Aldol additions thermodynamic control

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... 

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. 

Scheme 16. Thermodynamically controlled FruA-catalyzed aldol additions to 3-hydroxyaldehydes...

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. 

The syn diastereoselectivity of the cyclisations most likely arises from kinetic control in which chelation of Sm(III) to the 1,3-dicarbonyl controls the orientation of the ketone prior to addition of the organosamarium (Scheme 5.79). However, thermodynamic control in which the diastereo-isomeric products equilibrate by a retro-aldol-aldol sequence may operate in... 

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,... 

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). 

The bulk of this chapter has dealt with kinetically controlled aldol addition processes. However, one of the characteristics of aldol reactions involving Group I and Group II enolates is that they are frequently subject to ready reversibility (see Volume 2, Chapter 1.5). Under appropriate conditions, aldol reactions can be carried out under conditions of thermodynamic control. Furthermore, it is usually found that the stereoisomer ratio formed under equilibrating conditions is quite different from the kinetic isomer mixture. 

Dehydration of the aldol products of a Refoimatsky reaction does not normally occur under the usual reaction conditions but is often accomplished in a separate step to prepare unsaturated esters. Acid-promoted dehydration of -hydroxy esters can give significant amounts of nonconjugated unsaturated esters by either kinetic or thermodynamic control. Mirrington and cowoikers found that acetates can be prepared directly from Refoimatsky reaction mixtures by addition of acetyl chloride. Base-promoted elimination of the acetates produced conjugated esters in high yield. For the reaction shown in Scheme 14, the thermodynamic ratio of products (32) (33) is 40 60 and four different acid-promoted dehydration procedures gave at best a 68 32 ratio of products. ... 

In the presence of coordinating additives such as HMPA, DMPU or TMEDA, the trend outlined in Scheme 3.4 may not hold [36,41-43]. For example, in the presence of HMPA, LDA deprotonation of 3-pentanone affords a 5 95 mixture of E(0)- and Zf 0)-enoiates under conditions of thermodynamic control (equilibration by reversible aldol addition) [39,41], but a 50 50 mixture under kinetic control [41,42]. 

Thermodynamic control. Note that it is also possible for the aldolate adduct to revert to aldehyde and enolate, and equilibration to the thermodynamic product may afford a different diastereomer (the anti aldolate is often the more stable). The tendency for aldolates to undergo the retro aldol addition increases with the acidity of the enolate amides < esters < ketones (the more stable enolates are more likely to fragment), and with the steric bulk of the substituents (bulky substituents tend to destabilize the aldolate and promote fragmentation). On the other hand, a highly chelating metal stabilizes the aldolate and retards fragmentation. The slowest equilibration is with boron aldolates, and increases in the series lithium < sodium < potassium, and (with alkali metal enolates) also increases in the presence of crown ethers. ... 

Na, and K) enolates. Lithium enolates are not ideal nucleophiles for thermodynamically controlled conjugate addition. Better results are often observed with sodium or potassium enolates, which are more dissociated and thus more likely to revert. Litnium binds strongly to oxygen and so tends to prevent reversible aldol addition, which leads to loss of conjugate addition product. Potassium f-butoxide is the ideal base for this example as it is hindered and so will not attack the ester but is basic enough to deprotonate the ketone to a certain extent. 

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