Aldolization thermodynamics

In an intramolecular aldol condensation of a diketone many products are conceivable, since four different ends can be made. Five- and six-membered rings, however, wUl be formed preferentially. Kinetic or thermodynamic control or different acid-base catalysts may also induce selectivity. In the Lewis acid-catalyzed aldol condensation given below, the more substituted enol is formed preferentially (E.J. Corey, 1963 B, 1965B). 

In the condensation of 2-butanone with citral, if the reaction temperature is kept at 0—10°C, higher yields of the isomethyl pseudoionones, which are the more thermodynamically stable isomers, are obtained. The aldol iatermediates have more time to equilibrate to the more stable isomers at the lower temperature. The type of base used and a cosolvent such as methanol are also very important ia getting a high yield of the isomethyl pseudoionones (168). 

The aldol addition can be carried out under either ofitwo broad sets of conditions, with the product being determined by kinetic factors undenone set of conditions and by thermodynamic factors under the other. To achieve kinetic control, the enolate that is to... 

For the other broad category of reaction conditions, the reaction proceeds under conditions of thermodynamic control. This can result from several factors. Aldol condensations can be effected for many compounds using less than a stoichiometric amount of base. Under these conditions, the aldol reaction is reversible, and the product ratio will be determined by the relative stability of the various possible products. Conditions of thermodynamic control also permit equilibration among all the enolates of the nucleophile. The conditions that permit equilibration include higher reaction temperatures, protic solvents, and the use of less tightly coordinating cations. 

When the aldol reaction is carried Wt under thermodynamic conditions, the product selectivity is often not as high as under kinetic conditions. All the regioisomeric and stereoisomeric enolates may participate as nucleophiles. The adducts can return to reactants, and so the difference in stability of the stereoisomeric anti and syn products will determine the product composition. 

Trifluoromethyl alkyl ketones also undergo directed aldol condensations under thermodynamic conditions in the presence of piperidine and acetic acid [2, d] Under these reaction conditions, the product suffers a facile dehydration to form the unsaturated trifluoromethyl ketones (equations 2 and 3)... 

Various competitive reactions can reduce the yield of the desired Michael-addition product. An important side-reaction is the 1,2-addition of the enolate to the C=0 double bond (see aldol reaction, Knoevenagel reaction), especially with a ,/3-unsaturated aldehydes, the 1,2-addition product may be formed preferentially, rather than the 1,4-addition product. Generally the 1,2-addition is a kinetically favored and reversible process. At higher temperatures, the thermodynamically favored 1,4-addition products are obtained. 

Steric hindrance also seems to provide information as to whether yn-aldolates or cmb-adducts predominate in the equilibrium. Considering the chair conformations of the syn- and owz -aldolates, the latter seems to be thermodynamically more stable since it avoids the axial position of the substituent Y which it occupies in the s> -isomer. Indeed, the azzb-diastereomcr is favored in most reversible aldol additions ... 

Thermodynamically controlled aldol additions leading to the formation of nonracemic products are rare and will be discussed below. 

Figure 10.24 Diastereoselectivity in FruA catalyzed aldol additions to 3-hydroxyaldehydes under thermodynamic control, and synthesis of L-fucose derivatives based on thermodynamic preference.

Figure 10.32 Applications of bidirectional chain extension for the synthesis of disaccharide mimetics and of annulated and spirocyclic oligosaccharide mimetics using tandem enzymatic aldol additions, including racemate resolution under thermodynamic control.

Owing to the fully reversible equilibrium nature of the aldol addition process, enzymes with low diastereoselectivity will typically lead to a thermodynamically controlled mixture of erythro/threo-isomers that are difficult to separate. The thermodynamic origin of poor threo/erythro selectivity has most recently been turned to an asset by the design of a diastereoselective dynamic kinetic resolution process by coupling of L-ThrA and a diastereoselective L-tyrosine decarboxylase (Figure 10.47)... 

The general mechanistic features of the aldol addition and condensation reactions of aldehydes and ketones were discussed in Section 7.7 of Part A, where these general mechanisms can be reviewed. That mechanistic discussion pertains to reactions occurring in hydroxylic solvents and under thermodynamic control. These conditions are useful for the preparation of aldehyde dimers (aldols) and certain a,(3-unsaturated aldehydes and ketones. For example, the mixed condensation of aromatic aldehydes with aliphatic aldehydes and ketones is often done under these conditions. The conjugation in the (3-aryl enones provides a driving force for the elimination step. 

