Xylochemicals and where to find them

Abstract

This article surveys a range of important platform and high value chemicals that may be considered primary and secondary ‘xylochemicals’. A summary of identified xylochemical substances and their natural sources is provided in tabular form. In detail, this review is meant to provide useful assistance for the consideration of potential synthetic strategies using xylochemicals, new methodologies and the development of potentially sustainable, xylochemistry-based processes. It should support the transition from petroleum-based approaches and help to move towards more sustainability within the synthetic community. This feasible paradigm shift is demonstrated with the total synthesis of natural products and active pharmaceutical ingredients as well as the preparation of organic molecules suitable for potential industrial applications.

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Jonathan Groß

Jonathan Groß obtained his BSc. (2017) and MSc degree (2018) in Chemistry at JGU Mainz, studying the valorization of renewable resources and natural product synthesis. In 2016/2017, he stayed with Professor D. Stephan at the University of Toronto, Canada, where he worked on new frustrated Lewis-pairs for the activation of small molecules. Since 2019, he is a PhD student in the Opatz lab, focusing on green chemistry and computational methods for structure elucidation.

Caroline Grundke

Caroline Grundke obtained her BSc degree in chemistry at JGU Mainz in 2016 and her MSc degree in 2018, studying the non-toxic cyanide sources in organic chemistry. She then joined the Opatz lab as a PhD student. Her research interests focus on the photochemical synthesis of α-aminonitriles with special emphasis on sustainability and green chemistry, as well as their possible involvement in prebiotic chemistry.

Johannes Rocker

Johannes Rocker finished his apprenticeship as chemical laboratory assistant in 2013. Afterwards, he studied chemistry at JGU Mainz and obtained his BSc degree in 2016, followed by his MSc degree in 2018. He then continued working in the Opatz lab as a PhD student, focusing on photoredox catalysis with helicenes as well as on ligand design for human serum albumin.

Anthony J. Arduengo

Anthony J. Arduengo is presently Professor of the Practice in the School of Chemistry and Biochemistry at the Georgia Institute of Technology in Atlanta, Georgia. He was graduated from Georgia Tech in 1974 with a BS in Chemistry and in 1976 with a PhD. He has held numerous positions in industry and academia over the course of his career. He is a co-founder (together with Till Opatz) of the STANCE consortium (Technology for a Sustainable Chemical Economy) focusing on sustainable chemical technologies employing biomass. Current research efforts in the Arduengo group have significant focus in the pharmaceutical synthesis area.

Till Opatz

Till Opatz holds a chair of Organic Chemistry at JGU Mainz. He graduated from Frankfurt University in 1997 and completed his PhD with H. Kunz in Mainz in 2001. After a postdoctorate at Utrecht University (Netherlands), he returned to JGU for his habilitation (2006). In 2007, he was appointed associate Professor at Hamburg University in 2007 and returned to Mainz as a full Professor in 2010. His research interests are method development, natural product synthesis and sustainable chemistry.

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Introduction

Humankind's discovery and use of petroleum (from medieval Latin, from Latin petra ‘rock’ (earlier Greek) plus Latin oleum ‘oil’) likely substantially predates recorded history. Some of the earliest known records already contain mentions of “rock oil” in one form or another, with some of the earliest references relating its use as a fuel (light source).¹ An early (but, in context a relatively ‘modern’) textual reference to petroleum refining is found in a 1596 translation by J. Frampton of reports by Nicolás Monardes “De Las Drojas De Las Indias”² As a fuel source, the combustion of petroleum releases heat, light, oxides of carbon, and water. This latter use remained the chief utility (excepting occasional application as a salve or ointment) of petroleum for most of the history of modern humans. Only much later did the science of chemistry – specifically, organic synthesis – develop sufficiently that the very limited structural types found in petroleum could be adequately elaborated into the range of functionality and reactivity required to produce modern materials and pharmaceuticals.³ Previously, contemporaneous biomass provided chemists with a wealth of functionality, reactivity and structural types that were elaborated into man-made materials. A chief disadvantage of biomass is that a suitable starting point (material) must be found in the natural pallet of chemicals. Furthermore, the chemistry developed for one particular natural starting material will likely not be applicable for reaching the same end from a different starting point. Petroleum, though structurally simpler than most natural products, provides a relatively well-defined and abundant starting point, from which more sophisticated chemicals can be assembled. The diversity of structural types that can now be derived from petroleum is a result of the wide variety of synthetic transformation and optimization that have been developed in the most recent 200 years.

