Asymmetric transfer hydrogenation to aromatic and aliphatic ketones catalyzed by ruthenium complexes linked to both faces of [beta]-cyclodextrin

A novel ATH catalyst comprising of Ru(II) complexes linked to both faces of β-CD is presented. The huge advantage of this system is that it is possible to reduce aromatic as well as notorious difficult aliphatic ketones in good to excellent enantioselectivities (scheme 63). The catalytic reactions were performed in aqueous solution in the presence of 10 mol% catalyst and excess sodium formate.
Initial studies were performed with ligand 79 carrying non chiral aminoethanol on the primary face of β-CD synthesised in one step from monotosylated β-CD 68. The stereoselection varying from 6% ee (R) to 47% (R) for various aromatic carbonyl compounds was addressed to preorganization of the substrate in the hydrophobic cavity of β-CD such that si addition of the hydride to the carbonyl group is preferred in the reactive complex.
Screening of several chiral amino alcohols revealed that β-CD-SAP 92 bearing relatively little sterically demanding chiral methyl group serves as excellent ligand for the ATH to various aromatic and challenging aliphatic ketones (scheme 64). A drastically increase of enantioselectivities up to 97% ee (S) was observed in a mixture of H2O/DMF 3:1 with moderate to good conversions. The chiral centre in α-position to the hydorxy group at the side chain has a strong influence on the stereo outcome. Furthermore the catalytic system was able to reduce β-ketoesters enantioselectively and diketones regioselectively.
A number of monosulfonated diamines and α-pycolyl amines were connected to the primary face of β-CD and applied to ATH. Neither of them could improve β-CD-SAP 79 in terms of reactivity and stereoselectivity.
In continuing studies amino alcohols were linked in five steps and overall yields up to 20% to the secondary face of β-CD. It was anticipated that the stereo outcome of ATH reactions with such ligands would differ from the one’s observed with ligands modified on the primary face due to a distortion of the hydrophobic cavity of β-CD. This desymmetrization is caused by a conformational change of the modified sugar ring from 4C1 to more stable 1C4. Interestingly enantioselectivities up to 98% (S) were achieved using β-CD-AE-2F 220 carrying non chiral amino ethanol on the secondary face. This is a striking result since asymmetric reactions using β-CD’s as the only chiral unit are rarely exceeding 50% ee.
In addition to this it was found that methyl amine attached to the secondary face of β-CD act as excellent ligand in ATH reactions. It could be demonstrated that Ru binds to the amino nitrogen and the hydroxyl group at position 2 of the modified sugar unit. Various aromatic and aliphatic ketones were reduced in exquisite yields and enantioselectivities around 90%.