Traxler model

The fact that (Z)-lithium enolatcs generally display a higher simple diastereoselectivity giving. vyn-aldols compared to (E)-enolates affording nn/i-aldols is a challenge to the Zimmer-man-Traxler model, and has become the source of extended speculation. 

TS, which is usually based on the chair (Zimmerman-Traxler) model. This pattern is particularly prevalent for the allylic borane reagents, where the Lewis acidity of boron promotes a tight cyclic TS, but at the same time limits the possibility of additional chelation. The dominant factors in these cases are the E- or Z-configuration of the allylic reagent and the conformational preferences of the reacting aldehyde (e.g., a Felkin-type preference.)... 

Excellent (3-facial selectivity on the enolate was observed, but there was a lower facial selectivity on the aldehyde partner. The cation was of tremendous importance, as seen from the reversal of selectivity when going from lithium to zinc or magnesium enolates [12] (Scheme 40). This is explained by a Zimmerman-Traxler model in which a... 

The stereoelectronic requirements for carbonyl addition are that electron donation occurs by interaction of die donor with the it orbital of the carbonyl group. To meet the stereoelectronic requirements and explain the diastereoselectivity, the Zimmerman-Traxler model is used. Interaction of the lithium cation with the oxygen of die enolate and of die carbonyl electrophile leads to a six-membered... 

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 simple diastereoselectivity of aldol reactions was first studied in detail for the Ivanov reaction (Figure 13.45). The Ivanov reaction consists of the addition of a carboxylate enolate to an aldehyde. In the example of Figure 13.45, the diastereomer of the /1-hydroxycarboxylic acid product that is referred to as the and-diastereomer is formed in a threefold excess in comparison to the. vy/j-diastereoisomer. Zimmerman and Traxler suggested a transition state model to explain this selectivity, and their transition state model now is referred to as the Zimmer-man-Traxler model (Figure 13.46). This model has been applied ever since with good success to explain the simple diastereoselectivities of a great variety of aldol reactions. 

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 application of the Zimmerman-Traxler model to the specific case of the Ivanov reaction of Figure 13.45 is illustrated in Figure 13.46. The reaction proceeds preferentially through... 

Fig. 13.46. Explanation of the anti-selectivity of the Ivanov reaction of Figure 13.45 by means of the Zimmerman-Traxler model. The stereodescriptors Re and Si are defined as follows. Suppose you are looking down on the plane of an alkene, in which an sp2-hybridized C atom is connected to three different substituents. You are on the Re side of the double bond if the Cahn-Ingold-Prelog priorities of these substituents decrease going clockwise, and on the Si side otherwise.

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. 

Fig. 10.41. Explanation of the anh-selectivity of the Ivanov reaction of Figure 10.40 by means of the Zimmerman-Traxler model. The...

Figure 6.3 Schematic illustration of the generation of inhibitor-insensitive kinase mutants. The interaction of ATP-site competitors with kinase domains has been structurally characterized through the so-called Traxler model [10]. The part of the inhibitor that corresponds to the adenine ring binds to the hinge region of the kinase domain via H bonds. Next to the hinge region are the hydrophobic back pocket and the surface-exposed front pocket, which do not play a role in ATP binding. However, these pockets are extremely critical determinants in inhibitor binding, since the...

Syn-, anti- and acetate aldol derivatives can be synthesized by choosing appropriate enolization protocols (Scheme 5) [20]. With lithium, boron and tin Lewis acids,. tyn-aldols can be obtained via (Z)-enolates [21]. If enolization is carried out with lithium or tin, there are enough open coordination sites available to position the aldehyde and the enolate in accordance with the chelate model for the sultam auxiliary and with the Zim-mermann-Traxler model. The combination of these models predicts the formation of 22, which is indeed experimentally obtained. If Lewis acids with only two open coordination sites are used... 

The asymmetric synthesis of (—)-denticulatin A (30) shows an interesting application of the boron aldol chemistry (Scheme 6) [23]. In a group-selective aldol reaction between the weso-aldehyde 27 and (5)-28, the hydroxyalde-hyde 29 was formed with > 90 % de, which spontaneously cyclized to the lactol 31. The configuration at the stereocenters of C-2 and C-3 in 29 is in accordance with the induction through the sultam auxiliary as well as with preference of an a-chiral aldehyde to react to the ant/-Felkin diastereomer in an aldol reaction which is controlled by the Zimmermann-Traxler model [24, 25]. 

At present there are >100 protein kinase-inhibitor structures in publidy available structural databases which span 28 kinases and a variety of inhibitor structural classes. Based upon an analysis of these data a classification of ATP binding regions has been proposed by Traxler and Furet [59] and Bower (personal communication from Michael J. Bower, December 1999). In the subsequent discussion a slightly modified version of this classification will be used to organize the trends seen across kinases and inhibitor dasses (see Fig. 2.2). In the Traxler model, five sites were proposed of which three (adenine, sugar and phosphate-binding sites) can be directly related to ATP and two additional lipophilic sites which lay outside of the region occupied by ATP. In the Bower model, an additional polar site on the surface of the protein was proposed. 

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. ... 

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