molecules

Review A Novel Strategy for Biomass Upgrade: Cascade Approach to the Synthesis of Useful Compounds via C-C Bond Formation Using Biomass-Derived Sugars as Carbon Nucleophiles

Sho Yamaguchi * and Toshihide Baba

Department of Chemical Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of Technology, 4259-G1-14 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8502, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-45-924-5417

Academic Editor: Bartolo Gabriele Received: 27 May 2016; Accepted: 18 July 2016; Published: 20 July 2016

Abstract: Due to the depletion of fossil fuels, biomass-derived sugars have attracted increasing attention in recent years as an alternative carbon source. Although significant advances have been reported in the development of catalysts for the conversion of carbohydrates into key chemicals (e.g., degradation approaches based on the dehydration of hydroxyl groups or cleavage of C-C bonds via retro-aldol reactions), only a limited range of products can be obtained through such processes. Thus, the development of a novel and efficient strategy targeted towards the preparation of a range of compounds from biomass-derived sugars is required. We herein describe the highly-selective cascade syntheses of a range of useful compounds using biomass-derived sugars as carbon nucleophiles. We focus on the upgrade of C2 and C3 oxygenates generated from glucose to yield useful compounds via C-C bond formation. The establishment of this novel synthetic methodology to generate valuable chemical products from monosaccharides and their decomposed oxygenated materials renders carbohydrates a potential alternative carbon resource to fossil fuels.

Keywords: cascade reaction; biomass conversion; carbohydrate; Sn catalyst; aldol reaction

1. Introduction Currently, raw materials that can be converted into both chemical products and energy sources are elaborated from petroleum-based carbon resources. However, owing to the depletion of fossil fuels, the use of alternative renewable carbon resources is imperative in the field of green and sustainable chemistry. Recently, a number of studies have focused on carbohydrates derived from lignocellulosic materials (i.e., non-food resources) as abundant natural carbon resources. These sources represent the largest division of terrestrial biomass, and hence, various strategies to allow their efficient use as chemical feedstock are currently being developed, with the overall aim of supplementing and ultimately replacing fossil fuels [1–6]. In particular, the degradation of lignocellulose-derived cellulose into glucose is one of the most active topics in biomass conversion, and as such, the transformation of glucose into useful chemical products has attracted attention over the years. Indeed, significant advances have been reported in the development of catalysts for the conversion of monosaccharides into useful chemicals, including degradation approaches based on the dehydration of hydroxyl groups or the cleavage of C-C bonds via a retro-aldol reaction (Scheme1)[ 7–13]. Under acidic conditions, the direct production of 5-hydroxymethyl furfural (HMF) proceeded under Brønsted acid catalysis [10]. Furthermore, glucose was decomposed to give erythrose (C4) and glycolaldehyde (GA, C2) via a

Molecules 2016, 21, 937; doi:10.3390/molecules21070937 www.mdpi.com/journal/molecules Molecules 2016, 21, 937 2 of 19 Molecules 2016, 21, 937 2 of 18 a[4 [4 + + 2 ]2] retro-aldol retro-aldol reaction. reaction. In In contrast, contrast, 1,3-dihydroxyacetone1,3-dihydroxyacetone (DHA,(DHA, C3) and glyceraldehyde (GLA, C3) were obtained via an isomerization of glucose to fructose followed by a [3 [3 + + 3] 3] retro-aldol retro-aldol reaction. reaction.

Scheme 1.1. TransformationTransformation of of lignocellulose-derived lignocellulose-derived glucose glucose into into C2 (glycolaldehyde), C3 (1,3-dihydroxyacetone and and glyceraldehyde), and and C4 C4 (erythrose) units units via an isomerization and a retro-aldol reaction.

As shown above, glucose can be theoretically converted into GA and erythrose via a [4 + 2] retro- As shown above, glucose can be theoretically converted into GA and erythrose via a [4 + 2] aldol reaction; however, isomerization to fructose followed by a [3 + 3] retro-aldol reaction is retro-aldol reaction; however, isomerization to fructose followed by a [3 + 3] retro-aldol reaction is thermodynamically favored over the glucose reaction. In 2010, Holm et al. reported a one-pot thermodynamically favored over the glucose reaction. In 2010, Holm et al. reported a one-pot transformation of mono- and disaccharides into alkyl lactate via carbon-carbon bond cleavage, transformation of mono- and disaccharides into alkyl lactate via carbon-carbon bond cleavage, dehydration, and a 1,2-hydride shift (Scheme 2) [9]. These alkyl lactates are useful chemicals, as they dehydration, and a 1,2-hydride shift (Scheme2)[ 9]. These alkyl lactates are useful chemicals, as can be employed as renewable solvents or as building blocks in polyester synthesis. For example, they can be employed as renewable solvents or as building blocks in polyester synthesis. For example, Lewis acidic homogeneous and heterogeneous Sn catalysts catalyze the conversion of mono- and Lewis acidic homogeneous and heterogeneous Sn catalysts catalyze the conversion of mono- and disaccharides to methyl lactate in methanol solution. In particular, Sn-Beta zeolite yields the optimal disaccharides to methyl lactate in methanol solution. In particular, Sn-Beta zeolite yields the optimal performances in the conversion of glucose into methyl lactate. Beta type zeolites are composed of a performances in the conversion of glucose into methyl lactate. Beta type zeolites are composed three-dimensional (3D) 12-membered ring pore structures (6.6 Å × 7.6 Å), which allow the larger of a three-dimensional (3D) 12-membered ring pore structures (6.6 Å ˆ 7.6 Å), which allow the carbohydrates to spread through the zeolite pore. The reaction pathway in the acid-catalyzed larger carbohydrates to spread through the zeolite pore. The reaction pathway in the acid-catalyzed conversion is highly sensitive to the type of acid employed. Brønsted acids catalyze monosaccharide conversion is highly sensitive to the type of acid employed. Brønsted acids catalyze monosaccharide dehydration, leading primarily to the formation of HMF and its decomposition products, while Lewis dehydration, leading primarily to the formation of HMF and its decomposition products, while Lewis acidic catalysts lead to retro-aldol reactions of the monosaccharides, and subsequent transformation acidic catalysts lead to retro-aldol reactions of the monosaccharides, and subsequent transformation to to their lactic acid derivatives. Therefore, to achieve high selectivity in the Lewis acid-catalyzed their lactic acid derivatives. Therefore, to achieve high selectivity in the Lewis acid-catalyzed pathway, pathway, it is important to reduce the catalytic effect of Brønsted acids. it is important to reduce the catalytic effect of Brønsted acids.

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Scheme 2. Conversion of monosaccharides to alkyl lactate via a retro-aldol reaction, dehydration, and Scheme 2. ConversionConversion of of monosaccharides monosaccharides to to alkyl alkyl lactat lactatee via via a a retro-aldol retro-aldol reaction, reaction, dehydration, dehydration, and 1,2-hydride shift. 1,2-hydride shift.

The conventional degradation methods of the C6 unit into a range of compounds are shown in The conventional degradation methods methods of of the the C6 C6 unit into a range of compounds are shown in Scheme 3. In the case of a retro-aldol reaction, alkyl lactates are obtained as outlined in Scheme 2. In Scheme 33.. In the the case case of of a a retro-aldol retro-aldol reaction, reaction, alkyl alkyl lactates lactates are are obtained obtained as as outlined outlined in inScheme Scheme 2. 2In. contrast, following the formation of HMF via sequential dehydration, further upgrade to various contrast,In contrast, following following the the formation formation of ofHMF HMF via via sequential sequential dehydration, dehydration, further further upgrade upgrade to to various compounds takes place following aldol condensations with ketones [14], methylfuran [15], or HMF [16]. compounds takes place following aldo aldoll condensations condensations with with ketones ketones [14], [14], methylfuran methylfuran [15], [15], or or HMF HMF [16]. [16]. Although C-C bond cleavage via a retro-aldol and sequential hydroxyl group dehydration proceeds Although C-C bond cleavage via a retro-aldol and sequential hydroxyl group dehydration proceeds smoothly, a limited range of products is obtained through such a degradation process. Therefore, the smoothly, a limited range of products is obtained through such a degradation process. Therefore, the development of a novel and efficient strategy targeted to the preparation of a wide range of compounds development of a novel and efficient efficient strategy targeted targeted to the the preparation preparation of of a a wide wide range range of of compounds compounds from biomass-derived sugars is required. We herein describe the highly selective cascade syntheses fromfrom biomass-derived sugarssugars isis required.required. We We herein herein describe describe the the highly highly selective selective cascade cascade syntheses syntheses of of a range of useful compounds using biomass-derived sugars as carbon nucleophiles. We focus on ofa rangea range of usefulof useful compounds compounds using using biomass-derived biomass-derived sugars sugars as carbonas carbon nucleophiles. nucleophiles. We We focus focus on theon the upgrade of C2 and C3 oxygenates generated from glucose to yield useful compounds through C-C theupgrade upgrade of C2of C2 and and C3 C3 oxygenates oxygenates generated generated from from glucose glucose to to yield yield useful usefulcompounds compounds throughthrough C-C bond formation reactions (Scheme 4). The establishment of a novel synthetic methodology to generate bond formation formation reactions (Scheme 4 4).). TheThe establishmentestablishment ofof aa novel synthetic methodology toto generategenerate valuable chemical products from monosaccharides and their decomposed oxygenated materials adds valuable chemical products from monosaccharides and their decomposed oxygenated materials adds adds value to carbohydrates, rendering them suitable as alternative carbon resources. value to carbohydrates, rendering them suitablesuitable as alternative carbon resources.

Scheme 3. Conventional degradation methods of C6 units to yield a range of products. SchemeScheme 3. ConventionalConventional degradation degradation methods methods of C6 units to yield a range of products.

