Next Article in Journal
Culture Dependent and Independent Analysis of Potential Probiotic Bacterial Genera and Species Present in the Phyllosphere of Raw Eaten Produce
Next Article in Special Issue
Multipoint TvDAAO Mutants for Cephalosporin C Bioconversion
Previous Article in Journal
Analysis of Chemically Labile Glycation Adducts in Seed Proteins: Case Study of Methylglyoxal-Derived Hydroimidazolone 1 (MG-H1)
Previous Article in Special Issue
Characterization of the First Bacterial and Thermostable GDP-Mannose 3,5-Epimerase
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 20
Issue 15
10.3390/ijms20153660
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Production of Hexaric Acids from Biomass

by
Riku Sakuta
and
Nobuhumi Nakamura
*
Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakacho, Koganei, Tokyo 184-8588, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(15), 3660; https://doi.org/10.3390/ijms20153660
Submission received: 29 June 2019 / Revised: 22 July 2019 / Accepted: 24 July 2019 / Published: 26 July 2019
(This article belongs to the Special Issue Industrial Enzymes: Structure, Function and Applications)
Browse Figures
Versions Notes

Abstract

:
Sugar acids obtained by aldohexose oxidation of both the terminal aldehyde group and the hydroxy group at the other end to carboxyl groups are called hexaric acids (i.e., six-carbon aldaric acids). Because hexaric acids have four secondary hydroxy groups that are stereochemically diverse and two carboxyl groups, various applications of these acids have been studied. Conventionally, hexaric acids have been produced mainly by nitric acid oxidation of aldohexose, but full-scale commercialization has not been realized; there are many problems regarding yield, safety, environmental burden, etc. In recent years, therefore, improvements in hexaric acid production by nitric acid oxidation have been made, while new production methods, including biocatalytic methods, are actively being studied. In this paper, we summarize these production methods in addition to research on the application of hexaric acids.

Graphical Abstract

1. Introduction

The International Energy Agency defines a biorefinery as “the sustainable processing of biomass into a spectrum of marketable products and energy”, which is the most comprehensive and commonly accepted definition [1]. Because inexpensive petroleum-derived chemicals are already mass produced, the production of bio-based chemicals has been limited to those with structures that are too complex for the fine-chemicals market to justify their expensive production costs [2]. However, nonrenewable resources are limited despite population growth. Accordingly, the increased consumer demand for environmentally friendly products has become a driving force for the use of biorefineries [2]. Emerging economies (e.g., the countries of Brazil, Russia, India and China (BRIC)) require increasing amounts of oil and other fossil-based products, in addition to the security of chemical and energy supplies for isolated regions such as islands [2]. Carboxylic acids have attracted considerable attention among the raw materials for bioderived chemicals. The US Department of Energy (DOE) has selected twelve chemicals from more than three hundred biomass-derived chemicals, based on cooperative research with industry and academia, to be developed using biorefinery production methods [3]. More than half of the twelve selected chemicals are carboxylic acids. Carboxylic acids obtained by the oxidation of monosaccharides and oligosaccharides are referred to as sugar acids [4,5,6]. The oxidation of aldose (aldohexose when the carbon number is six) at its aldehyde group to form a carboxyl group produces aldonic acid (aldohexonic acid), whereas the corresponding oxidation at its terminal hydroxy group results in a different monocarboxylic acid, (aldo)uronic acid ((aldo)hexuronic acid). Aldaric acid (hexaric acid) is a dicarboxylic acid produced by oxidizing both groups (Figure 1). Because aldaric acids have been studied for numerous types of applications, improved methods for their production are urgently needed. d-Glucaric acid, the aldaric acid of d-glucose or l-gulose, was selected by the DOE as one of the twelve chemicals [3]. Hence, this article summarizes biorefinery methods relating to aldaric acids with six carbon atoms (hexaric acids; Figure 1), including d-glucaric acid.

2. Classification of Aldohexoses and Hexaric Acids

Aldohexoses have four stereocenters, resulting in sixteen configurational isomers (Figure 1). Relative-configuration classification divides these stereoisomers into eight groups with the following common names: altrose, allose, idose, galactose, glucose, gulose, talose, and mannose. In contrast, hexaric acids have the same functional group at both ends of their structure; thus, the hexaric acids of altrose and talose and those of glucose and gulose are the same compounds. Moreover, the hexaric acids of allose and galactose are meso-compounds, because of their symmetry. In short, relative-configuration classification divides hexaric acids into altraric acid, allaric acid, idaric acid, galactaric acid, glucaric acid, and mannaric acid; because allaric acid and galactaric acid are meso-compounds, the total number of configurational isomers is ten (Figure 2) [7]. Because hexaric acids have four stereochemically diverse secondary hydroxy groups and two carboxyl groups, their applications as platform chemicals have been studied as described below. Of the hexaric acids, d-glucaric, meso-galactaric, and d-mannaric acids have been the most studied as starting compounds for biorefineries, in part because the raw materials for these hexaric acids are abundant. Therefore, several compounds, such as l-mannaric acid [8,9] and d-idaric acid, [10,11] which are used as the starting compounds for human immunodeficiency virus (HIV) protease inhibitors, are regarded as exceptions in this report. The focus of this article is on studies investigating the applications and production methods for d-glucaric acid, meso-galactaric acid, and d-mannaric acid.

3. Applications of Hexaric Acids

Because hexaric acids have four stereochemically diverse secondary hydroxy groups and two carboxyl groups, they have been studied since the 1950s as platform chemicals for producing chelating agents and corrosion inhibitors [10,11,12,13,14,15,16,17,18,19,20,21], precursors for polyamides [22,23,24,25,26,27,28,29,30,31,32,33,34,35,36], polyesters [37,38,39,40,41], polyanhydrides [42], polycations [43], coordination polymers including metal–organic frameworks [44,45,46,47,48], pendant polymers [49], macromolecules [50,51], cross-linkers in hydrogels [52], medicines [8,9,10,11,49,51,53], and other compounds including platform chemicals, like adipic acid and furan dicarboxylic acid [54,55,56,57,58,59,60,61,62].

3.1. Monomers

The use of hexaric acids as monomers produces polycondensates that are nontoxic, biodegradable, and more hydrophilic than those derived from petrochemicals [36]. Research on polyamide syntheses derived from hexaric acids started in the 1950s [22] and continues, particularly in the laboratory of Kiely. This group has synthesized polyamides from three monomers, d-glucaric acid, meso-galactaric acid, and d-mannaric acid, to investigate the influence of stereochemistry on the physical properties of polymers [31]. The polyamides were synthesized in methanol from either a hexaric acid diester or a methylated hexaric acid lactone, which were synthesized by a condensation reaction of a hexaric acid and methanol, with even-number-chain-length alkylenediamines having two to twelve carbon atoms as the monomers (Figure 3A–C).
A comparison between poly(alkylene galactaramide)s synthesized from meso-galactaric acid and poly(alkylene d-glucaramide)s from d-glucaric acid revealed that the melting points of poly(alkylene galactaramide)s were all higher than those of poly(alkylene d-glucaramide)s when the length of the alkylenediamine used was the same. Furthermore, it was found that, while the poly(alkylene d-glucaramide)s composed of alkylenediamines with two and four carbon atoms were water soluble, only the poly(alkylene galactaramide) produced from ethylenediamine was water soluble (Table 1). meso-Galactaric acid has a highly symmetric structure in which the carbon chain extends in a zigzag, bearing alternating hydroxy groups as confirmed by crystallography [63]. Through these hydroxy groups, meso-galactaric acids can interact via intermolecular hydrogen bonding [63]. In the case of d-glucaric acid, which is asymmetric, the 1,3-steric repulsions between the hydroxy groups at the C2 and C4 positions result in a bent molecular structure rather than an extended-zigzag structure [64]. Kiely et al. reported that the stereochemical differences between hexaric acids were responsible for the differences in the physical properties between the polyamides [31]. Because the galactaric acid moiety is extended, poly(alkylene galactaramide)s readily become linear. The adoption of a linear structure could increase both the hydrogen bonding between the galactaric acid moieties and the van der Waals forces derived from alignment of the alkylenediamine moieties. In contrast, poly(alkylene d-glucaramide)s tend to form a bent structure because the d-glucaric acid moiety is bent, preventing attractive forces from developing between the polymers. The authors concluded that the differences in interchain attraction underlay the differences in melting points and water solubility between these compounds. Poly(alkylene d-mannaramide)s have head-to-tail type stereoregularity because of the hydroxy groups bound symmetrically along the carbon chain of d-mannaric acid moiety. Because the 1,3-steric repulsions are not present in d-mannaric acid, the authors assumed that the acid tends to form extended-zigzag structures, resulting in melting points and water solubility similar to those of poly(alkylene galactaramide)s. Polymer syntheses that take advantage of physical property differences derived from the different stereochemical properties of aldaric acids have been reported. For example, a polymer derived from d-glucaric acid has an amorphous nature because the attractive interactions between the polymers are weak, which is advantageous for synthesizing materials that have good film-forming and adhesive properties [30]. The nature of meso-galactaric acid-derived polymers, which tend to form linear structures, was used to improve the thermophysical properties of polyanhydrides [42]. Henkensmeier et al. reported that they were able to change the physical properties of a polymer by combining d-glucaric acid and meso-galactaric acid; their method allowed for precisely adjusting the glass transition temperatures of silicone surfactants [34].

