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polymerization reaction, which was seen as polymer type peaks in
the 1H NMR spectra of the crude mixture. Deacetylation of pure 5
yielded a mixture of products, although polymer peaks similar to
those observed in the direct deacetylation reaction were not
observed by NMR spectroscopy. It is possible that unknown
impurities in the crude mixture facilitate the polymerization
reaction, which does not take place with the pure compound.
Kojic acid could then be extracted with ethanol with subsequent
precipitation of some impurities by addition of acetone or diethyl
ether followed by filtration. After evaporation of the solvents, the
remaining impurities could be dissolved in acetone leaving kojic
acid as a powder. The isolated kojic acid had a purity of 495%
with 20% yield on a 1.3 g scale based on glucosone. While the
yield is likely to be improved by future optimization of the
purification procedures, as it stands, this method already shows
considerable promise for producing kojic acid from glucose with a
minimal number of isolation and purification steps.
To conclude, we have developed a new chemo-enzymatic
preparative route to kojic acid, a valuable biomolecule with a broad
range of applications, obtained currently in significant quantities
only as a side-stream of a fermentation process. The new method
produces crude kojic acid from glucose in a few steps in the
multigram scale. Further optimization of the preparative procedure
and purification processes will potentially increase the supply of
this valuable molecule, independent of fermentation routes, con-
tributing to further research opportunities for biorefineries.
The authors thank the Magnus Ehrnrooth foundation,
Waldemar von Frenckell foundation and the EU Horizon 2020
research and innovation program, project SWEETWOODS (792061).
PhD Jani Rahkila is gratefully acknowledged for help with NMR
analysis. PhD Risto Savela is gratefully acknowledged for HRMS
analysis.
Scheme 3 A tentative mechanism for the formation of products 4 (a) and
5 (b).
the role of acetyl groups in the reaction and the possible direct
conversion of glucosone to kojic acid, pure glucosone was
dissolved in base in the absence of acetic anhydride. No
product was formed in either pyridine or 1 M NaOH, indicating
that the presence of acetyl groups in glucosone is necessary for
the elimination to products 4 and 5 to take place.
Next, in order to investigate the influence of purity of the
starting material on the yield of the reaction, acetylation of
crude glucosone from the enzymatic reaction, subjected only to
prior filtration and lyophilization, was compared to acetylation
of glucosone, purified by column chromatography, under the
previously optimized reaction conditions. Whereas the purified
glucosone afforded compounds 4 and 5 in 45% and 30% (1 : 0.7
ratio), respectively, a higher selectivity towards acetylated kojic
acid was obtained by use of the unpurified glucosone, provid-
ing 4 and 5 in 47% and 23% yields (1 : 0.5 ratio), respectively.
While challenging to study conclusively, it is possible that salt
residues from the enzymatic reaction influence the chemical
conversion of glucosone, favoring the formation of acetylated
kojic acid instead of the undesired byproduct.
Conflicts of interest
There are no conflicts to declare.
Notes and references
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Scheme 4 Acetylation/deacetylation of D-glucosone (3) to yield kojic
acid (1). i: (a) Ac2O, NaOAc, DMF, 24 h; (b) NaOMe, MeOH, 1 h.
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