Researchers at Gifu Pharmaceutical University led by Prof. Tsuyoshi Miura have been working on fluorous sulfonamide organocatalysts for some time now and have reported their results in various reactions. These include asymmetric aldol reactions and Michael additions which we have covered in the past. In these instances the fluorous tag was attached to one of the nitrogens of the phenylalanine derived organocatalyst through a sulfonamide. The researchers found that either enantiomer of the aldol product could be made starting from the diamine derived from L-phenyalanine by moving the sulfonamide from one nitrogen to the other. Organocatalyst 1 then leads to enantiomer A, while catalyst 2 produces enantiomer B. This is certainly more desired than starting from the D-phenylalanine which is considerably more expensive than Interestingly, however, while they reported using a fluorous sulfonamide in the case of 1, they only reported using the triflate for 2 and never mentioned a fluorous verion. So the fluorous sulfonamide 2 must not have provided very good results in forming the opposite enantiomer. In addition, as seen below, even with the triflate, in order to form enantiomer B, it required double the organocatalyst loading compared to the enantiomer A.
The same authors now report a fluorous version which can provide enantiomer B directly with lower catalyst and substrate loading. Instead of rendering the catalyst fluorous via the sulfonamide the fluorous tag is attached to the aromatic portion of the diamine catalyst. So in this case the diamine is derived from L-tyrosine rather than L-phenylalanine to provide catalyst 4. They then used 4 to catalyze the aldol reaction between cyclohexanone and p-nitrobenzaldehyde. Compared to 2 they were able to use half the amount of catalyst and half the amount of cyclyhexanone(see entry 5) to achieve comparable results. They then used fluorous solid phase extraction (FSPE) to recover and reuse the organocatalyst. The authors went on to test a number of difference ketone and benzaldehyde combinations to test the generality of the reaction. They found that while electron deficient benzldehydes are good substrates but that electron rich ones are not. Other cyclic ketones were tried but none of them gave results that were as good as cyclohexanone.
The results themselves are good, but somewhat limited due to the structural requirements of the reaction. From a fluorous perspective, however, there are some good takeaways here. First is that it demonstrates the flexibility of fluorous tagging. The authors were able to change where the fluorous tag was on organocatalyst 2 quite easily in order to achieve a better catalyst in 4. This was done without effecting the absolute stereochemistry. Second is that the same general purification procedure, FSPE, was used regardless of where the fluorous tag was through a ether bond or a sulfonamide. This then provides an opening for further refinements in the organocatalyst which will hopefully result in a more general reaction.