To date, petrochemical feedstocks such as natural gas, coal and petroleum are the fundament for the majority of all chemical raw materials, that may lead to carbon imbalance in the ecosphere (besides depletion of underground deposits) and ecological risks in terms of production. Some of the potential consequences like alterations in vegetation and soil, changes in the composition of the atmosphere and global water balance may have already emerged in the late 20th century.⁴ The result has been a paradigm shift recorded in the Rio Declaration on Environment and Development in 1992.⁵ Based on this, Anastas and Warner developed their well-known 12 principles of green chemistry^6,7 in 1998, which evolved as general guidelines for more eco-friendly methodologies, syntheses, technologies and processes over the past 20 years.^8–10 Additionally, more metrics and terms have been developed in the early 1990s to describe the extent of sustainability as well as the “greenness” of a given reaction.¹¹ For example, Trost's Atom Economy concept describes the molar mass ratio of the desired product and the total sum of all molecular masses of all the substances produced according to the chemical equation.^12–14 This was followed by the Environmental Factor (E-Factor) by Sheldon, indicating the environmental impact of a given process by describing the mass ratio of total waste and product production.^15–19 Even though the earliest available sources for pure organic compounds were animals, microorganisms and plants, the 19th and 20th century were dominated by the exploitation of fossil carbon sources for the emerging chemical industry.^20,21 Since the last 30 years, the need for renewable resources and especially for alternative carbon atom sources is constantly growing, displaying one of the major aspects of the field of Green Chemistry. One approach within this topic is to use wood as such a renewable alternative (‘Xylochemistry’), as it can be considered a source of atmospherically-bound CO₂, and can be counted as CO₂–neutral when no further fossil carbon is involved.^22,23 With a worldwide production of 5 × 10⁹ m³,^24,25 wood provides a broad variety of valuable oxygen-containing functionalities, e.g. hydroxyl or carbonyl groups as well as (enantiomerically pure) building blocks in contrast to fossil fuels, which lost the majority of their heteroatomic functionalities and their stereo-information through the process of kerogenesis.²⁶ Hence, their chemical diversity is limited and functional groups must be reconstructed in cost- and resource-intensive reaction sequences, which leads to additional purification steps, energy consumption and waste production.

In contrast, wood mainly consists of cellulose, hemicellulose and lignin, that affords the opportunity to use already existing waste-streams from paper production or agricultural waste products as well as wood itself. Furthermore, wood-derived materials act as renewable feedstocks for high value and platform chemicals alongside biofuels, while there is no competition with food production.^27–33 As there is already a rich body of existing literature concerning the topic of lignin valorization/depolymerization,^34–42 the reader shall be referred to this literature to gain a more detailed information about this spacious research field.^39,42–46 (Oligo)peptides, (oligo)saccharides as well as (oligo)nucleotides will not be discussed in detail in this context either, as the natural origin of these substances is evident and the criterion of transcendence is not fulfilled in these cases.^47–49

