Enzymatic preparation of (S)-3-amino-3-(o-tolyl)propanoic acid, a key intermediate for the construction of Cathepsin inhibitors

Add time:07/16/2019    Source:sciencedirect.com

Enantiomerically pure (S)-3-amino-3-(o-tolyl)propanoic acid [(S)-6], identified as the preferred enantiomeric form for the construction of novel β-amino acid derivatives as inhibitors of Cathepsin, was prepared through both indirect and direct enzymatic strategies. Resolution of hydroxymethylated β-lactam (±)-1 through Burkholderia cepacia lipase PSIM-catalysed R-selective butyrylation (E > 200) was first carried out in t-BuOMe. Treatment of the unreacted (S)-1 with 18% HCl then furnished the desired (S)-6·HCl. Next, Candida antarctica lipase B catalysed the ring cleavage of racemic 4-(o-tolyl)azetidin-2-one [(±)-2] with excellent R enantioselectivity (E > 200), either in t-BuOMe with added H2O as nucleophile or in H2O at 60 °C. Hydrolysis of the less reactive β-lactam enantiomer [(S)-2] with 18% HCl afforded (S)-6·HCl. A direct enzymatic route to enantiomeric (S)-6 was finally optimized through the lipase PSIM-catalysed S-enantioselective (E > 200) hydrolysis of racemic ethyl 3-amino-3-(o-tolyl)propanoate [(±)-3] in t-BuOMe with added H2O at 45 °C or in H2O at 3 °C.

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