Making natural products from renewable feedstocks: back to the roots?

This review highlights the utilization of biomass-derived building blocks in the total synthesis of natural products. An overview over several renewable feedstock classes, namely wood/lignin, cellulose, chitin and chitosan, fats and oils, as well as terpenes, is given, covering the time span from the initial beginning of natural product synthesis until today. The focus is put on the origin of the employed carbon atoms and on the nature of the complex structures that were assembled therefrom. The emerging trend of turning away from petrochemically derived starting materials back to bio-based resources, just as seen in the early days of total synthesis, shall be demonstrated.

Future challenges and outlook 4.
Conicts of interest 5.

Total synthesisa driving force for new developments
The synthesis of organic compounds of natural origin from simple starting materialsthe so-called total synthesishas attracted and fascinated chemists ever since the successful synthesis of "organic" urea from inorganic silver cyanate and ammonium chloride by Wöhler in 1828. 1 It should not be forgotten that the earlier isolation of pure morphine from opium by Sertürner in 1806 2 and his preparation of morphine salts in 1817 3 were further dening moments in organic chemistry.Total synthesis has since emerged to be one of the most challenging and prestigious disciplines among the chemical sciences, as underlined by the Nobel prizes awarded to R. B. Woodward and E. J. Corey.
The fascination with this eld arises from the diverse opportunities available in the application of natural products, combined with the possibility to provide these natural products independent of their natural source and to modify their structures at will.
5][6] Therefore, total synthesis, natural product isolation and structure elucidation have close ties.The search for new compounds with attractive biological activities or chemical structures has fueled the development of new analytical methods and synthetic chemists were never shy to tackle any attractive target molecule virtually regardless of its size.In contrast, the more challenging the target molecules were, the more effort was put into the development of new methods, technologies and theoretical concepts to make their preparation possible. 7,8This has made total synthesis an ideal proving ground for the utility of new synthetic developments.][11][12][13][14][15][16][17][18][19][20] Working on total synthesis projects provides excellent training for synthetic chemists and is generally appreciated by future employers in the chemical and pharmaceutical sector because of the profound experience gained. 21The extensive and diverse challenges of organic synthesis provide a "feeling" for the reactivity of chemical compounds and profound knowledge on how to extract the literature to solve the numerous problems encountered on the way to the target.Although the number of total synthesis publications dwelling on the detours and problems encountered which contribute to the unmatched challenge of this discipline seems to be, unfortunately, declining, the successful pursuit of a total synthesis project is frequently associated with high skills in problem-solving and high levels of tolerance for frustration by the practitioner. 22

Requirements of eco-friendly synthesis
The increasing awareness of sustainability in our modern society has also led to reverberations in chemical research and industry which culminated in the Rio Declaration on Environment and Development from The United Nations Conference on Environment and Development in 1992. 23Based on this declaration, Anastas and Warner have developed their twelve principles of green chemistry in 1998, 24 just as Anastas and Zimmermann phrased the related twelve principles of green engineering ve years later. 25Both catalogues are meant to be guidelines for the development of more eco-friendly syntheses, methodologies, technologies as well as processes and these are applicable to numerous facets of chemical research and production.However, the considerable potential of biocatalysis for "green" organic synthesis is not discussed therein.The present review will mainly focus on the use of renewable resources for the production of chemical building blocks and their value for organic synthesis.The reader shall also be referred to the rich body of existing literature providing more detailed information on the essence of green chemistry.  Furtmore, during the course of this paradigm shi in the world of chemistry, a number of terms and metrics to describe the extent of sustainability and "greenness" of certain reaction or process have been introduced. 53The rst metric that has been introduced is the Atom Economy concept of Trost, soon followed by the Environmental (E) factor of Sheldon.The former is dened as the ratio of the molecular mass of the desired product and the sum total of the molecular masses of all substances produced according to the stoichiometric equation. 54,550][61] Researchers of GlaxoSmithKline have recently developed the carbon efficiency, which is the percentage of carbon atoms remaining in the product relative to all carbon atoms present in the entirety of reactants. 62,63Since organic synthesis is about constructing carbon skeletons, the origin and fate of carbon atoms signicantly contributes to the sustainability of a certain organic product.Thus, the renewability of (starting) materials is a major aspect of green chemistry.
With few exceptions, chemical raw materials are currently produced from the fossil resources such as natural gas, coal and petroleum.Depletion of underground deposits, growing ecological risks associated with production as well as the carbon imbalance in the ecosphere resulting from the usage of these feedstocks makes them less favorable.Furthermore, the chemical diversity initially available from these sources is small and this has led to sometimes lengthy production processes but also to a rather limited primary product portfolio comprising alkanes, alkenes, alkynes and arenes.Any further functionalization such as the introduction of heteroatoms like oxygen, nitrogen, sulfur, phosphorus or halogens to generate advanced building blocks requires additional synthetic steps, oen in the form of multistep cascades, which lead to additional waste production and energy consumption.In spite of these shortcomings, there was little incentive so far to change this traditional and irreversible chemical carbon ow.
In contrast, biomass-derived renewable starting materials oen carry an appreciable degree of functionalization (heteroatoms, stereocenters) and can therefore represent useful advanced building blocks for synthesis.Because of their biogenetic relation or at least their structural proximity to nature-derived or -inspired target molecules, the step count required to convert them into suitable synthetic building blocks can be shorter than that available in the usage of their petrochemical counterparts.In addition to the renewability aspect and the option to close the carbon cycle, this is another advantage of bio-based starting materials.Here, we will mainly focus on the origin of the starting materials required to construct the carbon skeleton of natural products in order to illustrate their utility in total synthesis and organic synthesis of complex molecules in general.
