Transition states geometry, aldol reaction

Manufacture. Cinnamaldehyde is routinely produced by the base-cataly2ed aldol addition of ben2aldehyde /7(9(9-with acetaldehyde [75-07-0], a procedure which was first estabUshed in the nineteenth century (31). Formation of the (H)-isomer is favored by the transition-state geometry associated with the elimination of water from the intermediate. The commercial process is carried out in the presence of a dilute sodium hydroxide solution (ca 0.5—2.0%) with at least two equivalents of ben2aldehyde and slow addition of the acetaldehyde over the reaction period (32). 

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. 

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)... 

Denmark, S. E., Lee, W. Investigations on Transition-State Geometry in the Lewis Acid- (Mukaiyama) and Fluoride-Promoted Aldol Reactions. J. Org. Chem. 1994, 59, 707-709. 

With the Zr-BINOL catalyst, the anti-aldol adduct was obtained independently on the geometry of the employed silyl enolates E- and Z-(19) (Equation 5) [8]. These features, the detailed NMR analyses and theoretical calculations suggest the acyclic transition state in the reaction (Figure 15.1). 

Tollens addition between HCOH and CH3CHO and the intermolecular aldol addition of CH3CHO have been used as reaction models to study, by quantum-mechanical methods, the importance of water in aldol-like reactions carried out in aqueous media [22]. Water accelerates the addition process because it coordinates the reactants, making the geometry of the initial complex more suitable for the reaction, and stabilizes the transition state of the reaction. Water therefore acts as a catalyst. 

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

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. 

Type and geometry of substrate coordiation plays a key role in the final stereochemistry of the product [245,246]. Organolanthanide catalyzed condensation of carbonyl compounds with silylenolethers, known as the Mukaiyama addition reaction, is assumed to contain a 6-membered transition state with Ln-O linkages [247]. Formation of a 6-membered organolanthanide aldolate moiety was structurally proven in the reaction of Cpf LnR with ketones (Sect. 6.2.3) [248]. 

The stereochemical outcome was rationalized by a Zimmerman-Traxler type transition state 45.64 Assuming the titanium enolate of 42 has a Z-geometry and forms a 7-membered metallacycle with a chairlike conformation, a model can be proposed where a second titanium metal coordinates to the indanol and aldehyde oxygens in a 6-membered chairlike conformation. The involvement of two titanium centers was supported by the fact that aldehydes that were not precomplexed with titanium tetrachloride did not react (Scheme 24.7).63 Ghosh and co-workers further hypothesized that a chelating substituent on the aldehyde would alter the transition state 46 and consequently the stereochemical outcome of the condensation, leading to. vyn-aldol products 47.64 Indeed, reaction of the titanium enolate of 42 with bidentate oxyaldehydes proceeded with excellent. s v -diastereo-selectivity (Scheme 24.8).65... 

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. 

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 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. 

It seems likely that the reaction proceeds through a prototropic ene reaction pathway, a pathway that has not been previously recognized as a possible mechanism in the Mukaiyama aldol condensation. Usually an acyclic antiperiplanar transition-state model has been used to explain the formation of the syn diastereomer from either ( )- or (Z)-silyl enol ethers [91]. The cyclic ene mechanism, however, now provides another rationale for the syn diastereoselectivity irrespective of enol silyl ether geometry (Sch. 32). 

Another explanation takes into account that boat- and twist-shaped six-membered, closed transition states can successfully compete with the chair model. " Evans et al. pointed out that in a-unsubstituted enolate reactions, missing allyl strain interactions lead to lower selectivity in diastereoselective aldol reactions.Calculations indicate that a twist-boat can easily be formed from the U-configuration of a-unsubstituted enolates. The possible transition state in this case has a geometry like 34 and is favored by the chelating character of the complexation mode for the zinc cation and the outward-pointing substituents of the oxazolidinone moiety. This twist-boat transition state correctly predicts the stereochemical outcome of the reaction. 

When an aldehyde is reacted with a ketone-derived enolate under equilibrating conditions, the thermodynamically more stable 2,3-anti product predominates regardless of the geometry of the enolate. If, however, the reaction is kinetically controlled, the (Z)- and ( )-enolates furnish 2,3-syn and anti aldol products, respectively. This behavior has been interpreted in terms of a chair-type transition state known as the Zimmerman-Traxler model. ... 

The geometry of the aldol transition state was interpreted in terms of the variation in mode of the aldehyde/catalyst complexation [Felkin-Ahn (nonchelating) model versus chelating model] and size of KSA. The same complex efficiently catalyzes the Michael reaction of a,/9-unsaturated ketones with KSA [124],... 

---