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DOI: 10.1002/cssc.201902199
Communications
One-Pot Enzyme Cascade for Controlled Synthesis of
Furancarboxylic Acids from 5-Hydroxymethylfurfural by
H2O2 Internal Recycling
Hao-Yu Jia,[a] Min-Hua Zong,[a] Gao-Wei Zheng,*[b] and Ning Li*[a]
Furancarboxylic acids are promising biobased building blocks
in pharmaceutical and polymer industries. In this work, dual-
enzyme cascade systems composed of galactose oxidase
(GOase) and alcohol dehydrogenases (ADHs) are constructed
for controlled synthesis of 5-formyl-2-furancarboxylic acid
(FFCA) and 2,5-furandicarboxylic acid (FDCA) from 5-hydroxy-
methylfurfural (HMF), based on the catalytic promiscuity of
ADHs. The byproduct H2O2, which is produced in GOase-cata-
lyzed oxidation of HMF to 2,5-diformylfuran (DFF), is used for
horseradish peroxidase (HRP)-mediated regeneration of the
oxidized nicotinamide cofactors for subsequent oxidation of
DFF promoted by an ADH, thus implementing H2O2 internal re-
cycling. The desired products FFCA and FDCA are obtained
with yields of more than 95%.
ephthalic acid (TPA, 17) for the production of biobased polyes-
ter polyethylene furanoate (PEF).[6] FFCA is an active intermedi-
ate in the synthesis of FDCA from HMF. Therefore, it is general-
ly hard to obtain this substance by chemocatalytic oxidation of
HMF, owing to its tendency towards overoxidation into FDCA
under harsh reaction conditions, which may explain why previ-
ous reports on controlled synthesis of FFCA are scarce.[7] Dibe-
nedetto and co-workers reported the aerobic oxidation of HMF
into FFCA over metal oxides in water, with selectivities of ap-
proximately 90%.[8]
Biotransformations are usually performed under mild reac-
tion conditions, and biocatalysts are exquisitely selective, bio-
degradable, and environmentally friendly.[9] Recently, biocata-
lytic oxidation has received increasing attention as a green and
clean alternative to chemical processes,[10] especially for the
valorization of inherently unstable furans.[11] HMF oxidase
(HMFO) enabled cascade oxidation of HMF into FDCA.[12] In
general, the production of FDCA from HMF by a single enzyme
is rare and entails three consecutive oxidation reactions, be-
cause of the high substrate specificity of the enzymes. Thus,
multienzyme cascade reactions have become established for
the synthesis of FDCA.[13] McKenna et al. described a one-pot
tandem enzyme reaction using galactose oxidase (GOase) M3–5
and aldehyde oxidase PaoABC for the conversion of HMF into
FDCA.[14] Chemoenzymatic syntheses of FDCA[15] and FFCA[16]
using laccase–TEMPO (2,2,6,6-tetramethylpiperidine-N-oxyl) sys-
tems were reported by Wang et al. and Zhang et al., respec-
tively. However, in both cases excess amounts of TEMPO
(>80 mol%) were required to achieve good yields. Recently,
Payne et al. reported enzymatic carboxylation of 2-furoic acid
(6) to FDCA by using HmfF (de)carboxylase.[17] Aside from a
few examples,[14b,18] the substrate concentrations tested in
enzyme-catalyzed oxidation of HMF were quite low. In addition
to isolated enzymes, whole cells were also used as catalysts for
the synthesis of FDCA.[19]
Recently, the production of biobased chemicals and biofuels
from renewable and carbon-neutral biomass has attracted con-
siderable interest.[1] 5-Hydroxymethylfurfural (HMF, 1) is one of
top-value platform chemicals bridging the gap between bio-
mass and biobased chemicals, as well as between biomass and
biofuels.[2] The active functional groups present in HMF, includ-
ing the primary hydroxy and formyl groups and the furan ring,
are responsible for its high chemical reactivity. Therefore, this
substance could be upgraded into many value-added chemi-
cals by classical chemical reactions. For example, selective oxi-
dation of HMF furnished 2,5-diformylfuran (DFF, 2), 5-hydroxy-
methyl-2-furancarboxylic acid (HMFCA, 3), 5-formyl-2-furancar-
boxylic acid (FFCA, 4), and 2,5-furandicarboxylic acid (FDCA,
5),[3] whereas 2,5-bis(hydroxymethyl)furan (BHMF) was pro-
duced through HMF reduction.[4] The catalytic synthesis of DFF
and FDCA has been extensively studied,[5] because they are
versatile building blocks in the synthesis of polymers, fuels,
and drugs. For example, FDCA is a promising alternative to ter-
In previously reported (multi)oxidase cascade oxidations,
complete oxidation of 1 mol of HMF into FDCA required 2–
3 mol of O2.[12,13b,c,14,15] It is well known that O2 is poorly soluble
in water (approximately 8 mgLÀ1 from air),[20] so O2 mass trans-
fer represents a fundamental bottleneck for oxidase-catalyzed
cascade oxidation of HMF, especially at high substrate concen-
trations. This problem would become more significant in
whole-cell catalytic oxidations, because of a competition for O2
between the target reaction and endogenous respiration.[21] Al-
though O2 consumption would be lowered by internal O2 re-
generation from H2O2 in the presence of catalases, the stability
of catalases was generally unsatisfactory. Dehydrogenases
[a] Dr. H.-Y. Jia, Prof. M.-H. Zong, Prof. N. Li
State Key Laboratory of Pulp and Paper Engineering
School of Food Science and Engineering
South China University of Technology
381 Wushan Road, Guangzhou 510640 (China)
[b] Prof. G.-W. Zheng
State Key Laboratory of Bioreactor Engineering
East China University of Science and Technology
130 Meilong Road, Shanghai 200237 (China)
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
ChemSusChem 2019, 12, 1 – 6
1
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