Aldol reaction kinetic control

Control of Regioselectivity and Stereoselectivity. The recognition by Ireland and co-workers that Hexamethylphosphoric Triamide has a profound effect on the stereochemistry of lithium enolates has led to the examination of the effects of other additives, as the ability to control enolate stereochemistry is of utmost importance for the stereochemical outcome of aldol reactions. Kinetic deprotonation of 3-pentanone with Lithium 2,2,6,6-Tetramethylpiperidide at 0 C in THF containing varying amounts of HMPA or TMEDA was found to give predominantly the (Z)-enolate at a base ketone additive ratio of ca. 1 1 1, whereas with a base.ketone.additive ratio 1 0.25 1, formation of the ( )-enolate was favored (Table I). This remarkable result contrasts with those cases where HMPA base ratios were varied towards larger amounts of HMPA, which favored formation of the (Z)-enolate. ... 

Stannous triflate is an efficient catalyst for aldol-type condensations [ 23, 124, 125 Under conditions of kinetic control, it provides excellent diastereo-selectivity in various cross-aldol reactions (equation 61)... 

The aldol reaction is also important in the synthesis of more complex molecules and in these cases control of both regiochemistry and stereochemistry is required. In most cases, this is accomplished under conditions of kinetic control. In the sections that follow, we discuss how variations of the basic mechanism and selection of specific reagents and reaction conditions can be used to control product structure and stereochemistry. 

Aldol Reactions of Lithium Enolates. Entries 1 to 4 in Scheme 2.1 represent cases in which the nucleophilic component is a lithium enolate formed by kinetically controlled deprotonation, as discussed in Section 1.1. Lithium enolates are usually highly reactive toward aldehydes and addition occurs rapidly when the aldehyde is added, even at low temperature. The low temperature ensures kinetic control and enhances selectivity. When the addition step is complete, the reaction is stopped by neutralization and the product is isolated. 

The first element of stereocontrol in aldol addition reactions of ketone enolates is the enolate structure. Most enolates can exist as two stereoisomers. In Section 1.1.2, we discussed the factors that influence enolate composition. The enolate formed from 2,2-dimethyl-3-pentanone under kinetically controlled conditions is the Z-isomer.5 When it reacts with benzaldehyde only the syn aldol is formed.4 The product stereochemistry is correctly predicted if the TS has a conformation with the phenyl substituent in an equatorial position. 

Silyloxy)alkenes were first reported by Mukaiyama as the requisite latent enolate equivalent to react with aldehydes in the presence of Lewis acid activators. This process is now referred to as the Mukaiyama aldol reaction (Scheme 3-12). In the presence of Lewis acid, anti-aldol condensation products can be obtained in most cases via the reaction of aldehydes and silyl ketene acetals generated from propionates under kinetic control. 

V. KINETICALLY CONTROLLED ALDOL DIASTEREOSELECTION ACHIRAL REACTION PARTNERS... 

The ultimate goal of designing highly enantioselective aldol condensations demands that all stereochemical aspects of the bond construction process be kinetically controlled. Over the past 5 years, this objective has stimulated a great deal of research, and a wealth of new information is now becoming available on the important kinetic stereochemical control elements and possible transition state geometries for this reaction. 

Earlier studies had demonstrated that such enolates would participate in aldol condensations with aldehydes however, the stereochemical aspects of the reaction were not investigated (68). For the cases summarized in Table 25, the zirconium enolates were prepared from the corresponding lithium enolates (eq. [54]). Control experiments indicated that no alteration in enolate geometry accompanies this ligand exchange process, and that the product ratio is kinetically controlled (35). From the cases illustrated, both ( )-enolates (entries A-E) and (Z)-enolates (entries F-H) exhibit predominant kinetic erythro diastereoselection. Although a detailed explanation of these observations is clearly speculative, certain aspects of a probable... 

In contrast to the "classical solution" we have just discussed, we will now consider the aldol condensation -one of the most important carbon-carbon bond formation reactions [3], in both the laboratory and Nature l - as an example of the "contemporary solution" to the problem of acyclic stereoselection. As a reversible reaction, the design of highly stereoselective aldol and related reactions demands that all the stereochemical aspects involved in the C-C bond formation are kinetically controlled. 

Darzens reaction of (-)-8-phenylmethyl a-chloroacetate (and a-bromoacetate) with various ketones (Scheme 2) yields ctT-glycidic esters (28) with high geometric and diastereofacial selectivity which can be explained in terms of both open-chain or non-chelated antiperiplanar transition state models for the initial aldol-type reaction the ketone approaches the Si-f ce of the Z-enolate such that the phenyl ring of the chiral auxiliary and the enolate portion are face-to-face. Aza-Darzens condensation reaction of iV-benzylideneaniline has also been studied. Kinetically controlled base-promoted lithiation of 3,3-diphenylpropiomesitylene results in Z enolate ratios in the range 94 6 (lithium diisopropylamide) to 50 50 (BuLi), depending on the choice of solvent and temperature. ... 

