Crams rule

Only one of the possible epimers at C-20 is formed. According to the Cram rule, the expected product of this reaction should have the 20a-hydroxy configuration. Condensation of (71) with several alkylmagnesium... 

High anti-diastereoselectivity (95 5 dr) and enantioselectivity of the major isomer (99% ee) were obtained when utilizing the combination of (R,R)-catalyst and (S)-aldehyde. This stereochemical outcome (Scheme 6.169) was explained in terms of the Cram rule proposed transition-state model. The substituent on the aldehyde would be located in an onti-relationship to the nitronate. As the largest subshtuent (RJ should be in an anti position to the carbonyl group of the carbonyl substrate, the combination of (R,R)-catalyst 186 and (S)-substrate (TS 1) was favored rather than that of (S,S)-catalyst 183 and (S)-substrate (TS 2) because of the steric repulsion between Rs (smallest substituent) and nitronate (Scheme 6.170). 

Sometimes the Lewis acid that coordinates with the carbonyl oxygen is sufficiently bulky that it seriously influences the stereochemistry of attack. Sometimes these reaction products, which seem opposite of the expected Cram Rule analysis, are termed "anti-Cram" products. Compare the "normal" situation with the influence of a sterically bulky Lewis acid ... 

The cyclocondensation of the diene (1) with (R)-glyceraldehyde acetonide (9) results in high asymmetric induction at C5 of the dihydropyrone (10). The configuration (S) was established by degradation to 2-deoxyribonolactone (11). The result is in accord with the Cram rule for addition to chiral carbonyl compounds. The paper also describes conversion of the pyrone (10) to chiral 2,4-dideoxy-D-glucose. 

The Cram rule as originally formulated is only valid when there is no chelating group attached to the substrate and so neglects any dipolar interactions with the nucleophile. Moreover, there is considerable torsional strain between the L and the R groups. Several subsequent models" have addressed these shortcomings, the Felkin-Anh model being the most popular. 

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. 

Bakers yeast is used almost exclusively for reduction, principally of ketones, by a dehydrogenase which usually follows the Prelog-Cram rule. As with chemical reductions, highest enantioselectivity obtains with aromatic aldehydes and aryl methyl ketones. /3-Keto esters arc also reduced with high canantiosclectivity by yeast. Some j8-kcto acids can also be reduced efficiently to (R)-jS-hydroxy acids. 

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. 

The stereoselectivity of the reaction was elucidated for the enaminone 354 by NMR and X-ray studies. Base treatment generates predominantly the enolate 355, which possesses a twisted diene structure, and the enamine has an E-configuration. Addition of aldehydes to the enolate 355 follows the Cram rule in an antiselective manner to give mainly the adducts 356 having threo configurations, Scheme 100 (86JOC3068 88JA7901). 

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). 

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