Xylochemical synthesis approaches are not only of interest for future industrial scale processes, but have also found their way into laboratory scale synthesis methodologies, particularly in natural product total synthesis. Since the term ‘Xylochemistry‘ was coined in 2015, several natural product total syntheses such as ilicifoline B,²³ (−)-oxycodone,⁵⁰ (−)-thebaine,⁵¹ lamellarin G trimethyl ether,⁵² shancigusin C and bletistrin G⁵³ as well as 2-aminophenoxazinone-type natural products⁵⁴ have been described. Additionally, antibacterial balsacones have been reported by the Pichette group,⁵⁵ while some current HIV protease inhibitors⁵⁶ as well as colorants and polyamides⁵⁷ have been reported by the Opatz group. The Sperry group demonstrated the use of chitin and chitosan as naturally occurring sources of nitrogen that can be implemented in a variety of N-substituted heterocycles.^58,59 Among other groups, the Barta lab worked on the valorization of lignin and its model compounds⁶⁰ to build up naturally occurring alkaloid scaffolds. Another approach was reported by the Moeller group, who made use of wood waste streams by developing an electrochemical synthesis of value-added building blocks from sawdust.⁶¹ One of the most recent examples for the implementation of xylochemical strategies in organic chemistry and its impact on daily consumables is the application of cashew nut shell liquid as a supplier for UV absorbers in sunscreen.⁶²

To the best of our knowledge, there is no current publication that summarizes a large multiplicity of (standard) chemicals and reagents that can be considered primary xylochemicals and additionally demonstrates their natural sources until this date. Furthermore, important secondary xylochemicals are listed, which are accessible via straightforward chemical transformations from primary xylochemicals. Thus, this review article should provide such an overview in tabular form and act as a work of reference.

Registry of xylochemicals

As described by Arduengo and Opatz, xylochemistry uses wood- or plant-based biomass as a source of raw materials for chemical synthesis instead of fossil carbon sources.^22,63 The following registry depicts the first 100+ xylochemicals with their molecular structures and lists their corresponding natural origin.^21,64 All substances are arranged in ascending order by the number of their carbon atoms and are highlighted either as primary xylochemicals (directly obtainable/isolable from plant/wood extracts, labelled with “P”) or secondary xylochemicals (available through a single transformation such as fermentation from primary xylochemicals, labelled with “S”). Where available, further information such as the yield isolated is provided. However, this information is provisional and it is likely possible to optimize the outcome through improved isolation procedures, specific breeding or genetic engineering in the future (vide supra). Besides compounds that carry a broad variety of oxygen-containing substituents, many hydrocarbons such as benzene, toluene, naphthalene, styrene and other unsaturated compounds have also been obtained from wood by pyrolysis/distillation procedures (see Table 1). Nevertheless, as all of the latter platform chemicals are already accessible with optimized outcomes of more than 99% from petrochemicals, this article will mainly focus on heteroatom-containing and functionalized hydrocarbons.

Table 1 Xylochemicals and their natural sources, ordered by the number of carbon atoms. The following abbreviations and synonyms were used: wood vinegar: wv; fermentation: fmt.; depolymerization: depol.; carbohydrates: sugars