Along with the utilization of biomass for fuel and energy production, the search for new sources of chemical feedstocks is a growing eld in current chemical research.[66][67] 1. 3

. Atom origin: historical developments
The concept of producing starting materials from natural resources is by no means new.In fact, before petroleum oil and coal deposits were discovered and exploited, the only available sources for pure organic compounds such as camphor, ethanol, methanol, hexadecanol, acetic acid, benzoic acid or benzaldehyde were microorganisms, plants and animals.Therefore, the young eld of organic synthesis was initially restricted to these natural feedstocks and chemists have sought out to expand this portfolio.Nevertheless, early-day chemists managed to synthesize natural productssome remarkable examples like von Baeyer's alizarin and quinalizarin 68 as well as indigo synthesis, 69-71 Ladenburg's coniine synthesis 72,73 or the synthesis of tyrian purple by Sachs and Sichel [74][75][76] are depicted in Schemes 1-4.
During this period, industrial organic chemistry was intensely focused on the production of dyes and pigments and the demand was growing for synthetic approaches instead of reliance on natural sources of these products.Therefore, productive sources of raw materials were needed and the industrial production of petroleum oil and coal provided the required carbon sources.These petrochemicals were available in quantities sufficient to satisfy the needs of the expanding chemical industry.Synthetic routes and products were planned according to the starting materials available from those sources.A prime example is the manufacturing of indigo which was at rst obtained from plant sources at an annual rate of 19 000 t in 1897 which dropped to 1000 t in 1914 as synthetic methods based on petrochemicals became available. 77Around the same time, the industrial production of synthetic pharmaceuticals gained importance, e.g. the industrial scale production of acetylsalicylic acid 78 and of salvarsan, 79 which were both already produced from petrochemicals.The chemical industry developed to an important basis for economic growth in Western countries.
Despite the shi towards petrochemicals as new starting materials, biomass-derived feedstocks never were completely eliminated.The chiral pool, which is the collection of chiral terpenes, amino acids and carbohydrates and other chiral compounds available from nature, 80 was for many decades the only source of enantiopure catalysts and building blocks. 81][84][85][86][87] The anthropogenic rise in atmospheric CO 2 levels casts shadows upon the continued extensive use of petrochemical resources. 88With the largest fraction of fossil fuels being used for heating and/or cooling and transportation, the opinion that the use of fossil resources for chemistry will always be possible in future economic settings is still widespread.This is at least in part based on the assumption that mankind will acknowledge the overriding importance of synthetic chemistry and that this area will remain unaffected by any future changes in our carbon economy, hence making any adaption of feedstocks towards a higher sustainability obsolete.On the other hand, it is entirely possible that this belief will suffer the same fate as the presumption that chlorouorocarbons or tetrachloromethane will always be available at a reasonable price for laboratory-scale applications or that the number of chemicals available from commercial suppliers cannot ever decrease.It thus makes sense that researchers are now reviving the use of natural feedstocks in organic synthesis which had moved in the background more than a century ago.Although outstanding achievements have already been made in the valorization of biomass as a chemical feedstock, the full substitution of petrochemicals is still a distant dream.

Natural product syntheses using renewable feedstocks
The main intention of the present review is the appreciation of syntheses that were performed based on renewable carbon sources and that follow some of the concepts of sustainable chemistry.The potential of those approaches is highlighted to provide inspiration to fellow researchers.In contrast to the synthesis of polymers [89][90][91] or other functional materials, [92][93][94][95][96] the concept of total synthesis using renewable carbon sources is not widespread.Total synthesis is already operating under very stringent conditions and the way of accomplishing the ultimate goal is oen subordinated, with the application of any suitable method and effort being justied, at least in an academic setting.To compare several functioning approaches to the same target molecule, aspects like step count and overall yield are commonly applied, yet soer or less well-dened aspects such as "elegance" also play a role.
The following syntheses demonstrate that the challenge of avoiding fossil resources can be tackled at the same time.The key criterion for the inclusion of total syntheses in this review is the origin of carbon atoms and the renewability of the starting materials used.Other aspects of sustainable chemistry such as the use of benign solvents, of catalytic methods instead of stoichiometric transformations, the avoidance of protecting groups and critical reagents or the step efficiency will be addressed and discussed where relevant.Furthermore, we primarily selected examples where starting materials were used in a so-called "class-transcendent" fashion (i.e. the product belongs to a different class of compounds than the starting material) to demonstrate the full potential of the starting materials and the capability of combining different sources.We pay tribute to the fact that a synthesis of a saccharide from a terpene is more challenging and remarkable than a synthesis from another saccharide.In fact, (oligo)peptide, (oligo)saccharide and (oligo)nucleotide natural products will not be covered, as the transcendence criterion is not fullled in these cases and the natural origin of the starting materials is rather obvious.For a better visualization, we use a color coding for the carbon atoms of each moiety derived from the respective biomass resources presented herein.
Wood-(or lignin-) derived carbons are colored in blue, (hemi)cellulose-as well as carbohydrate-based moieties are shown in green, compounds obtainable from fats and oils are colored in orange, purple was chosen for chitin-and chitosanderived groups, and terpene and terpenoids are shown in red.
Heteroatoms are also colored in this code if they are introduced from the respective bio-based material.Otherwise, inserted heteroatoms will be black.These ve classes of renewable starting materials were selected as they represent the most intensely investigated and used sources for starting materials to date.Starting materials of natural origin not covered by the above list specied in this review (e.g.amino acids) are also colored black.Petrochemistry-derived carbon atoms that remain in the nal product will not occur in this review, but for the sake of simplicity, carbons of this kind introduced transiently will also be depicted in black.

