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 acid analogues of aspergillomarasmine A (AMA) and ethylenediamine-N,N′-disuccinic acid (EDDS) were prepared via a robust chemoenzymatic approach. These compounds display potent inhibition of the bacterial resistance enzyme NDM-1.
Flavoenzymes are oxidoreductases that catalyze an extensive range of different types of reactions.An advanced and powerful approach to achieving transformations that are normally outside the realm of flavoenzymes is the synergistic combination of photocatalysis and biocatalysis. Here we report the identification of a promiscuous flavin-dependent nitroreductase, BaNTR1, that is able to promote enantioselective photobiocatalytic reductions of a broad range of structurally diverse ketones to yield the corresponding alcohols with high conversion (up to >99%) and outstanding enantiopurity (up to >99:1 e.r). Noteworthy, BaNTR1 was able to promote the photoenzymatic reduction of various α,ßunsaturated ketones to give the corresponding optically pure alcohols without reducing the C=C or C≡C bond, illustrating its remarkably high chemoselectivity. Our results highlight the usefulness of photocatalysis for expanding the catalytic repertoire of nitroreductases to include highly enantio-and chemoselective reductions of non-native ketone substrates to produce optically pure alcohols. This includes difficult to prepare allyl alcohols that are not accessible via photoenzymatic conversions using ene-reductases.
Chiral dihydrobenzoxazinones and dihydroquinoxalinones
serve as
essential building blocks for pharmaceuticals and agrochemicals. Here,
we report short chemoenzymatic synthesis routes for the facile preparation
of these complex heterocycles in an optically pure form. These synthetic
routes involve a highly stereoselective hydroamination step catalyzed
by ethylenediamine-
N
,
N′-
disuccinic
acid lyase (EDDS lyase). This enzyme is capable of catalyzing the
asymmetric addition of various substituted 2-aminophenols to fumarate
to give a broad range of substituted
N-
(2-hydroxyphenyl)-
l
-aspartic acids with excellent enantiomeric excess (ee up to
>99%). This biocatalytic hydroamination step was combined with
an
acid-catalyzed esterification–cyclization sequence to convert
the enzymatically generated noncanonical amino acids into the desired
dihydrobenzoxazinones in good overall yield (up to 63%) and high optical
purity (ee up to >99%). By means of a similar one-pot, two-step
chemoenzymatic
approach, enantioenriched dihydroquinoxalinones (ee up to >99%)
were
prepared in good overall yield (up to 78%) using water as solvent
for both steps. These chemoenzymatic methodologies offer attractive
alternative routes to challenging dihydrobenzoxazinones and dihydroquinoxalinones,
starting from simple and commercially available achiral building blocks.
The Front Cover shows the usefulness of the photocatalyst Ru(bpy)3Cl2 under irradiation with blue light for expanding the catalytic repertoire of a flavin‐dependent nitroreductase, using glucose dehydrogenase (GDH) for regeneration of the essential NADH cofactor. In their Research Article, A. Prats Luján, M. F. Bhat et al. report the discovery of a flavoenzyme, BaNTR1, that is able to promote enantio‐ and chemoselective photoenzymatic reductions of a broad range of ketones to yield the corresponding alcohols with high conversions and outstanding enantiopurity. Most importantly, BaNTR1 was able to promote the photoenzymatic reduction of various α,ß‐unsaturated ketones to give the corresponding optically pure alcohols without reducing the C=C or C≡C bond, demonstrating its astoundingly high chemoselectivity. More information can be found in the Research Article by A. Prats Luján, M. F. Bhat et al.
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