Chemo-enzymatic preparation of chiral 3-aminopyrrolidine derivatives |
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Authors: | Hans Iding Beat Wirz |
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Institution: | a Non-clinical Development—Biotechnology, F. Hoffmann-La Roche Ltd, Basel, Switzerland b Pharmaceutical Research Basel—Discovery Chemistry, F. Hoffmann-La Roche Ltd, Basel, Switzerland |
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Abstract: | A new simple method for the enantioselective enzymatic hydrolysis of N-protected D-asparagine esters suitable for the use on the preparative scale is presented. Due to major obstacles observed under conventional reaction conditions—racemization of the retained ester and a strong enzyme inactivation—a comparatively low pH together with an organic co-solvent had to be employed. Under these conditions, nearly all tested proteases demonstrated good activity and excellent enantioselectivity giving access to the corresponding d-esters and L-asparagines in high optical purities (>95% ee) and good chemical yields (>40%). From the unnatural d-asparagine derivative, sequential cyclization, selective deprotection and reduction yielded efficiently benzyl protected (R)-3-aminopyrrolidine, a homo-chiral building block utilized in numerous drug candidates. |
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Keywords: | Resolution d-asparagine" target="_blank">d-asparagine l-asparagine" target="_blank">l-asparagine Enzyme Protease Enantioselective Hydrolysis Biotransformation |
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