Transition state/structure Zimmerman-Traxler

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 ketone enolate A of Figure 13.47 is generated in a Z-selective fashion (as we saw in Figure 13.15). The bulky and branched enolate substituent destabilizes the Zimmerman-Traxler transition state C by way of the discussed 1,3-diaxial interaction, while the transition state structure B is not affected. Hence, the aldol addition of enolate A occurs almost exclusively via transition state B, and the -configured aldol adducts D (Figure 13.47) are formed with a near-perfect simple diastereoselectivity. The acidic workup converts the initially formed trimethysilyloxy-substituted aldol adducts into the hydroxylated aldol adducts. 

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. 

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. 

When TiCU is used as a catalyst with substituted dienes such as (14), a predominant route is the Mu-kaiyama aldol process, " When diene (14) reacts with benzaldehyde the trans (anti) product is observed. When compound (42) is used as the aldehyde, one observes exclusive formation of the (erythro) aldol products (Table 14). These stereochemical results can be rationalized by using a Zimmerman-Traxler transition state (Scheme 18). Chelation by the metal of the aldehyde a-alkoxy group causes it to be placed in a pseudo axial position in the transition state structure. This results in a stereochemical relationship that gives syn aldol products. ... 

Gosh independently reported another anti-selective aldol addition process employing aminoindanol-derived esters 114 (Equation 11) [72]. These were subjected to enolization with excess TiCl, and Hiinig s base to furnish titanium 2-enolates, as determined by NMR spectroscopy. Addition reactions with a variety of aliphatic and unsaturated aldehydes, precomplexed with TiCl4, furnished the anti aldol adducts such as 116 in 44—97% yields and up to 99 1 anti/syn ratios of diastereomers. The stereochemical outcomes of the reactions have been attributed to chelated Zimmerman-Traxler transition state structures, such as 115. It is interesting to note that benzaldehyde, as the only aromatic aldehyde examined, yielded a 1 1.1 mixture of antijsyn products. 

The additions of allyl-, crotyl-, and prenylborane or -boronate reagents to aldehydes are among the most widely studied, well developed, and powerful reactions in stereoselective synthesis. The additions not only display excellent levels of absolute induction in enantioselective synthesis, but also exhibit superb levels of reagent control in diastereoselective additions. The additions of ( )- or (Z)-crotyl pinacol boronates to aldehydes have been observed to give predominantly 1,2-anti- and 1,2-syn-substituted products, respectively (Scheme 5.3) [31, 50]. The inherent stereospecificity of the reaction is consistent with a closed, cyclic Zimmerman-Traxler transition state structure [51], In the accepted model, coordination of the aldehyde to the allylation reagent results in synergistic activation of both the electrophile and the nucleophile... 

The following examples show how open and closed transition states may be invoked by the choice of the reaction type. For instance, aldol-type addition normally proceeds via a closed transition state because the metal ion is shifted from the enolate oxygen to the carbonyl oxygen in an ene-like mechanism ( Zimmerman-Traxler transition state 9). The crucial interactions in the Zimmerman-Traxler transition state 16 are those between the 1,3-diaxially oriented substituents around the chair-like structure. R2 adopts the location shown, thus R3 avoids the 1,3-interaction and assumes an equatorial position. Therefore, the diastereomeric ratio depends mainly on the ( )/(Z) configuration of the enolate. Whereas (Z)-enolates 13 afford syn-config-urated enantiomers, 17 and 18, the corresponding ( )-enolates 14 lead to anti-configurated adducts 19 and 20 10. 

The condensation step a gave a 3 1 mixture of isomers 2. Assuming that the stereoselectivity of the reaction can be rationalised by a Zimmerman-Traxler transition state model, what should be the structure of the predominant isomer ... 

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). 

The reader should recognize that these five-membered-ring transition states are considerably more flexible than, for example, a chair structure such as the Zimmerman-Traxler transition state in aldol additions cf. Scheme 5.1). This flexibility complicates the analysis of the various effects. A few examples serve to illustrate how these effects influence the configuration of the double bond and stereocenters in the product. 

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. 

The diagrams below continue the story. The aldehyde has to attack the front face of the auxiliary, but it also has to do so through what we termed in Chapter 33 a Zimmerman-Traxler transition state —a six-membered, chair-like cyclic structure which allows the enolate to attack the aldehyde while simultaneously transferring the metal (here the boron) from the enolate oxygen to the new hydroxyl group. 

Oxazolidinone-, oxazolidinethione-, oxazolidineselone-, and thiazolidine-thione-based enolates react svith aldehydes via the svell-established six-membered Zimmerman-Traxler [3] chair-like transition state. Exhaustive studies and analysis by Crimmins have established the theoretical basis of these reactions [33]. These transition states can proceed svithout chelation betsveen carbonyl or thiocarbonyl (84) or svith an additional chelation to titanium (85), as shosvn in Scheme 2.9. To proceed via the chelated transition structure 85, one of the ligands on titanium (typically chloride) must be displaced by the carbonyl or thiocarbonyl group. Although these groups are not sufficiently nucleophilic to completely displace this ligand on their o vn. 

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. 

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