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.
Aspartic acid derivatives with branched N‐alkyl or N‐arylalkyl substituents are valuable precursors to artificial dipeptide sweeteners such as neotame and advantame. The development of a biocatalyst to synthesize these compounds in a single asymmetric step is an as yet unmet challenge. Reported here is an enantioselective biocatalytic synthesis of various difficult N‐substituted aspartic acids, including N‐(3,3‐dimethylbutyl)‐l‐aspartic acid and N‐[3‐(3‐hydroxy‐4‐methoxyphenyl)propyl]‐l‐aspartic acid, precursors to neotame and advantame, respectively, using an engineered variant of ethylenediamine‐N,N′‐disuccinic acid (EDDS) lyase from Chelativorans sp. BNC1. This engineered C–N lyase (mutant D290M/Y320M) displayed a remarkable 1140‐fold increase in activity for the selective hydroamination of fumarate compared to that of the wild‐type enzyme. These results present new opportunities to develop practical multienzymatic processes for the more sustainable and step‐economic synthesis of an important class of food additives.
Aspartic acid derivatives with branched N‐alkyl or N‐arylalkyl substituents are valuable precursors to artificial dipeptide sweeteners such as neotame and advantame. The development of a biocatalyst to synthesize these compounds in a single asymmetric step is an as yet unmet challenge. Reported here is an enantioselective biocatalytic synthesis of various difficult N‐substituted aspartic acids, including N‐(3,3‐dimethylbutyl)‐l‐aspartic acid and N‐[3‐(3‐hydroxy‐4‐methoxyphenyl)propyl]‐l‐aspartic acid, precursors to neotame and advantame, respectively, using an engineered variant of ethylenediamine‐N,N′‐disuccinic acid (EDDS) lyase from Chelativorans sp. BNC1. This engineered C–N lyase (mutant D290M/Y320M) displayed a remarkable 1140‐fold increase in activity for the selective hydroamination of fumarate compared to that of the wild‐type enzyme. These results present new opportunities to develop practical multienzymatic processes for the more sustainable and step‐economic synthesis of an important class of food additives.
N‐substituted L-aspartic acids are important chiral building blocks for pharmaceuticals and food additives. Here we report the asymmetric synthesis of various N‐arylalkyl‐substituted L‐aspartic acids using ethylenediamine‐N,N′‐disuccinic acid lyase (EDDS lyase)...
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