3.2. Application of Hexaric Acid Polymers: An Example

Applications of synthetic polymers, including as drug delivery carriers, have been reported. Liu and Reineke et al. reported polyamides composed of hexaric acid moieties and secondary amines as the repeating units that could replace viruses as nucleic acid medicine carriers (Figure 3E–G) [35]. Conventionally, polyethylene imines (PEIs) and chitosan have been studied as substitutes for viruses. The PEIs used in this study showed high gene-transport efficiencies in almost all cell lines used in the study, and chitosan displayed no cytotoxicity. However, each polymer also had a drawback: longer PEIs showed strong cytotoxicities, and chitosan had an inferior transport efficiency. The synthesized polyamides in this study had an abundance of secondary amines and hydroxy groups, and showed both good biocompatibilities and high transport efficiencies. Similar to PEI and chitosan, the synthesized polyamides formed viral-like electrostatic complexes with plasmid DNA (pDNA), termed polyplexes, which were taken up through the endocytotic pathway and dissociated within the endosome. The stereochemistry between the hexaric acid moiety and the number of amines in the repeating units greatly changed the binding affinity to pDNA, its volume in the binding complex, and its transportation efficiency into cells. The polymers derived from meso-galactaric acid showed higher transport efficiencies than those derived from d-glucaric acid or d-mannaric acid.

3.3. Macromolecules

Macromolecules derived from hexaric acids have also been studied for use in drug delivery systems [50,51]. Gu et al. synthesized amphiphilic macromolecules by bonding the hydroxy groups and a terminal carboxylic group of the hexaric acids, commencing with meso-galactaric acid, to alkyl chains and poly(ethylene glycol)s, respectively (Figure 4) [51].
The resulting amphiphilic macromolecules, which showed low critical micelle concentrations, were studied for use as drug carriers for hydrophobic anticancer agents and gene therapy agents. Furthermore, these amphiphilic macromolecules were found to treat atherosclerosis by preventing macrophage intake of oxidized low-density lipoproteins.

3.4. Chelating Agents, Coordination Polymers and Metal–Organic Frameworks

Complexation of the carboxyl and hydroxy groups of hexaric acids with metals has been used in applied research. For example, such products have been investigated for use as agents to remove metals from polluted environments and incinerator plants, as corrosion inhibitors, and as Ca-sequestering agents, several of which have been commercialized [6]. The chelation ability of hexaric acids was exploited for the synthesis of coordination polymers and metal–organic frameworks (MOFs). Abrahams et al. synthesized coordination polymers derived from hexaric acids and metals. For example, they used d-glucaric acid and Zn to form a coordination polymer with two types of isolated, parallel channels, one of which was hydrophilic and the other hydrophobic [44]. The hydroxy groups of d-glucaric acid were exposed in the hydrophilic channels, while the hydrophobic channels had C-H bonds along the channel wall. Water molecules were in both channels, especially in the hydrophilic channel where they were hydrogen bonded. The water molecules in the hydrophobic channels were easily exchanged for azobenzene, I2, elemental sulfur, hydrocarbons, CCl4 and CI4. This material was expected to be applicable to the simultaneous introduction of two different species into the different channels.
Wong et al. synthesized a porous structure from meso-galactaric acid and terbium that could detect guest molecules (Figure 5) [46]. This structure formed a two-dimensional networked complex that created vertical one-dimensional channels when stacked in layers. Crystallography of this MOF revealed that the layers were connected through hydrogen bonding via water molecules; however, heating removed the water molecules without destroying the structure. In aqueous solutions, this MOF could remove I−, Br−, Cl−, F−, CN−, and CO32− and small amounts of SO42− and PO43−. These anions were assumed to be removed by forming hydrogen bonds with the meso-galactaric acid moieties. The fluorescent properties of terbium, a lanthanide element, were successfully utilized to monitor the intake of anions into the MOF. Desorption of the anions from the MOF was confirmed by placing the absorbed complexes in pure water.

3.5. Other Platform Chemicals

Hexaric acids have also been studied for use as the starting materials for other platform chemicals [54,55,56,57,58,59,60,61,62], including adipic acid [59,60,61,62], furan dicarboxylic acid (an alternative to terephthalic acid) [57], and pyrrole [55].
Li et al. reported the highly efficient conversion of meso-galactaric acid, via muconic acid, into adipic acid through an oxorhenium-complex-catalyzed deoxydehydration (DODH) reaction and following a Pt/C-catalyzed transfer hydrogenation [59]. Ionic liquid was integrated as a reaction medium into this DODH reaction in another paper [61]. The use of ionic liquid enabled an efficient separation of muconic acid by simple decantation. The recovered ionic liquid, which contained an expensive Re catalyst, was used up to four times without much of a decrease in yields. d-Glucaric acid can also be a starting compound for adipic acid. Recently, a catalyst system that provided adipate esters from d-glucaric acid in a single operation was reported, in which hydrogen was used as a terminal reductant [62].
According to the report by Thiyagarajan et al. [58], although the first report of furan-2,5-dicarboxylic acid from meso-galactaric acid was published in 1876, little attention has been paid to this route because isolated yields were moderate and meso-galactaric acid was not readily available. In terms of the availability of hexaric acids including meso-galactaric acid, it will be improved by the research mentioned in following sections. As for synthesis of furan-2,5-dicarboxylic acid from meso-galactaric acid, some works were reported. For example, one-step synthesis of dibutyl furandicarboxylates from meso-galactaric acid and 1-butanol, in the presence of sulfuric acid, was reported [57]. In this paper, the diester of furan-2,5-dicarboxylic acid was synthesized because it can be distilled or recrystallized by the use of existing solvents and can be polymerized directly using diols.

4. Hexaric Acid Production Using Inorganic Catalysts

The earliest attempts of hexaric acid preparation were reported in the late 1800s (oxidation of carbohydrates with HNO3, of which the reaction origin could be traced back to lactose oxidation by Liebig and is still used today [65,66]). However, the yields using this method are limited to approximately 40% because of side reactions. Moreover, this method results in the excessive production of nitrogen oxide gas because of the rapid and highly exothermic nature of the oxidation reaction. These drawbacks have prevented the mass production of hexaric acids using this method [67,68]. Kiely’s group have improved d-glucaric and d-mannaric acid production via nitric acid oxidation to solve these problems, enabling industrial mass production of these hexaric acids (Figure 6) [67,69].
In their studies, the amount, rate, and temperature of the d-glucose and d-mannose additions were controlled by a computer to prevent rapid temperature increases caused by the oxidation of the saccharides by nitric acid and the resulting generation of large amounts of nitrogen dioxide and other gases. Relatively low reaction temperatures (25–40 °C) were accomplished. Furthermore, a positive oxygen pressure on the reaction system generated nitric dioxide from nitric monoxide, and the dissolution of the dioxide into water reproduced nitric acid, enabling reproduction and recycling of the nitric acid (Figure 7). The removal of nitric acid from the reaction mixture was also improved.
To date, nitric acid has been removed by evaporation by heating under reduced pressure. However, complete removal is difficult because nitric acid and water form a negative azeotrope. Moreover, the relatively severe conditions used in this method allow for further oxidation reactions to occur in an uncontrolled manner. Therefore, nitric acid removal by nanofiltration and diffusion dialysis was also investigated in Kiely’s study. Selective nitric acid removal was achieved by both methods. However, because the addition of a large amount of water and pH adjustment was necessary, nanofiltration was not practical. Diffusion dialysis required neither the addition of water, the adjustment of pH, nor large amounts of energy for nitric acid removal. Further recycling of the removed nitric acid was easy. However, a problem remains in that the removed nitric acid solution contains a large amount of the products. Moreover, the yield of the reaction was not improved, remaining at 45% for d-glucaric acid. In addition to nitric acid oxidation, the production of hexaric acids by oxidation with bromine and manganese(III) sulfate has been reported [70,71,72,73]. Recently, ozonic oxidation has been proposed to solve several of the problems of conventional conversions, including their high environmental burden, byproduct generation, slow reaction rates, and high costs [74,75].
In addition to the use of strong oxidants, catalytic oxidation with transition metals has been explored. The Pt-catalyzed production of a hexaric acid, d-mannaric acid, was reported in 1938 [76]. Production of hexaric acids catalyzed by metals has been of industrial interest since the 1940s [77,78,79,80,81]. Following these antecedent works, several studies have been reported [68,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98]. Although Pt [76,82,83,84,91,92,97] and Au [68,84,85,86,89,94,95,96] have been used as catalysts frequently, other elements like Ti [87,88], Mn [90], Fe [98], Mo [93], and Pd [91,99] can also be incorporated in catalyst composites. Aldohexoses [84,85,86,87,88,90,91,92,93,94,95,97,98], aldohexonic acids [82,83,84], and hexuronic acid [68,89,96], in addition to the corresponding sugar alcohol [76,85], can be starting compounds for the metal-catalyzed production of hexaric acids. In addition to the use of oxidants like H2O2 and O2, electrochemical [85,90] and photochemical [87,88] oxidation of the substrates has been examined. Recently, catalysis under autogenous pH conditions has attracted attention, although alkaline conditions were favored for some traditional efficient catalysis reactions [95,96,97].
Hexaric acid separation from the reaction mixture was based on various methodologies, including precipitation by lowering the pH and the use of ion exchange resins [67,69,100]. For example, d-glucarate was isolated by pH change (basification of the reaction mixture to pH 9.5, which was followed by acidification to pH 3–4 [67]). meso-Galactarate was also separated from the culture supernatant by acid precipitation, where 97% recovery was achieved with 97.5% purity at pH 6.5 [100]. d-Glucarate and d-mannarate were separated from each reaction mixture by ion exchange resins following their analyses [67,69].

