Zimmerman-Traxler, chair-like transition

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). 

Allylic boronates belong to the Type 1 class of reagents and are involved in a closed, Zimmerman—Traxler chair-like transition state whereby... 

A few years ago, Blagonev and Ivanov described the bis-deprotonation of aryl acetic acids by Grignard reagents. These magnesinm dianions, known as Ivanov reagents, react with aldehydes and ketones. Reaction between dianions of phenylacetic acid and benzaldehyde yields the anti S-hydroxy acid as the major diastereomer anti/syn 69/22) (equation 113). This result is in agreement with the formation of a cyclic chair-like transition state according to the model of Zimmerman-Traxler . 

The Ivanov reaction is the preparation of a 3-hydroxy acid by reaction of the magnesium dianion of a carboxylic acid with an aldehyde or ketone." In a seminal paper, Zimmerman and Traxler investigated the Ivanov reaction of phenylacetic acid and benzaldehyde and obtained anti and syn 3-hydroxy acids (127) and (128) in 69% and 22% yields, respectively (equation 85). The observed stereochemistry was rationalized with a cyclic, chair-like transition state in which a magnesium cation is chelated by one oxygen each of the carboxylate enolate and the aldehyde (the Zimmerman-Traxler transition state ). 

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. 

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. 

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

The diastereoselectivity observed on carbonyl addition of ( )-alkenyltitanium derivatives is in accordance with the reaction proceeding via a chair-like six-membered Zimmerman Traxler transition state. The following facts are diagnostic ... 

The most widely accepted transition state hypothesis for aldol reactions is the Zimmerman Traxler model29 which involves a six-membered chair-like assembly of the rcaetants. This... 

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. 

Typically, the product of an aldol reaction and its stereochemistry are predictable by using the formalism of the chair-like Zimmerman-Traxler transition state.However, if the formalism is used in this case, the stereochemistry of the product is predicted incorrectly. Using chelating metal ions (in this case zinc), favored transition states such as 31 should be formed. The heteroaryl substituent of aldehyde 8 is equatorially oriented and the substituents of the oxazolidinone auxiliary point outward. However, the favored transition state predicts the formation of the minor diastereomer epi-10. In transition state 32, the substituents of the Evans auxiliary point to the aldehyde, which destabilize this transition state and make it unfavored. The product predicted by this transition state is the major diastereomer 10, which is an astonishing result. 

A possible chair-like Zimmerman-Traxler transition state (41) is depicted above. The chiral acetonide residue of enolate 40 forms a six-membered chelate with the zinc cation and the methyl groups shield effectively the -z-face of 40. Therefore, aldehyde 14 is attacked from the re-face of 40. 

Computational studies suggest that the mechanism of the proline catalyzed aldol cyclization is best described by the nucleophilic addition of the neutral enamine to the carbonyl group together with hydrogen transfer from the proline carboxylic acid moiety to the developing alkoxide. A metal-free partial Zimmerman-Traxler-type transition state involving a chair-like arrangement of enamine and carbonyl atoms and the participation of only one proline molecule has been established [118,119]. On the basis of density functional theory (DFT) calculations Cordova and co-workers [120,121] have studied the primary amino acid intermolecular aldol reaction mechanism. They demonstrated that only one amino acid molecule is involved in the... 

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). 

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... 

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... 

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. 

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). 

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