	Compound	Natural source
		wv,^65 oxidation of sugars (75%)^65,66
	Formic acid
		Dry distillation of wood,^67 hydrogenation of lignin^68
	Methanol
		wv,^65 fmt. of sugars,^69 oxidation of carbohydrate biomass (up to 27%),^66 wood pyrolysis^65
	Acetic acid
		Ethanol dehydration (>98%)^27,70–72
	Ethylene
		From Kraft black liquor with elemental sulfur^73
	Dimethyl sulfide
		ABE-fmt. of sugars^27,74,75
	Ethanol
		Catalytic oxidation of ethanol (up to 96%)^76
	Ethylene oxide
		Microwave-assisted processes (18%), sugar cane, sugar beets^77
	Glycolic acid
		Wood-sorrels (Oxalis),^78 from sawdust^79
	Oxalic acid
		wv^65
	Allyl alcohol
		Catalytic conversion of glycerol/water mixtures (up to 62%)^80
	Acrolein
		Dehydration of 3-hydroxypropionic acid (derived from biomass)^81,82
	Acrylic acid
		wv,^65 fmt. of sugars (71.8 g L^−1)^69,83,84
	Propionic acid
		From biomass^82
	3-Hydroxypropionic acid
		Leaves of lucerne and green/growing wheat plants,^85 mature Leguminosae leaves, green alfalfa plants^86,87
	Malonic acid
		fmt. of sugars (up to 90%), corn or sugar beets,^75,88 oxidation of carbohydrate biomass^66,77
	Lactic acid
		Oxidation of D-fructose and L-sorbose (85%)^89
	Glyceraldehyde
		ABE-fmt. of sugars,^27,90 wood pyrolysis with addition of calcium carbonate^65
	Acetone
		Co-product of biodiesel production (50 wt%)^91,92
	Glycerol
		fmt. of sugars (>40 g L^−1)^93
	Acetoin
		Catalytic gas phase synthesis from grain-/potato-based ethanol^94
	1,3-Butadiene
		ABE-fmt. of sugars (34 wt%)^27,74
	1-Butanol
		fmt. of sugars (up to 25%)^95,96
	(2R,3R)-butanediol
		Catalytic decarbonylation of furfural (>98%)^97
	Furan
		wv^65
	Crotonic acid
		fmt. of sugars,^75,98–102 dry distillation of amber,^103 biochemical transformation of sugar (1.3 mol succinate per mol glucose)^104
	Succinic acid
		Cleavage of ascorbic acid,^105 grapes (berries) and wine, Geraniaceae, Vitaceae and Leguminosae families^106
	Tartaric acid
		Green alfalfa,^86 wheat,^87 fmt. of sugars (37.9 ± 2.6 g L^−1)^107
	Malic acid
		wv,^65 fmt. of sugars (21 g L^−1)^69,108
	Butanoic acid
		Dehydrated malic acid, oxidation of furfural (47%), butanol, levulinic acid, hydroxymethylfurfural^109,110
	Maleic acid
		fmt. of sugars (16.2 ± 0.2 g L^−1),^107Fumaria officinalis^69
	Fumaric acid
		wv^65
	Angelic acid
		wv,^65 distillation of valerian root^69
	Valeric acid
		Lignocellulose^111 (60–70% based on hexose content),^112 sugars^113,114
	Levulinic acid
		fmt. of sugars (glucose),^75 by product of the pyrolysis of citric acid^115
	Itaconic acid
		Hydrogenation of arabinose from hemicellulose (up to 78%)^31,75
	Xylitol
		Mosses, ferns, trees, polyisoprenes from rubber tree,^116 pyrolysis of rubber products^117
	Isoprene
		From levulinic acid through catalytic hydrogenation (>99%),^118 lignocellulose^119
	γ-Valerolactone
		Pentose-containing biomass like corn cobs, sugar cane residues,^97,109,111,120 wood hydrolysates^121
	Furfural
		Hydrogenation of furfural^122
	2-Methyltetrahydrofuran
		wv,^65 fractionation of coconut oil^69
	Caproic acid
		Hydrogenation of glucose,^75 from cellulose (up to 85%)^31,75
	Sorbitol
		Juice of manna-ash (Fraxinus ornus l.), olive trees/leaves,^123,124 catalytic hydrogenation of glucose-fructose mixtures or cellulose (up to 85%)^75
	Mannitol
		Dry distillation of Acacia catechu,^125 lignin^126,127
	Catechol
		Lignin depol.,^128 pine wood lignin (9.6 mol%)^129
	Phenol
		Wood tar^130
	Resorcinol
		From phloretin,^131 (apple tree leaves, manchurian apricot)^132,133
	Phloroglucinol
