Application of Threonine Aldolases for the Asymmetric Synthesis of α‐Quaternary α‐Amino Acids

• Published in: ChemCatChem Vol. 10; no. 16; pp. 3453 - 3458
• Main Authors: Blesl, Julia, Trobe, Melanie, Anderl, Felix, Breinbauer, Rolf, Strohmeier, Gernot A., Fesko, Kateryna
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 21-08-2018; John Wiley and Sons Inc
• Subjects: Aldehydes; Aldolase; Aliphatic compounds; Amino acids; Asymmetric catalysis; Enzyme catalysis; Hydroxyisobutyric acid; Phenylalanine; Pseudomonas; Quaternary stereogenic centers; Stereoselectivity; Synthesis; Threonine aldolases; Quaternary stereogenic centers; Amino acids; Enzyme catalysis; Asymmetric catalysis; Threonine aldolases
• ISSN: 1867-3880; 1867-3899
• DOI: 10.1002/cctc.201800611

We report the synthesis of diverse β‐hydroxy‐α,α‐dialkyl‐α‐amino acids with perfect stereoselectivity for the α‐quaternary center through the action of l‐ and d‐specific threonine aldolases. A wide variety of aliphatic and aromatic aldehydes were accepted by the enzymes and conversions up to >80 % were obtained. In the case of d‐selective threonine aldolase from Pseudomonas sp., generally higher diastereoselectivities were observed. The applicability of the protocol was demonstrated by performing enzymatic reactions on preparative scale. Using the d‐threonine aldolase from Pseudomonas sp., (2R,3S)‐2‐amino‐3‐(2‐fluorophenyl)‐3‐hydroxy‐2‐methylpropanoic acid was generated in preparative amounts in one step with a diastereomeric ratio >100 favoring the syn‐product. A Birch‐type reduction enabled the reductive removal of the β‐hydroxy group from (2S)‐2‐amino‐3‐hydroxy‐2‐methyl‐3‐phenylpropanoic acid to generate enantiopure l‐α‐methyl‐phenylalanine via a two‐step chemo‐enzymatic transformation.
Just one more step: The direct biocatalytic assembly of β‐hydroxy‐α,α‐dialkyl‐α‐amino acids is outlined. Through the application of l‐ or d‐selective threonine aldolases with donor specificities beyond glycine, a wide variety of amino acid products can be created in a single step.