International Journal of Molecular Sciences Review Production of Hexaric Acids from Biomass 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 * Correspondence: [email protected] Received: 29 June 2019; Accepted: 24 July 2019; Published: 26 July 2019 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. Keywords: aldaric acids; biorefinery; biofuel cell; bioprocess; biorefinery; carbohydrates; electrochemistry; green chemistry; oxidation; sustainable chemistry 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 [4–6]. 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 (Figure1). 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; Figure1), including d-glucaric acid. Int. J. Mol. Sci. 2019, 20, 3660; doi:10.3390/ijms20153660 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, x FOR PEER REVIEW 2 of 20 articleInt. J. Mol. summarizes Sci. 2019, 20, biorefinery 3660 methods relating to aldaric acids with six carbon atoms (hexaric acids;2 of 20 Figure 1), including ᴅ-glucaric acid. Figure 1. Structures of aldose and its acids. Figure 1. Structures of aldose and its acids. 2. Classification of Aldohexoses and Hexaric Acids 2. Classification of Aldohexoses and Hexaric Acids Aldohexoses have four stereocenters, resulting in sixteen configurational isomers (Figure1). Relative-configurationAldohexoses have classification four stereocenters, divides resulting these stereoisomers in sixteen intoconfigurational eight groups isomers with the (Figure following 1). Relative-configurationcommon names: altrose, classification allose, idose, divides galactose, these stereoisomers glucose, gulose, into talose, eight andgroups mannose. with the In following contrast, commonhexaric acids names: have altrose, the same allose, functional idose, groupgalactose, at both glucose, ends ofgulose, their structure;talose, and thus, mannose. the hexaric In contrast, acids of hexaricaltrose and acids talose have and the those same of function glucoseal and group gulose at areboth the ends same of compounds. their structure; Moreover, thus, the the hexaric hexaric acids acids of altrose allose and and galactose talose and are thosemeso -compounds,of glucose and because guloseof are their the symmetry.same compounds. In short, Moreover, relative-configuration the hexaric acidsclassification of allose divides and galactose hexaric acids are intomeso altraric-compounds, acid, allaric because acid, idaricof their acid, symmetry. galactaric In acid, short, glucaric relative- acid, configurationand mannaric classification acid; because divides allaric acidhexaric and acids galactaric into altraric acid are acid,meso allaric-compounds, acid, idaric the totalacid, numbergalactaric of acid,configurational glucaric acid, isomers and mannaric is ten (Figure acid;2)[ because7]. Because allaric hexaric acid and acids galactaric have four acid stereochemically are meso-compounds, diverse thesecondary total number hydroxy of groupsconfigurational and two carboxylisomers is groups, ten (Figure their applications2) [7]. Because as platformhexaric acids chemicals have havefour stereochemicallybeen studied as described diverse secondary below. Of thehydroxy hexaric groups acids, dand-glucaric, two carboxylmeso-galactaric, groups, andtheird -mannaricapplications acids as platformhave been chemicals the most studiedhave been as starting studied compounds as described for below. biorefineries, Of the in hexaric part because acids, theᴅ-glucaric, raw materials meso- galactaric,for these hexaric and ᴅ-mannaric acids are acids abundant. have been Therefore, the most several studied compounds, as starting suchcompounds as l-mannaric for biorefineries, acid [8,9] inand partd-idaric because acid, the [raw10,11 materials] which arefor these used hexaric as the starting acids are compounds abundant. Therefore, for human several immunodeficiency compounds, suchvirus as (HIV) ʟ-mannaric protease acid inhibitors, [8,9] and are ᴅ regarded-idaric acid, as exceptions[10,11] which in this are report.used as The the focusstarting of thiscompounds article is for on humanstudies investigatingimmunodeficiency the applications virus (HIV) and protease production inhibitors, methods are for regardedd-glucaric as exceptions acid, meso-galactaric in this report. acid, Theand dfocus-mannaric of this acid. article is on studies investigating the applications and production methods for ᴅ- glucaric acid, meso-galactaric acid, and ᴅ-mannaric acid. Int. J. Mol. Sci. 2019, 20, 3660 3 of 20 Int. J. Mol. Sci. 2019, 20, x FOR PEER REVIEW 3 of 20 Figure 2. Structures of hexaric acids. 3. Applications of Hexaric Acids 3. Applications of Hexaric Acids Because hexaric hexaric acids acids have have four fourstereochemically stereochemically diverse diverse secondary secondary hydroxy hydroxy groups and groups two andcarboxyl two groups, carboxyl they groups, have theybeen havestudied been since studied the 1950s since as the platform 1950s as chemicals platform for chemicals producing for producingchelating agents chelating and corrosion agents and inhibitors corrosion [10–21], inhibitors precursors[10–21 for], precursorspolyamides for [22–36], polyamides polyesters[22 –[37–36], polyesters41], polyanhydrides[37–41], polyanhydrides [42], polycations [42], polycations [43], coordination [43], coordination polymers polymers including including metal–organic metal–organic frameworks [44–48],[44–48], pendant polymers [49], [49], macromol macromoleculesecules [50,51],[50,51], cross-linkcross-linkersers in hydrogels hydrogels [52], [52], medicines [[8–11,49,51,53],8–11,49,51,53],and and other other compounds compounds including including platform platform chemicals, chemicals, like adipiclike adipic acid andacid furan and dicarboxylicfuran dicarboxylic acid [54 acid–62 ].[54–62]. 3.1. Monomers 3.1. Monomers The use of hexaric acids as monomers produces polycondensates that are nontoxic, biodegradable, The use of hexaric acids as monomers produces polycondensates that are nontoxic, and more hydrophilic than those derived from petrochemicals [36]. Research on polyamide syntheses biodegradable, and more hydrophilic than those derived from petrochemicals [36]. Research on derived from hexaric acids started in the 1950s [22] and continues, particularly in the laboratory of polyamide syntheses derived from hexaric acids started in the 1950s [22] and continues, particularly Kiely. This group has synthesized polyamides from three monomers, d-glucaric acid, meso-galactaric in the laboratory of Kiely. This group has synthesized