5. Hexaric Acid Production Using Biocatalysts

Hexaric acid production using biocatalysts has also been studied. Biocatalysts, which are regenerable, enable environmentally friendly hexaric acid production. Furthermore, the substrate and reaction specificity of biocatalysts commonly omit the need for strict purification processes to extract the saccharides from the biomass [6].
Although a variety of dehydrogenases and oxidases are known to oxidize hexoses at the C1 position, few reports describe direct enzymatic oxidation of hexoses at the C6 position, such as eukaryotic and bacterial organisms that use uridine diphosphate (UDP)- and guanosine diphosphate (GDP)-bound hexoses as substrates to oxidize the C6 position. The products of these reactions are UDP- and GDP-uronic acids, which serve as the starting compounds for synthesizing polysaccharides, ascorbic acid, and other biomolecules [6,101,102,103,104,105].
Because direct oxidation of hexose at the C6 position is difficult, combinations of biocatalysts have been used to produce hexuronic acids. For instance, Moon et al. reported a method for the production of d-glucaric acid using genetically modified Escherichia coli (E. coli, Figure 8) [106]. In recombinant E. coli, phosphotransferase activity produces d-glucose-6-phosphate, which is then converted by myo-inositol-1-phosphate synthase into myo-inositol-1-phosphate. A phosphatase then converts the myo-inositol-1-phosphate into myo-inositol, which is then converted to d-glucuronic acid (the hexuronic acid of d-glucose) by myo-inositol oxidase. Moon’s report also describes the production of d-glucaric acid from the oxidation of d-glucuronic acid by nicotinamide adenine dinucleotide (NAD)-dependent uronate dehydrogenase (UDH). Because the yield of this reaction was low, improvements in the production system have been made [107,108,109,110,111,112]. Galactose oxidase is an uncommon enzyme that can oxidize hexoses at the C6 position. For example, d-galactose oxidation catalyzed by this enzyme produces d-galactohexodialdose [113,114]. The enzymatic oxidation of d-galactohexodialdose cannot produce hexuronic acid or hexaric acid because bicyclic structures are formed; however, the oxidation of dialdose by sodium chlorite is reported to produce d-galacturonic acid, the hexuronic acid of d-galactose [115]. Recently, a mutation in this enzyme, changing its structure, was reported to enable glucose oxidation at the C6 position [107,116,117].
As described above, UDP- and GDP-uronic acids have been utilized to synthesize polysaccharides in vivo; thus, hexuronic acids are abundant in nature as the main component of polysaccharides [6,101,102,103,104,105]. For example, d-galacturonic acid can be derived from pectin [118,119,120,121]. Alginic acid hydrolysis produces d-mannuronic acid and l-guluronic acid, the hexuronic acids of d-mannose and l-gulose, respectively [122,123,124,125,126,127]. d-Glucuronic acid can be obtained from hemicellulose [128,129]. d-Glucuronic acid can also be obtained as a monomer from ulvan [123,130]. Therefore, some studies have used hexuronic acids derived from polysaccharides, which are not used as food, as the starting compounds for hexaric acids.
Mojzita et al. reported the production of meso-galactaric acid from d-galacturonic acid using recombinant microorganisms in which the gene for UDH had been introduced [100]. Many microorganisms that live on putrid plants have enzymatic pathways that catabolize d-galacturonic acid. Eukaryotic microorganisms use a reduction pathway that starts with the reduction of d-galacturonic acid into l-galactonic acid, catalyzed by d-galacturonic acid reductase, while bacteria use an oxidative pathway that first produces meso-galactaric acid in a reaction catalyzed by UDH. In their study, Mojzita et al. eliminated the gene for d-galacturonic acid reductase in two eukaryotic microorganisms, Aspergillus niger (A. niger) and Hypocrea jecorina (H. jecorina), and introduced the gene for UDH, which was derived from the bacterium Agrobacterium tumefaciens (A. tumefaciens). Neither strain with a single-gene deletion of the reductase grew on medium in which d-galacturonic acid was the sole carbon source. In contrast, meso-galactaric acid production in both strains was confirmed when deletion of the reductase was accompanied by introduction of the dehydrogenase (Figure 9). Because the amount of meso-galactaric acid obtained was small in the case of A. niger, it is assumed that A. niger metabolizes meso-galactaric acid derived from d-galacturonic acid. Although a high yield of meso-galactaric acid was achieved with H. jecorina, the addition of d-glucose as an energy source was necessary because d-galacturonic acid cannot be used as the sole carbon source. Furthermore, the addition of d-glucose was found to decrease the yield of meso-galactaric acid. The fermentation method used to produce meso-galactaric acid has been improved [131,132,133,134,135,136].
When chemicals are produced through an oxidative reaction, the electrons obtained from the substrate are usually transferred to electron accepters, such as O2. However, an enzymatic anode in a biofuel cell can serve as an electron acceptor. Enzymatic oxidative conversion on the anode can be combined with O2 reduction on the cathode to generate electricity. That is, the simultaneous production of chemicals and electricity is possible through oxidative conversion within enzymatic biofuel cells. This method reduces the energy required for producing chemicals and can even generate energy for other uses. The concept of a system that co-produces platform chemicals and electrical energy from biomass by demonstrating the simultaneous production of a hexaric acid and electrical energy using an enzymatic biofuel cell has been proposed [137,138,139]. The electrochemical oxidation of d-galacturonic acid and the production of meso-galactaric acid by a pyrroloquinoline quinone-dependent glucose dehydrogenase (PQQ-GDH)-modified electrode was confirmed [137,139]. The electrode was used as the anode in a biofuel cell with a bilirubin oxidase (BOD) cathode [139] (Figure 10). The cell generated electricity by using d-galacturonic acid and the hydrolysate of pectic acid as a fuel. This simultaneous production mechanism is applicable to other chemicals. We confirmed the oxidation of d-glucuronate and d-mannuronate, both catalyzed by PQQ-GDH, and the oxidation of l-guluronate, catalyzed by the PQQ domain of pyranose dehydrogenase from Coprinopsis cinerea (DHPDH) [138,139]. According to NMR measurements, the production of d-glucarate from the oxidation of d-glucuronate and l-guluronate and the production of d-mannarate from the d-mannuronate oxidation were confirmed. DHPDH is also suitable for use as an anode catalyst. These combinations of enzymes and chemicals are applicable to simultaneous production systems.

6. Conclusions

Hexaric acids are sugar acids that can be produced from biomass. Due to their stereochemical diversity, chelation abilities, and high solubility in water, numerous applications have been developed. These applications include their use as chelating agents and corrosion inhibitors and as precursors for various polymers, coordination polymers, macromolecules, cross-linkers in hydrogels, and medicines. The conventional production of hexaric acids is conducted by the oxidation of saccharides with nitric acids. To overcome the problems derived from the use of nitric acids, in addition to improving the nitric acid oxidation process, green chemical methods have been developed to produce hexaric acids. Transition metal catalysts and modified microorganisms have been utilized to produce hexaric acids from hexuronic acids under mild conditions. Quite recently, the production of hexuronic acids using high-frequency ultrasound irradiation without a catalyst has been reported [140]. In addition, the production of hexuronic acids by using metal catalysts has been developed [141]. Combining these technologies with the aforementioned technologies, the production of hexaric acids can be improved. Furthermore, hexaric acid was produced directly from aldohexoses by using modified microorganisms. The oxidation reaction of aldohexoses using enzymes is considered to have an advantage in terms of stereoselectivity. In the future, processes for producing hexaric acids using a biocatalyst including enzymes could be constructed.

Author Contributions

R.S. and N.N. wrote and edited the manuscript.

Funding

This research was partially funded by a Grant-in-Aid for JSPS Fellows (Grant No. 16J07225 to R.S.).

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

DOEThe US Department of Energy
PEIsPolyethylene imines
MOFMetal–organic framework
UDPUridine diphosphate
GDPGuanosine diphosphate
UDHUronate dehydrogenase
PQQPyrroloquinolone quinone
GDHGlucose dehydrogenase
BODBilirubin oxidase
DHPDHPQQ domain of pyranose dehydrogenase from Coprinopsis cinerea

