Enzyme-mediated synthesis of EEHP and EMHP, useful pharmaceutical intermediates of PPAR agonists

A new scaleable synthetic route to the title compounds has been developed. The reaction pathway is based on the α-chymotrypsin-catalysed hydrolysis of the racemic ethyl 2-ethoxy-3-(p-methoxyphenyl)propanoate or of the racemic ethyl 2-methoxy-3-(p-methoxyphenyl)propanoate to give the corresponding resolved (S)-esters with excellent ee. The acids were easily separated from the (S)-esters by a simple acid–base work-up. The overall yields of 1 and 2 were 16% and 17%, respectively.

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Ethyl (S)-2-ethoxy-3-(4-hydroxyphenyl)propanoateC13H18O4[α]D25=-21.3 (c 1.45, CHCl3)Source of chirality: enzyme resolution(S)

Ethyl (S)-2-methoxy-3-(4-hydroxyphenyl)propanoateC12H16O4[α]D25=-24.2 (c 1.56, CHCl3)Source of chirality: enzyme resolution(S)

Ethyl (R)-2-hydroxy-3-(4-methoxyphenyl)propanoateC12H16O4Ee = 90.4%[α]D25=-8.23 (c 1.50, EtOH)Source of chirality: enzyme resolution(R)

(S)-2-Hydroxy-3-(4-methoxyphenyl)propanoic acidC10H12O4Ee = 82.2%[α]D25=-9.60 (c 1.03, EtOH)Source of chirality: enzyme resolution(S)

Ethyl (S)-2-ethoxy-3-(4-methoxyphenyl)propanoateC14H20O4Ee = 93.0%[α]D25=-18.1 (c 1.34, CHCl3)Source of chirality: enzyme resolution(S)

Ethyl (S)-2-methoxy-3-(4-methoxyphenyl)propanoateC13H18O4Ee = 99.9%[α]D25=-16.9 (c 3.74, EtOH)Source of chirality: enzyme resolution(S)

(S)-2-Ethoxy-3-(4-methoxyphenyl)propanoic acidC12H16O4Ee = 93.0%[α]D25=-16.6 (c 1.21, CHCl3)Source of chirality: enzyme resolution(S)

(S)-2-Methoxy-3-(4-methoxyphenyl)propanoic acidC12H16O4Ee = 99.9%[α]D25=-25.2 (c 1.40, CHCl3)Source of chirality: enzyme resolution(S)