Why is only one of these products formed To understand this, you must recognize that aldol reactions are reversible and therefore are subject to equilibrium rather than kinetic control (Section 10-4A). Although the formation of 10 is mechanistically reasonable, it is not reasonable on thermodynamic grounds. Indeed, while the overall A/7° (for the vapor) calculated from bond energies is —4 kcal mole 1 for the formation of the aldol, it is +20.4 kcal mole-1 for the formation of 1Q.2 Therefore, the reaction is overwhelmingly in favor of the aldol as the more stable of the two possible products. 

Furthermore, since the aldol reaction is reversible, if any of these higher energy products were formed, they could open back up under the reaction conditions. The exclusive formation of P is an example of kinetic as well as thermodynamic control as the more stable product is formed fastest. 

Triethylgallium has been used as a non-nucleophilic base to generate enolates from ketones, both cyclic and acyclic, without forming carbonyl addition products.290 The gallium enolates can then be C-benzoylated, and can participate in aldol reactions. Unsymmetrical ketones preferentially enolized at the methylene, under kinetic control. 

Another important contribution is to the regioselectivity of enolate formation from unsym-metrical ketones. As we established in chapter 13, ketones, particularly methyl ketones, form lithium enolates on the less substituted side. These compounds are excellent at aldol reactions even with enolisable aldehydes.15 An application of both thermodynamic and kinetic control is in the synthesis of the-gingerols, the flavouring principles of ginger, by Whiting.16... 

The problem of diastereoselective aldol addition has been largely solved48,108). Under kinetic control Z enolates favor erythro adducts and E enolates the threo diastereomers, although exceptions are known. This has been explained on the basis of a six-membered chair transition state in which the faces of the reaction partners are oriented so as to minimize 1,3 axial steric interactions 481108). This means that there is no simple way to prepare erythro aldols from cyclic ketones, since the enolates are geometrically fixed in the E geometry. 

The aldol reaction catalyzed by Ab33F12 is outlined in Scheme 5.65. Regardless of the stereochemistry at C(2) of the aldehyde substrate shown (Scheme 5.65), its antibody catalyzed reaction with acetone resulted in a diastereoselective addition of acetone to the S/ -facc of the aldehyde. The products were formed with similar yields, and thus kinetic resolution was observed. However, the degree of facial stereochemical control of the reaction is surprising, since no stereochemical information was built into the hapten. For the... 

It is noteworthy that - in principle - other cyclization products can also result from the diketone 129. Evidently, conjugation to the aromatic ring stabilized the enolate formed by deprotonation of the acetyl side chain at C-1 of 129 in such a way that this anion reacted as the nucleophile in kinetically controlled aldol reactions. 

The stereoselectivities seem to be kinetically controlled. In fact, the ee of the aldol product was constant during the course of the reaction. Thus, we have succeeded in performing the first catalytic asymmetric aldol reaction between aldehydes and unmodified ketones by using heterobimetallic or heteropolymetallic catalysts. Several reactions have already been synthetically useful especially for tertiary aldehydes, leading to the catalytic asymmetric synthesis of key intermediates en route to natural products [63]. Further studies are currently in progress. 

The mechanism of the reaction is well-known. The first step is formation of a carbanion, followed by nucleophile addition to the carbonyl carbon atom halo-hydrin alcoholates are produced finally, ring-closure takes place by intramolecular substitution. The stereochemistry of the reaction is much disputed the reason why a unified viewpoint has not emerged is that the configuration of the end-product is influenced by the structure of the starting compound (including steric hindrance), the base employed, and solvation by the solvent, sometimes in an unclear manner. The stereochemical course of the reaction is controlled by the kinetic and thermodynamic factors in the second step the structure of the oxirane formed is decided by the reversibility of the aldolization and the reaction rate of the ring-closure. 

Fructose-1,6-diphosphate (FDP) aldolase catalyzes the reversible aldol addition of DHAP and D-glyceraldehyde-3-phosphate (G3P) to form D-fructose-1,6-diphosphate (FDP), for which eq 10 M in favor of FDP formation (Scheme 13.9). RAMA accepts a wide range of aldehyde acceptor substrates with DHAP as the donor to stereospecifically generate 3S,4S vicinal diols (Scheme 13.8). The diastereoselectivity exhibited by FDP aldolase depends on the reaction conditions. Racemic mixtures of non-natural aldehyde acceptors can be partially resolved only under conditions of kinetic control. When six-membered hemiacetals can be formed, racemic mixtures of aldehydes can be resolved under conditions of thermodynamic control (Scheme 13.10). 

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