References

  1. Cherubini, F. The biorefinery concept: Using biomass instead of oil for producing energy and chemicals. Energy Convers. Manag. 2010, 51, 1412–1421. [Google Scholar] [CrossRef]
  2. de Jong, E.; Higson, A.; Walsh, P.; Wellisch, M. Product developments in the bio-based chemicals arena. Biofuels Bioprod. Biorefin. 2012, 6, 606–624. [Google Scholar] [CrossRef]
  3. Werpy, T.; Peterson, G. Top Value Added Chemicals from Biomass: Volume I—Results of Screening for Potential Candidates from Sugars and Synthesis Gas; Technical Report Produced for the U.S. Department of Energy by the National Renewable Energy Laboratory: Washington, DC, USA, 2004. [Google Scholar]
  4. Climent, M.J.; Corma, A.; Iborra, S. Converting carbohydrates to bulk chemicals and fine chemicals over heterogeneous catalysts. Green Chem. 2011, 13, 520–540. [Google Scholar] [CrossRef]
  5. Isikgor, F.H.; Becer, C.R. Lignocellulosic biomass: A sustainable platform for the production of bio-based chemicals and polymers. Polym. Chem. 2015, 6, 4497–4559. [Google Scholar] [CrossRef]
  6. Mehtiö, T.; Toivari, M.; Wiebe, M.G.; Harlin, A.; Penttilä, M.; Koivula, A. Production and applications of carbohydrate-derived sugar acids as generic biobased chemicals. Crit. Rev. Biotechnol. 2016, 36, 904–916. [Google Scholar] [CrossRef]
  7. de Lederkremer, R.M.; Marino, C. Acids and their products of oxidation of sugars. Adv. Carbohydr. Chem. Biochem. 2003, 58, 199–306. [Google Scholar]
  8. Alterman, M.; Björsne, M.; Mühlman, A.; Classon, B.; Kvarnström, I.; Danielson, H.; Markgren, P.-O.; Nillroth, U.; Unge, T.; Hallberg, A.; et al. Design and synthesis of new potent C2-symmetric HIV-1 protease inhibitors. Use of l-mannaric acid as a peptidomimetic scaffold. J. Med. Chem. 1998, 41, 3782–3792. [Google Scholar] [CrossRef]
  9. Wachtmeister, J.; Mühlman, A.; Classon, B.; Kvarnström, I.; Hallberg, A.; Samuelsson, B. Impact of the central hydroxyl groups on the activity of symmetrical HIV-1 protease inhibitors derived from l-mannaric acid. Tetrahedron 2000, 56, 3219–3225. [Google Scholar] [CrossRef]
  10. Chakraborty, T.K.; Ghosh, S.; Jayaprakash, S.; Sharma, J.A.R.P.; Ravikanth, V.; Diwan, P.V.; Nagaraj, R.; Kunwar, A.C. Synthesis and conformational studies of peptidomimetics containing furanoid sugar amino acids and a sugar diacid. J. Org. Chem. 2000, 65, 6441–6457. [Google Scholar] [CrossRef]
  11. Chakraborty, T.K.; Ghosh, S.; Rao, M.H.V.R.; Kunwar, A.C.; Cho, H.; Ghosh, A.K. 2, 5-Anhydro sugar diacid and 2, 5-anhydro sugar diamine based C2 symmetric peptidomimetics as potential HIV-1 protease inhibitors. Tetrahedron Lett. 2000, 41, 10121–10125. [Google Scholar] [CrossRef]
  12. Mehltretter, C.L.; Alexander, B.H.; Rist, C.E. Sequestration by sugar acids. Ind. Eng. Chem. 1953, 45, 2782–2784. [Google Scholar] [CrossRef]
  13. Gónzalez-Portal, A.; Baluja-Santos, C.; Bermejo-Mártinez, F. Spectrophotometric determination of bismuth in pharmaceutical preparations using mucic acid. Analyst 1986, 111, 547–549. [Google Scholar] [CrossRef] [PubMed]
  14. Ramos, M.L.; Caldeira, M.M.; Gil, V.M.S. Multinuclear NMR study of the complexation of d-glucaric acid with molybdenum(VI) and tungsten(VI). Inorg. Chim. Acta 1991, 180, 219–224. [Google Scholar] [CrossRef]
  15. Ramos, M.L.; Caldeira, M.M.; Gil, V.M.S.; van Bekkum, H.; Peters, J.A. Multinuclear NMR study of the complexation of d-galactaric and d-mannaric acids with molybdenum(VI). Polyhedron 1994, 13, 1825–1833. [Google Scholar] [CrossRef]
  16. Ramos, M.L.; Caldeira, M.M.; Gil, V.M.S.; van Bekkum, H.; Peters, J.A. Multinuclear NMR study of complexation of d-galactaric and d-mannaric acids with tungsten(VI) oxoions. J. Coord. Chem. 1994, 33, 319–329. [Google Scholar] [CrossRef]
  17. Abbadi, A.; Gotlieb, K.F.; Meiberg, J.B.M.; Peters, J.A.; van Bekkum, H. New Ca-sequestering materials. Based on the oxidation of the hydrolysis products of lactose. Green Chem. 1999, 1, 231–235. [Google Scholar] [CrossRef]
  18. Saladini, M.; Ferrari, E.; Menabue, L. Co-ordination of transition metal ions by galactaric acid: A potentiometric and spectroscopic study. J. Inorg. Biochem. 2002, 92, 121–127. [Google Scholar] [CrossRef]
  19. Lakatos, A.; Bertani, R.; Kiss, T.; Venzo, A.; Casarin, M.; Benetollo, F.; Ganis, P.; Favretto, D. AlIII ion complexes of saccharic acid and mucic acid: A solution and solid-state study. Chem. Eur. J. 2004, 10, 1281–1290. [Google Scholar] [CrossRef]
  20. Abrahams, B.F.; McCormick, L.J.; Moubaraki, B.; Murray, K.S.; Robson, R.; Waters, T. Two Cu21 clusters with pseudo-D3 symmetry derived from the d-saccharate pentaanion, C6H5O85−. Chem. Eur. J. 2011, 17, 7454–7459. [Google Scholar] [CrossRef]
  21. Koefod, R.S. Corrosion-inhibiting deicer composition. U.S. Patent 7658861B2, 9 February 2010. [Google Scholar]
  22. Wolfrom, M.L.; Toy, M.S.; Chaney, A. Condensation polymers from tetra-o-acetylgalactaroyl dichloride and diamines. J. Am. Chem. Soc. 1958, 80, 6328–6330. [Google Scholar] [CrossRef]
  23. Bird, T.P.; Black, W.A.P.; Dewar, E.T.; Hare, J.B. Polyamides containing carbohydrate residues. J. Chem. Soc. 1963, 1208–1212. [Google Scholar] [CrossRef]
  24. Bird, T.P.; Black, W.A.P.; Dewar, E.T.; Hare, J.B. Polyamides containing carbohydrate residues. Part II. Benzylidenedioxy-derivatives. J. Chem. Soc. 1963, 3389–3391. [Google Scholar] [CrossRef]
  25. Ogata, N.; Sanui, K.; Hosoda, Y.; Nakamura, H. Active polycondensation of diethyl 2, 3, 4, 5-tetrahydroxyadipate with diamines. J. Polym. Sci. Polym. Chem. Ed. 1976, 14, 783–792. [Google Scholar] [CrossRef]
  26. Ogata, N.; Sanui, K.; Kayama, Y. Copolycondensation of hydroxyl diesters and active diesters with hexamethylenediamine. J. Polym. Sci. Polym. Chem. Ed. 1977, 15, 1523–1526. [Google Scholar] [CrossRef]
  27. Ogata, N.; Sanui, K.; Hosoda, Y.; Nakamura, H.; Kishi, H. Polycondensation of diethyl mucate with hexamethylenediamine in the presence of poly(vinyl pyridine). J. Polym. Sci. Polym. Chem. Ed. 1980, 18, 933–938. [Google Scholar] [CrossRef]
  28. Kiely, D.E.; Chen, L.; Lin, T.-H. Hydroxylated nylons based on unprotected esterified d-glucaric acid by simple condensation reactions. J. Am. Chem. Soc. 1994, 116, 571–578. [Google Scholar] [CrossRef]
  29. Chen, L.; Kiely, D.E. Synthesis of stereoregular head, tail hydroxylated nylons derived from d-glucose. J. Org. Chem. 1996, 61, 5847–5851. [Google Scholar] [CrossRef]
  30. Morton, D.W.; Kiely, D.E. Evaluation of the film and adhesive properties of some block copolymer polyhydroxypolyamides from esterified aldaric acids and diamines. J. Appl. Polym. Sci. 2000, 77, 3085–3092. [Google Scholar] [CrossRef]
  31. Kiely, D.E.; Chen, L.; Lin, T.-H. Synthetic polyhydroxypolyamides from galactaric, xylaric, d-glucaric, and d-mannaric acids and alkylenediamine monomers—Some comparisons. J. Polym. Sci. A Polym. Chem. 2000, 38, 594–603. [Google Scholar] [CrossRef]
  32. Orgueira, H.A.; Varela, O. Synthesis and characterization of stereoregular AABB-type polymannaramides. J. Polym. Sci. A Polym. Chem. 2001, 39, 1024–1030. [Google Scholar] [CrossRef]
  33. Mancera, M.; Roffé, I.; Rivas, M.; Galbis, J.A. New derivatives of d-mannaric and galactaric acids: Synthesis of a new stereoregular Nylon 66 analog from carbohydrate-based monomers having the d-manno configuration. Carbohydr. Res. 2003, 338, 1115–1119. [Google Scholar] [CrossRef]
  34. Henkensmeier, D.; Abele, B.C.; Candussio, A.; Thiem, J. Synthesis, characterisation and degradability of polyamides derived from aldaric acids and chain end functionalised polydimethylsiloxanes. Polymer 2004, 45, 7053–7059. [Google Scholar] [CrossRef]
