Cram model ‘rule

By application of Cram s rule or a more recent model on the reactivity of a-chiral aldehydes or ketones, a prediction can be made, which stereoisomer will be formed predominantly, if the reaction generates an additional chiral center. 

Cram s open-chain model 229 Cram s rule 229, 233 Cram chelate model 229 Cram cyclic model 229 Cram-Felkin-Anh model 191,207, 236 f 246 cubane 12,318 cyanoacetic acid 636 f. cyanohydrin, protected 145, 150 f. cyclic carbonate protection 541 f., 657, 659 f., 666, 670 cyclization -,6-endo 734 -, 5-exo 733 f. 

Like Cram s Rule, the Felkin-Cherest-Anh model, developed by Felkin and coworkers6, is an attempt to understand and predict the stereochemistry of addition to a carbonyl group. This model requires a "small 0" interpretation in which the largest group is oriented anti to the attacking nucleophile s trajectory. One should note that the Felkin-Cherest-Anh model neglects the interaction of the carbonyl oxygen. In this approach, the R/S or RJM interactions dominate. 

A number of models have been developed to predict the stereochemical outcome of the addition of a nucleophile to a carbonyl with a chiral a carbon. One of the first was Cram s rule which was developed on an empirical basis64. The generalization is shown in Figure 8a, where L, M and S represent large-, medium- and small-sized groups, respectively, attached to the chiral a carbon. The molecule is imagined to be oriented so... 

Diastereoselective addition of organometallic reagents to a-chiral aldehydes usually follows the Cram s rule or Felkin-Ahn model. However, the sense ot the Odiastereoselectivity in the catalysed addition of dialkylzinc to a-chiral aldehydes is determined not by the chirality of aldehyde but by the configuration of the chiral catalysts. By choosing the appropriate enantiomer of the chiral catalyst, one can obtain the desired diastereomer from the diastereoselective addition of dialkylzincs to a-chiral aldehydes.18 Either of the diastereomers of protected chiral 1,2-diols and 1,3-diols is synthesized using the appropriate enantiomer of the chiral catalysts [(15,2f )-l, (R,R)-15, and their enantiomers] from the addition of diorganozincs to protected a-hydroxy-19 and P-hydroxyaldehydes (Scheme 12.3).20... 

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). 

In the asymmetric alkylation of a-chiral aldehydes using dialkylzinc reagents, the stereochemistry is controlled by the configuration of the chiral catalyst, not by the stereochemistry in the a-position. It is different from the diastereoselec-tive alkylation using other organometallic reagents where the stereochemistry follows from Cram s rule or the Felkin-Ahn model. Each diastereomer with high ee was obtained by the choice of the appropriate enantiomer of chiral catalyst [(IS, 2R)- or (li ,2S)-DBNE 1] (Scheme 6) [18]. 

In general, under appropriate conditions, the stereoselectivity of the reaction is remcurkably high with ratios of 95 5 or more leading, eventually, to enantiomeric excesses above 90%. Similarly high stereoselectivity had been observed in a mmiber of eeurlier examples involving Cram s rule in the rigid model (13 ). 

Cram s rule (cyclic model) A model for predicting the major stereoisomer resulting from nucleophilic addition to an aldehyde or a ketone having an adjacent stereocenter that is capable of chelation (especially 5-membered ring chelation). After chelate formation, the nucleophile adds from the side opposite the larger of the remaining substituents on the a-stereocenter [48]. See Section 4.2. 

Felkin-Anh model See Cram s rule (open chain model). 

The predictive value of Cram s rule notwithstanding, the rationale was speculative, and as spectroscopic methods developed, it was called into question. For example, Karabatsos studied the conformations of substituted aldehydes [8] and dimethylhydrazones [9] by NMR, and concluded that one of the ligands at the a position eclipses the carbonyl. It was felt that in the addition reaction, the organometallic probably did coordinate to the carbonyl oxygen as Cram had suggested, and Karabatsos used the conformations of the dimethylhydrazone as a model for the metal-coordinated carbonyl. He concluded that since the aldehyde and the hydrazone have similar conformations, so should the metal-complexed carbonyl... 

Thus Karabatsos concluded that the rationale for Cram s rule was incorrect [10]. In 1967, he published a new model, which took into account the approach of the nucleophile from either side of all three eclipsed conformers [10]. He noted that the enthalpy and entropy of activation for Grignard or hydride additions to carbonyls are 8 to 15 kcal/mole and -20 to -40 eu, respectively. Since the barrier to rotation around the sp -sp carbon-carbon bond is much lower [12], the selectivity must arise from Curtin-Hammett kinetics [13,14]. Of the six possible conformers (Figure... 

Table 4.2. Cram s rule stereoselectivities (% ds) for aldol additions to aldehydes (negative value indicates anti-Cram is favored), assuming X is the large substituent in the Felkin-Anh model [28] ...

Cram s rule rigid, chelate, or cyclic model... 

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... 

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