Fluorous chiral 1,2-aminoalcohols in diethylzinc additions

Chiral aminoalcohols have been used extensively as building blocks in natural products synthesis, precursors to chiral auxiliaries like oxazolidinones, and as ligands for asymmetric catalysis. Given their importance it’s not surprising that there are numerous methods for the synthesis of chiral 1,2-aminoalcohols. Included among these are aminohydroxylation, nucleophilic nitrogen opening of epoxides, hydrolysis of aziridines, reduction of sulfinylimines, reduction of α-amino acids…in other words, there’s a lot of methods. Not surprisingly, fluorous 1,2-aminoalcohols have also been produced, most notably by Prof. Hultin’s group at the University of Manitoba.

Prof. Hultin produced fluorous aminoalcohols as precursors to chiral oxazolidinones, commonly known as Evans’ auxiliary. These fluorous Evans’ auxillaries have been used in reactions such as aldol reactions, asymmetric radical additions, and dipolar cycloadditions. Asymmetric inductions and reactivities were comparable to that observed with the non-fluorous oxazolidinones. The fluorous derivatives, however, have the added benefit of having a purification handle. This is quite typical in fluorous chemistry where a fluorous version exerts little or no effect on the chemical reactivity, but allows for facile separation by fluorous solid phase extraction or fluorous liquid-liquid extraction.

Late in 2007, however, Prof. Akira Ando and co-workers at Setsunan University described their work in synthesizing chiral fluorous 1,2-aminoalcohols and their use as chiral ligands in asymmetric diethylzinc additions. The twist, however, was that they hypothesized the fluorous group’s electron withdrawing would effect the Lewis acidity of the hydroxyl group, thereby positively impacting the asymmetric induction reaction. Their synthesis was essentially the same as Hultin’s with the exception that they formed the fluorous anion using a Grignard rather than tBuLi. Addition of the anion to a amino ester provided the aminoketone. Reduction of the ketone resulted in a mixture of anti and syn diastereomers.

The resultant aminoalcohols were then condensed with a number of aldehydes to form α-imino-alcohols which were then used as ligands in diethylzinc additions. It was found that the anti diastereomer provided consistently higher ee’s than the syn diastereomer. Ando and co-workers report that their studies continue. As such it is their good fortune that the anti isomer imparts the best ee’s, since Hultin has already reported that >99:1 anti:syn ratios could be obtained using LiAlH(OtBu)3 instead of NaBH4. While Prof. Ando did not use the fluorous tag for any purification aspects, it would certainly be interesting to see the results.

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