Cram rule chiral aldehyde reactions

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. 

Now, if we allow one enantiomer of the chiral aldehyde 59 to react with the two enantiomers of the chiral enolate M, in one case the two chiral reagents will both promote the same absolute configuration at the two new chiral centres (65a ). However, no such effect will be observed in the other possible combination (c/. 65) (Scheme 9.21). In the first case, the effective "Cram s rule selectivity" shown by the aldehyde will be greater than in its reactions with achiral enolates. For the selectivities chosen the "Cram anti-Cram ratio" should be in our example of the order of 100 1 (see below 9.3.4., Masamune s "double asymmetric induction"). 

Application of this condensation to aldehydes with an a-chiral center gives rise to two chiral centers, the relative stereochemistry of which can be related to the Prelog-Cram selectivity rule. Such a reaction was used for a short stereoselective synthesis of... 

We have developed a synthesis of antheridiol in which the key step is an aldol condensation of a C-22 aldehyde with the anion derived from 3-isopropyl-but-2-enolide (4) which gives directly the sidechain of antheridiol as illustrated by structures 2 and 3. In this reaction, chiral centers are created at C-22 and C-23. The stereochemistry at C-22 in the major product is that predicted by the Cram rule (i.e. R) and careful study of the reaction showed that the stereochemistry at C-23 is determined by the temperature at which the aldol reaction is carried out. If the temperature is maintained below -70 °C, the major product has the R configuration at C-23. Thus, this method could be used to construct the sidechain of brassinolide with correct stereochemistry at C-22 and C-23. 

The two faces of a chiral aldehyde are diastereotopic, and reaction with an achiral enolate can therefore give two diastereomeric products. Qualitatively, the major and minor products of such a reaction are determined by the intrinsic diastereofacial preference of the chiral aldehyde, which may be evaluated by the use of Cram s rule or one of its more modem derivatives. Quantitatively, the diastereomeric ratio in such a reaction is a function of the enolate. An example is seen in Scheme 8. 2-Phenylpropanal reacts with the lithium enolates of acetone, pinacolone, methyl acetate and N,N-dimethylacetamide to give 3,4-syn and 3,4-ant diastereomers in ratios of 3 1 to 4 1. With ethyl ketones and propionate esters, the diastereofacial ratio is approximately 6 1 and with methyl isobutyrate only a single isomeric product is produced. This tendency of more bulky nucleophiles to give higher diastereofacial ratios in reactions... 

The major and minor products obtained in aldol reactions of chiral aldehyde (168 equation 109) are not those predicted by Cram s rule, presumably because the lithium cation is chelated by the alkoxy and aldehyde oxygens, leading to a rigid six-meml red intermediate that undergoes attack primarily from its unsubstituted face. " Similar behavior, with somewhat higher diastereofacial selectivity (5 1), is seen with the magnesium enolate (equation 50). 

The aldol condensation, one of the oldest organic reactions, is emerging as a powerful method for control of relative and absolute stereochemistry in the synthesis of conformationally flexible compounds. Some of the research which has been carried out at Berkeley over the past five years is reviewed in this article. Points discussed are the factors that control simple erythro, threo diastereoselection, the use of double stereodifferentiation to influence the "Cram s rule" preference shown by chiral aldehydes, and some recent experiments that shed light on the role that the solvent and other nucleophilic ligands play in determining the stereochemistry of the reaction. 

In most cases, Crams rule (sec. 4.7.B) predicts the major isomer when the reaction partner (or partners) contain a chiral center. To understand how this rule applies to orientational and facial selectivity, we must understand the transition state of the reaction (invoke the Zimmerman-Traxler model or one of the other models for predicting diastereoselectivity). The Zimmerman-Traxler model is used most often, and if it is applied to 423 and 424, the syn selectivity can be predicted. The facial selectivity shown in 427 and 428 arises from the methyl group. In 428, the enolate approaches from the face opposite the methyl, leading to diminished steric interactions and syn product (429). If the enolate approaches via 427, the steric impedance of the methyl group destabilizes that transition state relative to 428. In both 427 and 428, a Cram orientation is assumed (see above) although other rotamers are possible. The appropriate rotamer for reaction therefore is that where Rl is anti to the carbonyl oxygen. Since the phenyl group is Rl, 427 and 428 are assumed to be the appropriate orientation for the aldehyde. If an aldehyde or ketone follows anti-Cram selectivity, this aldehyde orientation must be adjusted. 

You may hear Cram s rule used to explain the outcome of reactions Involving attack on chiral carbonyl compounds. Cram was the first to realize that these reactions could be predicted, but we now know why these compounds react In a predictable way. We will not describe Cram s rule because, although It often does predict the right product. In this case It does so for the wrong reason. Explanations and clear logical thinking are more Important than rules, and you must be able to account for and predict the reactions of chiral aldehydes and ketones using the Felkln-Anh model. 

When the electrophile is chiral, besides simple stereoselection, a second type of diastereoselectivity termed "distereofacial selectivity" is possible. This sort of diastereofacial preference, qualitatively predictable by Cram s rule for asymmetric induction or one of its modem descendants, is typical of additions to chiral aldehydes. Chiral a-methyl aldehydes show exceptional diastereofacial preferences in their I wis acid mediated reactions with enolsilanes. The reason for this selectivity may be due to an approach trajectory of the nucleophile closer to the chiral center when the carbonyl is bound to the Lewis acid. ... 

Now let us consider the reaction between an achiral enolate and a chiral aldehyde. As we have seen, the 2,3-diastereoselection is controlled only by the enolate geometry. However, the diastereofacial selection, and therefore the relation between the new centres and that on the aldehyde, is determined by Cram s rule or its variant. 

In all the examples commented upon so far, we have dealt with reactions with internal diastereoselective induction. However, when a chiral centre is already present in one of the components [12] we must refer then to a relative diastereoselective induction, and Cram s rule [13] must be taken into account when the chiral centre is present at the a-position of the aldehyde (28). For instance, in the reaction shown in Scheme 9.7 of the four possible diastereomers only two are formed, the Cram-i yn-aldol 30a being the predominant diastereomer (see below 9.3.3). 

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... 

If the aldehyde carries a chiral a-methyl group, as in 50, the major product is the syn-syn adduct, in accordance with the Cram and Felkin-Anh model (Table 4). For a reminder of the Cram and Felkin-Anh rules, see The Sakurai reaction . 

Note that the natural tendency of the aldehyde to undergo nucleophilic attack according to Cram s rule is overridden. The selectivity of this reaction surprised even the authors, who found the product was a400 1 mixture of u and / diastereomers at the two newly created stereogenic centres, with an overall asymmetric induction with respect to the chiral auxiliary of no less than 660 1. 

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