Zimmerman-Traxler model aldol reaction

The key idea of the Zimmerman-Traxler model is that aldol additions proceed via six-membered ring transition state structures. In these transition states, the metal (a magnesium cation in the case of the Ivanov reaction) coordinates both to the enolate oxygen and to the O atom of the carbonyl compound. By way of this coordination, the metal ion guides the approach of the electrophilic carbonyl carbon to the nucleophilic enolate carbon. The approach of the carbonyl and enolate carbons occurs in a transition state structure with chair conformation. C—C bond formation is fastest in the transition state with the maximum number of quasi-equatorially oriented and therefore sterically unhindered substituents. 

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 most intensely studied aldol addition mechanisms are those beUeved to proceed through closed transition structures, which are best understood within the Zimmerman-Traxler paradigm (Fig. 5) [Id]. Superposition of this construct on the Felkin-Ahn model for carbonyl addition reactions allows for the construction of transition-state models impressive in their abiUty to account for many of the stereochemical features of aldol additions [50a, 50b, 50c, 51]. Moreover, consideration of dipole effects along with remote non-bonding interactions in the transition-state have imparted additional sophistication to the analysis of this reaction and provide a bedrock of information that may be integrated into the further development and refinement of the corresponding catalytic processes [52a, 52b]. One of the most powerful features of the Zimmerman-Traxler model in its application to diastereoselective additions of chiral enolates to aldehydes is the correlation of enolate geometry (Z- versus E-) with simple di-astereoselectivity in the products syn versus anti). Consequently, the analyses of catalytic, enantioselective variants that display such stereospecificity often invoke closed, cyclic structures. Further studies of these systems are warranted, since it is not clear to what extent such models, which have evolved in the context of diastereoselective aldol additions via chiral auxiliary control, are applicable in the Lewis acid-catalyzed addition of enol silanes and aldehydes. 

Possible transition states for the reactions of type I and III crotyl organometallics with aldehydes are depicted in Scheme 7. Most of the available stereochemical evidence suggests that these reactions proceed preferentially through transition state (12) in which the metal is coordinated to the carbonyl oxygen syn to the smallest carbonyl substituent, H. This necessitates that R of RCHO adopt an equatorial position if the transition state is chair-like, an arrangement that is structurally similar to the Zimmerman-Traxler model commonly invoked for many aldol reactions. Transition states (13) and (14), however, may potentially intervene and are frequently cited to rationalize the production of minor diastereomers (17). 

It is important to state that there is no evidence that the Zimmerman-Traxler model represents the actual transition state for aldol-like reactions. Nonetheless, this model is a useful mnemonic, extensively used and makes reasonable predictions in many cases. It is used to predict structure-selectivity relationships for lithium. 

A.V. The Noyori Open-Chain Model. In the Mukaiyama reaction, the Zimmerman-Traxler and Evans models are not satisfactory for predicting diastereoselectivity. Several open (nonchelated) transition states have been considered as useful models. The condensation reaction of carboxylic acid dianions with aldehydes indicated that anti selectivity increased with increasing dissociation of the gegenion (the cation, M+),224 When analyzing an aldol condensation that does not possess the bridging cation required for the Zimmerman-Traxler model, an aldehyde and enolate adapt an eclipsed orientation as they approach. Noyori reported syn selectivity for the reaction of a mixture of (Z)-silyl enol ether 389 and ( )-silyl enol ether 390 with benzaldehyde in the presence of the cationic tris-(diethylamino) sulfonium (TAS).225 xhis reaction is clearly a variation of the Mukaiyama reaction, which does not usually proceed with good diastereoselectivity... 

The aldol addition reactions are believed to proceed by way of a chair-like six-membered cyclic transition state in which the ligated metal atom is bonded to the oxygen atoms of the aldehyde and the enolate (Zimmerman-Traxler model). For the reaction of a ds-enolate 46 with an aldehyde RCHO, the transition state could be represented as 48 (1.64). This places the R group of the aldehyde in a pseudoequatorial position in the chair-like conformation and leads to the syn aldol product. Likewise, reaction of the tran -enolate proceeds preferentially via the... 

After 124 had been converted into 125 (Scheme 14) through an ozonolysis reaction and an alcohol protection step, the Paterson group then transformed this ketone into a Z boron enolate (126, see column figure) expecting that its subsequent reaction with 88 would afford the l,2-.syn-disposed aldol product 128. Indeed, this reaction did provide primarily syn products as one would anticipate based on the Zimmerman—Traxler models shown in Scheme 1. Disappointingly, the desired syn product (128) was the minor adduct, as... 

The boron-mediated aldol reaction of an Evans s acyl oxazolidinone with an aldehyde affords the Evans-syn aldol adduct 9. The process proceeds via formation of the Z enolate that reacts with the aldehyde, presumably through a well ordered six-membered, chair-shaped Zimmerman-Traxler model... 

