A new class of efficient catalysts was developed for the asymmetric transfer hydrogenation of unsymmetrical ketones. A series of chiral N,S-chelates (6-22) was synthesized to serve as ligands in the iridium(I)-catalyzed reduction of ketones. Both formic acid and 2-propanol proved to be suitable as hydrogen donors. Sulfoxidation of an (R)-cysteine-based aminosulfide provided a diastereomeric ligand family containing a chiral sulfur atom. The two chiral centers of these ligands showed a clear effect of chiral cooperativity. In addition, aminosulfides containing two asymmetric carbon atoms in the backbone were synthesized. Both the sulfoxide-containing beta-amino alcohols and the aminosulfides derived from 1,2-disubstituted amino alcohols gave rise to high reaction rates and moderate to excellent enantioselectivities in the reduction of various ketones. The enantioselective outcome of the reaction was favorably affected by selecting the most appropriate hydrogen donor. Enantioselectivities of up to 97% were reached in the reduction of aryl-alkyl ketones.

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The solid-phase synthesis of new asymmetric transfer hydrogenation catalysts as well as the use of these silica supported systems in batch and flow reactors is reported. The ruthenium complex of NH-benzyl-(1R,2S)-(-)-norephedrine covalently tethered to silica showed a high activity and enantioselectivity in the reduction of acetophenone. In three consecutive batchwise catalytic runs, we obtained ee values of 88%. In a continuous flow reactor, a very constant catalytic activity was observed; no catalyst deactivation occurred over a period of one week. This has been ascribed to successful site isolation. Using optimized conditions in this flow reactor, the ee was as high as 90% at 95% conversion. The supported catalysts generally show the same trend in catalyst performance as in solution. The viability of our approach was further shown in one example, the ruthenium(II) complex of (1S,2R)-(+)-2-amino-1,2-diphenylethanol, for which an enantiomeric excess of 58% was observed, which is nearly three times higher than its homogeneous analogue.

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