Aldol reaction geometry

Non-chelation aldol reactions proceed via an "open" transition state to give syn aldols regardless of enolate geometry. 

The stereochemical outcome of the Michael addition reaction with substituted starting materials depends on the geometry of the a ,/3-unsaturated carbonyl compound as well as the enolate geometry a stereoselective synthesis is possible. " Diastereoselectivity can be achieved if both reactants contain a stereogenic center. The relations are similar to the aldol reaction, and for... 

The diastereoselectivity of this reaction contrasts dramatically with the generally low selectiv-ities observed for aldol reactions of lithium enolates of iron acyls. It has been suggested thal this enolate exists as a chelated species48 the major diastereomer produced is consistent with the transition state E which embodies the usual antiperiplanar enolate geometry. 

Boron enolates are often used for aldol reactions. Boron enolates are usually prepared from the corresponding carbonyl compounds, tertiary amine, and a boron source (e.g., dibutylboron triflates). The aldol reactions proceed via a six-membered transition state to give high diastereo-selectivity which depends upon the geometry of the boron enolates. 

Figure 1. Kinetic parameters for the selection of antibody-catalyzed aldol and retro-aldol reactions, reflecting the biocatalyst s ability to accept substrates that differ clearly with respect to their molecular geometry. No background reaction was observed for the self-condensation of cyclopentanone. The indicated value for cyclopentanone addition to pentanal was estimated using the published kuncat value of 2.28 X 10 M s for the aldol addition of acetone to an aldehyde. Reproduced with permission of the authors and the American Association for the Advancement of Science.

In addition to the structural effects due to the geometry of a substituted magnesium enolate, the stereochemistry of the reaction with a chiral aldehyde can be controlled, as described in equation 85. The aldol reaction based on the addition of magnesium enolate 56 to aldehyde 55 has been applied to the synthesis of monensin. The chiral center in the aldehyde induces the preferential approach of one diastereotopic face of the aldehyde by... 

Fig. 10 Why decarboxylation is inherently slower than an analogous retro-aldol reaction (itself a slow reaction). The angular distortion for sp2 to sp geometry is much larger than for sp3 to sp2 geometry, and the energy cost is proportional to the square of the angular distortion. Reproduced with permission from ref.9...

Asymmetric aldol reactions.4 The borane complex 3 can also serve as the Lewis acid catalyst for the aldol reaction of enol silyl ethers with aldehydes (Mukaiyama reactions).5 Asymmetric induction is modest (80-85% ee) in reactions of enol ethers of methyl ketones, but can be as high as 96% ee in reactions of enol ethers of ethyl ketones. Moreover, the reaction is syn-selective, regardless of the geometry of the enol. However, the asymmetric induction is solvent-dependent, being higher in nitroethane than in dichloromethane. 

Reactive immunogens incorporating elements of transition state mimicry have delivered even more efficient catalysts. Compound 17 (Scheme 4.8), for example, contains a tetrahedral sulfone to mimic the geometry of the acceptor site during C-C bond formation. It was used to produce antibodies that accelerate the retro-aldol reaction of 18 with a kcat/ Km of 3 x 105 m-1 s-1 and a rate acceleration over background (kcat/kuncat) °f 2 x 108 [59]. These are impressive results for a catalyst never optimized by natural selection. 

Aldol reaction,6 This triflate is an effective catalyst for an aldol-type reaction between silyl enol ethers and acetals at -78°. The reaction shows moderate to high svn-selectivity regardless of the geometry of the enol ether. 

Similar mechanisms account for the double bond geometry obtained in aldol reactions followed by dehydration to give a,(3-unsaturated carbonyl compounds. Any Z-alkene that is formed is equilibrated to Eby reversible Michael addition during the reaction. 

The cyclic transition state explains how enolate geometry controls the stereochemical outcome of the aldol reaction. But what controls the geometry of the enolate For lithium enolates of ketones the most important factor is the size of the group that is not enolized. Large groups force the enolate to adopt the cis geometry small groups allow the fram-enolate to form. Because we can t separate the lithium enolates, we just have to accept that the reactions of ketones with small R will be less dias ter eoselective. 

The six-member ed transition state for the reaction of an allylic borane or boron ate is very reminiscent of the cyclic transition state for the aldol reaction you met in Chapter 34. In this case the only change is to replace the oxygen of the enolate with a carbon to make the allyl nucleophile. The transition state for the aldol reaction was a chair and the reaction was stereospecific so that the geometry of the enolate determined the stereochemistry of the product aldol. The same is true in these reactions. -Crotyl boranes (or boronates) give anti homoallylic alcohols and Z-crotyl boranes (or boronates)... 

Diastereoselecttve aldol reactions. The diastereoselectivity in the Lewis acid-catalyzed aldol reaction of chiral oi-hydroxy aldehydes is independent of the geometry of the enol silyl ether. Also, the reaction does not involve prior Si-Ti or Si-Sn exchange. 

Sunoj also predicted the enantioselectivity offered by a series of bicyclic proline analogs in the aldol reaction of acetone with p-nitrobenzaldehyde. The two best performing catalysts are 59 and 60 both are predicted to give an ee greater than 90 percent, which exceeds the selectivity afforded by proline itself. The TS geometries all display the Houk-List characteristics. 

Such p-silyl enolate intermediates also react with aldehydes with high diastereoselectivity with respect to both new chiral centers being created, the relative stereochemistry in the aldol reaction being dependent upon the original geometry of the enolate double bond (Scheme 13). This aldol reaction has... 

---