Zimmerman-Traxler transition state, for

Figure 6.8 Proposed modes of action of hydrogen-bonding catalyst 16 Bidentate hydrogen bonding coordination of the zwitterion derived from Michael-type DABCO attack to methyl acrylate (1) and Zimmerman-Traxler transition state for the reaction of methyl acrylate with benzaldehyde (2).

In the following four chapters, readers will find some of the most frequently cited and most synthetically relevant examples of the Zimmerman-Traxler or six-membered transition state. In presenting reactions that go through a six-membered chairlike transition state, I pay special attention to including computational studies, in an effort to prove the existence of a six-membered chairlike transition state. Although not all six-membered transition states have been studied computationally, recent interest in using computers in studies of stereoselective reactions would certainly confirm the legitimacy of Zimmerman-Traxler transition states for many more reactions.5... 

Fig.5. The Zimmerman-Traxler transition states for aldol addition reactions...

One of the key features of such stereocontrolled aldol reactions is the predictability of the absolute stereochemistry of the enantiomers (or diastereo-mers) that will be formed as the major products. The preferred intermediate for an archetypal aldol reaction, proceeding by way of a metal enolate, can be tracked using the Zimmerman Traxler transition state and the results from the different variations of the aldol reaction can be interpreted from similar reasoning, and hence predictions made for analogous reactions1129]. 

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 six-membered ring transition state for the aidoi reaction was proposed by Zimmerman and Traxlerand is sometimes called the Zimmerman-Traxler transition state. 

Zimmerman-Traxler transition state model for (Z)-(O)- and ( )-(0)-enolates... 

Deprotonation of a-silyloxy ketones with LDA furnishes (Z)-lithium enolates, whereas treatment of ketones with n-Bu2BOTf in the presence of /-Pr2EtN gives the corresponding (Z)-(0)-boron enolates. Interestingly, reaction of the Li-enolates with r-PrCHO proceeds with opposite facial preference to that of the boron enolates. Thus, the Si face of the Li-enolate adds to the Si face of the aldehyde and the Si face of the boron enolate adds to the Re face of the aldehyde to furnish the chiral P-hydroxy ketone enantiomers shown below. The reason for the different face selectivity between the lithium enolate and the boron enolate is that lithium can coordinate with three oxygens in the aldol Zimmerman-Traxler transition state, whereas boron has only two coordination sites for oxygen. 

Scheme 23 shows how four possible diastereomers can arise from the combination of two sp -carbon centers C-1 and C-2 in a donor component 23-1 and an acceptor component 23-2. Species 23-3 and 23-4 are two diastereomers and 23-5 and 23-6 are their enantiomers.The problem of simple diastereoselection is the control of the diastereomer ratio 23-3-1-23-5/23-4-1-23-6. The enantiocontrol of 23-3 vs 23-5 or of 23-4 vs 23-6 cannot be achieved by simple diastereoselection in this case an external source of chirality has to be applied, for instance a chiral catalyst or the incorporation of stereogenic units in one of the components. Simple diastereoselection can be exerted in terms of closed and open transition states, depending on the mutual interaction of the termini X and Do, respectively. If these termini are linked via a six-membered chelate, a closed ( Zimmerman-Traxler ) transition state 23-7 with synperiplanar olefinic units is formed. On the other hand, if the termini have a repulsive interaction an open transition state 23-8 with an antiperiplanar arrangement of the olefinic units is adopted. Efficient stereocontrol via Zimmerman-Traxler transition states 24-1 to 24-4 is observed in aldol-type and allylborane carbonyl additions (Scheme 24). The crucial stereo differentiating interaction is the diaxial repulsion between Rax and R, which must be kept as low as possible. Only small substituents (nor-...

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. 

The reaction is cis-steieospecific when esters of acetic acid are used while, in the case of a-bromopropionic esters, a mixture of cis-trans aziridines is formed. The cu-selectivity shown by esters of acetic acid is not surprising. In fact, it may be explained by assuming an E geometry for both the enolate and the imine and a closed chair-like Zimmerman-Traxler transition state in which the imine side chain is in an axial position while the halogen atom is in an equatorial location. The subsequent nucleophilic di lacement oi the halogen atom in the resulting intermediate teads directly to the formation of the cis-aziridine (Scheme 19). 

The aldol reactions of titanium enolates generated in situ were reported by Harrison [27] to give excellent yield and selectivity for syn aldol products, as shown in Table 2.10. However, methyl ketones tended to eliminate under the reaction conditions and provided a,/i-unsaturated ketones. Reactions with propiophenone and benzaldehyde provided excellent yields of aldolates, with syn aldols being the major product (95 5 ratio). The stereochemical outcome was rationalized by Zimmerman-Traxler transition state model 67. 

A common example for auxiliary-contfolled anti-aldol reactions is the Masamnne-Abiko process since the procedure covers the synthesis of both enantiomers depending on the nature of the auxiliary, which is readily available in both enantiomeric forms [15]. This anti-selective aldol reaction has been performed by using enantiomerically pure carboxylic esters derived from (-)- or (-i-)-norephedrine. The method is applicable to a wide range of aldehydes with high selectivity (both antilsyn and diastereoselectivity of anti-isomer) [16]. A typical example of this aldol approach is depicted in Scheme 2.113. It is proposed that the reaction proceeds via a six-membered Zimmerman-Traxler transition state. 

This diastereoselectivity may be explained by a rapid equilibration of the ( )- and (Z)-aUylchromium(III) intermediates 5 and 6, which are preferentially a-bound to chromium at the primary allyl position. The (E)-aUylchromimn species is more highly favored and is thought to add to the aldehyde via a Zimmerman-Traxler transition state 7, in which both the y-substituent of the allylic system and the aldehyde substituent prefer equatorial positions (thus. Scheme 12.5). An exception to this remarkable anti-selectivity is observed in the reaction of y-monosubstimted allylic halides with very bulky aldehydes, for example, t-BuCHO, which may force the transition state to adopt a twist-boat rather than a chair conformation, thus, favoring the. syw-product. 

A good example of the qi/z-Evans aldol reaction is demonstrated by the Novartis synthesis of (+ymethylphenidate 204, a treatment for ADHD in children. Treatment of compound 199 with n-Bu2BOTf and DIPEA followed by aldehyde 200 afforded the 1,2-syn Aldol product 202. Initial Lewis acid complexation followed by deprotonation led to preferential (Z)-enolate formation. In this case, the use of a boron Lewis acid which can only coordinate to two heteroatoms led to syn stereochemistiy governed by a chair-like Zimmerman-Traxler transition state 201 (Scheme 14.72). Following mesylation of the secondary alcohol, the auxiliary was removed under reductive conditions and the resultant alcohol transformed into (-l-)-methylphenidate 204. 

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