Synthesis of aryl alkanediols having high optical purity

C - Chemistry – Metallurgy – 12 – P

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C12P 41/00 (2006.01) C12P 7/42 (2006.01) C12P 7/62 (2006.01)

Patent

CA 2065433

R- and S-1-Phenyl-1,3-propanediol, each of high optical purity, were prepared by a chemoenzymatic sequence starting with ethyl benzoylacetate. The first step was a catalytic hydrogenation of the .beta.-ketoester conducted at room temperature. The en- zymatic hydrolysis of the resulting hydroxyester proceeded in a facile manner using a commercial preparation of the lipase from Pseudomonas fluorescens. The enzymatic hydrolysis proceeded at a moderate rate (350 mg lipase/0.10 mol of racemic ester re- quired a 20-hour reaction time with an enantiomeric rate ratio (E value) of 36). The hydrolysis was run to 45-50 % conversion to afford isolated S-3-phenyl-3-hydroxypropionic acid of 85-90 % ee after separation from the residual ester (aqueous base extrac- tion). The optical purity of the hydroxy acid was determined by conversion to the methyl ester (CH3I, KHCO3, acetone) and de- rivatization with S-MTPA-CI, and ?H NMR analysis. A single recrystallization of the isolated acid afforded optically pure (>98 % ee) S-3-phenyl-3-hydroxypropionic acid in an overall 36% yield from the racemic ester. The acid was reduced with bo- rane in THF to afford optically pure S-diol in 97 % yield after crystallization. The overall sequence proceeded in 34 % total yield from racemic ester with an additional 45-55 % recovered as the antipodal ester. This antipodal ester is obtained in 85-95 % ee, and the corresponding hydroxy-acid was readily obtained (NaOH, CH3OH/H2O) and recrystallized to optical purity. Reduction then afforded R-1-phenyl-1,3-propanediol in 30 % to overall yield from racemic ester.

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