		Oxidation of hydroxymethylfurfural/methoxymethyl-furfural (59%)^134,135
	Furan-2,5-dicarboxylic acid
		Depol. of kraft lignin (175 g kg^−1),^136 wood combustion^137,138
	Benzene
		Raw wv from Pinus tabulaeformis carr^127
	Hydroquinone
		Green shell of walnuts,^139 citrus fruits^140
	Ascorbic acid/vitamin C
		wv,^65 rowan berries^141,142
	Sorbic acid
		Rowan berries (132 mg/100 g),^143 cranberry (0.12% of dry plant)^144
	Parasorbic acid
		Apparent in plants, also available from citric acid^87
	Aconitic acid
		Green alfalfa,^86 growing wheat,^87 industrially through fmt. of sugars (up to 100%),^69,145 citrus juice and pineapple waste^69
	Citric acid
		fmt. of sunflower oil (93 g L^−1) and purification by esterification^146
	Isocitric acid
		Green solvent alternative for DMF or NMP, from cellulose (from larch log, poplar wood, bagasse, corn cob, bilberry presscake),^147via hydrogenation of levoglucosenone (up to 100%)^147,148
	Cyrene
		From biomass derived levulinic acid and formaldehyde (up to 92%)^149
	5-Methyl-3-methylenedihydrofuran-2(3H)-one
		From biomass derived glucose, sucrose, cellulose (up to 76%)^150,151
	5-(chloromethyl)furfural
		Fructose and other sugars (85%)^75,114,152–154
	5-(hydroxymethyl)furfural
		Fruit kernels,^155 peach leaves,^156 from cinnamaldehyde^155
	Benzaldehyde
		Eucalyptus wood tar,^157 lignin depol.,^128 wood pyrolysis^158
	Cresoles
		Caesalpinia spinosa pods (25% yield),^159Rhus chinensis^160
	Gallic acid
		Eucalyptus wood extracts (detected via LC-MS),^161Terminalia myriocarpa extracts^162
	Methyl gallate
		Wood combustion,^65,163 tolu balsam^164,165
	Toluene
		Raw wv from Pinus tabulaeformis carr^127
	3-Methylcatechol
		Raw wv from Pinus tabulaeformis carr^127
	3-Methoxycatechol
		Raw wv from Pinus tabulaeformis carr^127
	4-Methylcatechol
		Distillation of guaiac resin,^65,166 wood tar oil,^65 wv,^65 bio-oil from lignin pyrolysis (up to 26%)^167
	Guaiacol
		From gum benzoin^69,103
	Benzoic acid
		From Salicaceae^168,169
	Hydroxybenzoic acids
		From Alchornea cordifolia^169
	Dihydroxybenzoic acids
		wv,^65 wood tar^170
	Xylenoles
		Oxidation of vanillin from lignin^169,171
	Vanillic acid
		Lignin (4.5–7.0%,^172 2.8%^173),^174 aspen wood (0.95–17.5%),^175 Eucalyptus wood^176
	Vanillin
		Wood pyrolysis (detected via GC)^177
	Veratrole
		Birch wood (combustion)^163
	Xylenes
		Raw wv from Pinus tabulaeformis carr^127
	2,6-Dimethoxyphenol
		Leaves of Syringa vulgaris (2.5% via GC),^178Quercus infectoria,^179 acai palm oil (1073 ± 62 mg L^−1)^180
	Syringic acid
		Cinnamon bark,^181 (1.5% of dried bark),^182Pseudocinnamomum^183
	Cinnamaldehyde
		Cinnamon bark^184
	Cinnamic acid
		Lignin depol.^185
	p-coumaryl alcohol
		Grapevine pruning (0.15%),^186 wheat straw (0.66%),^187 maize stems (1.08%)^187
	p-coumaric acid
		Lignin oxidation, poplar lignin (30%),^188 aspen wood (0.77–36.2% at temperatures between 100–215 °C),^175 maple wood (Klason lignin, 31.8%)^189
	Syringaldehyde
		Hydrogenation of hardwood lignin (76%)^68
	4-Propylcyclohexanol
		Raw wv from Pinus tabulaeformis carr^127
	2,6-Dimethoxy-4-methylphenol
		From wood of Abies sibirica^190
	Veratraldehyde
		Fractional distillation of Eucalyptus oil from leaves (1.0–2.4% of fresh weight)^191
	1,8-Cineol
		Roots of Lactuca sativa var. Angustana cv. (3.7 mg/228 g dried plant),^192 leaves of Chloranthus anhuiensis^193 and alpinia flabellate (11 mg/800 g dried plant)^194
	Trimethoxybenzaldehyde
		Sassafras oil^195 (80-93%),^196,197Ocotea odorifera oil (42%)^198
	Safrol
		From safrol (98%)^199
	Isosafrol
		Reduction of ferulic acid (68%),^200 lignin depol^185
