Zimmerman-Traxler transition state model

The stereoselectivity can be explained with the Zimmerman-Traxler Model, which predicts a six-membered cyclic transition state leading to excellent stereoselectivity for ont/ -substituted products. 

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... 

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 formation of syn-64 and anti-64 diastereomer aldol products emerges from the transition states 69 and 70, respectively. Thus, the Zimmerman-Traxler model [80] involving a six-membered like assembly of the reactants provide a reasonable explanation of the (Z)-syn, (E)-anti correlation. 

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.iv. The Evans Model. It is known that (Z) enolates are more stereoselective than ( ) enolates even when r1 is not large. The Zimmerman-Traxler model transition states 352-355 do not account for this observation. It has been suggested that the transition states are not chair-like, but skewed, as in 381-384.221 In this representation (Z) enolate 381 leads to the syn aldol. Similarly, (Z) enolate 382 gives the anti aldol, ( ) enolate 383 give the anti aldol and E) enolate 384 is the precursor to the syn aldol. The major steric interactions in this model are those for r1 r3 and r2 - r3. For both (Z) and E) enolates, the r1 r3 interaction favors 381 and 383, respectively. The r2 r3 interaction is more important for the E) enolate and... 

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... 

In most cases, Crams rule (sec. 4.7.B) predicts the major isomer when the reaction partner (or partners) contain a chiral center. To understand how this rule applies to orientational and facial selectivity, we must understand the transition state of the reaction (invoke the Zimmerman-Traxler model or one of the other models for predicting diastereoselectivity). The Zimmerman-Traxler model is used most often, and if it is applied to 423 and 424, the syn selectivity can be predicted. The facial selectivity shown in 427 and 428 arises from the methyl group. In 428, the enolate approaches from the face opposite the methyl, leading to diminished steric interactions and syn product (429). If the enolate approaches via 427, the steric impedance of the methyl group destabilizes that transition state relative to 428. In both 427 and 428, a Cram orientation is assumed (see above) although other rotamers are possible. The appropriate rotamer for reaction therefore is that where Rl is anti to the carbonyl oxygen. Since the phenyl group is Rl, 427 and 428 are assumed to be the appropriate orientation for the aldehyde. If an aldehyde or ketone follows anti-Cram selectivity, this aldehyde orientation must be adjusted. 

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... 

Once again, consideration of the chelated, cyclic transition state, known as the Zimmerman-Traxler model, provides the rationale for this diastereo-selectivity. In the most favorable chair-Uke transition state, the aldehyde R group is in an equatorial position. This preferred orientation produces the syn product from the (Z)-enolate and the anti product from the (i )-enolate. Each transition state shown is forming a single enantiomer product attack by the enolate to the opposite face of the aldehyde would give rise to the other enantiomer. 

This allylation protocol was used in the total synthesis of amphidinolide to give homoallylic alcohol 12 in 72% yield and 17 1 dr (eq 5). Initial transmetallation of stannane 10 with (R,R)-1 via allylic transposition yielded an intermediate borane. Introduction of aldehyde 11 at -78 °C provided for a facile condensation reaction leading to 12. Stereocontrol was induced from the 1,2-diphenylethane sulfonamide auxiliary and could be predicted from a Zimmerman-Traxler model with minimized steric repulsions. The high level of selectivity obtained in this case was a result of a matched diastereomeric transition state featuring the inherent Felkin-Ahn selectivity for nucleophilic attack in aldehyde 11, with the (5)-configuration of the benzoate of 10, as well as the (7 ,7 -antipode of auxiliary 1, resulting in threefold stereodifferentiation. 

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... 

An important modification of the classical Zimmerman-Traxler model, vhich still relies on the idea of a pericyclic-like transition state, considers... 

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-... 

The most widely accepted transition state model of the aldol addition is the Zimmerman-Traxler model [72]. Originally postulated in a seminal paper dating from 1957 for the addition of Ivanov reagents [73] - dianions of phenylacetic acid with MgX as counterions (cf. Section 2.1) - to benzaldehyde, the model postulates a sbc-membered chair-like transition state. This hypothesis was adapted to a numerous aldol additions performed with a large variety of enolates of hthium, boron, and other metals. The strength of this model is a convincing explanation for the cis-syn, trans-anti correlation, as outlined in Scheme 4.30. 

For the enolates of alkali metals and magnesium, their known tendency for aggregation was put forward against the Zimmerman-Traxler model that assumes monomeric enolates as the reactive species. However, even the aggregation is compatible with the model if one assumes a sbc-membered transition state to operate at tetrameric lithium enolates, as postulated by Seebach and coworkers [74]. The fact that a more precise cis-sy -correlation is observed for enolates of boron, titanium, or tin is also compatible with the Zimmerman—Traxler model. For these stronger Lewis acids (compared to alkali metals or magnesium), the six-membered transition state will be tighter, so that steric effects become more important. 

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. 

The Zimmerman-Traxler like transition state model can involve either a chair or boat geometry. 

A Zimmerman-Traxler transition state model is postulated in order to rationalize the ul topicity of this aldol addition [i.e., the (S)-enolate preferentially attacks the 7 e-face of the aldehyde]33. In the two alternative transition states 3a [ul topicity (S)jRe] and 3b [Ik topicity (S)/Si, the substituents at the stereogenic center of the enolatc are oriented in such a way that... 

Although the chiral propanoates I and 5 are similar and the reaction conditions are almost identical, the stereochemical outcomes arc explained by completely different transition state models. Predominant attack of the ketene acetal 2 to the Ai-face of 2-methylpropanal is interpreted by assuming a Zimmerman-Traxler like model, which minimizes steric hindrance in a plausible way65. 

The preference of the (5, .S )-boron cnolatc to attack almost exclusively the Si-face of an aldehyde is rationalized by assuming the Zimmerman-Traxler transition state model. It is postulated that the methyl group of the propyl residue directs the 3-elhylpenlane-3-thiol group towards the borolane moiety, the chirality of which is thus effectively transferred34. 

The configurational course depends on the enolatc configuration and the metal ion which determines whether a cyclic (e.g., Zimmerman-Traxler type) or an acyclic transition state is traversed. At present the following transition state models have been proposed. 

A proposed simplified mechanism for the conjugate addition/aldol cyclization, as depicted in Scheme 2.25, is based on detailed mechanistic studies performed on related Rh-catalyzed enone conjugate additions [45]. A model accounting for the observed relative stereochemistry invokes the intermediacy of a (Z)-enolate and a Zimmerman-Traxler-type transition state as shown in 2-110 to give 2-111. 

---