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Diastereoselective Hydrolysis of Branched Malonate Diesters by Porcine Liver Esterase: Synthesis of 5‐Benzyl‐Substituted C α ‐Methyl‐β‐proline and Catalytic Evaluation
Author(s) -
Kotapati Hari Kiran,
Robinson Jamarii D.,
Lawrence Daniel R.,
Fortner Kimberly R.,
Stanford Caleb W.,
Powell Douglas R.,
Wardenga Rainer,
Bornscheuer Uwe T.,
Masterson Douglas S.
Publication year - 2017
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201700605
Subject(s) - chemistry , enantiopure drug , malonate , diastereomer , organic chemistry , enantiomeric excess , hydrolysis , mannich reaction , amino esters , catalysis , enantioselective synthesis
Malonate diesters with highly branched side chains containing a preexisting chiral center were prepared from optically pure amino alcohols and subjected to asymmetric enzymatic hydrolysis by Porcine Liver Esterase (PLE). Recombinant PLE isoenzymes have been utilized in this work to synthesize diastereomerically enriched malonate half‐esters from enantiopure malonate diesters. The diastereomeric excess of the product half‐esters was further improved in the later steps of synthesis either by simple recrystallization or flash column chromatography. The diastereomerically enriched half‐ester was transformed into a novel 5‐substituted C α ‐methyl‐β‐proline analogue (3 R ,5 S )‐ 1c , in high optical purity employing a stereoselective cyclization methodology. This β‐proline analogue was tested for activity as a catalyst of the Mannich reaction. The β‐proline analogue derived from the hydrolysis reaction by the crude PLE appeared to catalyze the Mannich reaction between an α‐imino ester and an aldehyde providing decent to good diastereoselectivities. However, the enantioselectivities in the reaction was low. The second diastereomer of the 5‐benzyl‐substituted C α ‐methyl‐β‐proline, (3 S ,5 S )‐ 1c was prepared by enzymatic hydrolysis using PLE isoenzyme 3 and tested for its catalytic activity in the Mannich reaction. Amino acid, (3 S ,5 S )‐ 1c catalyzed the Mannich reaction between isovaleraldehyde and an α‐imino ester yielding the “ anti ” selective product with an optical purity of 99 % ee .