Asymmetric induction 1,2-addition, Cram Model

In addition to the previously described models many of the 1,3-asymmetric inductions can be explained by the extended Cram model 4, especially the allyl-metalation reactions6. 

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. 

Very few examples of asymmetric 1,4-induction are reported in connection with the addition of acidic Ti complexes to chiral y-alkoxycarbonyl compounds. According to the Cram model, the chelation is expected to afford a flexible seven-membered ring intermediate, resulting in less efficient induction (equation 34). An early example of asymmetric 1,4-induction is provided by the reaction of o-phthalal-dehyde (96 equation 35) with 2 equiv. of MeTi(OPr )3 which affords an 83 17 molar mixture of racemic- 97) and meso-(98), whereas Ae analogous reaction with MeMgl leads to a 1 1 mixture of the above diastereomers. 

Despite the great deal of attention devoted to nucleophilic additions to a-chiral carbonyls, the source of stereoselectivity in these reactions (predicted by Cram s rules of asymmetric induction ) remains largely unresolved. Neither direct structural studies nor correlation of reactant and product stereochemistries have yielded any conclusive support for a single comprehensive model. Similarly, the effect of Lewis acids on these systems is only understood at the level of chelation-controlled additions (vide infra). 

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... 

Scheme 1.2. Intraligand vs. interligand asymmetric induction (a) Diastereoselective addition via Cram s cyclic model ([49], cf., Section 4.2). (b) Asymmetric synthesis of a pure enantiomer via diastereoselective addition to a carbonyl with a chiral auxiliary [50].

This chapter begins with a detailed examination of the evolution of the theory of nucleophilic attack on a chiral aldehyde or ketone, from Cram s original rule of steric control of asymmetric induction to the Felkin-Anh-Heathcock formulation. Then follows a discussion of Cram s simpler rigid model (chelate rule), then carbonyl additions using chiral catalysts and chiral (nonenolate) nucleophiles. The chapter concludes with asymmetric 1,4-additions to conjugated carbonyls and azomethines. 

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... 

A study of the stereochemical outcome of the addition of lithium enolates to a-alkoxyaldehydes has shown that the predominant product is not that predicted by application of Cram s cyclic model for asymmetric induction. Assuming the alkoxy-group to be the largest group a- to the aldehyde, the major product is that predicted by Felkin s model (Scheme 59). ... 

Show your understanding of the Cram and Felkin-Ahn models for asymmetric induction in carbonyl addition reactions by predicting (or rationalizing) the stereochemical course of the following reactions. (Calcimycin-3)... 

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