Zimmerman-Traxler transition structure

The high levels of, sy -diastereoselectivity suggest aldolization through a closed Zimmerman-Traxler-type transition structure via intermediacy of the Z-enolate. When the transformation is performed using PhSiDj, a single deuterium is incorporated at the /3-position of the product as an equimolar mixture of epimers, inferring rapid isomerization of the kinetically formed cobalt enolate prior to cyclization or reversible aldol addition. The stereochemistry of the deuterated product was established by single crystal neutron diffraction analysis (Scheme 44). 

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 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. 

The models become more complex when they take the structure of the base into account. A simple and very popular hypothesis was proposed for esters by Ireland and coworkers in pioneering work23. This model supposes that a monomeric LDA is the active species and that the lithium-carbonyl interaction leads to a six-membered cyclic Zimmerman-Traxler chair-like transition state24, at which a more-or-less concerted proton transfer occurs. The resulting preference for the E enolate observed in THF and the Z preference in THF-HMPA mixtures, an issue discussed in more detail below, could even be accounted through steric considerations (Scheme 4). 

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). 

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. ... 

Scheme 5.1 illustrates the transition structure most often invoked to explain the selectivities observed in TC-transfer 1,2-carbonyl additions (cf. Figure 4.1) the so-called Zimmerman-Traxler transition structure [1]. This model, which was originally proposed to rationalize the selectivity of the Ivanov reaction, has its shortcomings (as will be seen) and suffers from an oversimplification when applied to enolates, in that it illustrates a monomeric enolate cf. section 3.1 and ref. [2-4]). Nevertheless, it serves the very useful purpose of providing a simple means to rationalize relative and absolute configurations in almost all of the asymmetric 1,2-additions we will see. The favored transition structure has Ik topicity (Si/Si... 

Type 1. Reagents that are stereospecific in the sense that an -crotyl isomer affords the anti addition product Ik topicity) and a Z-crotyl isomer affords the syn product ul topicity). The transition structure is thought to be a closed chair, analogous to the Zimmerman-Traxler transition structure (Scheme... 

Type 3. Allyl organometallics that are (usually) generated in situ and which equilibrate to the more stable E-crotyl species, then add via a closed, Zimmerman-Traxler transition structure producing anti adducts preferentially [8]. 

If both the Z(0)- and the (0)-enolates can be made, and if both follow the Zimmerman-Traxler models (i.e., chair transition structures), then both syn and anti adducts should be available (Scheme 5.11, path a vs. b or c V5. d). Since both enantiomers of the auxiliary are available, any desired combination of relative and absolute configurations in the products would be available. 

Note that each E(0)- or ZfOj-enolate will have a choice of two Zimmerman-Traxler transition structures. Thus (see Scheme 5.11), a Z(0)-enolate may add through nonchelated path a or chelated path c, both of which afford syn adducts, but of opposite absolute configuration at the two new stereocenters. Likewise, an E(0)-enolate may add via path b or d, affording diasteomeric anti adducts. 

Zimmerman-Traxler transition structure, as shown on the lower left [79], however the open structure shown in the lower right, which does not require coordination of the bulky silyloxy group to titanium, should also be considered. The aldehyde may be oriented to avoid the large tert-butyldimethylsilyl (TBS) group as shown, with the R group away from the TBS. Both of these models have the aldehyde approaching the enol ether from the front face, opposite the side that is shielded by the sulfonamide. Note also that the siloxy group is oriented downward, to avoid the sulfonamide. An anti-selective addition (92% ds) was also reported for the reaction of the E(0)-eno ether of this auxiliary with isobutyraldehyde [79]. 

Following an early lead from the Meyers group [94,95], Paterson used the readily available diisopinocampheyl (Ipc) boron triflate to make Z(0)-boron enolates of 3-pentanone [93] and other ketones [96], which add to aldehydes to produce syn adducts in 83 - 96% es (Scheme 5.16 and Table 5.6). Based on molecular mechanics calculations [55,56], the transition structure analysis shown in Scheme 5.16 was suggested to rationalize the enantioselectivity. The axial boron ligand rotates so that the C-H bond is over the top of the Zimmerman-Traxler six-membered ring, and the equatorial ligand orients with its C-H bond toward the... 

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. 

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