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In fact, this methoxy catalyst had been tested in the aldol reaction and was found to generate the S aldol product from acetophenone albeit in 77.5/22.5 er.
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The reason for the large energy difference between transition states derived from complexes vii and viii (i.e., ketone in equatorial positions 1 and 2) is the twisted conformation that the catalyst adopts around the silicon center (see Figure 3A). The 6,6′-substituents are located in the upper right and lower left quadrants of the complex. Because the ketene acetal is bound at an axial position, for aldolization to occur the ketone has to turn down out of the equatorial plane. In position 1, this is acceptable as the bottom right quadrant of the complex is unoccupied (the catalyst occupies the top right). However, in position 2 the R-group of the ketone is forced into the same quadrant of the complex as the 6,6′-subtituent, thereby increasing the energy of this orientation.
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This is of course, the basis for the elimination of reaction pathways via complex viii as discussed above. (40) The magnitude of the entropy change, in rising to the transition state, is likely to be different for each of the diastereomeric transition states. These changes in ΔS can be extremely significant as was clearly shown by Ingold in the Finkelstein substitution of organic halides (Ingold, C. K.; De La Mare, P. B. D.; Mackie, J. D. H. J. Chem. Soc. 1955, 3200-3236). The modest improvements in enantioselectivity observed in changing a methyl to an n-butyl group represent a very small change in the steric requirement of the catalyst and may be better understood in the decrease in entropy of the alkoxy side chain in the vi-Re pathway. The major interaction present in the complex vi-Re is between the ketone and the alkoxy substituent of the catalyst. At the transition state the n-butyl chain will be forced into one conformation, freezing out several rotational degrees of freedom.
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