Wood/lignin
A major component of lignocellulose is lignin, the largest source of aromatics on earth, as wood-derived biomass consists of up to 35% of lignin. 97Lignin is an amorphous cross-linked biopolymer that, in combination with cellulose and hemicelluloses, confers structural stability to plants. 98The complexity of its structure and its chemical stability make this biopolymer difficult to break down into useful building blocks. 99,100Nevertheless, the benets of its use would be its carbon-neutrality and the lack of competition with food production (not considering the competition for potentially arable land). 101Therefore, it is a promising alternative to petroleum resources. 102,103Lignin can be derived from wood pulp and is a waste product of paper production.It is biosynthetically derived from three phenylpropanoid monolignol monomers, differing only in their oxygenation pattern (Scheme 5).
2.1.1.Valorization of wood/lignin.Various approaches for lignin depolymerization have been developed (oxidative, reductive, pyrolysis, hydrogenolysis, deoxygenation) 99,104-108 and these can deliver several platform chemicals such as vanillin (4) which proved useful for the synthesis of natural products (Scheme 5). 109,110ore advanced strategies for lignin valorization are the focus of ongoing research and promise to convert wood-derived industrial waste or residues from agriculture into carbonneutral, renewable building blocks.However, numerous issues such as lignin repolymerisation, low overall efficiency, structural variability and problems with product separation and purication need to be addressed. 100[116] Scheme 6 Synthesis of (AE)-usnic acid ((AE)-12) via oxidative coupling of acetophenone moieties 10.Scheme 7 Enantioselective synthesis of (+)-garcibracteatone ((+)-20) mimicking biosynthesis.
2.1.2.Natural product syntheses using wood/lignin derived starting materials 2.1.2.1.(AE)-Usnic acid.Barton et al. published a two-step synthesis of (AE)-usnic acid ((AE)-12) by oxidative coupling of acetylated phloroglucinol 10 using potassium ferricyanide and subsequent acid-catalyzed dehydration (Scheme 6).Acetophenone 10 can be synthesized in two steps from natural phloroglucinol (5) 117 through Vilsmeier-Haack reaction followed by aldehyde reduction and subsequent acetylation with acetic anhydride. 118,119n advantage of this synthesis is the use of the environmentally benign solvents.Ferricyanide is a green oxidant and no carbon atom is "lost" during the synthesis (high atom economy).The reported yields are unfortunately low.
The avoidance of protecting groups and the construction of a complex molecular scaffold from simple starting materials in a short route are the highlights of this sequence.
2.1.2.3.Lupinalbin H.The avonoid lupinalbin H (28) was rst isolated by Tahara et al. from the methanolic extract of the roots of yellow lupin (Lupinus luteus cv Topaz). 131Its rst synthesis in 2011 by van Heerden et al. used a Suzuki-Miyaura reaction, followed by an oxidative cyclohydrogenation and a nal 6p-electrocyclization (Scheme 8). 1324][135] The hydroxy groups were protected and the arene regioselectively iodinated at C-5 to select the site of borylation.
The synthesis of fragment 24 was reported in 2010 by the same group starting from trihydroxyacetophenone 22. 136 The isolation of the latter from plants has been reported. 137,138eaction with DMF-dimethyl acetal, theoretically accessible from the wood-derived renewables DMF 139 and (MeO) 2 SO 2 (prepared by reaction of MeOH with SO 3 ), 140 and subsequent iodination led to fragment 24. 141y coupling of both precursors in the presence of a palladium catalyst, isoavone 25 was obtained, and aer deprotection, oxidation furnished lupinalbin A (26).This naturallyoccurring phytoestrogen was condensed with prenal (27) (accesible via catalytic aerobic oxidation of prenol) 128,142 to complete the synthesis of 28. 143The authors were able to formally derive all carbon-and heteroatoms from renewable sources.The choice of solvents and reagents (e.g.DDQ) was however traditional and less compatible with the principles of green chemistry.
2.1.2.4.(AE)-Tylophorine.Opatz et al. reported a short synthesis of the phenanthroindolizine alkaloid (AE)-tylophorine ((AE)-36) 144 with a Stevens rearrangement as the key step and devoid of any protecting group manipulations (Scheme 9). 145hree of ve overall steps can be performed in a one-pot procedure and no chromatographic purication was required, which is in accordance with "green" principles of pollution prevention. 24arting materials veratrole (29) and diacetyl (30) can be obtained from biomass 146,147 and were subjected to an acid catalyzed reaction furnishing phenanthrene derivative 31, which was brominated under free radical conditions.Reaction with a-amino nitrile 33 afforded spirocyclic compound 34, which underwent a Stevens rearrangement to furnish natural (AE)-tylophorine ((AE)-36) aer reduction with NaCNBH 3 . 145he a-amino nitrile 33 was synthesized from pyrrolidine and sodium cyanide, the former can be derived from proline e.g.via a Pd-catalyzed decarboxylation reaction. 145,148rawbacks of the route are the use of toxic solvents and reagents, which are to be avoided according to "green" principles.It should be noted that natural tylophorine is almost racemic. 149.1.2.5.(AE)-Gracilamine.The natural product (AE)-gracilamine ((AE)-45) was isolated in 2005 150 and its rst synthesis was reported in 2012 by Ma et al. 151 The key step in the formation of spirocyclic intermediates 38a and 38b was an intramolecular oxidative phenol coupling (Scheme 10).152 The starting materials for this reaction, piperonal (6) and tyramine (37), can be obtained from renewable sources.[153][154][155] Reduction of spirocyclic compound 38a and 38b with LiAlH 4 followed by protection with TBDPSCl, ring opening using TrocCl gave benzyl alcohols 39a and 39b aer treating with AgNO 3 in the presence of H 2 O.