  35. Liu, Y.; Reineke, T.M. Hydroxyl stereochemistry and amine number within poly(glycoamidoamine)s affect intracellular DNA delivery. J. Am. Chem. Soc. 2005, 127, 3004–3015. [Google Scholar] [CrossRef] [PubMed]
  36. Muñoz-Guerra, S. Carbohydrate-based polyamides and polyesters: An overview illustrated with two selected examples. High Perform. Polym. 2012, 24, 9–23. [Google Scholar] [CrossRef]
  37. Black, W.A.P.; Dewar, E.T.; Hare, J.B. Polyesters containing carbohydrate residues. J. Chem. Soc. 1963, 5724–5727. [Google Scholar] [CrossRef]
  38. Zamora, F.; Hakkou, K.; Alla, A.; Rivas, M.; de Ilarduya, A.M.; Muñoz-Guerra, S.; Galbis, J.A. Butylene copolyesters based on aldaric and terephthalic acids. Synthesis and characterization. J. Polym. Sci. Part A Polym. Chem. 2009, 47, 1168–1177. [Google Scholar] [CrossRef]
  39. Lavilla, C.; Alla, A.; de Ilarduya, A.M.; Benito, E.; García-Martín, M.G.; Galbis, J.A.; Muñoz-Guerra, S. Carbohydrate-based polyesters made from bicyclic acetalized galactaric acid. Biomacromolecules 2011, 12, 2642–2652. [Google Scholar] [CrossRef]
  40. Lavilla, C.; Alla, A.; de Ilarduya, A.M.; Benito, E.; García-Martín, M.G.; Galbis, J.A.; Muñoz-Guerra, S. Bio-based poly(butylene terephthalate) copolyesters containing bicyclic diacetalized galactitol and galactaric acid: Influence of composition on properties. Polymer 2012, 53, 3432–3445. [Google Scholar] [CrossRef]
  41. Lavilla, C.; Alla, A.; de Ilarduya, A.M.; Benito, E.; García-Martín, M.G.; Galbis, J.A.; Muñoz-Guerra, S. Carbohydrate-based copolyesters made from bicyclic acetalized galactaric acid. J. Polym. Sci. Part A Polym. Chem. 2012, 50, 1591–1604. [Google Scholar] [CrossRef]
  42. Mehtiö, T.; Nurmi, L.; Rämö, V.; Mikkonen, H.; Harlin, A. Synthesis and characterization of copolyanhydrides of carbohydrate-based galactaric acid and adipic acid. Carbohydr. Res. 2015, 402, 102–110. [Google Scholar] [CrossRef]
  43. Pan, D.W.; Davis, M.E. Cationic mucic acid polymer-based siRNA delivery systems. Bioconjug. Chem. 2015, 26, 1791–1803. [Google Scholar] [CrossRef]
  44. Abrahams, B.F.; Moylan, M.; Orchard, S.D.; Robson, R. Zinc Saccharate: A Robust, 3D coordination network with two types of isolated, parallel channels, one hydrophilic and the other hydrophobic. Angew. Chem. Int. Ed. 2003, 42, 1848–1851. [Google Scholar] [CrossRef]
  45. Abrahams, B.F.; Moylan, M.; Orchard, S.D.; Robson, R. Channel-containing lanthanide mucate structures. CrystEngComm 2003, 5, 313–317. [Google Scholar] [CrossRef]
  46. Wong, K.-L.; Law, G.-L.; Yang, Y.-Y.; Wong, W.-T. A highly porous luminescent terbium–organic framework for reversible anion sensing. Adv. Mater. 2006, 18, 1051–1054. [Google Scholar] [CrossRef]
  47. Abrahams, B.F.; Grannas, M.J.; McCormick, L.J.; Robson, R.; Thistlethwaite, P.J. Chiral and achiral linear coordination polymers from aldaric acids. CrystEngComm 2010, 12, 2885–2895. [Google Scholar] [CrossRef]
  48. Busschaert, N.; Caltagirone, C.; van Rossom, W.; Gale, P.A. Applications of Supramolecular Anion Recognition. Chem. Rev. 2015, 115, 8038–8155. [Google Scholar] [CrossRef] [PubMed]
  49. Kawaguchi, A.W.; Okawa, H.; Hashimoto, K. Synthesis of glycopolymers bearing mannaric pendants as inhibitors on the β-glucuronidase activity: The inhibition mechanisms of mannaric-and glucaric-compounds. J. Polym. Sci. Part A Polym. Chem. 2009, 47, 2032–2042. [Google Scholar] [CrossRef]
  50. Tian, L.; Yam, L.; Zhou, N.; Tat, H.; Uhrich, K.E. Amphiphilic Scorpion-like Macromolecules:  Design, Synthesis, and Characterization. Macromolecules 2004, 37, 538–543. [Google Scholar] [CrossRef]
  51. Gu, L.; Faig, A.; Abdelhamid, D.; Uhrich, K. Sugar-based amphiphilic polymers for biomedical applications: From nanocarriers to therapeutics. Acc. Chem. Res. 2014, 47, 2867–2877. [Google Scholar] [CrossRef]
  52. Pohjanlehto, H.; Setälä, H.; Kammiovirta, K.; Harlin, A. The use of N, N′-diallylaldardiamides as cross-linkers in xylan derivatives-based hydrogels. Carbohydr. Res. 2011, 346, 2736–2745. [Google Scholar] [CrossRef]
  53. Calcium-D-Glucarate. Available online: https://www.ncbi.nlm.nih.gov/pubmed/12197785 (accessed on 25 July 2019).
  54. Butler, C.L.; Cretcher, L.H. The preparation of allomucic acid and certain of its derivatives. J. Am. Chem. Soc. 1929, 51, 2167–2170. [Google Scholar] [CrossRef]
  55. Williams, S.R.; Maynard, H.D.; Chmelka, B.F. Synthesis of 13C-enriched pyrrole from 2-13C d-galactose. J. Label. Compd. Radiopharm. 1999, 42, 927–936. [Google Scholar] [CrossRef]
  56. Pellissier, H. Syntheses of 1-induronyl synthons. A review. Org. Prep. Proced. Int. 2002, 34, 441–465. [Google Scholar] [CrossRef]
  57. Taguchi, Y.; Oishi, A.; Iida, H. One-step synthesis of dibutyl furandicarboxylates from galactaric acid. Chem. Lett. 2008, 37, 50–51. [Google Scholar] [CrossRef]
  58. Thiyagarajan, S.; Pukin, A.; van Haveren, J.; Lutz, M.; van Es, D.S. Concurrent formation of furan-2, 5-and furan-2, 4-dicarboxylic acid: Unexpected aspects of the Henkel reaction. RSC Adv. 2013, 3, 15678–15686. [Google Scholar] [CrossRef]
  59. Li, X.; Wu, D.; Lu, T.; Yi, G.; Su, H.; Zhang, Y. Highly efficient chemical process to convert mucic acid into adipic acid and DFT studies of the mechanism of the rhenium-catalyzed deoxydehydration. Angew. Chem. Int. Ed. 2014, 53, 4200–4204. [Google Scholar] [CrossRef] [PubMed]
  60. Zhang, H.; Li, X.; Su, X.; Ang, E.L.; Zhang, Y.; Zhao, H. Production of adipic acid from sugar beet residue by combined biological and chemical catalysis. ChemCatChem 2016, 8, 1500–1506. [Google Scholar] [CrossRef]
  61. Shin, N.; Kwon, S.; Moon, S.; Hong, C.H.; Kim, Y.G. Ionic liquid-mediated deoxydehydration reactions: Green synthetic process for bio-based adipic acid. Tetrahedron 2017, 73, 4758–4765. [Google Scholar] [CrossRef]
  62. Larson, R.T.; Samant, A.; Chen, J.; Lee, W.; Bohn, M.A.; Ohlmann, D.M.; Zuend, S.J.; Toste, F.D. Hydrogen gas-mediated deoxydehydration/hydrogenation of sugar acids: Catalytic conversion of glucarates to adipates. J. Am. Chem. Soc. 2017, 139, 14001–14004. [Google Scholar] [CrossRef]
  63. Jeffery, G.A.; Wood, R.A. The crystal structure of galactaric acid (mucic acid) at−147°: An unusually dense, hydrogen-bonded structure. Carbohydr. Res. 1982, 108, 205–211. [Google Scholar] [CrossRef]
  64. Taga, T.; Kuroda, Y.; Osaki, K. Interactions of calcium ions with carbohydrates: X-ray diffraction and NMR spectroscopic studies on the potassium salt and the calcium salt of d-glucaric acid. Bull. Chem. Soc. Jpn. 1977, 50, 3079–3083. [Google Scholar] [CrossRef]
  65. Sohst, O.; Tollens, B. Über krystallisirte Zuckersäure (Zuckerlactonsäure). Justus Liebig’s Ann. Chem. 1888, 245, 1–27. [Google Scholar] [CrossRef]
  66. Easterfield, T.H. XXXIV.—The oxidation of mannitol by nitric acid. d.-Mannosaccharic acid. J. Chem. Soc. Trans. 1891, 59, 306–310. [Google Scholar] [CrossRef]
  67. Smith, T.N.; Hash, K.; Davey, C.-L.; Mills, H.; Williams, H.; Kiely, D.E. Modifications in the nitric acid oxidation of d-glucose. Carbohydr. Res. 2012, 350, 6–13. [Google Scholar] [CrossRef] [PubMed]
  68. Rautiainen, S.; Lehtinen, P.; Chen, J.; Leskelä, M.; Niemelä, K.; Leskelä, M.; Repo, T. Selective oxidation of uronic acids into aldaric acids over gold catalyst. RSC Adv. 2015, 5, 19502–19507. [Google Scholar] [CrossRef] [Green Version]
  69. Carpenter, C.A.; Hardcastle, K.I.; Kiely, D.E. Modifications in the nitric acid oxidation of d-mannose: X-ray crystal structure of N, N′-dimethyl d-mannaramide. Carbohydr. Res. 2013, 376, 29–36. [Google Scholar] [CrossRef] [PubMed]