The most videly accepted transition state hypothesis for aldol additions is the Zimmerman-Traxler model. This vas originally developed to explain the stereochemical outcome of the Ivanoff reaction - addition of the dianion of carboxylic acids vith magnesium counter-ions to aldehydes and ketones... 

For many aldol reactions, a Zimmerman-Traxler model is most conveniently used to rationalize the stereochemical outcome of these reactions. It may be used here again to explain the higher enantioselec-tivities exhibited by (91) compared to (95). In transition state (F) for the reaction of an aldehyde with re-... 

Despite the similarity of the structures of the silicon enolates 186 and 189 and essentially identical reaction conditions, the rationale for the stereochemical outcome, offered by the authors, is completely opposite the predominant approach of silyl ketene acetal 186 to isobutyraldehyde was assumed to occur through a Zimmerman-Traxler-llke transition state 192 where the titanium salt is embedded in the cycle. On the contrary, an open transition state model 193 was proposed for the Mukalyama reaction of silicon enolates 189. Both models of intuitive character give an explanation for the favored topicity the attack of the enolate to the Si-face of the aldehydes. Thus, the fact that ti-configured aldols are formed diastereoselectlvely Is in accordance with the tr ws-enolate/ nti-aldol correlation predicted by the Zimmerman-Traxler model, but an open model might be suitable to explain the stereochemical outcome as well. Both the Helmchen and the Oppolzer auxiliary were applied as acetates to give cx-unbranched-fi-hydroxycarboxylic acids. 

Aldol reactions of magnesium enolates are frequently more diastereoselective than the corresponding reactions of lithium enolates. The aldol condensation proceeds via a cyclic transition state in agreement with the Zimmerman-Traxler chelated model . 

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... 

The simple diastereoselectivity of aldol reactions was first studied in detail for the Ivanov reaction (Figure 13.45). The Ivanov reaction consists of the addition of a carboxylate enolate to an aldehyde. In the example of Figure 13.45, the diastereomer of the /1-hydroxycarboxylic acid product that is referred to as the and-diastereomer is formed in a threefold excess in comparison to the. vy/j-diastereoisomer. Zimmerman and Traxler suggested a transition state model to explain this selectivity, and their transition state model now is referred to as the Zimmer-man-Traxler model (Figure 13.46). This model has been applied ever since with good success to explain the simple diastereoselectivities of a great variety of aldol reactions. 

The aldol reactions of the titanium Z-enolates proceeded smoothly with various aldehydes precomplexed with titanium chloride at -78° C. The diastereose-lectivity is high to excellent, with the single exception of benzaldehyde. The high degree of diastereoselection associated with this current asymmetric anti-aldol process can be rationalized by a Zimmerman-Traxler type of six-membered chairlike transition state Al9fl (Scheme 2.2r). The model is based on the assumptions that the titanium enolate is a seven-membered metallocycle with a chairlike conformation, and a second titanium metal is involved in the transition state, where it is chelated to indanolyloxy oxygen as well as to the aldehyde carbonyl in a six-membered chairlike transition-state structure. 

As a Stereochemical Prohe in Nucleophilic Additions. Historically, the more synthetically available enantiomer, (4R)-2,2-dimethyl-l,3-dioxolane-4-carhoxaldehyde, has been the compound of choice to probe stereochemistry in nucleophilic additions. Nevertheless, several studies have employed the (45)-aldeh-yde as a substrate. In analogy to its enantiomer, the reagent exhibits a moderate si enantiofacial preference for the addition of nucleophiles at the carbonyl, affording anti products. This preference for addition is predicted by Felkin-Ahn transition-state analysis, and stands in contrast to that predicted by the Cram chelate model. Thus addition of the lithium (Z)-enolate shown (eq 1) to the reagent affords an 81 19 ratio of products with the 3,4-anti relationship predominating as a result of preferential si-face addition, while the 2,3-syn relationship in each of the diastere-omers is ascribed to a Zimmerman-Traxler-type chair transition state in the aldol reaction. ... 

The observed stereoselectivity in the Evans aldol reaction can be explained by the ZImmerman-Traxler transition state model. There are eight possible transition states, four of which would lead to the anti aldol product. These, however, are disfavored due to the presence of unfavorable 1,3-diaxial interactions (not depicted below). The possible transition states leading to the syn aldol product are shown below. The preferred transition state leading to the product is transition state A, where the dipoles of the enolate oxygen and the carbonyl group are opposed, and there is the least number of unfavored steric interactions. 

General reviews include the direct aldol/" aldoi and related processes,the Zimmerman-Traxler TS model used to explain the stereochemistry of the aldoi condensation,catalysis of direct asymmetric aldols by prolinamides versus prolinef/zioamides, " " the catalytic asymmetric aldoi reaction in aqueous media (considering both organometallic and organocatalytic approaches), " the use of BINAP oxide in enantioselective direct aldols,and the use of metal enolates as synthons. " ... 

---