Alcohols 39a and 39b were oxidized to aldehydes 40a and 40b.Through the condensation reaction of aldehyde 40a and leucine ethyl ester (41), imine 42 was formed, which reacted in a [3 + 2]cycloaddition with the corresponding azomethine ylide under formation of the natural product scaffold 43 containing all of the carbon atoms required.The nal product 45 was obtained by deprotection, cyclization and reduction using NaBH 4 . 151n this synthesis, all carbon-and hetero atoms can be obtained from renewable sources.
commenced with the Mukaiyama aldol condensation of syringaldehyde (7) with PMB-protected 4-hydroxy-acetophenone (46), both derivable from lignin (Scheme 11). 158,159To obtain chalcone 48 with a p-quinol moiety in ring A, the corresponding ketone 47 was dearomatized oxidatively.To this end, the choice of the right protective group was crucial since derivatives such as OMOM, OTBDMS, OTBDPS, OTHP, and OBn led to negative results during the synthesis.Furthermore, the dearomatization did not proceed with a free OH-group because of a competing Baeyer-Villiger reaction taking place instead. 157Only a single protective group is required and there is no loss of carbon atoms throughout the synthesis.
2.1.2.7.Taiwaniaquinones and taiwaniaquinols.The total synthesis of the racemic taiwaniaquinoids was reported by Li et al. in 2013. 160he synthesis commenced with the preparation of common intermediate 54 with a an trans A/B ring junction on a gram scale (Scheme 12).1,2,4-Trimethoxybenzene is available from renewable resources and can be transformed into benzaldehyde 49 in several steps. 161,162This was then subjected to a Wittig olenation, followed by a Pd-catalyzed Suzuki-Miyaura coupling with iododiene 51 to afford diene 52.Through a Bi(OTf) 3 -catalyzed cationic cyclization and a Wolff-type ring contraction as the key steps, intermediate 54 was obtained.From there on, the natural products taiwaniaquinones A (57)   and F (58), and taiwaniaquinols B (59) and D (60) were prepared in 2-3 steps in racemic form. 160uinones A 57 and F 58 were accessed by epimerization of aldehyde 54 followed by oxidation (taiwaniaquinone F ( 58 All four natural products synthesized occur in the same plant species. 163ethylenetriphenylphosphorane (50) was prepared from triphenylphosphine and iodomethane, 164 available from methanol (wood spirit) and HI. 165ododiene 51 can be prepared in three steps from 6methylhept-5-en-2-one, which can be isolated from several plant species. 166,167heme 14 Closing synthesis of taiwaniaquinol B (59) and D (60).Enantiopure fragment 67 could be prepared in several steps from 61 (Scheme 15). 173Diol 63 was obtained by Wittig olenation, dihydroxylation, reduction and subsequent tosylation afforded compound 64.Aer epoxidation and O-protection, compound (AE)-65 was subjected to a hydrolytic kinetic resolution using a cobalt catalyst to obtain enantiopure syn-epoxide 66 in 96% ee.A regioselective reductive ring-opening led to fragment 67.
The synthesis of the natural product surinamensinol B (70) 185 commenced with O-benzylation of vanillin (4) followed by Wittig olenation and reduction to arylpropanol 69.The latter was coupled with fragment 67 and the natural product 70 was obtained aer acid-catalyzed deprotection. 184he Wittig phosphonium ylide 62 employed twice in this sequence can be prepared from PPh 3 and ethyl bromoacetate accessible from acetic acid or malonic acid via bromination 186 and subsequent esterication. 187While the synthesis of PPh 3 from biomass should be feasible but likely is lengthier than the classical petrochemical approach, the recycling from the oxide through the dichloride is well-known. 188hile "green" solvents are employed in several places, the extensive use of protecting groups and the hydrolytic kinetic resolution step with a maximum yield of 50% are less favorable.
2.1.2.10.(+)-Oxycodone.In 2019, Hudlicky et al. reported a synthesis of (+)-oxycodone ((+)-87), the non-natural enantiomer of this opioid. 189Its natural antipode 190 is widely applied in pain management. 191The synthesis commenced with the microbial dihydroxylation of phenethyl acetate (81) (available through fermentation of corn, barley and sweet molasses), 192 selective hydrogenation of the less hindered C]C-double bond and a Mitsunobu reaction with iodophenol 80 (Scheme 17).The latter compound can be derived from natural isovanillin (77) via iodination, 193 Wittig olenation with (methoxymethyl)triphenylphosphonium chloride (79) and reaction with methanolic HCl. 194Wittig salt 79 is theoretically accessible from the reaction of formaldehyde with MeOH and HCl, affording chloromethyl methyl ether, 195 and subsequent reaction with PPh 3 . 196Intramolecular Heck reaction of ether 83 followed by dihydroxylation furnished diol 84.Through mesylation and DBU-catalyzed elimination, a ketone was obtained.Subsequent pinacol-type coupling with deprotected aldehyde and protection yielded carbonate 85.Methanolysis of the acetate followed by Mitsunobu coupling, carbonate hydrolysis and two-step dehydration led to tosylamide 86.The synthesis was completed via Parker radical amination and oxidation of deprotected alcohol yielding (+)-oxycodone ((+)-87). 189Tosylmethylamine can be prepared from methanol and tosylamide 197 (product of toluenederived TsCl with sodium cyanate or ammonia). 198,199he authors could have derived all carbon atoms in the product from renewable resources.The use of a highly stereoselective microbial dihydroxylation and of several "green" solvents (MeOH, Me 2 CO, H 2 O) are an advantage, yet toxic reagents and the use of non-green protecting groups had to be included.95) in 2015. 114he synthesis of 95 200 commenced with methylation and hydrogenation of the wood-derivable natural product ferulic acid (9), 201 followed by a Bischler-Napieralski cyclization and addition of in situ generated HCN 202 to furnish a-amino nitrile 91 (Scheme 18).In a cascade reaction with dibromide 92, berberine alkaloid pseudopalmatine ( 93) is formed, subsequent oxidation and dimerization furnished alkaloid ilicifoline B (95). 114 Dibromide 92 is accessible from veratrole (29), a pyrolysis product of wood. 203Formaldehyde and dimethyl sulfate can be obtained from methanol. 140,204he authors used entirely wood-derivable building blocks, so-called xylochemicals, instead of conventional petrochemicals for the construction of the natural product carbon scaffold.In the light of "green" chemistry, the use of a non-toxic cyanide source and solvents like toluene, MeOH, H 2 O or EtOH is Scheme 19 First enantioselective synthesis of (À)-viridin ((À)-111) and (À)-viridiol ((À)-112).
positive, yet undesired solvents like dioxane, CH 2 Cl 2 should generally be avoided.
