Anti-Cram

Chelation Control Model- "Anti-Cram" selectivity... 

Table 9. Anti-Cram Alkylation of a-Methyl Aldehydes I R2M - 78 °C...

As well as the modified cuprate reagents, Grignard reagents in the presence of the highly sterically demanding methylaluminum bis(2,4,6-tri-fcrr-butylphenoxide) (MAT, 8) also show considerable anti-Cram selectivity35 36 (Table 9). 

In fact, the highest anti-Cram selectivity reported to date (96% de) was observed with the MAT-mediated addition of methylmagnesium bromide to 2-(l-cyclohexenyl)propanal3 i 36. The stereochemical outcome of this addition reaction can be explained as follows on treatment of the carbonyl compound with the large aluminum reagent, the sterically least hindered complex 9 is formed. Subsequent addition of the nucleophile from the side opposite to the bulky aluminum reagent produces the anti-Cram diastereomer preferentially. 

With a-alkyl-substituted chiral carbonyl compounds bearing an alkoxy group in the -position, the diastereoselectivity of nucleophilic addition reactions is influenced not only by steric factors, which can be described by the models of Cram and Felkin (see Section 1.3.1.1.), but also by a possible coordination of the nucleophile counterion with the /J-oxygen atom. Thus, coordination of the metal cation with the carbonyl oxygen and the /J-alkoxy substituent leads to a chelated transition state 1 which implies attack of the nucleophile from the least hindered side, opposite to the pseudoequatorial substituent R1. Therefore, the anb-diastereomer 2 should be formed in excess. With respect to the stereogenic center in the a-position, the predominant formation of the anft-diastereomer means that anti-Cram selectivity has occurred. 

In contrast to the results obtained with the jS-alkoxy-a-alkyl-y-lactol 16 (vide supra), a chelation-directed, anti-Cram selective nucleophilic addition to the a-methyl-y-lactol 1 was not only observed with methyllithium and methylmagnesium bromide but also with (triisopropoxy)methyl-titanium72. In fact, the highest diastereoselectivity (> 98 % de) was observed with the titanium reagent in dichloromethane as reaction solvent. A seven-membered chelate 3 with the a-methyl substituent in a pscudoequatorial position has been postulated in order to explain the stereochemical outcome. 

Methylmagnesium chloride has been added to various d-(4-substituted-phenyl) <5-oxo esters 15 (X = H, Cl 13, F, Cl, Br, OC11,) which provides the diastereomeric -lactones 1642. The electronic properties of the phenyl 4-substituent have no significant influence on the diastereoselectivity. Except for the 4-methoxyphenyl compound, which is unreactive even at 60 °C, a ratio of ca. 40 60 in favor of the anti-Cram product is observed at 60 "C in tetrahydrofuran as reaction solvent. Lowering the reaction temperature to 0 °C slightly increases the anti-Cram selectivity in the case of the 4-fluoro-, 4-chloro-, and 4-bromo-substituted compounds. On the other hand, a complete loss of reactivity is observed with the <5-phenyl- and <5-(4-methylphenyl)-substituted h-oxo esters. 

Some special features arise from pericyclic reactions. In the reaction of an a-methyl-branched aldehyde with ( )-crotylboronates, Cram selectivity is enhanced, whereas the Z-isomers show moderate anti-Cram selectivity23 - 25 (see Section D.1.3.3.3.3.1.3.). These findings can most likely be applied generally. 

In addition, more detailed transition state models have been proposed which account for the unusually high diastereoselectivity5,6. The suggestion is that the additional steric demands created by the axial metal ligands (L) are responsible for the energy difference between the Cram and anti-Cram transition states. 

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. 

Reduction of acyclic a-methyl ketones. Reduction of ketones such as 1 with hydrides such as LiAlH, results in the anti or syn isomer as the predominant product. Bouvault-Blanc reduction, Birch reduction, and Sml2 reduction all favor anti Cram... 

Notice that the aldol condensation of the boron enolate 49 with the aldehyde (S)-53 affords, after recrystallisation, the diastereomerically homogenous 5yn-anti-Cram aldol adduct 52a. The stereochemical control in this process is remarkable. 

Diastereomer analysis on the unpurified aldol adduct 52b revealed that the total syn anti diastereoselection was 400 1 whereas enantioselective induction in the syn products was 660 1. On the other hand, Evans in some complementary studies also found that in the condensation of the chiral aldehyde 53 with an achiral enolate 56a only a slight preference was noted for the anti-Cram aldol diastereomer 58a (58a 57a = 64 36). In the analogous condensation of the chiral enolate 56b. however, the yn-stereoselection was approximately the same (57b 58b > 400 1) as that noted for enolate 49 but with the opposite sense of asymmetric induction (Scheme 9.17). Therefore, it can be concluded that enolate chirality transfer in these systems strongly dominates the condensation process with chiral aldehydes. 

In fact, even if simple stereoselection can be reasonably controlled, using syn and anti selective reagents S mixtures of "Cram " and "anti-Cram" diastereomers are always obtained as shown in Scheme 9.19, where only the (Z)-enolate is formed ... 

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"). 

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 ... 

---