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Scheme 4. Upgrade of C2 and C3 oxygenates (generated from C6 units) via C-C bond formation. Scheme 4. Upgrade of C2 and C3 oxygenates (generated from C6 units) via C-C bond formation. 2. CascadeSchemeScheme Synthesis 4. 4. UpgradeUpgrade Using of of C2 C2 Biomass-Derived and and C3 C3 oxygenates oxygenates Oxygenates(generated (generated from from as CarbonC6 C6 units) units) Nucleophiles via C-C bond formation. 2. Cascade Synthesis Using Biomass-Derived Oxygenates as Carbon Nucleophiles 2.2. Cascade CascadeIn 2012, SynthesisSynthesis Holm et al.Using Using reported Biomass-Derived Biomass-Derived the conversion Oxygenatesof Oxygenates various sugars as as Carbon Carbon into alkyl Nucleophiles Nucleophiles lactate using heterogeneous Sn-Beta zeoliteIn 2012, [11]. Holm Pentoses et al. reported are converted the conversion to methyl of va riouslactate sugars in slightly into alkyl lower lactate yields using than heterogeneous those obtained In 2012, Holm et al. reported the conversion of various sugars into alkyl lactate using heterogeneous for hexosesInSn-Beta 2012, zeolite(Table Holm [11]. 1, et entriesPentoses al. reported1,2 are vs.converted entries the to conversion 3–7),methyl which lactate of isin various slightlyin accordance lower sugars yields with into than a alkyl thosereaction lactate obtained pathway using Sn-Beta zeolite [11]. Pentoses are converted to methyl lactate in slightly lower yields than those obtained heterogeneousinvolvingfor hexoses the retro-aldolSn-Beta (Table 1, zeolite entriescondensation [ 111,2]. vs. Pentoses entries of these are3–7), suga converted whichrs to isform in to accordance methyla triose lactate and with GA ina forreaction slightly the pentoses, pathway lower yields and for hexoses (Table 1, entries 1,2 vs. entries 3–7), which is in accordance with a reaction pathway thantwo triosesinvolving those obtainedfor the the retro-aldol hexoses. for hexoses Whencondensation (Table reacting1 ,of entries theseGA (forma suga 1,2rs vs.lly to entries forma C2-sugar) a triose 3–7), andin which the GA presence isfor in the accordance pentoses, of a Sn andcatalyst, with a involving the retro-aldol condensation of these sugars to form a triose and GA for the pentoses, and reactionaldoltwo condensation pathwaytrioses for involvingthe takes hexoses. place, the When retro-aldolleading reacting to condensationtheGA (formaformationlly a of C2-sugar)of these methyl sugars in lactate, the presence to form methyl aof triose a vinylSn catalyst, and glycolate, GA for two triosesaldol condensation for the hexoses. takes When place, reactingleading to GA the (forma formationlly a of C2-sugar) methyl lactate, in the methyl presence vinyl of glycolate,a Sn catalyst, theand pentoses, methyl 4-methoxy-2-hydroxybutanoate and two trioses for the hexoses. (Table When reacting2, entry 8 GA and (formally Scheme a5). C2-sugar) in the presence aldolof a Sn andcondensation catalyst, methyl 4-methoxy-2-hydroxybutanoate aldol takes condensation place, leading takes to place,the (Table formation leading 2, entry toof 8 theandmethyl formationScheme lactate, 5). of methyl methyl vinyl lactate, glycolate, methyl andvinyl methyl glycolate, 4-methoxy-2-hydroxybutanoate and methyl 4-methoxy-2-hydroxybutanoate (Table 2, entry 8 (Table and Scheme2, entry 5). 8 and1 Scheme5). TableTable 1. Conversion1. Conversion of of various various sugarssugars inin methanol methanol using using Sn-Beta Sn-Beta 1. .

Table 1. Conversion of various sugars in methanol using Sn-Beta 1..

YieldYield (%) (%) EntryEntry SubstrateSubstrate Conversion Conversion (%)(%) MLML MVG MVG MMHB MMHB 1 Xylose 98 42 YieldYield7 (%) <2 Entry1 SubstrateSubstrateXylose Conversion Conversion 98 (%) (%) 42 7 <2 2 Ribose 96 ML 38ML MVG MVG8 <2 MMHB MMHB 2 3 RiboseGlucose 96 98 51 38 10 8 <2 <2 1 Xylose Xylose 98 98 42 42 7 <2 <2 3 4 GlucoseFructose 98 98 54 51 11 10 <2 <2 2 Ribose Ribose 96 96 38 38 8 <2 <2 4 5 FructoseMannose 98 96 47 54 9 11 <2 <2 3 Glucose Glucose 98 98 51 51 10 <2 <2 5 6 MannoseGalactose 96 95 45 47 5 9 <2 <2 4 Fructose Fructose 98 98 54 54 11 <2 <2 56 7 Galactose MannoseSucrose 96 95 92 47 57 45 5 95 0 <2 <2 5 Mannose 96 47 9 <2 67 8 Glycolaldehyde GalactoseSucrose 95 92 - 45 16 57 27 55 6 0 <2 1 6 Galactose 95 45 5 <2 Yields78 of methylGlycolaldehyde lactate Sucrose (ML), methyl vinyl glyc 92olate - (MVG) and methyl 57 16 4-methoxy-2-hydroxybutanoate27 5 6 0 (MMHB)87 for theGlycolaldehyde conversionSucrose of various sugars- 92 cata lyzed by Sn-Beta 16 57 zeolite. 275 Reaction conditions:0 6 1 Yields of methyl lactate (ML), methyl vinyl glycolate (MVG) and methyl 4-methoxy-2-hydroxybutanoate 1 Yieldssubstrate of8 methyl (300 Glycolaldehydemg), lactate methanol (ML), methyl (10 g), Sn-Beta vinyl glycolate (100 - mg), (MVG) 160 °C, and 16 methylh. 16 4-methoxy-2-hydroxybutanoate 27 6 (MMHB) for the conversion of various sugars catalyzed by Sn-Beta zeolite. Reaction conditions: 1 (MMHB) for the conversion of various sugars catalyzed by Sn-Beta zeolite. Reaction conditions: substrate Yields of methyl lactate (ML), methyl vinyl glyc˝ olate (MVG) and methyl 4-methoxy-2-hydroxybutanoate substrate(300 mg), (300 methanol mg), (10methanol g), Sn-Beta (10 (100 g), Sn-Beta mg), 160 (100C, 16 mg), h. 160 °C, 16 h. (MMHB) for the conversion of various sugars catalyzed by Sn-Beta zeolite. Reaction conditions: substrate (300 mg), methanol (10 g), Sn-Beta (100 mg), 160 °C, 16 h.

Scheme 5. Sn-Catalyzed formation of GA in methanol and subsequent conversion of GA and its enediol (GLA) into vinyl glycolate esters.

Scheme 5.5. Sn-Catalyzed formation formation of of GA in methanol and subsequent conversion of GA and its enediol (GLA) into vinyl glycolate esters.esters. Scheme 5. Sn-Catalyzed formation of GA in methanol and subsequent conversion of GA and its enediol (GLA) into vinyl glycolate esters.

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Molecules 2016, 21, 937 5 of 18 Inspired by the above coupling with glycolaldehydes, in 2013, Sels et al. reported a catalytic routeInspired toward by a seriesthe above of recently coupling discovered with glycolaldehyde four-carbons, αin-hydroxy 2013, Sels acids et al. andreported their a esters catalytic from route the towardaccessible a series and renewableof recently glycolaldehydediscovered four-carbon (GA), which α-hydroxy is prepared acids and via their the [4 esters + 2] retro-aldolfrom the accessible reaction andof glucose renewable [17– 19glycolaldehyde]. They reported (GA), the which use of is GA prepared as both via an the aldol [4 + donor 2] retro-aldol and an aldol reaction acceptor, of glucose with [17–19].an intermolecular They reported aldol the reaction use of GA followed as both an by aldol a sequential donor and retro-Michael an aldol acceptor, reaction, with dehydration,an intermolecular and aldol1,2-hydride reaction shift followed affording by methyl-4-methoxy-2-hydroxybutanoatea sequential retro-Michael reaction, dehydration, (MMHB). Indeed,and 1,2-hydride Sn halides shift are affordingunique in methyl-4-methoxy-2-hydro converting the small glycolaldehydexybutanoate molecule (MMHB). into Indeed, MMHB Sn in halides methanol, are unique with Brønsted in converting acids theand small other glycolaldehyde Lewis acid catalysts molecule yielding into MMHB mainly in glycolaldehyde methanol, withdimethyl Brønsted acetalacids and (GADMA) other Lewis (Table acid2). catalystsWhen this yielding reaction mainly was performedglycolaldehyde in non-alcoholic dimethyl acetal solvents, (GADMA) such as(Table acetonitrile, 2). When an this intramolecular reaction was performedcyclization proceededin non-alcoholic preferentially, solvents, to such give aas 5-membered acetonitrile, lactone, an intramolecular namely α-hydroxy- cyclizationγ-butyrolactone proceeded preferentially,(HBL) (Scheme to6 ).give a 5-membered lactone, namely α-hydroxy-γ-butyrolactone (HBL) (Scheme 6). AsAs mentioned mentioned in in the the Introduction, Introduction, the the balance balance be betweentween the the Lewis Lewis and and Brønsted Brønsted acidities acidities derived derived fromfrom the the Sn Sn halide halide salts salts is is crucial crucial in in determining pr productoduct selectivity. selectivity. In In the the Figure Figure 4 4 of of ref ref [18], [18], the influenceinfluence of of Brønsted:Lewis Brønsted:Lewis acid acid ratio ratio on on the the overal overalll reaction reaction rate was also investigated. The The highest highest raterate of of formation of the desired product waswas observedobserved withwith aa HH++/Sn ratio ratio of of 3, 3, and and was was independent independent ofof the oxidation state of the Sn salt.salt. These resultsresults showedshowed thatthat thethe HH++/Sn ratio ratio was was closely closely related related to to thethe rapid rapid hydrolysis hydrolysis of ac acetalsetals or the dehydration.

