Aldol reaction thermodynamic control

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. 

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. 

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. 

At low temperatures, the Zn enolate derived from dimethyl 3-methylpent-2-endioate 39 reacts with aldehydes in a one-pot aldolisation and cyclisation to yield the syn-dihydropyran-2-one 40. At the higher temperatures necessary to achieve reaction with a-aminoaldehydes, the anri-products predominate indicating thermodynamic control (Scheme 22) <99T7847>. An aldol condensation features in the asymmetric synthesis of phomalactone. The key step is the reaction of the enolate of the vinylogous urethane 41 with crotonaldehyde which occurs with 99% syn-diastereoselectivity and in 99% ee (Scheme 23) <99TL1257>. 

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. 

Whereas the thermodynamic route described above relied on reagent control to establish the spongistatin C19 and C21 stereocentres, the discovery of highly stereoselective 1,5-anti aldol reactions of methyl ketones enabled us to examine an alternative,16 substrate-based stereocontrol route to 5. Regioselective enolisation of enantiomerically pure ketone 37, derived from a readily available biopolymer, gave end... 

Very recently, Belokon and North have extended the use of square planar metal-salen complexes as asymmetric phase-transfer catalysts to the Darzens condensation. These authors first studied the uncatalyzed addition of amides 43a-c to aldehydes under heterogeneous (solid base in organic solvent) reaction conditions, as shown in Scheme 8.19 [47]. It was found that the relative configuration of the epoxyamides 44a,b could be controlled by choice of the appropriate leaving group within substrate 43a-c, base and solvent. Thus, the use of chloro-amide 43a with sodium hydroxide in DCM gave predominantly or exclusively the trans-epoxide 44a this was consistent with the reaction proceeding via a thermodynamically controlled aldol condensation... 

Substituted 3-phenylsulfonyl-5-hydroxymethyl-THFs (e.g. 44) have been prepared chemo-, regio-, and diastereo-selectively via reaction of a y,5-cpoxycarbanion with aldehydes, RCHO.156 The initial aldol-type addition is non-diastereoselective, but reversible. The subsequent cyclization is selective, and exerts overall thermodynamic 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 thermodynamic control of conjugate addition allows even enals that are very electrophilic at the carbonyl carbon to participate successfully. Any aldol reaction, which must surely occur, is reversible and 1,4-addition eventually wins out Acrolein combines with this five-membered diketone under very mild conditions to give a quantitative yield of product, The mechanism is analogous to that shown above,... 

Two dialkyl boranes arc in common use. The bicyclic 9-borabicyclo[3.3.1] nonane (9-BBN), introduced in Chapter 34 as a reagent for diastereoselcctive aldol reactions, is a stable crystalline solid. This is very unusual for an alkyl borane and makes it a popular reagent. It is made by hydroboration of cyclo-octa-1,5-diene. The second hydroboration is fast because it is intramolecular but the third would be very slow. The regioselectivity of the second hydroboration is under thermodynamic control. 

P-Keto esters and -keto amides, each substituted between the two carbonyl units with a 2-[2-(tri-methylsilyl)methyl] group, also undergo Lewis acid catalyzed, chelation-controlled cyclization. When titanium tetrachloride is used, only the product possessing a cis relationship between the hydroxy and ester (or amide) groups is product yields range from 65 to 88% (Table 8). While loss of stereochemistry in the product and equilibration of diastereomers could have occurred via a Lewis acid promoted retro aldol-aldol sequence, none was observed. Consequently, it is assumed that the reactions occur under kinetic, rather than thermodynamic, control. In contrast to the titanium tetrachloride promoted process, fluoride-induced cyclization produces a 2 1 mixture of diastereomeric products, and the nonchelating Lewis acid BF3-OEt2 leads to a 1 4.8 mixture of diastereomers. 

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). 

When 2-azidoaldehydes are used as substrates in the RAMA-catalyzed aldol reaction with dihydroxy acetone phosphate (DHAP), the azidoketones thus obtained can be reduced into the corresponding primary amines. Subsequent equilibration to imine intermediates, followed by reduction, generates the corresponding pyrrolidines (Scheme 13.16) [22,33]. 1,4-Dideoxy-1,4-imino-D-arabinitol 11 was prepared from azidoacetaldehyde. Both 2R,5R) and 2S,5R)-bis(hydroxymethyl)-(3R,4R)-dihydroxypyrrolidine (12 and 13) were derived from racemic 2-azido-3-hydroxypropanol. The aldol product resulting from kinetic control was converted into the (2R,2R) derivative 12, whereas the product resulting from thermodynamic control gave the... 

Types of aldol reaction under thermodynamic control... 

With 1,5-dicarbonyl compounds, two modes of ring closure are often possible. In the example shown below, the more stable (higher-substituted) enone is formed preferentially (thermodynamic control). The observed distribution of products is the result of equilibration via retro-aldol reaction. 

Changing from thermodynamic to kinetic conditions (LDA), it is possible to carry out crossed aldol reactions with good control, as exemplified below. 

---