	Coniferyl alcohol
		Rice straw (0.87%),^187 rice bran^201 (178.3 μg mg^−1),^202 grapevine pruning (0.41 mg g^−1),^186 wheat straw (1.24%)^187
	Ferulic acid
		Oxidation of asarone (65%)^203,204
	Asaronic acid
		Chenopodium oil (67%),^205Peumus boldus oil (31%)^206
	Ascaridole
		Sulfate turpentine,^207Origanum acutidens oil (ca. 2%),^208Chenopodium ambrosioides oil (26%)^209
	p-cymene
		Camphor wood^69,208
	Camphor
		Blumea balsamifera leaves (0.5% (−)-borneol, less isoborneol)^210
	(iso)borneol
		Clove (leaves and buds, 180 mg g^−1),^211,212 bay leaves, cinnamon bark and leaves^213
	Eugenol
		Clove (leaves and buds, 180 mg g^−1),^211,212 bay leaves, cinnamon bark and leaves^213
	Isoeugenol
		Turkish Origanum acutidens,^208 thyme oil (up to 50%)^69
	Thymol
		Origanum acutidens oil (87%),^208Satureja montana extracts (53-66%),^214 oils of thyme (up to 60%), majorana (49%), Origanum dictamnus (up to 82%)^215
	Carvacrol
		Turkish Origanum acutidens,^208Cotinus coggygria oil (8.8%),^216 or leave distillates (52%)^69
	Myrcene
		Mentha piperita oil (30-55%),^217Mentha canadensis oil (63-69%)^218
	(–)-Menthol
		Mentha piperita oil (14–32%),^217Mentha canadensis oil (8–16%)^218
	(–)-Menthone
		(R)-(−)-Limonene: orange oil (92%)^219 (3.8 wt% of orange peel),^220 lemon, bergamot, dill, mint, among others,^219 (S)-(−)-limonene: oaks and pines, Eucalyptus stageriana^221
	Limonene
		Chenopodium ambrosioides oil (63%),^209 majoram oil (10%),^222 terpene fraction of orange oil,^69 american turpentine oil^69
	α-terpinene
		Majoram oil (14%),^222 cardamom oil (up to 11%)^223
	γ-terpinene
		Spruce needle oil,^224 sulfate turpentine (65%)^207
	α-pinene
		From turpentine, from α-pinene^69
	β-pinene
		(S)-(+)-carvone: Carum carvi oil (50–70%),^225 (R)-(−)-Carvone: oil of spearmint (up to 69%)^69,226
	Carvone
		Western red cedar (Thuja plicata donn) heartwood 5.8% (w/w) of extractive,^227 taiwan hinoki (0.2 mg g^−1 sawdust)^228
	Hinokitiol
		Coriandrol ((S)-(+)-linalool): coriander (60–70%), Orthodon linalooliferum (80%) licareol ((R)-(−)-linalool): extracts of Cinnamomum camphora or cajenne rosewood (80–85%)^69,229
	Linalool
		Lignin depol.^185
	Sinapyl alcohol
		Rapeseed hulls (450 mg kg^−1),^230 mustard meal^231
	Sinapinic acid
		Bark of pine trees,^232 rice bran oil,^233 indonesian sausage fruit^234
	Methyl ferulate
		Acorus (70% in extract),^235,236Asarum^237
	Asarone
		Black locust wood (0.5% of dry weight)^238
	Dihydrorobinetin
		Catechu black from Acacia catechu (2–10% catechin),^69 grape seed extract (approx. 6% of combined flavanol monomers, including (−)-epicatechin and (+)-catechin), tea extract^69
	(epi)catechin
		Humulus lupulus (40% of volatiles),^239 spearmint oil (up to 30%),^226 sage oil (13%)^240
	Humulene
		Ginger oil (35%)^241
	Zingiberene
		Tall oil^242–244
	Palmitic acid
		Hydrogenation of palmitic acid (20%)^245
	Cetyl alcohol
		Tall oil (45–49%)^242–244
	Oleic acid
		Tall oil (45–48%)^242–244
	Linoleic acid
		Tall oil^242–244
	Stearic acid
		Hydrogenation of C18 fatty acids (up to 83%)^246,247
	Stearyl alcohol
		Dehydrogenation of abietic acids from resin oils^248,249
	Retene
		Wood rosin^250
	Abietic acid
		Rosemary leaves (1.2% of dry plant)^251–253 and sage^69,253
	Carnosol
		Cashew nut shell liquid from Anacardium occidentale (up to 90%)^62,254
	Cardanol
		Cashew nut shell liquid from Anacardium occidentale^62,254
	Cardol
		Cashew nut shell liquid (82%)^255 from Anacardium occidentale, Anacardiaceae, Gingkoaceae, and Myristicaceae^62,256
	Anacardic acid