The starting material 3-hydroxymethylfuran (100) for the synthesis of the second fragment can be obtained by reduction of naturally occurring 3-furoic acid. 211,212Subsequent silylation, reaction with 2-bromopropene (102) and chlorination led to compound 103.2-Bromopropene ( 87) is accessible from wood-derived acetone 213 in two steps via reaction with hydrazine and subsequent bromination. 214,215Compound 103 was reacted with allylmagnesium chloride 104, followed by ring closing metathesis and stannylation reaction affording second fragment 105.Allylmagnesium chloride (104) can be obtained from allylic alcohol (available from biomass) 216,217 via chlorination and reaction with magnesium. 218,219nantiopure compound (+)-107 already bears the complete carbon skeleton of viridin (111) and was obtained from fragments 99 and 105 via Liebeskind coupling and Heck cyclization.Upjohn dihydroxylation, double Swern oxidation and O-methylation yielded methoxy enone 108.Site-and diastereoselective reduction followed by treatment with AcOOH and MeOH delivered a mixture of hydroxy ketal diastereomers (+)-109 and (À)-110.
2.1.2.13.(AE)-Latine and (AE)-cherylline.The hydrobenzoin substrates 124a and 124b were synthesized via a Wittig epoxidation/ring-opening one-pot protocol from substituted benzaldehydes accessible from biomass. 109,201,220,221The authors prepared 2,2-diarylacetaldehyde 125a and 125b via a pinacol rearrangement using an eco-friendly catalyst and microwave irradiation under solvent-free conditions (Scheme 20).This key step was followed by one-pot reductive amination, Pictet-Spengler and hydrogenation reactions and only one chromatographic purication to afford the desired isoquinoline alkaloids 129 and 130. 220 (AE)-Cherylline ( 129) and (AE)-latine ( 130) are both secondary metabolites of Crinum latifolium L (Amaryllidaceae). 222he authors provided an efficient and solvent-economical route in which half of the reactions operate at ambient temperature so that no additional heating is required.In general, one-pot approach are also favorable in the light of "green" chemistry.
Based on this procedure, the authors were also able to synthesize the natural opioid (À)-oxycodone ((À)-87), wheras the synthesis of its optical antipode was achieved by Hudlicky et al. along a different synthetic route (vide supra). 189,227nder "green" aspects, switching of protecting groups is not ideal.Furthermore, several of undesired solvents (DMF, THF, CH 2 Cl 2 ) as well as toxic or hazardous reagents (1,4-cyclohexadiene, DMAP, HCO 2 H, Et 3 N) had to be used.

Cellulose
Cellulose (113) and hemicelluloses account for up to 80% of the dry biomass of plants in which they form the cell walls.While the chemical structures of hemicelluloses are very heterogeneous, cellulose consists exclusively of b(1 / 4) linked poly-Dglucose, making it a non-edible carbohydrate source for most animals including humans.It is a very abundant and promising sustainable feedstock for chemical raw materials.
2.2.1.Valorization of cellulose.In view of the large body of research regarding the valorization of cellulose and considering the amount of literature and reviews available, we restricted the presented chemical starting materials to the molecules relevant for the syntheses covered in this review (Scheme 21).For detailed information on the utilization of cellulose for fuel [228][229][230] and chemical raw material production [231][232][233] as well as for macromolecular chemistry, 228 we refer the reader to the references given.
One of the most important small molecules obtainable from cellulose (as well as of hexoses in general) in high yields is 5hydroxymethylfurfural (5-HMF, 119) [234][235][236] and related compounds that can either be obtained from 5-HMF (119) or directly from cellulose.4][245][246] Another interesting raw material is levoglucosenone (LGO, 115), which bears several useful Scheme 22 Valorization of cellulose for selected platform chemicals.
This very straightforward approach provides access to enantiopure (À)-hongconin (145) in a short sequence utilizing cellulose-derived 115 as a chiral synthon and wood-derived 139 as an aromatic building block.Although the procedures used are based on less green methods, only one protecting group transformation had to be performed.
Although the solvents used during these syntheses are ecologically less favorable, the number of protecting group manipulations is minimal and makes this route a straightforward approach to two natural products from bio-based starting materials.
