Aldol Condensations Catalysed by Cyclodextrin Derivatives

We prepared a series of eatalysts with relatively simple groups attached to a cyclodextrin that would be able to catalyse an aldol condensation between acetone and some bound aromatic aldehydes, when the acetone formed an enamine with a catalytic group such as a simple amine. We observed catalyses as high as 270-fold relative to the uncatalysed aldol condensation with some of these cyclodextrin derivatives. 

We also examined aldol condensations of the dialdehyde 17. Without the special catalysis afforded by the cyclodextrin i w-imidazoles there was an almost random reaction to form compounds 18 and 19, as either aldehyde acted as the enofizing group. However, the cyclodextrin imidazole catalysts directed the selective formation of products 19, with no selectivity among its stereoisomers. Interestingly, the least selective catalyst for 17 was the cyclodextrin mono-imidazole, the AD isomer of the fcw-imidazole was more selective, and the most selective was the AB isomer. Obviously these results indicate that the cyclodextrin imidazole catalysts promote enolization of the aldehyde group closest to the cyclodextrin, as expected, but the subtlety of preferences among the bw-imidazole isomers is not yet understood in this case. 

Cytochrome P-450 describes a group of enzymes that use a heme group to perform oxidations, including in particular oxidations of carbon-hydrogen bonds. Many model systems had been examined for such processes, but they had not included any defined binding of a substrate in such a way as to achieve pre-selected functionalization of particular carbon atoms. Thus we initiated a series of studies of such systems in which we used cyclodextrins as binding groups for the substrates to hold them, in water, in such a position as to achieve selective functionalizations. 

In general we used steroids as the substrates. They are rigid and make it easier to achieve selectivity without concern about the substrate conformation, and the selective oxidation of steroids in particular positions is actually of practical interest. Currently there are steroid hormones that are produced by biochemical oxidation using the enzymes P-450, but we wished to produce mimics that would not have the disadvantage of enzymatic reactions - with their problems in dealing with proteins and fermentation. 

One problem with our system was that the catalyst itself was oxidized fairly easily, so we did not get many catalytic turnovers. Others working on cytochrome models had shown that the catalyst was much more oxidatively stable when the phenyl rings were perfluorinated. Thus we synthesized a perlluorinated version (24) of our previous compound, easily prepared from the porphyrin with four pentafluorophenyl groups by simple reaction with j8-cyclodextrin 6-thiol, which selectively replaced the para fluorines in the phenyl rings. While with the previous catalyst we only achieved three to five turnovers before the catalyst was destroyed, the new fluorinated catalyst performed the same selective hydroxylation of C-6 in the steroid with 187 turnovers. 

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