Chelating transition state models

The authors proposed a chelating transition state model to explain these results (Fig. 8.14). The thermodynamically more stable intermediate resulting from initial lithium amide addition should have the amino group on the face opposite to the bulky tert-butyl group. Due to the same steric effect, the HMPA ligand should also occupy a position on the p face. The electrophile approaches the enolate from the ot face and gives the trans product. For bulky amines, either the aza enolate does not form due to severe steric hindrance or the aza enolate is inactive for the same reason. 

Figure 8.14. Chelating transition state model for addition of lithium amides to oxazolinylnaphthalenes.

Figure 2. Chelated transition-state model for syn substrate.

Application of our usual chelated transition state models allows us to rationalize the effect of the 2-alkyl substituent. For syn systems, conformations containing axial sulfoxides (e.g., 19), which could occur for very small (axial) 2-alkyl substituents (e.g., proton), would be expected to provide only low levels of selectivity. 

Panek and co-workers demonstrated that the reaction of (5)-2-benzyloxypropa-nal (17) with the allylic silane (5)-18 under the influence of Bp3-OEt2 gave the syn homoallylic alcohol 19 with excellent level of Felkin induction [35]. Interestingly, the high level of syn selectivity was also observed in the condensation of 17 and (/ )-18. On the other hand, the reaction of 17 with (5)-18 in the presence of TiCLj produced anti homoallylic alcohol 20 almost exclusively, whereas the reaction with (R)-18 promoted by TiCL afforded syn homoallylic alcohol 21. Presumably, the reactions proceeded through a Cram chelate transition state model... 

Reversing the order of introduction of the alkyl groups at the p-position afforded, as expected, major diastereoisomers of opposite absolute configuration for example, the (S)-(-) antipode of (59) is available by employing the appropriate substrate and n-hexyl organometallic reagent. The results are rationalized by reference to chelated transition state model (60), attack of the nucleophile being favoured from the least hindered face of the prochiral P-carbon atom (i.e. from the same side as sulfoxide lone pair) (Scheme 4.32). 

Chelated transition state models have been proposed to account for the high stereoselectivities induced by the DiTOX system in many synthetic transformations. These are highlighted below for the case of enolate alkylation. 

With a-alkyl-substituted chiral carbonyl compounds bearing an alkoxy group in the -position, the diastereoselectivity of nucleophilic addition reactions is influenced not only by steric factors, which can be described by the models of Cram and Felkin (see Section 1.3.1.1.), but also by a possible coordination of the nucleophile counterion with the /J-oxygen atom. Thus, coordination of the metal cation with the carbonyl oxygen and the /J-alkoxy substituent leads to a chelated transition state 1 which implies attack of the nucleophile from the least hindered side, opposite to the pseudoequatorial substituent R1. Therefore, the anb-diastereomer 2 should be formed in excess. With respect to the stereogenic center in the a-position, the predominant formation of the anft-diastereomer means that anti-Cram selectivity has occurred. 

Darzens reaction of (-)-8-phenylmethyl a-chloroacetate (and a-bromoacetate) with various ketones (Scheme 2) yields ctT-glycidic esters (28) with high geometric and diastereofacial selectivity which can be explained in terms of both open-chain or non-chelated antiperiplanar transition state models for the initial aldol-type reaction the ketone approaches the Si-f ce of the Z-enolate such that the phenyl ring of the chiral auxiliary and the enolate portion are face-to-face. Aza-Darzens condensation reaction of iV-benzylideneaniline has also been studied. Kinetically controlled base-promoted lithiation of 3,3-diphenylpropiomesitylene results in Z enolate ratios in the range 94 6 (lithium diisopropylamide) to 50 50 (BuLi), depending on the choice of solvent and temperature. ... 

Most interestingly, reaction of 393 with nitrones gave a 2-(di-alkenyl)-substituted oxazoline 402. A chelation-based transition state model was proposed to rationalize this unusual cis selectivity. " The 2-(trans-alkenyl)-substituted oxazoline can be obtained using the analogous des-chloro lithiated 2-aIkyloxazo-line. " ... 

Murakami and Taguchi utilized a diastereoselective Grignard addition to a substituted-chiral oxazoline aldehyde 524 (Scheme 8.170) in an improved stereoselective synthesis of D-n7 o-phytosphingosine. The good stereoselectivity observed for 525 can be rationalized by a Felkin-Ahn transition state model although a chelation control mechanism could not be mled out. 

For carbonyl addition, three transition state models have been proposed the Felkin-Anh model36, the chelate Cram model37 and the dipolar Cornforth model37 . 

The Reason for Cram and Anti-Cram Selectivity and for Felkin-Anh and Cram Chelate Selectivity Transition State Models... 

In additions of hydride donors to a-chiral carbonyl compounds, whether Cram or anti-Cram selectivity, or Felkin-Anh or Cram chelate selectivity occurs is the result of kinetic control. The rate-determining step in either of these additions is the formation of a tetrahedral intermediate. It takes place irreversibly. The tetrahedral intermediate that is accessible via the most stable transition state is produced most rapidly. However, in contrast to what is found in many other considerations in this book, this intermediate does not represent a good transition state model for its formation reaction. The reason for this deviation is that it is produced in an... 

After Cram had discovered the selectivities now named after him, he proposed the transition state model for the formation of Cram chelate products that is still valid today. However, his explanation for the preferred formation of Cram products was different from current views. Cram assumed that the transition state for the addition of nucleophiles to a-alkylated carbonyl compounds was so early that he could model it with the carbonyl compound alone. His reasoning was that the preferred conformation of the free a-chiral carbonyl compound defines two sterically differently encumbered half-spaces on both sides of the plane of the C=0 double bond. The nucleophile was believed to approach from the less hindered half-space. 

Transition states for reduction according to our usual model of chelation-controlled 2-acyl 1,3-dithiane 1-oxide reactivity, together with steric approach control were proposed to rationalize the high levels of observed stereoselectivity. Previous work by Solladie suggests that ketone reduction by the DIBAL/ZnCl2 system does indeed involve such chelated transition states.15... 

This prediction was verified by X-ray structure determination of one of the major product diastereoisomers produced in the anti series. The structure was found to be consistent with our proposed transition-state models, and the intermediate formation of a chelated Z-enolate. 

SCHEME 92. Proposed transition state models for Chelation-controlled benzylation of 5-hydroxy-4-n-butylpentanoic ester and the corresponding glycolic ether derivatives444 4453... 

The mechanism of the Mukaiyama aldol reaction largely depends on the reaction conditions, substrates, and Lewis acids. Linder the classical conditions, where TiCl4 is used in equimolar quantities, it was shown that the Lewis acid activates the aldehyde component by coordination followed by rapid carbon-carbon bond formation. Silyl transfer may occur in an intra- or intermolecular fashion. The stereochemical outcome of the reaction is generally explained by the open transition state model, and it is based on steric- and dipolar effects. " For Z-enol silanes, transition states A, D, and F are close in energy. When substituent R is small and R is large, transition state A is the most favored and it leads to the formation of the anf/-diastereomer. In contrast, when R is bulky and R is small, transition state D is favored giving the syn-diastereomer as the major product. When the aldehyde is capable of chelation, the reaction yields the syn product, presumably via transition state h. ... 

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