor (formaldehyde and benzaldehyde, for instance). Intramolecular aldol condensations of 1,4- and 1,5-diketones are also successful and provide a good way to make five-and six-inembered rings. 

Three tactical approaches were surveyed in the evolution of our program. As outlined in Scheme 2.7, initially the aldol reaction (Path A) was performed direcdy between aldehyde 63 and the dianion derived from tricarbonyl 58. In this way, it was indeed possible to generate the Z-lithium enolate of 58 as shown in Scheme 2.7 which underwent successful aldol condensation. However, the resultant C7 P-hydroxyl functionality tended to cyclize to the C3 carbonyl group, thereby affording a rather unmanageable mixture of hydroxy ketone 59a and lactol 59b products. Lac-tol formation could be reversed following treatment of the crude aldol product under the conditions shown (Scheme 2.7) however, under these conditions an inseparable 4 1 mixture of diastereomeric products, 60 (a or b) 61 (a or b) [30], was obtained. This avenue was further impeded when it became apparent that neither the acetate nor TES groups were compatible with the remainder of the synthesis. 

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... 

The aldol formed by the aldol reaction, especially if heated, can react further. The heating causes dehydration (loss of H2O), and the overall reaction involving an aldol reaction followed by dehydration is the aldol condensation. The product of an aldol condensation, favored by the presence of extended conjugation, is an a,(3-unsaturated aldehyde (an enal) or ketone. The mechanism for dehydration (Figure 11-13) begins where the mechanism of the aldol reaction (Figure 11-12) ends. This process works better if extended conjugation results. The aldol reaction and condensation are reversible. 

Aldol condensations are reversible, and with ketones the equilibrium is unfavorable for the ondensation product. To effect condensations of ketones, the product is continuously removed from he basic catalyst. )3-Hydroxycarbonyl compounds are readily dehydrated to give a,j3-unsaturated arbonyl compounds. With Ar on the carbon, only the dehydrated product is isolated. 

Aldol condensation with aldehydes and ketones gives hydroxy compounds (265 — 267) which usually spontaneously lose water (by a reverse Michael addition) to give unsaturated compounds (268). 

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. 

The reaction is reversible, but the equilibrium can be shifted to the point of complete reduction by removal of the acetaldehyde with a stream of dry hydrogen or nitrogen. This has the additional advantage of preventing side reactions such as an aldol condensation between the original aldehyde and acetaldehyde. The method of reduction with aluminum ethoxide was found applicable to several aldehydes but to only a few ketones of special types. 

The use of enzymes for the aldol reaction complements traditional chemical approaches. In the early twentieth century a class of enzymes was recognized that catalyzes, by an aldol condensation, the reversible formation of hexoses from their three carbon components.3 The lyases that catalyze the aldol reaction, are referred to as aldolases. More than 30 aldolases have been characterized to date. These aldolases are capable of stereospecifically catalyzing the reversible addition of a ketone or aldehyde donor to an aldehyde acceptor. Two distinct mechanistic classes of aldolases have been identified (Scheme 5.1).4... 

An aldol condensation involves a series of reversible equilibrium steps. In general, formation of product is favored by the dehydration of the B-hydroxy ketone to form a conjugated enone. Here, dehydration to form conjugated product can t occur. In addition, the B C equilibrium favors B because of steric hindrance. 

The same distinctions may be drawn for base catalysed reactions. Thus, for example, the reverse of the aldol condensation reaction is dependent only on the concentration of hydroxide ions, i.e. it is a specific base catalysed reaction while the base catalysed bromination of a ketone is an example of a general base catalysed reaction. 

These carbanions can be formed (Figure 5.8) by proton abstraction from ketones resulting in aldol condensations, by proton abstraction from acetyl CoA, leading to Claisen ester condensation, and by decarboxylation of p-keto acids leading to a resonance-stabilised enolate, which can likewise add to an electrophilic centre. It should be noted that the reverse of decarboxylation also leads to formation of a carbon—carbon bond (this is again a group transfer reaction involving biotin as the carrier of the activated CO2 to be transferred). 

Aldol condensations of zinc enolates under conditions of thermodynamic control are reasonably discussed in terms of the relative stability of the two chelated aldolates (19), which leads to the syn aldol, and (20), which leads to the anti aldol. If R is larger than R, the anti chelate, with R and R trans in a six-atom ring, is expected to be the more stable form. Heathcock has noted that the most common mechanism for equilibration of aldolate stereochemistry is reverse aldolization (reversal of equation 29). Aldolates obtained by reaction of an enolate with ketone substrates are expected to undergo reverse aldolization at a faster rate than those obtained with aldehyde substrates, in part for steric reasons. Similarly, aldolates derived from ketone enolates are expected to undergo reverse aldolization at a faster rate than those derived from the more basic ester or amide enolates. 

It is not clear whether enolization is avoided under the lithium-free, high-concentration conditions, or whether it occurs reversibly enough to permit eventual conversion of the ketone to the alkene. However, the most successful procedures involve alkoxide bases (159, 168-170) or require the presence of excess phosphonium salt (171). Proton exchange and reversible enolate formation are likely under these conditions, and aldol condensation pathways would also be reversible when potassium or sodium bases are used. Thus, excellent yields of alkenes are possible with the most hindered substrates, provided that other pathways for irreversible enolate decomposition are not available. 

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