The aldol reaction can be applied to dicarbonyl compounds in which the two groups are favorably disposed for intramolecular reaction. Kinetic studies on cyclization of 5-oxohexanal, 2,5-hexanedione, and 2,6-heptanedione indicate that formation of five-membered rings is thermodynamically somewhat more favorable than formation of six-membered rings, but that the latter is several thousand times faster.170 A catalytic amount of acid or base is frequently satisfactory for formation of five- and six-membered rings, but with more complex structures, the techniques required for directed aldol condensations are used. 

A novd example of a catalytic enantioselective domino process1201 is the inter-intramolecular nitro-aldol reaction described by Shibasaki et al which generates substituted indanones. As catalyst a praseodym-heterobimetallic complex with binaph-thol as chiral ligand is employed. Treatment of keto-aldehyde 41 with nitromethane in the presence of the catalyst 46 at -40 °C and successive warming to room temperature affords diredly the produd 42 in an overall yield of 41 % and 96 % ee after several recrystallizations (scheme 9). As intermediates the nitromethane adduct 43 and the hemiacetal 44 can be proposed. In a second aldol reaction 44 leads to 45 which isomerizes to the thermodynamically more stable epimer 42. 

Diastereomeric excesses of up 56% have been claimed for the preparation of a-amino-P-hydroxy acids via the aldol condensation of aldehydes with f-butyl N-(diphenylmethylene)glycinate [63]. It might be expected that there would be thermodynamic control of the C-C bond formation influenced by the steric requirements of the substituents, but the use of cinchoninium and cinchonidinium salts lead to essentially the same diastereoselectivity. The failure of both tetra-n-butylammo-nium and benzyltriethylammonium chloride to catalyse the reaction is curious. 

It has been well established that either kinetic or thermodynamic principles can be employed in the aldol process to define product stereochemistry. When conditions are chosen such that the condensation process is rendered reversible, the more stable threo metal aldolate complex 3 with diequatorial substituents Rj and R3 is usually the dominant diastereomer observed (2,5,14). 

In a frequently cited investigation, House studied the condensations of a variety of metal enolates with aldehydes under conditions of thermodynamic control (14). In the cyclohexanone enolate-benzaldehyde condensation (eq. [5]), it was observed that the zinc enolate (14°C, 5 min) afforded a 5 1 ratio of aldol adducts 5T and... 

R3 R2 and R2 Ri gauche interactions however, for the same set of substituents, an increase in the steric requirements of either Rj or R3 will influence only one set of vicinal steric interactions (Rj R2 or R3 R2). Some support for these conclusions has been cited (eqs. [6] and [7]). These qualitative arguments may also be relevant to the observed populations of hydrogen- and nonhydrogen-bonded populations of the aldol adducts as well (see Table 1, entries K, L). Unfortunately, little detailed information exists on the solution geometries of these metal chelates. Furthermore, in many studies it is impossible to ascertain whether the aldol condensations between metal enolates and aldehydes were carried out under kinetic or thermodynamic conditions. Consequently, the importance of metal structure and enolate geometry in the definition of product stereochemistry remains ill defined. This is particularly true in the numerous studies reported on the Reformatsky reaction (20) and related variants (21). 

A large number of studies have addressed the condensation of cyclic ketones with both aliphatic and aromatic aldehydes under conditions that reflect both thermodynamic (cf. Table 2) and kinetic control of stereochemistry. The data for cyclohexanone enolates are summarized in Table 8. Except for the boryl enolates cited (6), the outcome of the kinetic aldol process for these enolates... 

Extensive studies have been carried out on the metal enediolates of carboxylic acids and the influence of substrate structure on kinetic aldol diastereoselection (eq. [26]). For all but the most sterically demanding substituents (Rj = t-C4H9, mesityl, 1-adamantyl) the condensations exhibit only modest threo diastereoselection (Table 13). The reader is referred to Table 4 for the analogous thermodynamically controlled aldol data. 

See Table 4, entry D, for the analogous thermodynamically controlled aldol condensation. 

The first chapter in this volume is a particularly timely one given the recent surge of activity in natural product synthesis based upon stereocontrolled Aldol Condensations. D. A. Evans, one of the principal protagonists in this effort, and his associates, J. V. Nelson and T. R. Taber, have surveyed the several modem variants of the Aldol Condensation and discuss models to rationalize the experimental results, particularly with respect to stereochemistry, in a chapter entitled Stereoselective Aldol Condensations. The authors examine Aldol diastereoselection under thermodynamic and kinetic control as well as enantioselection in Aldol Condensations involving chiral reactants. 

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