2.2.2.4.(À)-Jiadifenolide.Jiadifenolide (168), a neurotrophic sesquiterpenoid, 284,285 was synthesized by Theodorakis et al. 286 from cyclopentadienone (161) which is available from methyl levulinate (160) in a single step (Scheme 26). 287Allylation with allyl acetate and Michael addition to methyl vinyl ketone (MVK) furnished intermediate 162, 288,289 which was converted to enantioenriched diketone 163 via organocatalysis with D-proli- namide in high enantiopurity.Allyl acetate as an ester of allyl alcohol is available from glycerol 217 while MVK is produced from acetone (available from wood by pyrolysis) 290,291 and formaldehyde (available from methanol) via aldol condensation or Mannich reaction. 292,293Regio-and stereoselective reduction, silyl protection, carboxylation with methyl magnesium carbonate (MMC) and trapping with Meerwein's salt as well as methylation via the TMS-enolate gave intermediate 164 as a single isomer.MMC is made from magnesium methanolate and carbon dioxide and can therefore be considered to be renewable. 294Global reduction, TBS protection of the primary alcohol and oxidation of the secondary alcohol restored the carbonyl group, which was converted to the respective vinyl triate to perform carbomethoxylation.Aer desilylation, spontaneous lactonization occurred to form 165, which was oxidized to the respective epoxide.Oxidative cleavage of the terminal olen and oxidation of the resulting aldehyde triggered "6-exo-tet" epoxide opening to form the desired lactone 166 aer TBS-deprotection.For this sequence, a direct Ru IIIbased oxidation of the terminal alkene to the carboxylic acid was investigated but was unsuccessful and led to decomposition.Therefore, the more circumstantial two-step sequence had to be used.Directed epoxidation and direct treatment of the acidic solution with DMP led to the a,b-unsaturated ketone, acid-catalyzed epoxide opening and transesterication to the thermodynamically favored 5-membered lactone.Aer hydrogenation of the double bond and TES protection, intermediate 167 was obtained.Next, the remaining carbonyl group should be transformed into a methyl group.This seemingly simple transformation proved challenging and the conventional methylenation approaches (Wittig reaction, Ti-and Zn-based) failed.Therefore, the vinyl triate was prepared with Comins' reagent and Pd 0 -catalyzed cross coupling with AlMe 3 (accessible from Al and iodomethane) 295 gave the desired product.A nal three-step one-pot sequence of hydrogenation, hydroxylation via the enolate and oxaziridine 154 as well as Jones oxidation gave (À)-jiadifenolide ((À)-168) in 1.5% overall yield over 25 steps, representing the rst total synthesis of this natural product.
The foregoing synthesis is an excellent example of constructing a fairly complex and stereochemically demanding natural product from simple and bio-derivable building blocks.Inevitable detours had to be taken, which unfortunately decreased the eco-friendliness of the approach, yet the entire carbon backbone was constructed from renewable starting materials.
2.2.2.5.(+)-Chloriolide.In 2014, Schobert et al. synthesized the fungal 12-membered macrolide chloriolide (177) 276 from levoglucosenone ( 115) and (+)-lactic acid via a Wittig-type macrocyclization (Scheme 27). 277Starting from 115, ketone reduction, acetal hydrolysis and acetonide protection led to alcohol 169, which was converted to the C 1 -homologated aldehyde 170 via transformation into a leaving group, nucleophilic substitution with cyanide and reduction.Sodium cyanide is currently produced by the Andrussow process from methane and ammonia and subsequent reaction with lye. 278,279Considering that synthetic natural gas and methane derived from agricultural waste and manure are widely established concepts, 280 even methane-derived NaCN could be produced on the basis of renewables.Another route to biomass-based HCN has been mentioned earlier. 281The cumulated ylide 175 which is prepared from the respective alkoxycarbonylmethylenephosphorane and therefore from an a-haloacetic acid derivative 282,283 was used to synthesize ylide ester 176 aer TBS deprotection.Acetonide cleavage and Wittig-cyclization gave enantiopure (+)-177.The presented work makes use of simple chiral bio-based starting materials to build a fairly complex natural product.
2.2.2.6.(À)-Aspergillides.For a formal synthesis of the cytotoxic aspergillides A and B (186 and 187) [296][297][298] Loh and Koh selected 5-HMF (119) and levulinic acid (122) as biomassderived starting materials (Scheme 29). 299The tetrahydropyran moiety was synthesized from 119 which was benzyl protected and subjected to an aldol reaction.Oxidation of the racemic product and asymmetric transfer hydrogenation furnished bhydroxyester 180.Although the non-stereoselective aldol reaction/oxidation/asymmetric reduction sequence does not look very eco-friendly at rst glance, it turned out to be the only suitable way to access enantiopure 180.Asymmetric Mukaiyama aldol reactions as well as dynamic enzymatic kinetic resolutions of racemic 180 were attempted but neither of them provided the desired outcome in terms of yield and enantiomeric excess.Achmatowicz rearrangement and reductive deoxygenation gave a mixture of dihydro-and tetrahydropyran 181.Aer O-protection, hydrogenation removed the double bond and the benzyl group.The resulting primary alcohol was subjected to Swern oxidation and the following Takai iodoolenation (iodoform is e.g.available from the reaction of ethanol with I 2 in alkaline medium) 300 furnished the rst 5-HMF-derived building block 183.
On the other hand, levulinic acid (122) was reduced to the respective racemic diol, which was subjected to dynamic enzymatic kinetic resolution and the desired enantioenriched alcohol was TBDPS protected to obtain 184.Ester hydrolysis and iodination furnished the second building block 179 in excellent yield and ee (Scheme 28).Both building blocks were coupled by means of a Neigishi reaction with high selectivity in favor of the desired E-isomer.3][304] Aer cleavage of the silyl protecting groups, a MOM group was installed and the ester was saponied to yield seco-acid 185 which was already used by Fuwa et al. as an intermediate and was converted to (À)-186 by Yamaguchi esterication. 305Epimerization with potassium hydride gave (À)-187. 306hroughout this remarkable sequence, a number of steps were intentionally conducted in accordance with the principles of "green" chemistry.As already pointed out, the Neigishi coupling of 183 and 179 is an example of "greener" chemistry and the dynamic enzymatic kinetic resolution also ensures a high overall yield.
For the synthesis of (À)-193, the carbonyl group of 189 was converted into the oxime 191 which spontaneously underwent oxidative dimerization into enantiopure (À)-palythazine ((À)-193) upon exposure to air aer global deprotection and oxime reduction.The absolute conguration of (À)-palythazine ((À)-193) was proven through this stereospecic synthesis.These concise and straightforward syntheses make excellent use of biomass-based D-glucose as an enantiopure starting material (ex-chiral pool strategy) to prepare non-carbohydrate natural products.Acetone 290,291 was used as a potentially renewable C 3 -synthon.Additionally, in contrast to classic carbohydrate chemistry, only a single protecting group transformation was performed throughout the entire sequence.