  70. Fauvarque, J.-F.; Mestre, M.; Trévin, S.; Marzouk, H.; Jud, J.-M. Recent industrial experiences with electroorganic synthesis-industrial electrosynthesis of an insoluble compound-galactaric acid. Actual. Chim. 1998, 214, 48–50. [Google Scholar]
  71. Rangappa, K.S.; Anitha, N.; Nikath, M.A.; Rai, K.M.L.; Gowda, N.M.M. Oxidation of uronic acids by manganese(III) sulfate in acid solution: A kinetic and mechanistic study. Synth. React. Inorg. Met. Org. Chem. 2001, 31, 713–723. [Google Scholar] [CrossRef]
  72. Merbouh, N.; Bobbitt, J.M.; Brückner, C. 4-AcNH-tempo-catalyzed oxidation of aldoses to aldaric acids using chlorine or bromine as terminal oxidants. J. Carbohydr. Chem. 2002, 21, 65–77. [Google Scholar] [CrossRef]
  73. Ibert, M.; Marsais, F.; Merbouh, N.; Brückner, C. Determination of the side-products formed during the nitroxide-mediated bleach oxidation of glucose to glucaric acid. Carbohydr. Res. 2002, 337, 1059–1063. [Google Scholar] [CrossRef]
  74. Marcq, O.; Barbe, J.-M.; Trichet, A.; Guilard, R. Reaction pathways of glucose oxidation by ozone under acidic conditions. Carbohydr. Res. 2009, 344, 1303–1310. [Google Scholar] [CrossRef] [PubMed]
  75. Bonhoure, J.-P.; Abboud, H.; Aussenac, T.R.; Coste, C.U.; Hoang, L.; Ralainirina, R.; Rannou, A.C. New method for synthesising mucic acid using ozone. WIPO WO2013144483A1, 18 March 2013. [Google Scholar]
  76. Glattfeld, J.W.E.; Gershon, S. The Catalytic Dehydrogenation of Sugar Alcohols. J. Am. Chem. Soc. 1938, 60, 2013–2023. [Google Scholar] [CrossRef]
  77. Mehltretter, C.L.; Rist, C.E.; Alexander, B.H. Process for the preparation of D-glucosaccharic acid. U.S. Patent 2472168A, 7 June 1949. [Google Scholar]
  78. Boussie, T.R.; Dias, E.L.; Fresco, Z.M.; Murphy, V.J.; Shoemaker, J.; Archer, R.; Jiang, H. Production of adipic acid and derivatives from carbohydrate-containing materials. WIPO WO2010144862A2, 16 December 2010. [Google Scholar]
  79. van Es, D.S.; van Haveren, J.; Raaijmakers, H.W.C.; van der Klis, F.; van Engelen, G.P.F.M.; Frissen, A.E. Catalytic oxidation of uronic acids to aldaric acids. WIPO WO2013151428A1, 10 October 2013. [Google Scholar]
  80. Hong, C.H.; Kim, S.H.; Kim, Y.G.; Shin, N.R. Method for producing glucaric acid. U.S. Patent 9227904B1, 5 January 2016. [Google Scholar]
  81. Marion, P.; Derrien, E.; Pinel, C.; Besson, M. Process for the preparation of a mixture of aldaric acids or salts thereof. EP3088378A1, 2 November 2016. [Google Scholar]
  82. Dirkn, J.M.H.; van der Baan, H.S.; van den Broen, J.M.A.J.J. The preparation of d-glucaric acid by the oxidation of d-gluconic acid catalysed by platinum on carbon. Carbohydr. Res. 1977, 59, 63–72. [Google Scholar] [CrossRef]
  83. Dirkn, J.M.H.; van der Baan, H.S. The oxidation of gluconic acid with platinum on carbon as catalyst. J. Catal. 1981, 67, 14–20. [Google Scholar]
  84. Besson, M.; Flèche, G.; Fuertes, P.; Gallezot, P.; Lahmer, F. Oxidation of glucose and gluconate on Pt, Pt Bi, and Pt Au catalysts. Recl. Trav. Chim. Pays Bas 1996, 115, 217–221. [Google Scholar] [CrossRef]
  85. Parpot, P.; Nunes, N.; Bettencourt, A.P. Electrocatalytic oxidation of monosaccharides on gold electrode in alkaline medium: Structure–reactivity relationship. J. Electroanal. Chem. 2006, 596, 65–73. [Google Scholar] [CrossRef]
  86. Bujak, P.; Bartczak, P.; Polanski, J. Highly efficient room-temperature oxidation of cyclohexene and d-glucose over nanogold Au/SiO2 in water. J. Catal. 2012, 295, 15–21. [Google Scholar] [CrossRef]
  87. Colmenares, J.C.; Magdziarz, A. Room temperature versatile conversion of biomass-derived compounds by means of supported TiO2 photocatalysts. J. Mol. Catal. A Chem. 2013, 366, 156–162. [Google Scholar] [CrossRef]
  88. Colmenares, J.C.; Magdziarz, A.; Chernyayeva, O.; Lisovytskiy, D.; Kurzydłowski, K.; Grzonka, J. Sonication-Assisted Low-Temperature Routes for the Synthesis of Supported Fe–TiO2 Econanomaterials: Partial Photooxidation of Glucose and Phenol Aqueous Degradation. ChemCatChem 2013, 5, 2270–2277. [Google Scholar] [CrossRef]
  89. van der Klis, F.; Frissen, A.E.; van Haveren, J.; van Es, D.S. Waste not, want not: Mild and selective catalytic oxidation of uronic acids. ChemSusChem 2013, 6, 1640–1645. [Google Scholar] [CrossRef]
  90. Bin, D.; Wang, H.; Li, J.; Wang, H.; Yin, Z.; Kang, J.; He, B.; Li, Z. Controllable oxidation of glucose to gluconic acid and glucaric acid using an electrocatalytic reactor. Electrochim. Acta 2014, 130, 170–178. [Google Scholar] [CrossRef]
  91. Jin, X.; Zhao, M.; Vora, M.; Shen, J.; Zeng, C.; Yan, W.; Thapa, P.S.; Subramaniam, B.; Chaudhari, R.V. Synergistic effects of bimetallic PtPd/TiO2 nanocatalysts in oxidation of glucose to glucaric acid: Structure dependent activity and selectivity. Ind. Eng. Chem. Res. 2016, 55, 2932–2945. [Google Scholar] [CrossRef]
  92. Lee, J.; Saha, B.; Vlachos, D.G. Pt catalysts for efficient aerobic oxidation of glucose to glucaric acid in water. Green Chem. 2016, 18, 3815–3822. [Google Scholar] [CrossRef]
  93. Megías-Sayago, C.; Carrasco, C.J.; Ivanova, S.; Montilla, F.J.; Galindo, A.; Odriozola, J.A. Influence of the ionic liquid presence on the selective oxidation of glucose over molybdenum based catalysts. Catal. Today 2016, 278, 82–90. [Google Scholar] [CrossRef]
  94. Solmi, S.; Morreale, C.; Ospitali, F.; Agnoli, S.; Cavani, F. Oxidation of d-glucose to glucaric acid using Au/C catalysts. ChemCatChem 2017, 9, 2797–2806. [Google Scholar] [CrossRef]
  95. Derrien, E.; Mounguengui-Diallo, M.; Perret, N.; Marion, P.; Pinel, C.; Besson, M. Aerobic oxidation of glucose to glucaric acid under alkaline-free conditions: Au-based bimetallic catalysts and the effect of residues in a hemicellulose hydrolysate. Ind. Eng. Chem. Res. 2017, 56, 13175–13189. [Google Scholar] [CrossRef]
  96. Purushothaman, R.K.P.; van der Klis, F.; Frissen, A.E.; van Haveren, J.; Mayoral, A.; van der Bent, A.; van Es, D.S. Base-free selective oxidation of pectin derived galacturonic acid to galactaric acid using supported gold catalysts. Green Chem. 2018, 20, 2763–2774. [Google Scholar] [CrossRef]
  97. Armstrong, R.D.; Hirayama, J.; Knight, D.W.; Hutchings, G.J. Quantitative Determination of Pt-Catalyzed d-Glucose Oxidation Products Using 2D NMR. ACS Catal. 2019, 9, 325–335. [Google Scholar] [CrossRef]
  98. Chen, R.; Yang, C.; Zhang, Q.; Zhang, B.; Deng, K. Visible-light-driven selective oxidation of glucose in water with H-ZSM-5 zeolite supported biomimetic photocatalyst. J. Catal. 2019, 374, 297–305. [Google Scholar] [CrossRef]
  99. Besson, M.; Lahmer, F.; Gallezot, P.; Fuertes, P.; Fleche, G. Catalytic Oxidation of Glucose on Bismuth-Promoted Palladium Catalysts. J. Catal. 1995, 152, 116–121. [Google Scholar] [CrossRef]
  100. Mojzita, D.; Wiebe, M.; Hilditch, S.; Boer, H.; Penttilä, M.; Richard, P. Metabolic engineering of fungal strains for conversion of d-galacturonate to meso-galactarate. Appl. Environ. Microbiol. 2010, 76, 169–175. [Google Scholar] [CrossRef] [PubMed]
  101. Hassid, W.Z.; Putman, E.W. Transformation of sugars in plants. Annu. Rev. Plant Biol. 1950, 1, 109–124. [Google Scholar] [CrossRef]
  102. Lin, T.-Y.; Hassid, W.Z. Pathway of alginic acid synthesis in the marine brown alga, Fucus gardneri silva. J. Biol. Chem. 1966, 241, 5284–5297. [Google Scholar] [PubMed]
  103. Nyvall, P.; Corre, E.; Boisset, C.; Barbeyron, T.; Rousvoal, S.; Scornet, D.; Kloareg, B.; Boyen, C. Characterization of mannuronan C-5-epimerase genes from the brown alga Laminaria digitata. Plant Physiol. 2003, 133, 726–735. [Google Scholar] [CrossRef] [PubMed]
