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

Abstract

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 <i>Pseudomonas</i> 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 <i>Pseudomonas</i> sp., (2<i>R</i>,3<i>S</i>)-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 <i>syn</i>-product. A Birch-type reduction enabled the reductive removal of the β-hydroxy group from (2<i>S</i>)-2-amino-3-hydroxy-2-methyl-3-phenylpropanoic acid to generate enantiopure l-α-methyl-phenylalanine via a two-step chemo-enzymatic transformation.