Chitin and chitosan
Chitin 199 and chitosan 200 are the chemical constituents of the exoskeleton of crustaceans and insects as well as of cell walls of molluscan organs and fungi.This makes it the second most abundant biopolymer (aer cellulose) 321 and the most abundant nitrogen containing biopolymer on earth. 322Similar to the structure of cellulose, chitin is a linear polysaccharide, but unlike cellulose it is composed of b(1 / 4)-linked 2-acetamido-2-deoxy-D-glucopyranose (N-acetylglucosamine, GlcNHAc 201) monomers (Scheme 32).As depicted in Scheme 32, the C-2-substituent of the sugar-derived monomer is either an acetamido-or a free amino group.The term chitin refers to the material with >50% of acetylated amino groups while the material with a lower degree of Nacetylation is called chitosan. 323.3.1.Valorization of chitin and chitosan.The utilization of chitin and chitosan for the production of biofuel, chemical raw materials or functional materials with applications in chemistry and pharmaceutics has been called the "shell bio-renery" 322,324 orhence its predominantly marine originthe "ocean-based biorenery". 325Although this is a very promising feedstock due to its abundance, its availability as a waste product from food production and its unique potential as a source for nitrogen containing raw materials, the eld of chitin valorization is just emerging.325][329][330][331][332] Therefore, we will focus on a small number of low molecular weight organic compounds obtainable from chitin or chitosan that are relevant for the synthesis of natural products within the scope if this review.As for other biopolymers, the compounds accessible from chitin and chitosan vary with the conditions used for depolymerization.
The natural material in the form of shrimp, crab or lobster shells has to be digested by grinding, deproteinization, demineralization, discoloration and drying prior to depolymerization. 333][336][337] GlcNHAc can be deacetylated to yield GlcNH 2 or be converted to two highly promising N-containing starting materials that are challenging to make from other resources.
The furan derivative 3-acetamido-5-acetylfuran (3A5AF, 203) can easily be prepared from 201 in a single step [338][339][340] or directly from 199. 338,341 3A5AF (203) can in turn be converted to L-rednose (204), which contains a b-aminoenone moiety rarely seen in carbohydrates, in a three step sequence. 342.3.2.Natural product syntheses using chitin/chitosan derived starting materials 2.3.2.1.(À)-Rhizochalinin C. Molinski's and Ko's synthesis of rhizochalinin C (217) 343,344 is a good example for the potential of the combinatorial use of biomass derived starting materials.345 Their approach to construct this L-threo, a,u-bifunctionalized sphingoid base combines the use of D-glucosamine from chitin/chitosan as an element of the chiral pool for extracting the stereocenters and fats/oils as well as hemicellulose derived starting materials to build the largest part of the carbon backbone.The key achievement of this work is the conversion of 202 into the useful synthons for L-threo sphingoid bases 209 and 210 by a sequence starting with a Barbier reaction with allyl bromide, followed by N-protection, glycol cleavage, reduction and diol protection (Scheme 34).The allyl bromide used for the Barbier reaction is derivable from glycerol which is produced on a megaton scale by hydrolysis of fats and oils 346 through allyl alcohol as an intermediate.217,347 The respective threo-diastereomers were subjected to olen metathesis and further functionalized to furnish the respective Western 214 and Eastern halves 215, which were coupled by a Horner reaction.Prior to the olen metathesis, a switch of the protecting groups was conducted to prepare the required deoxygenation.
The reactant for cross-metathesis with threo-209, tetradec-13enyl acetate (206), can be easily obtained by cross metathesis of methyl erucate (205) with ethylene, 348,349 followed by reduction and esterication (Scheme 33).Likewise, the olen 208 could be prepared from hemicellulose via furfural 207 which is hydrogenated to tetrahydrofurfuryl alcohol. 350A ring opening/ elimination sequence gave pent-4-ene-1-ol 351 which was esteri-ed to 208.The synthesis of the phosphonate 214 is conducted with diethyl methylphosphonate which in turn can be synthesized from methanol and triethyl phosphite. 352Hydrogenation under strongly acidic conditions ensured global deprotection and saturation of the Horner product 216 in a single step to furnish stereopure (À)-rhizochanilin C ((À)-217).This synthesis makes excellent use of a variety of sustainable building blocks to construct a rather demanding natural product.
Unfortunately, frequently used methods such as glycol cleavage, cross metathesis or Horner reactions are not very atom economic.
Starting from monothiolacetal 218, which was prepared from 201, 355 the conguration of the hydroxyl group at C-3 and the N-protecting group were switched (Scheme 35).Reductive acetal opening and nucleophilic attack of the nitrogen at C-5 led to pyrrolidine 221.Aer debenzylation and oxidation, a nucleophilic allylation was performed through attack of a Grignard reagent.Both diastereomers (threo-and erythro-222) were formed in this step.The synthesis of (À)-pochonicine ((À)-226) was conducted with the erythro-isomer but the threo-isomer was also advanced to obtain the respective C-1 and C-3 epimers of 226.The structure shown in Scheme 35 corresponds to the originally proposed conguration 353 but comparison of the analytical data proved to be inconsistent with that of the natural product.Dihydroxylation of the terminal olen again led to a mixture of diastereomers 224, whereas the 7-(S)-epimer led to (À)-226 and the 7-(R)-epimer to the respective C-3-epimer (not shown).Aer conversion to the hydrochloride, the observed optical rotation of the synthetic product proved to be opposite to the one of the isolated compound.
In this noteworthy work, four different diastereomers were synthesized from two common precursors to clarify the absolute conguration of this stereochemically demanding natural product.Unfortunately, the use of protecting group chemistry was inevitable due to the high degree of functionalization of the intermediates and nal product.
