Cram model

An open-chain transition state model, based on the improved Cram model (Section A.2.), was proposed for the prediction of the stereochemical outcome1 2. Under kinetic control, if the substituent R1 in the benzylic position is of medium size, the syn-isomer is formed as the major product2. 

A modified Cram model 7 and/or Felkin model 8 is proposed for the 1.2-asymmetric induction on chiral imines. 

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. 

In the presence of ZrCU or HC1, cyclization of y - a I k o x y a 11 y I s t a n n a n e 158 bearing (i )-(+)-l-phenylethylamine as a chiral auxiliary occurs to produce trans-fi-aminocyclic ether 159 with high de (91%). As shown in Scheme 3-55, asymmetric addition of an allyl group to the imine carbon can be explained by the modified Cram model 160. The attack of the allylic y-carbon approaches... 

This stereoselectlon can be explained by assuming an attack of the Grlgnard reagent via a non-cycllc Cram model (30). 

The chelate Cram model 6, p 125 has already shown how acyclic induction may be improved by forming a temporary cyclic species with a frozen conformation. This concept has been generalized in different ways. One is the incorporation of the acyclic substrate in a macrocyclic template. 

A modification of the Cram model, in which the medium sized group, M, eclipsed the carbonyl oxygen, was developed by Karabatsos5 however, it generally predicted the same product as the Cram model. In this model, which assumes two major conformations, the major product is that which is derived from attack at the less hindered side of the more stable conformer. 

There is evidence to suggest that competing dipole effects will alter the preferred conformation. Thus, for example, halogens will prefer a conformation in which the dipoles are anti to one another. This is often described as the Cornforth model In this model the highly polarized group will take the place of the L-group of the Cram model. 

Cornforth et al.54 introduced a variant of the Cram model to be used when one of the substituents is highly electronegative (halogens, etc.). The electronegative group X is oriented anti to the oxygen, to minimize dipolar interactions. In other words, X plays the role of the bulky substituent. 

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. 

M Figure 6-2, The Cram model for nucleophilic attack at acyclic carbonyl compounds. 

As chemists considered the origin of this diastereoselectivity, the reactant conformation that is considered to be the most important one has changed. The currently preferred Felkin-Ahn model places the largest substituent perpendicular to the carbonyl group. The major product results from the nucleophile approaching opposite to the largest substituent. This is the same product as predicted by the Cram model, although the interpretation is different. 

The presence of an a-alkoxy substituent does not always lead to Cram selectivity. Reduction of 262a gave 82% of the syn diastereomer, 263.2 Analysis of the Cram cyclic model for 262 (see 264) leads to an incorrect prediction of the anti-diastereomer (265) as the major product. The normal Cram model (see 262b) predicts the correct syn-diastereomer (263) but in reality, the solution to this problem requires that the alkoxy substituent at the C3 position be coordinated with the metal of the reducing agent. In 264, a five-membered... 

The Cram open-chain model assumed the presence of a reactive species that led to a higher energy eclipsed conformation in the final product. The Cram open-chain model fails to predict the correct diastereoselectivity for many acyclic molecules that contain heteroatom substituents. 76 The Cram model also fails to predict the correct diastereomer when the relative size Rs and Rm are close. One attempt to correct the deficiencies of the... 

The Felkin-Ahn and Cram models are best applied to acyclic systems. Problems arise when any of these models are used to predict the products generated by the reduction of cyclic ketones. These problems will be analyzed and new models for predicting diastereoselectivity in the reduction of cyclic molecules will be discussed in Section 4.7.C. 

The Cram model does not predict the correct stereochemistry of reduction products derived from cyclohexanone derivatives. anti-Periplanar hyperconjugative effects have been invoked to explain the observed results. The Felkin-Ahn model suggests an interaction such as that shown in 297. 91 An alternative proposal was put forth by Cieplak, shown in 298, 92 and it was found that the incipient bond (the one being formed) was electron deficient, in line with Cieplak s proposal. Cieplak s model has led to some controversy, and a... 

Predict the correct diastereomeric product using (a) the appropriate Cram model and (b) the Felkin-Ahn... 

---