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Xylochemical synthesis approaches

One of the numerous issues for the earth's ecosystem is the use of fossil resources for the synthesis of chemical commodities and everyday products. For instance, the UV-absorbers utilized in current sunscreens and photostabilizers are often small organic molecules derived from petroleum. To propose an alternative solution, the groups of Opatz and de Koning opted for a xylochemical synthesis of UV absorbers starting from either cardanol (1) or anarcardic acid,⁶² both being major components of the bio-renewable and non-edible carbon source cashew nut shell liquid (CNSL).^257–260 Starting from these two primary xylochemicals, a series of compounds with promising UV-A and UV-B absorption characteristics belonging to the major commercial classes of UV absorbers (hydroxybenzophenones, triazines, xanthones and flavones) were synthesized (Scheme 1). The color code of all schemes individually traces the origin of the respective atoms.

Scheme 1 Cashew nut shell liquid derived potential UV-Absorbers synthesized by Opatz and de Koning et al.⁶²

The first total synthesis of the dimeric alkaloid ilicifoline B (11)²⁶¹ was reported in 2015 from the groups of Opatz and Arduengo,²³ who exclusively utilized wood-derived carbon sources like ferulic acid (7), methanol (8) and veratrole (9). They also reported an asymmetric synthesis of (−)-dihydrocodeine (15) with methyl ferulate (12) and methyl gallate (14) as the staring materials, a xylochemical version of a synthesis developed earlier (Scheme 2).²⁶² Both syntheses demonstrate that the use of wood-derived building blocks can be a sustainable alternative in classical synthetic approaches. In the case of dihydrocodeine, the hitherto most efficient asymmetric synthesis could be surpassed in terms of overall yield even though no carbon input from fossil sources was required with the exception of solvents and reagents.²²

Scheme 2 Total Synthesis of ilicifoline B (11) and (−)-dihydrocodeine (15) using a xylochemical approach.^23,262

Another example for the application of xylochemical synthesis strategies was reported in 2019.⁵⁰ (−)-Oxycodone (19), a naturally occurring²⁶³ but mostly semisynthetic opioid related to naturally occurring thebaine,^264,265 was synthesized starting from wood-derived methyl gallate (14) and vanillin via the regio- and diastereoselective formation of a 4a-2′-coupled morphinandienone 17 as the key step, followed by Ru-catalyzed Noyori asymmetric transfer hydrogenation (Scheme 3).^266,267

Scheme 3 Xylochemical total synthesis of (−)-thebaine (18) and (−)-oxycodone (19).^50,51

Nevertheless, nitrogen-containing fine chemicals remain a challenging task for xylochemical synthesis approaches, as they are not directly attainable from lignocellulosic biomass. To this end, the Sperry group has used chitin (20), the second-most abundant biopolymer, as a cheap natural source of nitrogen, to show a proof-of-concept synthesis of the anticancer alkaloid proximicin A (23) in seven steps.⁵⁹ Additionally, all of the reagents applied in this synthesis sequence are traceable back towards renewable resources. With this strategy, the group was also able to demonstrate the synthesis of various 3-aminocyclopentanones, 4-aminocyclopentene-1,3-diones and a 4-aminocyclopentenone by applying the chitin-derived furfural 22 in a Piancatelli-like rearrangement (Scheme 4).²⁶⁸

