Cram’s model

Consider now 4-fcrfbutylcyclohexanone, a configurationally rigid molecule. The carbonyl plane defines two half-spaces, the lower of which contains only the axial hydrogens at C2 and C6. Even so, the nucleophile generally arrives from above (90% in the reduction by LiAlH4). These results cannot be explained by Cram s model and other factors have been invoked. For instance, Dauben et al.56 suggested that equatorial attack is under steric approach control whereas axial attack is under product development control ... 

Karabatsos87 introduced a variant of Cram s model based on the following assumptions (1) the transition states for addition to carbonyls are reactant-like (2) the reactive conformations are then the most stable ones, which have a neighboring o bond eclipsing the carbonyl group (cf. p. 188) and (3) the nucleophile approaches from the less hindered side. Assumption (2) is questionable even in the reactant-like transition state, the stable and reactive conformations may be completely different. Karabatsos s model was the first to draw attention on the importance of conformational factors in asymmetric induction. 

Abstract This chapter deals with the facial selectivity of nucleophilic additions to carbonyl compounds. This is explained using models such as the Cram s model, Anh-Felkin modification of Cram s model, Houk s transition structure model, Houk s electrostatic model, Cieplak s a —> cr model, and cation coordination model. The intricacies, variations, and predicted selectivities of these models are elaborated with examples. It has been argued that the Cieplak s cr > cr model is applicable to only those reactions that proceed through product-like transition structures. Using the cation coordination model, the facial selectivities of a number of substrates, including the better anrf-selectivity of endo,endo-2,3-die hyl-l -norbomanone in comparison to that of en[Pg.71]

Keywords Cram s model Anh-Felkin modification Houk s transition structure model Houk s electrostatic model Cieplak s a —> a model Cation coordination model (a —> n model) Carbonyl pyramidalization a —> interaction Reactant-like and product-like transition structures... 

Anh-Felkin Modification of Cram s Model for Asymmetric Synthesis... 

Even if one ignores the difficulty related to the angle of attack, the first two factors which destabilize the TS were serious liabilities of the Cram s model and needed to be addressed. Anh and Felkin considered a different reactant conformer in which... 

Let us consider the reaction of (S)-3-phenyl-2-butanone, 1. The two conformers of the reactant are la (Eq. 6) and lb (Eq. 7), following the Anh-Felkin modification of Cram s model. The conformer la will predominate over lb because the latter suffers from steric interactions between the two methyl groups that are gauche to each other. The conformers la and lb will generate the products (S,S)-2n and (R, S)-2b, respectively, on reaction with ethyl magnesium iodide. Since la is the predominant conformer, (S,S)-2a is formed as the major product, and (R,S)-2b constitutes the minor product. 

Although the predominant product from the reaction of 5 with LiAlH4 is well explained by the Anh-Felkin modification of Cram s model, the question that arises is what truly guarantees the conformation 5b An ab initio calculation of (R)-5 at HF/6-31G level of theory predicts the conformer 5c (Eq. 12) to be the lowest on the potential energy surface. In this conformer, the Cc-h bond on the asymmetric... 

Let us consider the nucleophilic addition to a carbonyl group adjacent to a stereogenic center. Following Anh-Felkin s modification of Crams s model for asymmetric induction, the reaction can follow either of the pathways shown in... 

Figure 4.2. (a-c) Cram s models for predicting the major isomer of a nucleophilic addition to a carbonyl having a stereocenter in the a position [2,6]. (d) Cornforth s dipole model for a-chloro ketones [7], S, M, and L refer to the small, medium, and large groups, respectively. 

The extent of asymmetric induction in systems containing an adjacent stereogenic center has been discussed by Morrison and Mosher. 61 Cram suggested a model for asymmetric induction in ketones such as 236 that has come to be known as Cram s open chain model (Cram s model), or simply Cram s rule.2 2,263 This model assumes a kinetically controlled reaction (nonequilibrating and noncatalytic) for asymmetric 1,2-addition to aldehydes and ketones. The three groups attached to the chiral center are Rs (small substituent), Rm (middle-sized substituent), and Rl (large substituent). Determining the relative size of the substituents is... 

Cram s model does not always predict the stereochemical result of kinetically controlled reductions with aluminum isopropoxide (Cram and Greene, 1953). For example, i -(—)-3-cyclohexyl-2-butanone is reduced to predominantly ZR,2R-erythro carbinol (erythro/threo = 1.9). Apparently special steric forces are important in this reduction. Recent work (Shiner and Whittaker, 1963) has shown that aluminum isopropoxide is trimeric or tet-rameric. It is therefore conceivable that some hydride transfers will involve Al(OR)3 units that are not coordinated to the carbonyl groups they reduce. These transfers may occur preferentially from the side opposite that exposed to a coordinated Al(OR).3 unit. Such competitive mechanistic pathways might well yield an isomer ratio not in agreement with that produced by less complex reducing agents. 

A. Cram s model, B. Karabatsos model, and C. the Felkin-Ahn model for nucleophilic addition to a carbonyl. 

The stereoselectivity of the addition of pinacolone enolsilane 1 to P-alkoxy aldehydes bearing two stereocenters depends on the ability of the metal to form intermediate chelates. Those metals that monocoordinate the carbonyl group form Fel-kin products and the stereochemistry of these aldols is predicted by the Felkin-Anh s model. For metals chelating both the carbonyl and alkoxy groups, anti-Felkin products are obtained. In these cases the cyclic-Cram s model has to be used to predict the stereochemical outcome of the reaction. Therefore, non-chelated (Felkin-Ahn) and chelated models (cyclic-Cram) have been successively applied to understand the stereochemistry of the final reaction products. 

Control of the stereoselectivity in nucleophilic additions to the carbonyl group. Facial selectivity. Felkin Anh s and Cram s models. Reactivity of TMS enol ethers towards electrophiles. 

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