Biocatalytic Asymmetric Synthesis of N-Aryl-Functionalized Amino Acids and Substituted Pyrazolidinones

Abstract

N-arylated α-amino acids and pyrazolidin-3-ones are widely being used as chiral building blocks for pharmaceuticals and agrochemicals. Here we report a biocatalytic route for the asymmetric synthesis of various N-arylated aspartic acids applying ethylenediamine-N,N′-disuccinic acid lyase (EDDS lyase) as a biocatalyst. This enzyme shows a broad substrate scope, enabling the addition of a variety of arylamines to fumarate with high conversions, yielding the corresponding N-arylated aspartic acids in good isolated yields and with high enantiomeric excess (ee > 99%). Furthermore, we developed a chemoenzymatic method toward the synthetically challenging chiral 2-aryl-5-carboxylpyrazolidin-3-ones, using arylhydrazines as bis-nucleophilic donors in the EDDS lyase catalyzed hydroamination of fumarate followed by an acid-catalyzed intramolecular amidation, achieving good overall yields and high optical purity (ee > 99%). In addition, we successfully combined the EDDS lyase catalyzed hydroamination and acid-catalyzed cyclization steps in one pot, thus providing a simple chemoenzymatic cascade route for synthesis of enantiomerically pure pyrazolidin-3-ones. Hence, these biocatalytic methods provide convenient alternative routes to important chiral N-arylated aspartic acids and difficult 2-aryl-5-carboxylpyrazolidin-3-ones.

Aminocarboxylic acids related to aspergillomarasmine A (AMA) and ethylenediamine-N,N′-disuccinic acid (EDDS) are strong zinc-binders and inhibitors of the metallo-beta-lactamase NDM-1

“…Recently, we reported that ethylenediamine-N,N 0 -disuccinic acid (EDDS) lyase naturally catalyzes a reversible two-step sequential addition of ethylenediamine (2) to two molecules of fumaric acid (3), giving (S)-N-(2-aminoethyl)aspartic acid (AEAA, 4) as an intermediate and (S,S)-EDDS (5) as the final product (Table 1A). 12 EDDS lyase was subsequently found to have broad substrate promiscuity, [13][14][15] accepting a wide range of amino acids with terminal amino groups (6a-k) for regio-and stereoselective addition to fumarate, thus providing a straightforward biocatalytic method for the asymmetric synthesis of AMA (1a), AMB (1b), and related aminocarboxylic acids (1c-k, Table 1B). 13 To further explore the substrate scope of EDDS lyase, as well as to prepare a small library of EDDS derivatives as potential NDM-1 inhibitors, 16 we here describe the EDDS-lyase catalyzed reaction of fumaric acid with various diamines containing different aliphatic linkers between the two amino functional groups (7a-i) ( Table 2).…”

Recent Applications of Carbon‐Nitrogen Lyases in Asymmetric Synthesis of Noncanonical Amino Acids and Heterocyclic Compounds

“…Her current research interests include exploring the reactivity of enzymes from natural product biosynthesis pathways for producing pharmaceutically relevant molecules. [16][17][18][19][20][21] Ph, aryl H H RgPAL, AvPAL, PcPAL phenylalanine, β-aryl α-alanines [6,[22][23][24][25][26] chelating compound widely used in industry for a wide range of applications, such as soil remediation, paper manufacturing, waste water treatment and so on. (S,S)-EDDS was isolated as a secondary metabolite from the actinomycete Amycolatopsis japonicum, hypothetically serving as a scavenger of zinc (zincophore) and its bioproduction was strictly repressed by zinc.…”

“…Another synthetic application of EDDS lyase was demonstrated by the biocatalytic asymmetric synthesis of various Narylated l-aspartic acids and the chemoenzymatic synthesis of challenging 2-aryl-5-carboxylpyrazolidin-3-ones ( Figure 5). [19] Especially, pyrazolidinones are widely found as core structures in pharmaceutically active molecules including lipoxygenase inhibitors ( Figure 4) and anti-Alzheimer agents. [19] EDDS lyase accepted a broad range of arylamines and arylhydrazines as substrates for addition to fumarate, giving the corresponding N-arylated l-aspartic acids and N-(arylamino)aspartic acids, respectively, with good isolated yields and excellent enantiopurity.…”

“…[19] Especially, pyrazolidinones are widely found as core structures in pharmaceutically active molecules including lipoxygenase inhibitors ( Figure 4) and anti-Alzheimer agents. [19] EDDS lyase accepted a broad range of arylamines and arylhydrazines as substrates for addition to fumarate, giving the corresponding N-arylated l-aspartic acids and N-(arylamino)aspartic acids, respectively, with good isolated yields and excellent enantiopurity. Furthermore, a one-pot chemoenzymatic synthesis route combining the EDDS lyase mediated biotransformation with an acid-catalyzed cyclization step was developed, giving rise to a series of chiral pyrazolidin-3-one derivatives ( Figure 5), with 61-70 % isolated yield and > 99 % ee.…”

Transition Metal‐Free, Base‐Induced Arylation of Amino Acids: Synthesis of N‐(para‐Substituted phenyl)amino‐2‐carboxylic acids

“…The N ‐(hetero)arylation of amino acids with heteroaryl and aryl halides have been carried out using copper and palladium as well as combined catalysts with different types of ligands and N ‐heterocyclic carbenes . The catalytic N ‐arylation of amino acid esters and N ‐modification with phenol are also known whilst the use of biocatalysts is gaining momentum . Other notable arylation methods include nucleophilic aromatic substitution, three‐component aryne coupling reaction and hypervalent iodine chemistry .…”