Cram rule selectivity

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"). 

Heathcock, C H, White, C T, Morrison, J J, van Derveer, D, Double stereodifferentiation as a method for achieving superior Cram s rule selectivity in aldol condensations with chiral aldehydes, J. Org. Chem., 46, 1296-1309, 1981. 

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. 

An example should make this clear. The aldehyde (64) carries.a chelating group, suggesting that, in the presence of magnesium bromide, the facial selectivity is of the chelated Cram-rule type.l22] Note the syn selectivity due to the Z-enolate (65). 

Addition of metalated, enantiomerically pure a-sulfinyl dimethylhydrazones (e.g., 9) to racemic a-chiral aldehydes 10 proceeds with good to excellent diastereo- and enantioselectivi-ty12. Diastereomeric ratios increase with increasing steric demand of the acetaldehyde substituent R1 compared to the methyl group, and each diastereomer is obtained with high enantiomeric excess. In the aldol-lype addition to 2-phenylpropanal, one of the four possible stereoisomers is formed selectively. The relative (syn) and absolute (R.R) configuration is in accord with Cram s and related rules as well as H-NMR data of closely related compounds. 

Normally, the addition of C-nucleophiles to chiral a-alkoxyaldehydes in organic solvents is opposite to Cram s rule (Scheme 8.15). The anti-Cram selectivity has been rationalized on the basis of chelation control.142 The same anti preference was observed in the reactions of a-alkoxyaldehydes with allyl bromide/indium in water.143 However, for the allylation of a-hydroxyaldehydes with allyl bromide/indium, the syn isomer is the major product. The syn selectivity can be as high as 10 1 syn anti) in the reaction of arabinose. It is argued that in this case, the allylindium intermediate coordinates with both the hydroxy and the carbonyl function leading to the syn adduct. 

For purposes of illustration, consider the erythro selective reaction illustrated in eq. [69]. For aldehydes containing an adjacent asymmetric center (R, Rl = medium and large alkyl substituents), the bias for nucleophilic addition from a given diastereotopic face of the aldehyde is predicted empirically by Cram s rule (the open-chain... 

It is also of interest to note that high diastereofacial selectivity could be achieved. A 10 1 ratio of diastereomeric products (epimeric at C7) was obtained at -120°C, and the major isomer isolated in a 62% yield (liquid chromatography) is of syn stereochemistry, following Cram s rule. 

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... 

Of the large number of reducing agents, the most useful are DIBAH and lithium tri-i -butylborohydride. Regardless of the nature of R, DIBAH reduces 3 mainly to the alcohol 4 (the tzn/i-Cram product) in 60-80% de. Reduction with L-Selectride usually proceeds in the opposite sense and in aeeordanee with Cram s chelate rule, but high selectivity is observed only when R is a primary or tertiary alkyl group. 

Hydride reductions of (7) can be controlled to give either the (R) or (5) secondary hydroxy compound with good selectivity by choice of the reducing agent. Lithium Tri-s-butylborohydride (L-Selectride ) provided the (5)-alcohol (according to Cram s chelate rule) and Diisobutylaluminum Hydride (DIBAL) gave the (R)-carbinol in excess (eq 7). The DIBAL results were rationalized in terms of the open-chain Comforth dipole model. ... 

In the alkylation of a-chiral aldehydes with no ability to chelate with organometal-lic compounds such as Grignard reagents, erythro alcohols are usually obtained preferentially according to the Cram s rule [127], and high Cram selectivity can be achieved with alkyltitanium reagents developed by Reetz [128]. In contrast, application of amphiphilic alkylation to a-chiral aldehydes enables one to achieve the hitherto difficult anti-Cram selectivity, affording threo alcohols selectively as shown in Sch. 91 [125]. 

The next milestone appeared in the 1950s in the context of the development of asymmetric reactions. Various stereochemical reactions induced by facial discrimination of the carbonyl group have always been pivotal in this field. Cram s rule inspired an explosion of studies on diastereoselective reactions followed by enan-tioselective versions. The recent outstanding progress in the non-linear effect of chirality or asymmetric autocatalysis heavily relies on the carbonyl addition reactions. Thanks to these achievements, natural products chemistry has enjoyed extensive advancement in the synthesis of complex molecules. It is no exaggeration to say that we are now in a position to be able to make any molecules in as highly selective a manner as we want. 

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). 

When the electrophile is chiral, besides simple stereoselection a second type of diastereoselectivity, termed diastereofacial selectivity , is possible. This sort of diastereofacial preference, qualitatively predictable by Cram s rule for asymmetric induction or one of its more modem descendants, " is typical for additions to chiral aldehydes. 

Two examples of 1.2-asymmetric induction in the reduction of simple, i.e., nonheteroatom-sub-stituted ketones with dimethylphenylsilane and tris(diethylamino)sulfonium difluorotrimethyl-silicate have been reported4. The predominant stereoisomers are those predicted by Cram s rule, and the diastereomeric ratios suggest that this may be one of the better methods for achieving Cram (Felkin-Anh) selectivity in ketone reductions. 

We have examined a purely logical way in which the "Cram s rule problem" can be attacked — double stereodifferentiation. For example, either reactant in an aldol condensation can be chiral and exhibit diastereoface selectivity. Suppose we have an aldehyde which reacts with achiral enolates to give the two possible erythro adducts in a 10 1 ratio ... 

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... 

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