  104. Rehm, B.H.A. Bacterial polymers: Biosynthesis, modifications and applications. Nat. Rev. Microbiol. 2010, 8, 578–592. [Google Scholar] [CrossRef] [PubMed]
  105. Zhang, P.; Shao, Z.; Jin, W.; Duan, D. Comparative characterization of two GDP-mannose dehydrogenase genes from Saccharina japonica (Laminariales, Phaeophyceae). BMC Plant Biol. 2016, 16, 62. [Google Scholar] [CrossRef] [PubMed]
  106. Moon, T.S.; Yoon, S.-H.; Lanza, A.M.; Roy-Mayhew, J.D.; Prather, K.L.J. Production of glucaric acid from a synthetic pathway in recombinant Escherichia coli. Appl. Environ. Microbiol. 2009, 75, 589–595. [Google Scholar] [CrossRef] [PubMed]
  107. Lippow, S.M.; Moon, T.S.; Basu, S.; Yoon, S.-H.; Li, X.; Chapman, X.; Robison, K.; Lipovšek, D.; Prather, K.L.J. Engineering enzyme specificity using computational design of a defined-sequence library. Chem. Biol. 2010, 17, 1306–1315. [Google Scholar] [CrossRef] [PubMed]
  108. Shiue, E.; Prather, K.L.J. Improving d-glucaric acid production from myo-inositol in E. coli by increasing MIOX stability and myo-inositol transport. Metab. Eng. 2014, 22, 22–31. [Google Scholar] [CrossRef]
  109. Shiue, E.; Brockman, I.M.; Prather, K.L.J. Improving product yields on D-glucose in Escherichia coli via knockout of pgi and zwf and feeding of supplemental carbon sources. Biotechnol. Bioeng. 2015, 112, 579–587. [Google Scholar] [CrossRef]
  110. Reizman, I.M.B.; Stenger, A.R.; Reisch, C.R.; Gupta, A.; Connors, N.C.; Prather, K.L.J. Improvement of glucaric acid production in E. coli via dynamic control of metabolic fluxes. Metab. Eng. Commun. 2015, 2, 109–116. [Google Scholar] [CrossRef]
  111. Gupta, A.; Hicks, M.A.; Manchester, S.P.; Prather, K.L.J. Porting the synthetic d-glucaric acid pathway from Escherichia coli to Saccharomyces cerevisiae. Biotechnol. J. 2016, 11, 1201–1208. [Google Scholar] [CrossRef] [PubMed]
  112. Gupta, A.; Reizman, I.M.B.; Reisch, C.R.; Prather, K.L.J. Dynamic regulation of metabolic flux in engineered bacteria using a pathway-independent quorum-sensing circuit. Nat. Biotechnol. 2017, 35, 273–279. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Schoevaart, R.; Kieboom, T. Galactose dialdehyde: The forgotten candidate for a protein cross-linker? Carbohydr. Res. 2001, 334, 1–6. [Google Scholar] [CrossRef]
  114. Schoevaart, R.; Kieboom, T. Galactose dialdehyde as potential protein cross-linker: Proof of principle. Carbohydr. Res. 2002, 337, 899–904. [Google Scholar] [CrossRef]
  115. Schoevaart, R.; Kieboom, T. Application of galactose oxidase in chemoenzymatic one-pot cascade reactions without intermediate recovery steps. Top. Catal. 2004, 27, 3–9. [Google Scholar] [CrossRef]
  116. Sun, L.; Bulter, T.; Alcalde, M.; Petrounia, I.P.; Arnold, F.H. Modification of galactose oxidase to introduce glucose 6-oxidase activity. ChemBioChem 2002, 3, 781–783. [Google Scholar] [CrossRef]
  117. Moon, T.S.; Nielsen, D.R.; Prather, K.L.J. Sensitivity analysis of a proposed model mechanism for newly created glucose-6-oxidases. AIChE J. 2012, 58, 2303–2308. [Google Scholar] [CrossRef]
  118. Richard, P.; Hilditch, S. d-galacturonic acid catabolism in microorganisms and its biotechnological relevance. Appl. Microbiol. Biotechnol. 2009, 2, 597–604. [Google Scholar] [CrossRef]
  119. Pedrolli, D.B.; Monteiro, A.C.; Gomes, E.; Carmona, E.C. Pectin and pectinases: Production, characterization and industrial application of microbial pectinolytic enzymes. Open Biotechnol. J. 2009, 3, 9–18. [Google Scholar] [CrossRef]
  120. Voragen, A.G.J.; Coenen, G.-J.; Verhoef, R.P.; Schols, H.A. Pectin, a versatile polysaccharide present in plant cell walls. Struct. Chem. 2009, 20, 263–275. [Google Scholar] [CrossRef] [Green Version]
  121. Babbar, N.; Dejonghe, W.; Gatti, M.; Sforza, S.; Elst, K. Pectic oligosaccharides from agricultural by-products: Production, characterization and health benefits. Crit. Rev. Biotechnol. 2016, 36, 594–606. [Google Scholar] [CrossRef] [PubMed]
  122. D’Ayala, G.G.; Malinconico, M.; Laurienzo, P. Marine derived polysaccharides for biomedical applications: Chemical modification approaches. Molecules 2008, 13, 2069–2106. [Google Scholar] [CrossRef] [PubMed]
  123. Vera, J.; Castro, J.; Gonzalez, A.; Moenne, A. Seaweed polysaccharides and derived oligosaccharides stimulate defense responses and protection against pathogens in plants. Mar. Drugs 2011, 9, 2514–2525. [Google Scholar] [CrossRef] [PubMed]
  124. Foley, P.M.; Beach, E.S.; Zimmerman, J.B. Algae as a source of renewable chemicals: Opportunities and challenges. Green Chem. 2011, 13, 1399–1405. [Google Scholar] [CrossRef]
  125. Kerton, F.M.; Liu, Y.; Omari, K.W.; Hawboldt, K. Green chemistry and the ocean-based biorefinery. Green Chem. 2013, 15, 860–871. [Google Scholar] [CrossRef] [Green Version]
  126. Michalak, I.; Chojnacka, K. Algae as production systems of bioactive compounds. Eng. Life Sci. 2015, 15, 160–176. [Google Scholar] [CrossRef]
  127. Lee, K.Y.; Mooney, D.J. Alginate: Properties and biomedical applications. Prog. Polym. Sci. 2012, 37, 106–126. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  128. Saha, B.C. Hemicellulose bioconversion. J. Ind. Microbiol. Biotechnol. 2003, 30, 279–291. [Google Scholar] [CrossRef] [PubMed]
  129. Scheller, H.V.; Ulvskov, P. Hemicelluloses. Annu. Rev. Plant Biol. 2010, 61, 263–289. [Google Scholar] [CrossRef]
  130. Lahaye, M.; Robic, A. Structure and functional properties of ulvan, a polysaccharide from green seaweeds. Biomacromolecules 2007, 8, 1765–1774. [Google Scholar] [CrossRef] [PubMed]
  131. Benz, J.P.; Protzko, R.J.; Andrich, J.M.S.; Bauer, S.; Dueber, J.E.; Somerville, C.R. Identification and characterization of a galacturonic acid transporter from Neurospora crassa and its application for Saccharomyces cerevisiae fermentation processes. Biotechnol. Biofuels 2014, 7, 20. [Google Scholar] [CrossRef] [PubMed]
  132. Biz, A.; Sugai-Guérios, M.H.; Kuivanen, J.; Maaheimo, H.; Krieger, N.; Mitchell, D.A.; Richard, P. The introduction of the fungal d-galacturonate pathway enables the consumption of d-galacturonic acid by Saccharomyces cerevisiae. Microb. Cell Fact. 2016, 15, 144. [Google Scholar] [CrossRef] [PubMed]
  133. Kuivanen, J.; Wang, Y.M.J.; Richard, P. Engineering Aspergillus niger for galactaric acid production: Elimination of galactaric acid catabolism by using RNA sequencing and CRISPR/Cas9. Microb. Cell Fact. 2016, 15, 210. [Google Scholar] [CrossRef] [PubMed]
  134. Barth, D.; Wiebe, M.G. Enhancing fungal production of galactaric acid. Appl. Microbiol. Biotechnol. 2017, 101, 4033–4040. [Google Scholar] [CrossRef] [PubMed]
  135. Leh, D.S.; Biz, A.; de Paula, D.H.F.; Richard, P.; Gonçalves, A.G.; Noseda, M.D.; Mitchell, D.A.; Krieger, N. Conversion of citric pectin into d-galacturonic acid with high substrate loading using a fermented solid with pectinolytic activity. Biocatal. Agric. Biotechnol. 2017, 11, 214–219. [Google Scholar] [CrossRef]
  136. Paasikallio, T.; Huuskonen, A.; Wiebe, M.G. Scaling up and scaling down the production of galactaric acid from pectin using Trichoderma reesei. Microb. Cell Fact. 2017, 16, 119. [Google Scholar] [CrossRef] [PubMed]
  137. Sakuta, R.; Takeda, K.; Igarashi, K.; Ohno, H.; Nakamura, N. Pyrroloquinoline quinone-dependent glucose dehydrogenase anode: d-Galacturonic acid oxidation and galactaric acid production. J. Mol. Catal. B Enzym. 2016, 133, S76–S79. [Google Scholar] [CrossRef]
  138. Sakuta, R.; Takeda, K.; Igarashi, K.; Ohno, H.; Nakamura, N. Enzymes suitable for biorefinery to coproduce hexaric acids and electricity from hexuronic acids derived from biomass. Energy Technol. 2018, 6, 273–279. [Google Scholar] [CrossRef]