1 Table 2. Conversion of glycolaldehyde into α-hydroxy acidacid estersesters andand GADMAGADMA inin CHCH33OH ..

YieldYield (%) (%) Entry Entry CatalystCatalyst Time Time (h) (h) GADMAGADMA MMHB MMHB MVG MVG 11 nonenone 26 26 47 47 0 00 0 22 HClHCl 22 22 56 56 0 00 0 33 NaOHNaOH 20 20 0 0 0 00 0 4 SnCl4¨ 5H2O 1 54 10 <1 4 SnCl4·5H2O 1 54 10 <1 5 SnCl4¨ 5H2O 20 3 58 3 5 SnCl4·5H2O 20 3 58 3 6 SnCl2¨ 2H2O 1 51 14 <1 76 SnCl2SnCl¨ 2H22O·2H2O 211 51 1 14 55<1 4 87 AlCl3SnCl¨ 6H22O·2H2O 2021 471 55 74 0 9 CrCl ¨ 6H O 20 71 <1 0 8 3AlCl23·6H2O 20 47 7 0 2 10 SnCl4¨ 5H2O 1 - 50 2 9 CrCl3·6H2O 20 71 <1 0 1 ˝ Reactions carried2 out at 90 C using 1.25 M GA in MeOH, 5 mol % of catalyst (20 mol % for HCl, 10 mol % for 10 SnCl4·5H2O2 1 - 50 2 NaOH). Yields were derived from GC; Reaction using 0.625 M erythrose in CH3OH, with 10 mol % catalyst. 1 Reactions carried out at 90 °C using 1.25 M GA in MeOH, 5 mol % of catalyst (20 mol % for HCl, 10

mol % for NaOH). Yields were derived from GC; 2 Reaction using 0.625 M erythrose in CH3OH, with 10 mol % catalyst.

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Scheme 6.6.Cascade Cascade reaction reaction of glycolaldehydeof glycolaldehyde (GA) to(GA) give to glycolaldehyde give glycolaldehyde dimethyl acetaldimethyl (GADMA) acetal (GADMA)and α-hydroxy and α acids-hydroxy (methyl acids vinyl (methyl glycolate vinyl and glycolate methyl an 4-methoxy-2-hydroxybutanoate)d methyl 4-methoxy-2-hydroxybutanoate) in alcoholic insolution, alcoholic and solution,α-hydroxy- andγ α-butyrolactone-hydroxy-γ-butyrolactone (HBL) in non-alcoholic (HBL) in non-alcoholic solvents. solvents.

The above-mentioned above-mentioned reactions reactions based based on an on aldol an reaction aldol reaction between betweenthe biomass-derived the biomass-derived oxygenates (e.g.,oxygenates glycolaldehyde (e.g., glycolaldehyde (GA)) are comparable (GA)) are to comparable the formose to reaction, the formose in which reaction, sugars in are which prepared sugars from are preparedformaldehyde from and formaldehyde a sequential and aldol a sequentialcondensation aldol (Scheme condensation 7) [20–25]. (Scheme Although7)[ 20application–25]. Although of the formoseapplication reaction of the has formose previously reaction been hasconfined previously to the beenselective confined synthesis to theof unprotected selective synthesis sugars, an of intermolecularunprotected sugars, coupling an intermolecular reaction between coupling GA (C2) reaction and oxygenates between GA of (C2) different and oxygenates carbon numbers of different will increasecarbon numbers the number will of increase potential the products. number of potential products.

Scheme 7. PreparationPreparation of unprotected sugar mole moleculescules based on the formose reaction.

3. Cascade Cascade Synthesis Synthesis of of Useful Useful Four-Carbon Four-Carbon Pr Productsoducts via via an an Intermolecular Intermolecular Aldol Aldol Reaction Reaction between Biomass-Derived Triose SugarsSugars andand FormaldehydeFormaldehyde A previously previously discussed, discussed, the the isomerization isomerization of glucose of glucose and the and [3 the + 3] [3 retro-aldol + 3] retro-aldol reaction reaction of fructose of arefructose thermodynamically are thermodynamically more favorable more favorable than the than [4 + the2] retro-aldol [4 + 2] retro-aldol reaction. reaction. Thus, to Thus, efficiently to efficiently obtain chemicalobtain chemical products products from frombiomass-derived biomass-derived sugars sugars,, the thedevelopment development of ofa anovel novel synthetic synthetic strategy strategy employing C3 units is desired. Our group therefore focused on a novel route to the cascade synthesis of 5-membered lactones [26,27], [26,27], which can be utilized not only as fine fine chemicals, but also as raw materials [28–33]. [28–33]. This This route route employed employed a biomass-deri biomass-derivedved triose sugar (1,3-dih (1,3-dihydroxyacetone,ydroxyacetone, DHA) as the carbon nucleophile and aldehydes as the electrophi electrophilesles (Scheme8 8).). Indeed,Indeed, ifif suchsuch anan efficientefficient routeroute to useful compounds from biomass-derivedbiomass-derived sugars can be established, the demand for carbohydrates as alternative carbon resources willwill increase.increase.

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SchemeScheme 8.8. SyntheticSynthetic 8. Synthetic routeroute routeto to the tothe the useful useful useful four-carbon four-carbon four-carbon product, product,product,α α-hydroxy- α-hydroxy--hydroxy-γ-butyrolactone-butyrolactoneγ-butyrolactone (HBL) (HBL) (HBL) via via via an intermolecularan intermolecularan intermolecular aldol aldol reaction aldol reac reaction betweention between between 1,3-dihydroxyacetone 1,3-dihydroxyacetone 1,3-dihydroxyacetone (DHA) (DHA) (DHA) and and and formaldehyde. formaldehyde. formaldehyde.

3.1. Tin-Catalyzed Conversion of the Biomass-Derived Triose Sugar 1,3-Dihydroxyacetone (DHA) to 3.1. Tin-Catalyzed Conversion ofof thethe Biomass-DerivedBiomass-Derived TrioseTriose SugarSugar 1,3-Dihydroxyacetone1,3-Dihydroxyacetone (DHA)(DHA) toto α-Hydroxy-γ-butyrolactone (HBL) in the Presence of Formaldehyde α-Hydroxy-γ-butyrolactone (HBL) in the PresencePresence ofof FormaldehydeFormaldehyde As mentioned above, 5-membered lactones are useful not only as fine chemicals but also as raw As mentioned above, 5-membered lactones are useful not only as fine chemicals but also as raw Asmaterials. mentioned In particular, above, 5-membered lact lactonesones possessing are useful a hydroxyl not only group as fine in chemicalsthe α-position but are also also as raw materials.attractive In particular, synthetic targets, 5-membered with the lactoneslact majorityones possessing of chemical a hydroxyl[34–45] or groupenzymatic in the [46–48] α-position syntheses are also attractivebeing synthetic syntheticbased on targets,multistep targets, with processes.with the the majority Formajority example, of chemicalof Kagayamachemical [34– 45[34–45]et ]al. or reported enzymatic or enzymatic the [multi-step46–48 [46–48]] syntheses synthesis syntheses being basedbeingof based on α-hydroxy- multistep on multistepγ-butyrolactone processes. processes. For (HBL), example, For one example, of Kagayamathe simplest Kagayama et5-membered al. et reportedal. reported lactones, the the multi-step from multi-step 1,3-dioxorane synthesis synthesis of αof-hydroxy- α-hydroxy-and methylγ-butyrolactoneγ -butyrolactoneacrylate, which (HBL), are (HBL), relatively one one of the cheapof the simplest co simplestmmercially 5-membered 5-membered available lactones, compounds, lactones, from from in 1,3-dioxorane the 1,3-dioxorane presence and methyland methylof an acrylate, N-hydroxyphthalimide acrylate, which which are relativelyare (NHPI)relatively cheapcatalyst cheap commercially (Scheme commercially 9) [37]. available The available addition compounds, ofcompounds, 1,3-dioxarane in thein to the presencemethyl presence of anof anN-hydroxyphthalimide acrylateN-hydroxyphthalimide under oxygen in (NHPI) the(NHPI) presence catalyst catalyst of NHPI (Scheme (Scheme followed9)[ 9)37 [37]. ].by The treatmentThe addition addition with of of acids 1,3-dioxarane1,3-dioxarane and subsequent toto methylmethyl acrylateNaBH under4 reduction oxygen of the in resulting the presence adduct of afforded NHPI followedHBL in good by yield. treatmenttreatment This method with acids acidstherefore andand provides subsequentsubsequent an efficient approach to HBL, which is difficult to synthesize by conventional means. However, the NaBH 4 reduction of the resulting adduct afforded HBL in good yield. This This method method therefore therefore provides development4 of a more efficient and a widely applicable approach from cheap and easily available an efficient approach to HBL, which is difficult to synthesize by conventional means. However, the an efficientstarting approach materials would to HBL, be whichextremely is difficultwelcomed to in synthesize terms of green by conventionaland sustainable means. chemistry. However, the development of a more efficientefficient andand aa widelywidely applicableapplicable approachapproach fromfrom cheapcheap andand easilyeasily availableavailable starting materials wouldwould bebe extremelyextremely welcomedwelcomed inin termsterms ofof greengreen andand sustainablesustainable chemistry.chemistry.

Scheme 9. A novel route to α-hydroxy-γ-butyrolactone (HBL) via a three-component radical coupling of 1,3-dioxoranes, acrylates, and molecular oxygen.

The synthetic target of this process is HBL, which was obtained as a byproduct in the reaction Scheme 9. A novel novel route route to to αα-hydroxy--hydroxy-γ-butyrolactone-butyrolactone (HBL) via a three-component three-component radical coupling of GA in non-alcoholic solvents, as shown in Scheme 6. However, in the novel route, the reaction of 1,3-dioxoranes, acrylates, and molecular oxygen. ofbetween 1,3-dioxoranes, DHA and acrylates, formaldehyde and molecular was examined, oxygen. with the catalysts used and yields of the identified products (i.e., HBL, LA and VG) being given in Table 3 [26,27]. A number of metal chloride catalysts The synthetic target of this process is HBL, which was obtained as a byproduct in the reaction Thepreviously synthetic reported target for of DHA this processactivation is HBL,were screened, which was including obtained AlCl as3, aZrCl byproduct4, and TiCl in4, the but reaction these of of GA in non-alcoholic solvents, as shown in Scheme 6. However, in the novel route, the reaction GA incatalysts non-alcoholic had no effect solvents, on the as reaction. shown inHowever, Scheme when6. However, SnCl4·5H in2O the was novel employed, route, HBL the reactionwas obtained between DHAbetweenin and 42% DHA formaldehyde yield, and and formaldehyde LA wasand examined,VG werewas examined,generated with the as catalystswith by-products the usedcatalysts in and 12% used yields and and of6% theyields yield, identified ofrespectively the identified products (i.e.,products HBL,(entry (i.e., LA 2). andInHBL, addition, VG) LA being and the VG)combination given being in Table given of 3anhydrous[ in26 Tabl,27].e A SnCl3 number[26,27].4 with A ofa smallnumber metal amount chloride of metal of catalystswater chloride increased previously catalysts previously reported for DHA activation were screened, including AlCl3, ZrCl4, and TiCl4, but these reported for DHA activation were screened, including AlCl3, ZrCl4, and TiCl4, but these catalysts had catalysts had no effect on the reaction. However, when SnCl4·5H2O was employed, HBL was obtained no effect on the reaction. However, when SnCl4¨ 5H2O was employed, HBL was obtained in 42% yield, andin 42% LA andyield, VG and were LA generated and VG aswere by-products generated in 12%as by-products and 6% yield, in respectively12% and 6% (entry yield, 2). respectively In addition, (entry 2). In addition, the combination of anhydrous SnCl4 with a small amount of water increased

Molecules 2016, 21, 937 8 of 19 Molecules 2016, 21, 937 8 of 18 thethe reaction combination efficiency, of anhydrous giving HBL SnCl in4 with 63% ayield small (entry amount 8). Homogeneous of water increased Sn halides the reaction were efficiency,therefore confirmedgiving HBL to indisplay 63% yield specific (entry catalytic 8). Homogeneous activity for the Sn desired halides coupling were therefore reaction confirmed between DHA to display and formaldehyde.specific catalytic activity for the desired coupling reaction between DHA and formaldehyde.

Table 3. Conversion of DHA and formaldehyde into HBL, VG, and LA in the presence of Sn catalysts 1..

Yield (%) Entry Catalysts Conversion of DHA (%) Yield (%) Entry Catalysts Conversion of DHA (%) HBL VG LA HBL VG LA 1 HCl >99 0 0 21 1 HCl >99 0 0 21 2 SnCl4·5H2O >99 42 6 12 2 SnCl4¨ 5H2O >99 42 6 12 3 SnCl2·2H2O >99 24 3 13 3 SnCl2¨ 2H2O >99 24 3 13 2 2 4 4 SnCl2SnCl¨ 2H22O·2H2O >99>99 37 37 4 4 16 16 5 5 nBu3nSnClBu3SnCl >99>99 2525 3 3 12 12 6 SnO 95 0 0 <1 6 2SnO2 95 0 0 <1 3 7 SnCl4 >99 40 4 17 7 3 SnCl4 >99 40 4 17 8 SnCl4 >99 63 8 20 4 8 SnCl4 >99 63 8 20 9 SnCl4 >99 70 5 5 4 109 AlCl3SnCl4 >99>99 070 5 0 5 5 1110 TiCl4AlCl3 >99>99 00 0 0 5 2 12 ZrCl >99 0 0 18 11 4TiCl4 >99 0 0 2 13 Sn(OAc)2 >99 0 0 5 12 ZrCl4 >99 0 0 18 14 Sn(OTf)2 >99 0 0 36 1513 noneSn(OAc)2 79>99 0 0 0 0 5 4 1 Reaction conditions:14 DHASn(OTf) (1.25 mmol),2 paraformaldehyde>99 (1.31 mmol), catalyst0 (0.1710 mmol),36 1,4-dioxane (4.0 mL), Ar, 315 h, 140 ˝C. Unlessnone otherwise noted, the total 79 amount of water in all 0 entries was0 fixed4 at 0.86 mmol. 2 3 4 1 Yields are based on DHA; 4 M HCl in 1,4-dioxane (0.34 mmol) was added; No additional water; Excess Reactionparaformaldehyde conditions: (3.75 DHA mmol) (1.25 was employed. mmol), paraformaldehyde (1.31 mmol), catalyst (0.171 mmol), 1,4-dioxane (4.0 mL), Ar, 3 h, 140 °C. Unless otherwise noted, the total amount of water in all entries 2 3.1.1.was Cascade fixed at Reaction 0.86 mmol. Mechanism Yields are based on DHA; 4 M HCl in 1,4-dioxane (0.34 mmol) was added; 3 No additional water; 4 Excess paraformaldehyde (3.75 mmol) was employed. To confirm that the reaction between DHA and formaldehyde to yield HBL proceeded via 3.1.1.an intermolecular Cascade Reaction reaction, Mechanism an incorporation experiment using formaldehyde-d2 was conducted. The reaction between DHA and formaldehyde-d using SnCl in the presence of a small amount of To confirm that the reaction between DHA 2and formaldehyde4 to yield HBL proceeded via an water generated HBL-d2 in 48% yield, where the deuterium atoms were incorporated adjacent to the intermolecular reaction, an incorporation experiment using formaldehyde-d2 was conducted. The ether oxygen atom (Scheme 10). Product formation in the batch experiments was monitored as a reaction between DHA and formaldehyde-d2 using SnCl4 in the presence of a small amount of water function of reaction time. After 60 min, the DHA supply had been almost completely exhausted, and generated HBL-d2 in 48% yield, where the deuterium atoms were incorporated adjacent to the ether the presence of the pyruvic aldehyde (PA) intermediate could be detected. DHA therefore appeared oxygen atom (Scheme 10). Product formation in the batch experiments was monitored as a function to firstly tautomerize rapidly to GLA, with PA forming as an intermediate, as implied by its higher of reaction time. After 60 min, the DHA supply had been almost completely exhausted, and the concentrations in the early stages of the reaction. Erythrulose was not detected, thus supporting the presence of the pyruvic aldehyde (PA) intermediate could be detected. DHA therefore appeared to hypothesis of a PA intermediate. firstly tautomerize rapidly to GLA, with PA forming as an intermediate, as implied by its higher concentrations in the early stages of the reaction. Erythrulose was not detected, thus supporting the hypothesis of a PA intermediate.

Molecules 2016, 21, 937 9 of 19 Molecules 2016, 21, 937 9 of 18

Molecules 2016, 21, 937 9 of 18

Scheme 10. Reaction of DHA and formaldehyde-dd22.

Based on the aboveabove results,results,Scheme twotwo 10. plausibleplausible Reaction of reaction reactionDHA and mechanismsmechanismsformaldehyde-d were2. proposed, as outlined in Scheme 11[ [27].27]. An initial tautomerization betwee betweenn DHA and GLA proceeds because elimination of the Based on the above results, two plausible reaction mechanisms were proposed, as outlined in hydroxyl group from the β-position of GLA appears more favorablefavorable than elimination from DHA due to theScheme arrangement 11 [27]. Anof theinitial atomic tautomerization orbitals. Sn betwee can thenn DHA coordinate and GLA withproceeds multiple because –OH elimination or =O moieties of the on to thehydroxyl arrangement group from of the the atomic β-position orbitals. of GLA Sn appears can then more coordinate favorable withthan elimination multiple –OH fromor DHA =O duemoieties PA due to its strong Lewis acid character, resulting in the formation of the activated complex and on PAto duethe arrangement to its strong of the Lewis atomic acid orbitals. character, Sn can resultingthen coordinate in the with formation multiple –OH of the or activated=O moieties complex on subsequent aldol reaction with formaldehyde to afford the diketone intermediate. The resulting molecule and subsequentPA due to its aldol strong reaction Lewis acid with character, formaldehyde resulting to in afford the formation the diketone of the intermediate. activated complex The resultingand moleculeis likelysubsequent prone is likely toaldol intramolecular prone reaction to intramolecularwith formaldehyde esterification esterification to inafford the thepresence indiketone the presenceof intermediate. HCl generated of HCl The generated resulting from the molecule fromSn halides, the Sn halides,thus isleading likely thus prone leadingto the to formation tointramolecular the formation of HBL esterification of (Route HBL (Route I). in In the contrast, I). presence In contrast, an of alternativeHCl an generated alternative route from route to the HBLto Sn HBL involveshalides, involves the thealdol aldolthus reaction leading reaction between to between the formation DHA DHA and of and HBL formaldehyde formaldehyde (Route I). In contrast,(Route (Route anII). II). alternative Following Following route initial initial to HBL aldol aldol involves coupling the and tautomerization,aldol reaction the between aldehyde DHA appears and formaldehyde prone to elimination (Route II). of Following the hydroxylhydroxyl initial groupgroup aldol inin coupling thethe ββ-position and of tautomerization, the aldehyde appears prone to elimination of the hydroxyl group in the β-position of the unsaturated carbon. Dehydration Dehydration at at the the C3 C3 positi positionon of erythrose provides the enone intermediate, the unsaturated carbon. Dehydration at the C3 position of erythrose provides the enone intermediate, which can lead to the formation of either VG or HB HBL.L. To validate these prop proposedosed reaction pathways, an experimentwhich can leadwith to erythrulose the formation was of eithercarried VG out, or HBaffordingL. To validate HBL in these only prop 9%osed yield reaction and VG pathways, in 31% yield. an experimentan experiment with with erythrulose erythrulose was was carried carried out,out, affording HBL HBL in in only only 9% 9% yield yield and andVG in VG 31% in yield. 31% yield. These results confirm that Route I was the main path followed in the proposed mechanism. TheseThese results results confirm confirm that that Route Route I wasI was the the main main pathpath followed in in the the proposed proposed mechanism. mechanism.

SchemeScheme 11. 11.Proposed Proposedreaction reaction pathways to to HBL, HBL, VG, VG, and and LA. LA.

However, a PAScheme induction 11. periodProposed was reaction observed, pathways with the to rate HBL, of LAVG, formation and LA. being higher than However,that of botha HBL PA inductionand VG. Furthermore, period was PA observed, was the only with reaction the rate intermediate of LA formation observed, being suggesting higher than that of both HBL and VG. Furthermore, PA was the only reaction intermediate observed, suggesting However,that the rate-determining a PA induction step period of this wasreaction observed, could be with an aldol the ratereaction of LA between formation the enol being form higher of PA than that theand rate-determiningformaldehyde. step of this reaction could be an aldol reaction between the enol form of PA that of both HBL and VG. Furthermore, PA was the only reaction intermediate observed, suggesting and formaldehyde. that the rate-determining step of this reaction could be an aldol reaction between the enol form of PA and formaldehyde.

Molecules 2016, 21, 937 10 of 19

3.1.2. Specific Catalysis by Sn Halides in the Synthesis of HBL Molecules 2016, 21, 937 10 of 18 As the balance between Lewis and Brønsted acidity influences product yields, the interaction between3.1.2. the Specific Lewis Catalysis acidic (Sn) by Sn and Halides Brønsted in the acidic Synthesis (HCl) of HBL species derived from the Sn chloride salts in the reactionAs mediumthe balance is crucialbetween to Lewis the overall and Brønsted rate of acid thisity cascade influences reaction. product The yields, balance the betweeninteraction Lewis and Brønstedbetween the acidity Lewis is acidic therefore (Sn) and key Brønsted to understanding acidic (HCl) this species cascade derived reaction, from the allowing Sn chloride optimization salts in of higherthe yields reaction and medium selectivities. is crucial Investigation to the overall intorate of the this influence cascade reaction. of the HCl/Sn The balance ratio between on product Lewis yields + confirmedand Brønsted that the acidity optimal is therefore H /Sn ratio key forto understa this systemnding was this 4 cascade for both reaction, SnCl4¨ 5Hallowing2O or SnCloptimization2¨ 2H2O[ 27]. of higher yields and selectivities.119 Investigation into the influence of the HCl/Sn ratio on product yields Furthermore, based on Sn NMR studies, a solution of SnCl4¨ 5H2O in CD3CN-d3 generates the confirmed that the optimal H+/Sn ratio for this system was 4 for both SnCl4·5H2O or SnCl2·2H2O [27]. 6-coordinate complex SnCl4(H2O)2, which is the active catalytic species in this system. Based on Furthermore, based on 119Sn NMR studies, a solution of SnCl4·5H2O in CD3CN-d3 generates the 6- these results and the rate-determining step identified in Scheme 11 (i.e., an intermolecular aldol coordinate complex SnCl4(H2O)2, which is the active catalytic species in this system. Based on these reaction), following ligand exchange between the active SnCl (H O) species and PA, the reaction is results and the rate-determining step identified in Scheme 11 (i.e.,4 2an intermolecular2 aldol reaction), accelerated by an aldol reaction and subsequent elimination of the diketone intermediate (Scheme 12). following ligand exchange between the active SnCl4(H2O)2 species and PA, the reaction is accelerated This thereforeby an aldol accounts reaction forand the subsequent observed elimination effects upon of the the diketone addition intermediate of water, as (Scheme identified 12). in This Table 3, entrytherefore 9. accounts for the observed effects upon the addition of water, as identified in Table 3, entry 9.

Scheme 12. Proposed route to HBL from PA in the presence of a SnCl4(H2O)2 catalyst. Scheme 12. Proposed route to HBL from PA in the presence of a SnCl4(H2O)2 catalyst.

Prior to this study, the synthesis of HBL was particularly challenging, and so this novel coupling Priorbetween to thisDHA study, and formaldehyde the synthesis could of HBL aid was in establishing particularly wood challenging, biomass andas a sosource this novelfunctional coupling betweencompounds. DHA and Furthermore, formaldehyde the results could presented aid in establishing herein could wood lead to biomass the development as a source of functionalmore compounds.sustainable Furthermore, heterogeneousthe tin catalysts, results presented such as zeolites herein or couldsilica containing lead to theimmobilized development Sn, which of more sustainablehave the heterogeneous potential for Sn tinregeneration. catalysts, such as zeolites or silica containing immobilized Sn, which have the potential for Sn regeneration. 3.2. A Sugar-Accelerated Tin-Catalyzed Cascade Synthesis of α-Hydroxy-γ-butyrolactone 3.2. Afrom Sugar-Accelerated Formaldehyde Tin-Catalyzed Cascade Synthesis of α-Hydroxy-γ-butyrolactone from Formaldehyde Formaldehyde,Formaldehyde, which which is is produced produced industriallyindustrially by by the the catalytic catalytic oxidation oxidation of methanol, of methanol, is a is a naturally-occurring organic compound and is an important precursor to many other materials and naturally-occurring organic compound and is an important precursor to many other materials and chemical compounds. In the presence of basic catalysts, formaldehyde undergoes the formose reaction chemical compounds. In the presence of basic catalysts, formaldehyde undergoes the formose reaction to produce carbohydrates, as previously outlined in Scheme 7 [20–25]. Butlerov proposed a mechanism to producefor this carbohydrates, reaction, where as two previously formaldehyde outlined molecules in Scheme condense7[ 20– 25to ].form Butlerov GA, which proposed subsequently a mechanism for thisreacts reaction, via an aldol where reaction two with formaldehyde another equivalent molecules of formaldehyde condense to to afford form GLA. GA, The which aldose-ketose subsequently reactsisomerization via an aldol of reaction GLA then with yields another DHA, equivalentwhich can react of formaldehyde with formaldehyde, to afford GA, and GLA. GLA; The subsequent aldose-ketose isomerizationisomerization of GLA results then in the yields formation DHA, of which tetrose, can pentose, react with and formaldehyde,hexose, respectively. GA, To and date, GLA; successful subsequent isomerizationexamples resultsof the formose in the formationreaction, developed of tetrose, exclus pentose,ively andfor the hexose, selective respectively. syntheses Toof unprotected date, successful examplessugars, of have the formosebeen carried reaction, out under developed either basic exclusively or mineral for conditions. the selective However, syntheses to the ofbest unprotected of our sugars,knowledge, have been with carried the exception out under of saccharide either basic synthesis, or mineral application conditions. of the formose However, reaction to to the produce best of our other important chemicals has not been reported. This is likely due to issues regarding control of the knowledge, with the exception of saccharide synthesis, application of the formose reaction to produce formose reaction, i.e., the coupling frequency of formaldehyde and handling of the product mixtures. other importantIn 2015, chemicals our group has reported not been a novel reported. tin chlori Thisde-catalyzed is likely due cascade to issues synthesis regarding of HBL control from of the formoseformaldehyde reaction, i.e.,alone. the We coupling observed frequency that the addition of formaldehyde of mono- and and disaccharides handling of had the an product accelerating mixtures. Ineffect 2015, on HBL our formation, group reported as outlined a novel in Table tin 4 chloride-catalyzed[49,50]. When glucose cascadewas used synthesis as an accelerator of HBL for from formaldehyde alone. We observed that the addition of mono- and disaccharides had an accelerating

Molecules 2016, 21, 937 11 of 19 Molecules 2016, 21, 937 11 of 18 Molecules 2016, 21, 937 11 of 18 Molecules 2016, 21, 937 11 of 18 Molecules 2016, 21, 937 11 of 18 effectMolecules on HBL 2016 formation,,, 2121,, 937937 as outlined in Table4[ 49,50]. When glucose was used as an accelerator for this11 of 18 thisthis reaction, reaction, HBL HBL yields yields increased increased dramatically dramatically (entries (entries 1 and 1 and 2 vs. 2 vs.entries entries 3 and 3 and 4). The4). The results results reaction,this reaction, HBL yields HBL increased yields increased dramatically dramatically (entries 1 and(entries 2 vs. 1 entries and 2 3vs. and entries 4). The 3 resultsand 4). suggested The results suggestedthis reaction, that the HBL presence yields of increased adjacent dramaticallycarbonyl and (entries hydroxyl 1 andgroups, 2 vs. i.e., entries an α -hydroxy3 and 4). carbonylThe results thatsuggestedthis the reaction, presence that HBL ofthe adjacent presenceyields carbonylincreased of adjacent anddramatically hydroxylcarbonyl and(entries groups, hydroxyl 1 i.e., and an groups,2α vs.-hydroxy entries i.e., an carbonyl 3 αand-hydroxy 4). moiety, The carbonyl results is moiety,thissuggested isreaction, essential that HBL inthe achieving presenceyields increased th ofis acceleratingadjacent dramatically carbonyl effect. Indeed,and(entries hydroxyl the1 and cascade groups,2 vs. conversion entries i.e., an 3 αofand-hydroxy formaldehyde 4). The carbonyl results moiety,suggested is essential that the inpresence achieving of thadjacentis accelerating carbonyl effect. and Indeed, hydroxyl the groups,cascade conversioni.e., an α-hydroxy of formaldehyde carbonyl intoessentialsuggestedmoiety, HBL inis is achievingaccelerated essential that the in thispresence by achieving acceleratingthe addition of thadjacentis accelerating effect.of other carbonyl Indeed, compounds effect. and the Indeed, hydroxyl cascade bearing the conversion groups,cascade a terminal conversioni.e., of αan formaldehyde-hydroxy α-hydroxy-hydroxy of formaldehyde carbonyl carbonylcarbonyl into intomoiety, HBL is essentialis accelerated in achieving by the thadditionis accelerating of other effect. compounds Indeed, bearingthe cascade aα terminal conversion α-hydroxy of formaldehyde carbonyl moiety,HBLmoiety,into is acceleratedsuchHBL is as essentialis hydroxyacetoneaccelerated by thein achieving addition by the and th ofaddition hydroxyacetphenoneisis other acceleratingaccelerating compounds of other effect.effect. compounds bearing Indeed, Indeed,(entries a terminalthebearing the5, 8 cascade and a9 terminal-hydroxyvs. conversion entries α carbonyl -hydroxy6, of7, 10formaldehyde and moiety, carbonyl 11). moiety,into HBL such is accelerated as hydroxyacetone by the addition and hydroxyacetphenone of other compounds (entries bearing 5, 8 anda terminal 9 vs. entries α-hydroxy 6, 7, 10 carbonyl and 11). suchintomoiety,into as hydroxyacetoneHBLHBL such isis acceleratedaccelerated as hydroxyacetone and byby hydroxyacetphenone thethe additionaddition and hydroxyacetphenone ofof otherother (entries compoundscompounds 5, 8(entries and bearingbearing 9 vs.5, 8 entries andaa terminalterminal 9 vs. 6, 7,entries α 10-hydroxy-hydroxy and 6, 7, 11). 10 carbonylcarbonyl and 11). moiety, such as hydroxyacetone and hydroxyacetphenone (entries 5, 8 and 9 vs. entries 6, 7, 10 and 11). moiety, such Tableas hydroxyacetone 4. Screening of and accelerators hydroxyacetphenone bearing an α-hydroxy (entries(entries carbonyl 5,5, 88 andand moiety 99 vs.vs. entriesentries 1. 6,6, 7,7, 1010 andand 11).11). Table 4. Screening of accelerators bearing an α-hydroxy carbonyl moiety1 1. Table 4. Screening of accelerators bearing an α-hydroxy carbonyl moiety . 1 Table 4. Screening of accelerators bearing an α-hydroxy carbonyl moiety 1. Table 4. Screening of accelerators bearing an α-hydroxy carbonyl moiety 1. Table 4. ScreeningScreening ofof acceleratorsaccelerators bearingbearing anan α-hydroxy-hydroxy carbonylcarbonyl moietymoiety 11..

EntryEntry Catalysts Catalysts Accelerator Accelerator HBLHBL (mmol) (mmol) 2 2 YieldYield of HBL of HBL (%) (%) 2 2 Entry Catalysts Accelerator HBL (mmol) 2 Yield of HBL (%) 2 2 2 Entry Catalysts4 2 Accelerator HBL (mmol) 2 Yield of HBL (%) 2 11 Entry SnCl SnClCatalysts·5H4¨ 5HO 2O Accelerator- - HBL 0.02 (mmol) 0.02 2 Yield 1 of HBL 1 (%) 2 Entry1 SnClCatalysts4·5H2O Accelerator- HBL 0.02(mmol) 22 Yield of HBL 1 (%) 22 Entry1 SnClCatalysts4·5H2O Accelerator- HBL 0.02(mmol) Yield of HBL 1 (%) 2 1 SnClSnCl2·2H4·5H2O 2O - - 0.17 0.02 11 1 221 SnClSnCl2¨242H·2H·5H2O2O - 0.170.02 0.17 11 111 1 SnCl44·5H·5H22O - 0.02 1 12 SnCl2·5H·2H2O - 0.020.17 11 1 2 SnCl2·2H2O Glucose- 0.17 11 2 SnCl2·2H·2H2O GlucoseGlucose- 0.17 11 2 SnCl2·2H2O Glucose- 0.17 11 3 SnCl4·5H2O Glucose 0.33 - 33 SnClSnCl4¨45H·5H2O2O Glucose 0.330.33 - - 3 SnCl4·5H2O 0.33 - 3 SnCl4·5H2O 0.33 - 3 SnCl4·5H2O 0.33 - 3 SnCl44·5H·5H22O 0.33 - 3 4 SnCl2·2H2O Glucose 0.53 (0.41) 3 26 4 SnCl2·2H2O Glucose 0.53 (0.41) 3 26 4 SnCl ¨ 2H O Glucose 0.53 (0.41) 3 26 4 SnCl2 2·2H2 2O Glucose 0.53 (0.41) 3 26 4 SnCl2·2H2O 1,3-DihydroxyacetoneGlucose 0.53 (0.41) 3 26 4 SnCl2·2H2O 1,3-DihydroxyacetoneGlucose 0.53 (0.41) 33 26 5 4 SnCl 22·2H·2H22O 1,3-DihydroxyacetoneGlucose 0.52 0.53 (0.39) (0.41) 3 25 2626 5 1,3-Dihydroxyacetone1,3-Dihydroxyacetone 0.52 (0.39) 3 25 1,3-Dihydroxyacetone 33 5 5 1,3-Dihydroxyacetone 0.520.52 (0.39) (0.39) 3 2525 5 0.52 (0.39) 3 25 5 0.52 (0.39) 33 2525 SorbitolSorbitol Sorbitol 6 SorbitolSorbitol 0.16 10 6 Sorbitol 0.16 10 6 0.16 10 6 6 0.160.16 10 10 6 0.16 10 GlucosamineGlucosamine Glucosamine 7 GlucosamineGlucosamine <0.01 <1 7 Glucosamine <0.01 <1 7 <0.01 <1 7 7 <0.01<0.01 <1 <1 7 <0.01 <1 HydroxyacetoneHydroxyacetone 8 Hydroxyacetone 0.34 22 8 HydroxyacetoneHydroxyacetone 0.34 22 8 Hydroxyacetone 0.34 22 8 8 0.340.34 22 22 8 0.34 22 HydroxyacetphenoneHydroxyacetphenone Hydroxyacetphenone 9 9 Hydroxyacetphenone 0.390.39 25 25 9 HydroxyacetphenoneHydroxyacetphenone 0.39 25 9 0.39 25 9 9 0.390.39 25 25 AcetoinAcetoin Acetoin 10 Acetoin 0.06 4 10 AcetoinAcetoin 0.06 4 10 0.06 4 10 0.06 4 10 10 0.060.06 4 4 BenzoinBenzoin Benzoin 11 Benzoin 0.07 5 11 BenzoinBenzoin 0.07 5 11 0.07 5 11 0.07 5 11 11 0.070.07 5 5 1 Reaction conditions: Accelerator (0.625 mmol), paraformaldehyde (6.25 mmol), 1,4-dioxane (4.0 mL), 1 Reaction conditions: Accelerator (0.625 mmol), paraformaldehyde (6.25 mmol), 1,4-dioxane (4.0 mL), 1 2 catalyst1 Reaction (0.043 conditions: mmol), naphthalene Accelerator (0.625(20 mg), mmol), air atmosphere,paraformaldehyde 3 h, 160(6.25 °C; mmol), HBL 1,4-dioxane quantity (4.0was mL), 1 Reaction conditions: Accelerator (0.625 mmol), paraformaldehyde (6.25 mmol),2 1,4-dioxane (4.0 mL), catalyst11 Reaction (0.043 conditions: mmol), Accelerator naphthalene (0.625 (20 mmol), mg), airparaformaldehyde atmosphere, 3 (6.25h, 160 mmol), °C; 1,4-dioxane HBL quantity (4.0 mL),was 1 ReactionReaction conditions:conditions:1 AcceleratorAccelerator3 (0.625(0.625 mmol),mmol), paparaformaldehyderaformaldehyde (6.25(6.25 mmol),mmol),2 1,4-dioxane1,4-dioxane (4.0(4.0 mL),mL), determinedReactioncatalyst conditions:by(0.043 H-NMR mmol), Accelerator analysis; naphthalene (0.625 Derived mmol), (20 from paraformaldehydemg), formaldehyde. air atmosphere, (6.25 mmol), 3 h, 1,4-dioxane160 °C; 2 (4.0HBL mL), quantity catalyst was catalyst (0.043 1mmol), naphthalene3 (20 mg), air atmosphere, 3 h, 160 °C; 2 HBL quantity was determinedcatalyst (0.043 by mmol),H-NMR naphthaleneanalysis; Derived (20 mg), from air formaldehyde. atmosphere,˝ 2 3 h, 160 °C; 22 HBL 1quantity was (0.043catalyst mmol), (0.043 naphthalene 1mmol), (20 naphthalene mg), air atmosphere,3 (20 mg), 3 h, air 160 atmosphere,C; HBL quantity 3 h, was 160 determined °C; HBLHBL by quantityquantityH-NMR waswas determined by 1H-NMR analysis; 3 Derived from formaldehyde. determined3 by 1H-NMR analysis; 3 Derived from formaldehyde. analysis;determinedDerived by 1 from1H-NMR formaldehyde. analysis; 33 Derived from formaldehyde. 119Sndetermined NMR spectroscopy by H-NMR and analysis; X-ray DerivedabsorptionDerived fromfrom fine formaldehyde.formaldehyde. structure (XAFS) measurements clarified the 119Sn NMR spectroscopy and X-ray absorption fine structure (XAFS) measurements clarified the 119 oxidation119 statesSn NMR of spectroscopythe various tin and complexes, X-ray absorption allowing fine a potentialstructure mechanism(XAFS) measurements for HBL formation clarified the oxidation119 119Sn NMRstates spectroscopyof the various and tin X-ray complexes, absorption allowing fine structure a potential (XAFS) mechanism measurements for HBL clarified formation the oxidationSn119Sn NMR NMRstates spectroscopy spectroscopy of the various and and X-raytin X-ray complexes, absorption absorption allowing fine fine structure structurestructure a potential (XAFS) (XAFS)(XAFS) mechanism measurements measurementsmeasurements for HBL clarified clarifiedclarified formation the thethe fromoxidation four formaldehyde states of the molecules various tinto becomplexes, determin edallowing (Scheme a potential13). Upon mechanism heating, the for tetravalent HBL formation tin oxidationoxidationfrom four states statesformaldehyde of theof the various various molecules tin tin complexes, complexes,to be determin allowing allowinged a(Scheme potential a potential 13). mechanism Upon mechanism heating, for for HBL the HBL tetravalent formation formation tin complexfrom generatedfour formaldehyde from SnCl molecules2·2H2O and to the be acceleratordetermined is (Scheme initially 13).converted Upon heating,into a complex the tetravalent bearing tin complexfrom four generated formaldehyde from SnClmolecules2·2H2O to and be thedetermin acceleratored (Scheme is initially 13). convertedUpon heating, into athe complex tetravalent bearing tin fromcomplexfrom fourfour generated formaldehydeformaldehyde from SnClmoleculesmolecules2·2H2O toto and bebe thedetermindetermin acceleratored (Scheme is initially 13). convertedUpon heating, into athe complex tetravalent bearing tin an ene-diolcomplex ligand. generated A subsequent from SnCl 2aldol·2H2O condensation and the accelerator with formaldehyde, is initially converted followed into by a acomplex 1,2-hydride bearing ancomplex ene-diol generated ligand. Afrom subsequent SnCl2·2H aldol2O and condensation the accelerator with is initiallyformaldehyde, converted followed into a complexby a 1,2-hydride bearing complexan ene-diol generated ligand. Afrom subsequent SnCl22·2H·2H aldol22O and condensation the accelerator with is initiallyformaldehyde, converted followed into a complexby a 1,2-hydride bearing shiftan and ene-diol C-C bond ligand. formation A subsequent takes place. aldol Phenylglyo condensationxal (PG) with and formaldehyde, either GA or GLA followed are then by aproduced 1,2-hydride shiftan ene-diol and C-C ligand. bond formation A subsequent takes aldolaldol place. condensationcondensation Phenylglyoxal withwith (PG) formaldehyde,formaldehyde, and either GA followedfollowedor GLA are byby then aa 1,2-hydride1,2-hydride produced anshift ene-diol and C-C ligand. bond formationA subsequent takes aldol place. condensation Phenylglyoxal with (PG) formaldehyde, and either GA followedor GLA are by then a 1,2-hydride produced shift and C-C bond formation takes place. Phenylglyoxal (PG) and either GA or GLA are then produced shift and C-C bond formation takes place. Phenylglyoxal (PG) and either GA or GLA are then produced

Molecules 2016, 21, 937 12 of 19 from four formaldehyde molecules to be determined (Scheme 13). Upon heating, the tetravalent tin complex generated from SnCl2¨ 2H2O and the accelerator is initially converted into a complex bearing an ene-diol ligand. A subsequent aldol condensation with formaldehyde, followed by a 1,2-hydride shift andMolecules C-C 2016 bond, 21, 937 formation takes place. Phenylglyoxal (PG) and either GA or GLA are then12 produced of 18 via the retro-aldol reaction of a ligand, reducing the tetravalent tin complex to a divalent complex. via the retro-aldol reaction of a ligand, reducing the tetravalent tin complex to a divalent complex. Based Based on the proposed mechanism, the use of substrates bearing a non-terminal α-hydroxy carbonyl on the proposed mechanism, the use of substrates bearing a non-terminal α-hydroxy carbonyl moiety α moiety(e.g., (e.g., acetoin acetoin or benzoin), or benzoin), does not does lead not tolead an accelerating to an accelerating effect, as effect,the α-hydroxy as the carbonyl-hydroxy moiety carbonyl moietydonates donates the hydrogen the hydrogen atom of atom the α of-carbon the α to-carbon the aldol to reaction the aldol with reaction formaldehyde, with formaldehyde,thus terminating thus terminatingthe reaction. the reaction.

SchemeScheme 13. Proposed 13. Proposed route route to GA toand GA GLAand (intermediatesGLA (intermediates in the in synthesis the synthesis of HBL) of HBL) from fourfrommolecules four of formaldehydemolecules of formaldehyde in the presence in the of apresence tin catalyst of a tin complex catalyst and complex an accelerator. and an accelerator.

In contrast, Matsumoto et al. reported the selective synthesis of triose sugars from formaldehyde Inby contrast,the use of Matsumoto3-ethylbenzothiazolium et al. reported bromide the selectiveas a catalyst synthesis in the presence of triose ofsugars base [51]. from Interestingly, formaldehyde by theonly use C3 of products 3-ethylbenzothiazolium were obtained as bromide major products. as a catalyst These in results the presence allow an of effective base [51 comparison]. Interestingly, onlybetween C3 products acidic wereand basic obtained catalysis, as indicating major products. that the use These of acid results catalysts allow may an lead effective to the formation comparison betweenof compounds acidic and containing basic catalysis, more than indicating 3 carbon that atoms. the use of acid catalysts may lead to the formation of compounds containing more than 3 carbon atoms. 3.3. Application of Heterogeneous Catalysts in the Intermolecular Aldol Reaction between 3.3. Application1,3-Dihydroxyacetone of Heterogeneous and Formaldehyde Catalysts in the Intermolecular Aldol Reaction between 1,3-DihydroxyacetoneUp to this point, and we Formaldehyde have described the cascade synthesis of 5-membered lactones in the presence of homogeneous tin catalysts. However, from an industrial viewpoint, the use of renewable Up to this point, we have described the cascade synthesis of 5-membered lactones in the heterogeneous catalysts and a decrease in catalyst toxicity are desirable. In 2015, Román-Leshkov et presence of homogeneous tin catalysts. However, from an industrial viewpoint, the use of renewable al. reported the application of heterogeneous Sn catalysts in the catalytic C-C coupling between DHA heterogeneousand formaldehyde catalysts to form and HBL a decrease [52]. This in reaction catalyst proceeds toxicity on the are surface desirable. of the Insolid 2015, catalysts Román-Leshkov inspired et al.by reported a three-dimensional the application enzyme of architecture heterogeneous (Figure Sn 1)catalysts [53,54]. The in enzyme, the catalytic a class C-CII aldolase, coupling catalyzes between DHAa anddirect formaldehyde asymmetric toaldol form reaction HBL [52between]. This reactiondihydroxyacetone proceeds phosphate on the surface (DHAP) of theand solid various catalysts inspiredaldehydes by a three-dimensional based on cooperative enzyme activation architecture [55–63]. Inspired (Figure by1 )[this53 intriguing,54]. The mechanism, enzyme, a they class related II aldolase, catalyzesan enzymatic a direct asymmetricfunction to acid-base aldol reaction cooperative between catalysis dihydroxyacetone on the zeolite surface, phosphate where (DHAP) the Lewis and acidic various aldehydesframework based Sn on atom cooperative polarizes activation the carbonyl [55 group–63]. Inspiredof DHA, byand this an α intriguing-proton can mechanism, be removed they by the related an enzymaticbasic oxygen function atom to connected acid-base to cooperative Sn. This sequence catalysis (i.e., on thesoft zeoliteenolization surface, [64–67]) where results the Lewis in the acidic successful coupling reaction between DHA and formaldehyde. framework Sn atom polarizes the carbonyl group of DHA, and an α-proton can be removed by the basic oxygen atom connected to Sn. This sequence (i.e., soft enolization [64–67]) results in the successful coupling reaction between DHA and formaldehyde.

Molecules 2016, 21, 937 13 of 19 Molecules 2016, 21, 937 13 of 18 Molecules 2016, 21, 937 13 of 18

FigureFigure 1.1. Acid-baseAcid-baseAcid-base cooperativecooperative catalysiscatalysis inspiredinspired byby aa three-dimensionalthree-dimensional enzyme enzyme architecture. architecture.

Table 5 shows the catalyst screening results for this reaction, with the Sn-Beta zeolite giving the TableTable 55 showsshows thethe catalystcatalyst screeningscreening resultsresults forfor thisthis reaction,reaction, withwith thethe Sn-BetaSn-Beta zeolitezeolite givinggiving thethe highest selectivity, generating HBL in 60% yield and 98% conversion after 3 h [52]. For the reactions highesthighest selectivity, selectivity, generating HBL HBL in in 60% 60% yield and and 98% 98% conversion after after 3 3 h h [52]. [52]. For For the the reactions reactions performed in batch mode, Sn-Beta zeolite and SnCl4 afforded 68 and 70% yield, respectively, with performedperformed in in batch batch mode, mode, Sn-Beta Sn-Beta zeolite zeolite and and SnCl SnCl4 affordedafforded 68 68 and and 70% 70% yield, yield, respectively, respectively, with with almost complete conversion. The critical aldol condensation4 step is promoted by the cooperative almostalmost complete complete conversion. conversion. The The critical critical aldol aldol co condensationndensation step step is is promoted promoted by by the the cooperative catalysis of a Lewis acid Sn center and a Brønsted base oxygen atom in the Si-O-Sn framework. This catalysiscatalysis of of a aLewis Lewis acid acid Sn Sn center center and and a Brønsted a Brønsted base base oxygen oxygen atom atom in the in Si-O-Sn the Si-O-Sn framework. framework. This proposed mechanism is outlined in Scheme 14. Following coordination of the carbonyl oxygen atom proposedThis proposed mechanism mechanism is outlined is outlined in Scheme in Scheme 14. Foll 14owing. Following coordination coordination of the ofcarbonyl the carbonyl oxygen oxygen atom of DHA to the Lewis acidic Sn center, the α-proton can be removed by the weakly basic oxygen atom ofatom DHA of to DHA the toLewis the Lewisacidic acidicSn center, Sn center, the α-proton the α-proton can be can removed be removed by the byweakly the weakly basic oxygen basic oxygen atom in the Si-O-Sn framework (step 1). The electrophilicity of the carbonyl moiety is increased by the inatom the inSi-O-Sn the Si-O-Sn framework framework (step (step1). The 1). electrophilicity The electrophilicity of the of carbonyl the carbonyl moiety moiety is increased is increased by the by coordination of formaldehyde, and C-C bond formation and a proton transfer from the silanol moiety coordinationthe coordination of formaldehyde, of formaldehyde, and C-C and bond C-C formatio bond formationn and a proton and a protontransfer transfer from the from silanol the moiety silanol proceed (steps 2 and 3). A 1,2-hydride shift and dehydration then yield an enone intermediate proceedmoiety proceed (steps 2 (steps and 23). and A 3).1,2-hydride A 1,2-hydride shift shiftand anddehydration dehydration then then yield yield an an enone enone intermediate intermediate (steps 4–6). Finally, an intramolecular cyclization, 1,2-hydride shift, and elimination of the substrate (steps(steps 4–6). 4–6). Finally, Finally, an an intramolecular intramolecular cyclization, cyclization, 1,2-hydride 1,2-hydride shift, shift, and and elimination elimination of of the the substrate substrate from the catalyst surface provide the desired product (step 7). This proposed reaction pathway differs fromfrom the the catalyst catalyst surface surface provide provide the the desired desired produc productt (step (step 7). 7). This This proposed proposed reaction reaction pathway pathway differs differs from that postulated by our group for Sn halides, which involves the tautomerization and dehydration fromfrom that that postulated postulated by by our our group group for for Sn Sn halides, halides, which which involves involves the the tautomerization tautomerization and and dehydration dehydration of DHA to give PA. However, in both cases, the formation of Sn enolates is proposed through the ofof DHA DHA to to give give PA. PA. However, in both cases, the formation of of Sn enolates is is proposed proposed through through the the deprotonation of a C-H bond in the α-position to the carbonyl group of either DHA or PA. deprotonationdeprotonation of of a a C-H C-H bond bond in the α-position-position to to the the carbonyl carbonyl group of either DHA or PA.

Table 5. Results for the Lewis Acid catalyzed synthesis of HBL 1. TableTable 5. Results for the Lewis Acid catalyzed synthesis of HBL 1..

Yield (%) 2 Yield (%) 2 2 EntryEntry Catalysts Catalysts DHA DHA ConversionConversion (%)(%) Yield (%) Entry Catalysts DHA Conversion (%) HBLHBL LA LA HBL LA 11 Sn-BetaSn-Beta 98 98 60 60 99 3 12 Sn-BetaSn-Beta 3 9898 68 60 8 9 2 Sn-Beta3 98 68 8 2 3 Sn-BetaZr-Beta 98 99 68 3 2 8 33 Zr-BetaZr-Beta 99 99 3 3 2 2 4 Hf-Beta 99 7 3 44 Hf-BetaHf-Beta 99 99 7 7 3 3 555 Ti-BetaTi-BetaTi-Beta 96 96 96 6 6 33 3 666 Al-BetaAl-BetaAl-Beta 95 95 95 11 11 66 6 7 Sn-MCM-41 99 64 15 77 Sn-MCM-41Sn-MCM-41 99 99 64 64 1515 88 Sn-MFISn-MFI 90 90 61 6 6 98 SnOSn-MFI2/Si-Beta 53 90 61 3 6 <1 9 SnO2/Si-Beta 53 3 <1 109 SnO none2/Si-Beta 1253 <1 3 <1 <1 10 none 12 <1 <1 1 Reaction conditions:10 DHA (2.4none mmol), paraformaldehyde 12(7.2 mmol), 1,4-dioxane <1 (8.0 mL),<1 0.024 mmol metal 1 ˝ 2 1 Reactionin the added conditions: catalysts, DHA 20 bar (2.4 Ar mmol), at r.t., 160 paraformaldeC, 3 h; Determinedhyde (7.2 mmol), by GC/FID 1,4-dioxane and expressed (8.0 mL), relative 0.024 to mmol the Reaction conditions: DHA (2.43 mmol), paraformaldehyde (7.2 mmol), 1,4-dioxane (8.0 mL), 0.024 mmol initial molar amount of DHA; Reaction performed in the presence2 of water (2.4 mmol). metalmetal inin thethe addedadded catalysts,catalysts, 2020 barbar ArAr atat r.t.,r.t., 160160 °C,°C, 33 h;h; 2 DeterminedDetermined byby GC/FIDGC/FID andand expressedexpressed 3 relativerelative toto thethe initialinitial molarmolar amountamount ofof DHA;DHA; 3 ReactionReaction performedperformed inin thethe presencepresence ofof waterwater (2.4(2.4 mmol).mmol).

Molecules 2016, 21, 937 14 of 19 Molecules 2016, 21, 937 14 of 18

Scheme 14. Cooperative catalysis of a Lewis acid Sn centercenter and a Brønsted base oxygen atom in the Si-O-Sn framework.

4. Cascade Cascade Synthesis Synthesis of of 5-Membered 5-Membered Lactones Lactones Using Using Biomass-Derived Biomass-Derived Sugars Sugars and and a Range of Aldehydes The useuse of of aldehydes aldehydes instead instead of formaldehydeof formaldehyde can yieldcan yield a wide a rangewide ofrange products of products in the multistep in the HBLmultistep preparation HBL preparation process. Indeed, process. our Indeed, group our reported group thereported cascade the synthesis cascade synthesis of 5-membered of 5-membered lactones usinglactones a combinationusing a combination of DHA of and DHA various and various aldehydes aldehydes [68] (Scheme [68] (Scheme 15). 15). Such Such a synthetic a synthetic route route is particularlyis particularly advantageous, advantageous, as as 5-membered 5-membered lactones lactones can can be be utilized utilizednot not onlyonly asas finefine chemicalschemicals but also as raw materials. The majority of previous re reportsports on the chemical [[34–45]34–45] or enzymatic [[46–48]46–48] syntheses of 5-membered lactones are based on multistepmultistep processes, and so the development of a more efficientefficient and and widely widely applicable applicable approach approach from from inexpensive inexpensive and easily and available easily available starting materials starting ismaterials desirable. is desirable.

Scheme 15. Cascade reaction of DHA an andd aldehydes via sequential ( i) isomerization isomerization and dehydration of DHA; (iiii)) aldolaldol reaction;reaction; ((iiiiii)) cyclization;cyclization; andand ((iviv)) 1,2-hydride1,2-hydride shift.shift.

A wide range of 5-membered lactones, includ includinging both important chemicals and bioactive compounds werewere obtained,obtained, asas outlinedoutlined inin SchemeScheme 1616.. Furthermore, Furthermore, the the reaction reaction proceeded stereoselectively, with with the the cis cis product product being being obtained obtain ased the as major the major product. product. Stability Stability tests of thetests cis/trans of the cis/trans products along with DFT calculations showed that the observed diastereoselectivity was productscis/trans alongproducts with along DFT calculationswith DFT calculations showed that sh theowed observed that the diastereoselectivity observed diastereoselectivity was controlled was by controlled by the thermodynamic stabilities of the products [69]. In contrast, the use of aldehydes thecontrolled thermodynamic by the thermodynamic stabilities of the stabilities products [of69 the]. In products contrast, [69]. the use In ofcontrast, aldehydes the gaveuse of lower aldehydes yields, gave lower yields, likely due to their increased steric hindrance and decreased electrophilicity. likelygave lower due to yields, their increased likely due steric to their hindrance increased and steric decreased hindrance electrophilicity. and decreased electrophilicity.

Molecules 2016, 21, 937 15 of 19 Molecules 2016, 21, 937 15 of 18

SnCl4-5H2O 1,4-dioxane O O O o 160 C,1hx2 OH HO OH + O R H 1) Yield (%) DHA 2) Diastereoselectivity R (cis/trans)

O O O O O OH OH OH O O O O OH O OH

1) 23% 1) 24% 1) 22% 1) 19% 1) 25% 2) 81:19 2) 70:30 2) 75:25 2) 75:25 2) 77:23

O O O O O OH OH OH O OH O O O OH O

1) 31% 1) 30% 1) 26% 1) 30% 2) 75:25 2) 79:21 1) 31% 2) 72:28 2) 78:22 2) 75:25 O O O O O O OH OH OH O OH O OH O O Cl Cl Cl

Cl Cl 1) 21% 1) 34% 1) 32% 1) 31% 1) 35% 2) 80:20 2) 75:25 2) 78:22 2) 70:30 2) 77:23 Scheme 16. Cascade synthesis of a range of useful compounds using a biomass-derived triose sugar (DHA) asas thethe carboncarbon nucleophilenucleophile andand variousvarious aldehydesaldehydes asas electrophiles.electrophiles.

5. Conclusions Conclusions In this review, wewe havehave highlightedhighlighted thethe potentialpotential ofof biomass-derivedbiomass-derived sugars for the cascadecascade synthesis of valuable chemical products. Although significant significant advances have been reported in the development of catalysts for the conversion of carbohydratescarbohydrates into useful compounds, such as the degradation of hydroxyl groups or C-C bond cleavage via a retro-aldol reaction, only a limited range of productsproducts cancan be be obtained obtained through through these these processes. processes. To overcomeTo overcome such such challenges, challenges, we identified we identified novel syntheticnovel synthetic methodologies methodologies for the for preparation the preparation of such of compounds such compounds through through the use the of biomass-derived use of biomass- sugarsderived as sugars carbon as nucleophiles. carbon nucleophiles. A C2 glycolaldehyde (GA) obtained by a [4 + 2] retro-aldol reaction of glucose can be converted into erythrose (C4) viavia anan intermolecularintermolecular aldol reactionreaction followedfollowed byby dehydrationdehydration and aa 1,2-hydride1,2-hydride shift, yieldingyielding vinyl vinyl glycolate, glycolate, which which is ofis greatof great appeal appeal for use for as use a renewable as a renewable solvent solvent and as aand building as a blockbuilding for block polyester for synthesis.polyester synthesis. Furthermore, Furthermor 1,3-dihydroxyacetonee, 1,3-dihydroxyacetone (DHA), prepared (DHA), byprepared a sequential by a isomerizationsequential isomerization of glucose of and glucose a retro-aldol and a retro-aldo reaction ofl reaction fructose, of can fructose, be converted can be intoconverted 5-membered into 5- lactonesmembered via lactones an intermolecular via an intermolecular aldol reaction aldol with reaction formaldehyde with formaldehyde (C1). The use (C1). of solidThe use catalysts of solid as alternativescatalysts as alternatives to homogeneous to homogeneous Sn catalysts ledSn cataly to a greensts led and to sustainablea green and process. sustainable Indeed, process. the behavior Indeed, ofthe Sn-Beta behavior zeolites of Sn-Beta was zeolites comparable was tocomparable that of an to enzyme. that of an The enzyme. achievements The achievements described hereindescribed are thereforeherein are likely therefore to lead likely to novelto lead synthetic to novel strategiessynthetic strategies for the generation for the generation of a wide of range a wide of valuablerange of compoundsvaluable compounds from the combinationfrom the combination of biomass-derived of biomass-derived triose sugars triose and sugars electrophiles. and electrophiles. Acknowledgments: We gratefully acknowledge the work of Takeaki Matsuo (Tokyo Institute of Technology) in our laboratory, and are grateful to Ken Motokura (Tokyo Institute of Technology) for discussions relating to our research.

Molecules 2016, 21, 937 16 of 19

Acknowledgments: We gratefully acknowledge the work of Takeaki Matsuo (Tokyo Institute of Technology) in our laboratory, and are grateful to Ken Motokura (Tokyo Institute of Technology) for discussions relating to our research. Conflicts of Interest: The authors declare no conflict of interest.

References

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