Scheme 4 Chitin/Chitosan-derived starting material 22 and products thereof by Sperry et al.^59,268

By applying acidolysis strategies to lignin, the Barta group managed to directly afford three different substance classes of aromatic compounds that can be used as valuable aromatic monomers in further synthesis (Scheme 5). To this end, lignin model compounds 47, representing the β-O-4 linkage in natural lignin, were subjected to strong acids, and the resulting reactive intermediates were converted into more stable products in situ through either reaction with diols furnishing acetals, dehydrogenation to afford the respective diol, or through decarbonylation.²⁶⁹

Scheme 5 (a) Cleavage pathways of lignin through acidolysis followed by in situ conversion into stable products. (b) Construction of lignin-derived tetrahydro-2-benzazepines 58.^60,269

In 2019, the same group reported the construction of lignin-derived tetrahydro-2-benzazepines (58) through selective catalytic amination followed by cyclization using formaldehyde and choline chloride (ChCl)/oxalic acid (OA) as deep eutectic solvent.⁶⁰ These substances show promising biological activities²⁷⁰ and represent a scaffold in naturally occurring alkaloids²⁷¹ such as galanthamine,²⁷² among others.

In 2015, the Moeller group reported the use of sawdust for the electrochemical, sustainable construction of synthetic building blocks bearing electron-rich aromatic rings.⁶¹ Solvolysis of the crude sawdust material lead to either cinnamyl ether or aryl aldehyde products, depending on the reaction conditions (Scheme 6). One substance of each class of lignin-derived products was exemplarily converted electrochemically into a series of value-added synthetic substrates, which themselves could act as platform chemicals for the construction of diverse drugs (38a and 38b) and alkaloids (39–41), as monomers for polymer synthesis (42 and 43), as structural elements found in numerous biological systems (44) or as substrates for electrochemical oxidations (45 and 46).

Scheme 6 Solvolysis products of sawdust and conversion into electron-rich and value-added synthetic building blocks by the Moeller group.⁶¹

Concluding remarks

This review provides an overview of a variety of platform chemicals that may be obtained from wood-based biomass rather than from petrochemistry. Moreover, a variety of existing syntheses of natural products, drugs and everyday consumer products based on xylochemicals is presented. Nevertheless, there remains room for new discoveries and the improvement of existing technologies to reach the envisioned transition from optimized petroleum-based processes towards sustainable xylochemical approaches. Apart from renewable starting materials, as discussed in this review, the use of alternative, ideally sustainable solvents and reagents as well as work-up procedures, that suit the principles of green chemistry, are a major goal to bear in mind when planning a synthesis. Recommendations on the substitution of carcinogenic, toxic and otherwise undesirable solvents have already been published and adopted on industrial scale but are often disregarded in research laboratories.²⁷³ Until alternatives for problematic solvents and reagents are developed, recycling remains the responsible alternative. We hope this article will catalyze thinking and activity in the direction of renewable resources and sustainable chemistry. For the chemical community specifically, and for society in general, it would be advantageous to have access to renewable commodities containing nitrogen (e.g. pyridine, urea, guanidine, aniline, quinoline, phenylenediamine etc.), second row hetero elements (S, P) as well as the industrially and pharmaceutically relevant halogens (F, Cl, Br). The development of industrial processes for the isolation of monomeric building blocks (e.g. ethylene oxide, styrene, ethylene glycol, adipic acid, phthalic anhydride etc.) from woody biomass on an industrial scale would constitute a significant improvement over the current state of the art. In addition, there are numerous important simple substances and platform chemicals for which “green” industrial scale solutions are not yet available on larger scale (e.g. cyclohexanedione and the class of nitriles and isonitriles). Developments in this direction would constitute important additions to the xylochemical toolbox and can be regarded as attractive xylo-targets for future chemical innovation.

Conflicts of interest

There are no conflicts to declare.

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Footnote

† Contributed equally, ordered alphabetically by last name.

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