  139. Sakuta, R. Simultaneous production of biomass-derived platform chemicals and electricity. Ph.D. Thesis, Tokyo University of Agriculture and Technology, Tokyo, Japan, 27 March 2018. [Google Scholar]
  140. Amaniampong, P.N.; Karam, A.; Trinh, Q.T.; Xu, K.; Hirao, H.; Jérôme, F.; Chatel, G. Selective and catalyst-free oxidation of d-glucose to d-glucuronic acid induced by high-frequency ultrasound. Sci. Rep. 2017, 7, 40650. [Google Scholar] [CrossRef] [PubMed]
  141. Wojcieszak, R.; Cuccovia, I.M.; Silva, M.A.; Rossi, L.M. Selective oxidation of glucose to glucuronic acid by cesium-promoted gold nanoparticle catalyst. J. Mol. Catal. A Chem. 2016, 422, 35–42. [Google Scholar] [CrossRef]
Ijms 20 03660 g001 550
Figure 1. Structures of aldose and its acids.
Figure 1. Structures of aldose and its acids.
Ijms 20 03660 g001
Ijms 20 03660 g002 550
Figure 2. Structures of hexaric acids.
Figure 2. Structures of hexaric acids.
Ijms 20 03660 g002
Ijms 20 03660 g003 550
Figure 3. Schematic depiction of the syntheses of poly(alkylene galactaramide)s (A), poly(alkylene d-glucaramide)s (B), and poly(alkylene d-mannaramide)s (C) from their corresponding monomers and alkylenediamines [31] and the syntheses of poly(d-gulcaramidoamine)s (D), poly(galactaramidoamine)s (E), and poly(d-mannaramidoamine)s (F) from their corresponding monomers and secondary amines [35].
Figure 3. Schematic depiction of the syntheses of poly(alkylene galactaramide)s (A), poly(alkylene d-glucaramide)s (B), and poly(alkylene d-mannaramide)s (C) from their corresponding monomers and alkylenediamines [31] and the syntheses of poly(d-gulcaramidoamine)s (D), poly(galactaramidoamine)s (E), and poly(d-mannaramidoamine)s (F) from their corresponding monomers and secondary amines [35].
Ijms 20 03660 g003
Ijms 20 03660 g004 550
Figure 4. Sugar-based amphiphilic polymers (SBAPs) for biomedical applications [51]. oxLDL = oxidized low-density lipoproteins.
Figure 4. Sugar-based amphiphilic polymers (SBAPs) for biomedical applications [51]. oxLDL = oxidized low-density lipoproteins.
Ijms 20 03660 g004
Ijms 20 03660 g005 550
Figure 5. Crystal structure of the neutral metal–organic framework (MOF) (Tb(galactarate)1.5(H2O)2)·5H2O shown in a ball-and-stick representation, with the Tb(III) ions in a space-filling model. Water molecules in the channels have been omitted for clarity, and atoms are color coded as follows: C = black; H = white; O = red; Tb = turquoise [48].
Figure 5. Crystal structure of the neutral metal–organic framework (MOF) (Tb(galactarate)1.5(H2O)2)·5H2O shown in a ball-and-stick representation, with the Tb(III) ions in a space-filling model. Water molecules in the channels have been omitted for clarity, and atoms are color coded as follows: C = black; H = white; O = red; Tb = turquoise [48].
Ijms 20 03660 g005
Ijms 20 03660 g006 550
Figure 6. The nitric oxidation of (A) d-glucose and (B) d-mannose [67,69].
Figure 6. The nitric oxidation of (A) d-glucose and (B) d-mannose [67,69].
Ijms 20 03660 g006
Ijms 20 03660 g007 550
Figure 7. Common NO and NO2 reactions in water/O2 proposed in a previous report [69].
Figure 7. Common NO and NO2 reactions in water/O2 proposed in a previous report [69].
Ijms 20 03660 g007
Ijms 20 03660 g008 550
Figure 8. Designed pathway for the production of d-glucaric acid in E. coli. PTS = phosphoenolpyruvate-dependent phosphotransferase system; phosphatase = SuhB, an endogenous E. coli enzyme; PEP = phosphoenolpyruvate; MIOX = myo-inositol oxygenase; Udh = uronate dehydrogenase; [106].
Figure 8. Designed pathway for the production of d-glucaric acid in E. coli. PTS = phosphoenolpyruvate-dependent phosphotransferase system; phosphatase = SuhB, an endogenous E. coli enzyme; PEP = phosphoenolpyruvate; MIOX = myo-inositol oxygenase; Udh = uronate dehydrogenase; [106].
Ijms 20 03660 g008
Ijms 20 03660 g009 550
Figure 9. Engineering of the d-galacturonic acid pathway in fungi. Deletion of the gene encoding d-galacturonate reductase resulted in strains unable to utilize d-galacturonic acid as a carbon source. The expression of the bacterial udh gene, encoding an nicotinamide adenine dinucleotide (NAD)-dependent UDH (d-galacturonic acid dehydrogenase), resulted in fungal strains that were able to oxidize d-galacturonic acid to meso-galactaric acid. UDH forms a galactaro-lactone that spontaneously hydrolyzes [100].
Figure 9. Engineering of the d-galacturonic acid pathway in fungi. Deletion of the gene encoding d-galacturonate reductase resulted in strains unable to utilize d-galacturonic acid as a carbon source. The expression of the bacterial udh gene, encoding an nicotinamide adenine dinucleotide (NAD)-dependent UDH (d-galacturonic acid dehydrogenase), resulted in fungal strains that were able to oxidize d-galacturonic acid to meso-galactaric acid. UDH forms a galactaro-lactone that spontaneously hydrolyzes [100].
Ijms 20 03660 g009
Ijms 20 03660 g010 550
Figure 10. Schematic description of an enzymatic biofuel cell that simultaneously produces meso-galactaric acid and electricity from pectin extracted from biomass. PQQ-GHD = pyrroloquinoline quinone-dependent glucose dehydrogenase; BOD = bilirubin oxidase.
Figure 10. Schematic description of an enzymatic biofuel cell that simultaneously produces meso-galactaric acid and electricity from pectin extracted from biomass. PQQ-GHD = pyrroloquinoline quinone-dependent glucose dehydrogenase; BOD = bilirubin oxidase.
Ijms 20 03660 g010
Table
Table 1. Isolated yields, melting points, and water solubility of poly(alkylene hexaramide)s [31]. The original tables have been combined into this table.
Table 1. Isolated yields, melting points, and water solubility of poly(alkylene hexaramide)s [31]. The original tables have been combined into this table.
PolymersYieldmp (°C) aWater Solubility bMnc
Poly(ethylene d-glucaramide)93.3185Yes2036
Poly(tetramethylene d-glucaramide)88.3192–195Yes2725
Poly(hexamethylene d-glucaramide)89.4192–194No2552
Poly(octamethylene d-glucaramide)86.8195–200No3562
Poly(decamethylene d-glucaramide)89.8200–205No3218
Poly(dodecamethylene d-glucaramide)93.9200–205No2730
Poly(ethylene galactaramide)90.1205VS702
Poly(tetramethylene galactaramide)82.1230SS1179
Poly(hexamethylene galactaramide)85.2228NS2320
Poly(octamethylene galactaramide)79.4230NS4920
Poly(decamethylene galactaramide)82.2230NS2560
Poly(dodecamethylene galactaramide)87.4225NS2356
Poly(ethylene d-mannaramide)72180–206VS1410
Poly(tetramethylene d-mannaramide)77194–201VS1249
Poly(hexamethylene d-mannaramide)68205–210NS1247
a All polymers decomposed upon melting. mp = melting point. b VS = very soluble; SS = slightly soluble; NS = not soluble. c Mn = number average molecular weight.

Share and Cite

MDPI and ACS Style

Sakuta, R.; Nakamura, N. Production of Hexaric Acids from Biomass. Int. J. Mol. Sci. 2019, 20, 3660. https://doi.org/10.3390/ijms20153660

AMA Style

Sakuta R, Nakamura N. Production of Hexaric Acids from Biomass. International Journal of Molecular Sciences. 2019; 20(15):3660. https://doi.org/10.3390/ijms20153660

Chicago/Turabian Style

Sakuta, Riku, and Nobuhumi Nakamura. 2019. "Production of Hexaric Acids from Biomass" International Journal of Molecular Sciences 20, no. 15: 3660. https://doi.org/10.3390/ijms20153660

APA Style

Sakuta, R., & Nakamura, N. (2019). Production of Hexaric Acids from Biomass. International Journal of Molecular Sciences, 20(15), 3660. https://doi.org/10.3390/ijms20153660

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop