91364-11-3

A modular ligand library of α-amino acid hydroxyamides and thioamides was prepared from 10 different N-tert-butyloxycarbonyl-protected α-amino acids and three different amino alcohols derived from 2,3-O-isopropylidene-α-d-mannofuranoside. The ligand library was evaluated in the half-sandwich ruthenium- and rhodium-catalyzed asymmetric transfer hydrogenation of a wide array of ketone substrates, including simple as well as sterically demanding aryl alkyl ketones, aryl fluoroalkyl ketones, heteroaromatic alkyl ketones, aliphatic, conjugated and propargylic ketones. Under the optimized reaction conditions, secondary alcohols were obtained in high yields and in enantioselectivities up to >99%. The choice of ligand/catalyst allowed for the generation of both enantiomers of the secondary alcohols, where the ruthenium-hydroxyamide and the rhodium-thioamide catalysts act complementarily towards each other. The catalytic systems were also evaluated in the tandem isomerization/asymmetric transfer hydrogenation of racemic allylic alcohols to yield enantiomerically enriched saturated secondary alcohols in up to 98% ee. Furthermore, the catalytic tandem α-alkylation/asymmetric transfer hydrogenation of acetophenones and 3-acetylpyridine with primary alcohols as alkylating and reducing agents was studied. Secondary alcohols containing an elongated alkyl chain were obtained in up to 92% ee. (Figure presented.).

The title compounds and the corresponding L-gulo derivatives were synthesised in 6 steps from benzyl 2,3:5,6-di-O-isopropylidene-α-D-mannofuranoside.The Ki values, determined from inhibition studies with α-D-mannosidases from jack beans, almonds, and calf liver, and β-D-mannosidase from Aspergillus wentii, ranged from 70 to 400 μM for the mannitol derivative and from 1.2 to 20 μM for 5-amino-5-deoxy-D-mannopyranose, i.e., inhibition is E2-E4-fold stronger than with D-mannose.Marked enhancement of inhibition with increasing pH is ascribed to the ionisation of a carboxyl group at the active site, forming an ion pair with the protonated inhibitor.The inhibition equilibrium between the jack-bean enzyme and the mannose derivative was approached slowly with kapp 2.0E5 M-1.min-1.The mannose-derived inhibitor was also inhibitory against β-D-glucosidases from almonds and Asp. wentii, with Ki values only 20-150-times larger than those for the inhibition of these enzymes by 5-amino-5-deoxy-D-glucopyranose.This moderate discrimination in binding of D-gluco and D-manno derivatives is in marked contrast to the high specificity shown by the glucosidase in catalysing the hydrolysis of mannosidases.A similar low specificity with respect to binding, combined with highly specific catalysis, was also seen with the mannosidases acting on inhibitors and substrates with the D-gluco configuration.