Electrostatic repulsion, enolate conformation

The proportion of the /rans-O-alkylated product [101] increases in the order no ligand < 18-crown-6 < [2.2.2]-cryptand. This difference was attributed to the fact that the enolate anion in a crown-ether complex is still capable of interacting with the cation, which stabilizes conformation [96]. For the cryptate, however, cation-anion interactions are less likely and electrostatic repulsion will force the anion to adopt conformation [99], which is the same as that of the free anion in DMSO. This explanation was substantiated by the fact that the anion was found to have structure [96] in the solid state of the potassium acetoacetate complex of 18-crown-6 (Cambillau et al., 1978). Using 23Na NMR, Cornelis et al. (1978) have recently concluded that the active nucleophilic species is the ion pair formed between 18-crown-6 and sodium ethyl acetoacetate, in which Na+ is co-ordinated to both the anion and the ligand. 

The main features in the conformational analysis of these compounds, i.e. relative stabilities of syn and anti conformers, rotation energy barriers and eventually out of plane distortions of the anti conformers, result in manyfold weak interactions and it would be tedious and illusive to give their complete qualitative analysis. We can nevertheless display the most important of them and indicate the trends induced by the change of the nature of the substrate (enol or thioenol) or the position and the nature of substituents. Two interactions seems to be effective enough to be taken into account electrostatic repulsions and attractions, and ir orbital effects. 

Thus, L-aspartic acid was converted into the oxazoline 299 with different substituents X [99]. Enolate generation with base was followed by C-methylation to generate diastereomers syn-300 and anti-301. Remarkably, the syn/anti ratio strongly depends on X, the base, and the presence of HMPA. For X = MejN and LiNEt2, 301 is favored without HMPA, and the preference is much lower after addition of HMPA. For X = tBuS and NaHMDS, 301 is formed with high selectivity in the absence of HMPA, whereas 300 predominates after addition of HMPA (Scheme 3.60). These results may be interpreted via a chelate intermediate 302 in the formation of 301, with the attack anti to the nitrogen. Addition of HMPA breaks up the chelate, and the electrostatic repulsion between the heteroatoms induces an extended conformation 302. Now, the attack from the anti-position leads to 300 (Scheme 3.61). 

The utility of BF3-OEt2, a monodentate Lewis acid, for acyclic stereocontrol in the Mukaiyama aldol reaction has been demonstrated by Evans et al. (Scheme 10.3) [27, 28]. The BF3-OEt2-mediated reaction of silyl enol ethers (SEE, ketone silyl enolates) with a-unsubstituted, /falkoxy aldehydes affords good 1,3-anti induction in the absence of internal aldehyde chelation. The 1,3-asymmetric induction can be reasonably explained by consideration of energetically favorable conformation 5 minimizing internal electrostatic and steric repulsion between the aldehyde carbonyl moiety and the /i-substituents. In the reaction with anti-substituted a-methyl-/ -alkoxy aldehydes, the additional stereocontrol (Felkin control) imparted by the a-substituent achieves uniformly high levels of 1,3-anti-diastereofacial selectivity. 

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