Asymmetric synthesis of 1-phenylpropanol using polymer-supported chiral catalysts in simple bench-top flow systems†

Abstract

Reactions of aldehydes with diethylzinc catalysed by PS ephedrine or PS camphor derivatives in bench-top flow systems have been investigated. This type of reaction system allows the PS chiral catalysts to be conveniently used for extended periods. When the PS camphor derivative 3 was used in a flow system to catalyse the reaction of benzaldehyde with diethylzinc [Reaction (1)], 1-phenylpropanol 1 was initially obtained in a chemical yield of >95% and an ee of >94%, but after ca. 275 h in use the chemical yields had dropped to 50–60% and the ee to 81–84%. The deterioration in performance appears to be due to the gradual chemical degradation of the catalyst sites. It is suggested that this results from oxidation of the 3-exo-hydroxy group of the catalyst moiety. Thus, when, in future, PS catalysts are to be repeatedly recycled then it will not only be necessary to use a physically robust polymer, but it will also be necessary to select catalytic groups which do not chemically degrade significantly during the extended reaction periods. High % ee could be obtained in certain flow systems. Thus, under optimum conditions the use of both PS ephedrine and PS camphor derivatives as catalysts for Reaction (1) gave 1-phenylpropanol 1 in 97–99% ee. The result with the PS ephedrine derivative is surprising because when (1R,2S)-N-benzylephedrine 5 is used in batch systems under typical reaction conditions it affords (R)-alcohol 1 in only ca. 81% ee. The increase in the ee probably arises because the flow system produces the effect of a high mol% of catalyst and/or of diethylzinc and/or because the initial alkoxide reaction product, which acts as a catalyst and gives product with a very low % ee, is continuously removed from the reaction system. This result indicates that catalyst species can be formed from the PS ephedrine derivatives and from (1R,2S)-N-benzylephedrine 5 which produce very high enantioselectivities but which are not normally present in sufficient amounts to dominate the reaction system.