Minimal Artificial Acylase for the Kinetic Resolution of Racemic Alcohols

Recently, Ishihara and co-workers have studied minimal artificial enzymes to overcome various problems of enzymatic reactions. One of the research achievements, L-histidine-derived minimal artificial catalyst 1 was developed. Ishihara and co-workers reported 1 was a highly effective catalyst in the kinetic resolution of racemic alcohols with acylation. For example, the kinetic resolution of (+/-)-cis-1-(N-pyrrolidinecarbonyloxy)-2-cyclopentanol 2 was achieved by asymmetric acylation with isobutyric anhydride induced by 1 to obtain (1R,2S)- 3 and (1S,2R)- 2 in high optical purity [S(k_fast/k_slow) = 93]. Moreover, S value was increased to 132 if this reaction is done at -20 dgree C. Isobutyric anhydride is effective as the acylating agent.

Moreover, 1 can also be used as catalyst for the kinetic resolution of chain 1,2-diols, β-hydroxycarboxylic acids, and 2-amino alcohols after the suitable derivatization. In any case, acylation progresses by adding 0.5 equivalent molar of isobutyric anhydride to racemic alcohols, and achieves the conversion near 50%. Therefore, atom efficiency is extremely high.

The molecular weight of acylase is well over 10,000. On the other hand, the molecular weight of 1 is far small with 660, and 1 has only one chiral carbon atom of the histidine origin as chiral source. 1 has imidazole base of catalytic active center and sulfonamide proton which is required for the selective capture of substrates through the chiral carbon atom in the molecule. These are comprehensively at work, the kinetic resolution can be done effectively. Usually 1 is enough in the use of 5 mol% or less, in the kinetic resolution of 1 mmol of racemic alcohol, 1 have only to be used 0.05 mmol (33 mg) or less.