2.3.2.3.(À)-Allosamizoline.As mentioned earlier, a major advantage of bio-based starting materials is the oen high degree of functionalization, in particular with respect to stereogenic centers.Therefore, GlcNHAc and GlcNH 2 are ideal templates for the synthesis of stereochemically demanding natural products.3][364][365] For this potentially biomimetic approach, 366 two main routes emerged for the crucial intramolecular ring closure to form the cyclopentane ring (Scheme 36).While Simpkins and Whittle used a radical ring closure of thiocarbamate 228 and an oxime ether 229, 358,359 the Tatsuta and Kitahara groups opted for an oxidative cycloaddition to generate isoxazoline intermediate 235. 356,360ll three ways converge into the same carbamate intermediate 230 and they rely on the same carbon sources to construct 231.This work highlights how simple biomass-based building blocks, namely GlcNH 2 and dimethylamine (available from methanol and ammonia) 367 can be transformed into valuable natural products without the use of fossil carbon sources.
2.3.2.4.Proximicin A. The nitrogen-containing furan derivative 3A5AF (203) was utilized by Sperry and coworkers for a proof-of-concept synthesis of proximicin A (241), 368 a potential chemotherapeutic compound. 369,370It is the rst natural product synthesis that uses this unique bio-based starting material, which appears to be perfectly suited for the synthesis of 241.Proximicin A was produced in a seven-step sequence from chitin via the key intermediates 238 and 239 (Scheme 37) simultaneously obeying the fundamentals of green chemistry (Scheme 38).In this remarkable work, only "green" solvents ([BMim]Cl -1-butyl-3-methylimidazolium chloride, MeOH, H 2 O, DMC) and procedures were used while it still compared well with former "non-green" syntheses of 241 in terms of step count and yields. 369,370The non-toxic dimethyl carbonate (DMC), which can be made directly from methanol and carbon monoxide in the presence of CuCl and oxygen, [371][372][373] was used for the introduction of the carbamate moiety 374 instead of the conventional methyl chloroformate.Furthermore, the amide coupling of the intermediates 238 and 239 was conducted with the uronium-based coupling reagent COMU 375 ((1-cyano-2ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholinocarbenium hexauorophosphate) instead of the conventional, potentially explosive 1-hydroxybenzotriazole derivatives (e.g.TBTU, HATU, HBTU).

Fats and oils
Fats and oils, either of plant or animal origin, occur in the form of tri-, di-and monoglycerides with varying compositions of fatty acids depending on their origin.The annual production reaches almost 200 Mt and has been increasing over the last decades. 376,377Although this gure indicates a very large industrial product class, one has to keep in mind that the largest fraction of this amount is used for food and feed.Furthermore, with the advent of biodiesel, the ratio of utilization of fats and oils for food/feed versus industry was slowly shiing from 86 : 14 to 80 : 20 over the past few decades. 378If this ethical dilemma could be solved, fats and oils would represent a structurally ideal renewable feedstock not only for the production of chemical raw materials and synthetic chemistry but also for fuel and polymer production.2.4.1.Valorization of fats and oils.0][381] In terms of ne chemicals, plant oils have recently gained attention from surfactant and polymer science. 349,382][385] Aer saponication (the production of soap in this process is the origin of this word), the free fatty acids can be processed in various ways leading to different raw materials depending on the chain length, the degree of unsaturation and the position of the double bonds of the fatty acid.Glycerol is produced on a large scale through saponication of fats and oils 346 and e.g. can serve for the production of glyceraldehyde, 386,387 allylic alcohol, 217 acrolein, 388 and acrylic acid 179 as well as of polymers of the latter.The main methods to valorize free fatty acids for chemical production are esterication, reduction, allylic oxidation, addition, dihydroxylation, epoxidation, cycloaddition, metathesis and ozonolysis.The latter two methods permit the simple variation of the length of the carbon chain.For example, erucic acid (docos-13-enoic acid), which is very abundant in rapeseed and mustard oil, 389 can be converted to brassylic acid (tridecanedioic acid) derivatives by ozonolysis 390 or to 13-tetradecenoic acid derivatives by olen metathesis (see the synthesis of rhizochalinin, Scheme 34). 348,349Likewise, 9-decenoic acid is available from the abundant oleic acid 391,392 whereas meadowfoam seed oil, rich in eicos-5enoic acid ( 153), 393,394 can be converted to 1-pentadecanal ( 276) by ozonolysis. 395In natural product synthesis, starting materials derived from fats and oils usually serve for the introduction of alkyl chains and generally have to be combined with other building blocks to introduce heteroatoms and stereoinformation.
Methyl esters (+)-321 and (À)-321 were converted to the respective enantiopure olens ((+)-245 and (À)-245) 399 which served as the dipolarophiles in a 1,3-dipolar cycloaddition with the nitrones 242 and 250.Both are accessible from fatty acid starting materials.The terminal olen obtained from cross-metathesis of methyl ester of 153 with ethylene 349 can be converted to 242 by hydroformylation 400,401 and reaction with N-benzylhydroxylamine.Ozonolysis of methyl erucate (205) and reduction of the product gives tridecan-1,13-diol, which was converted to nitrone 250.The cycloadditions produced three different diastereomers, of which the cisthreo-and the trans-erythro-form could be converted to (+)-249.
Because of the different conguration of julioridine ( 253 materials in the form of lauric acid ( 258) and caprylic acid (255)  as the main carbon sources as well as allyl diisopinocampheylborane as a terpene/glycerol-derivable chiral allylating agent (Scheme 41).While lauric acid is very abundant in laurel oil (hence the name), in coconut milk and oil as well as in palm kernel oil, caprylic acid can also be found in coconut oil, albeit in much lower concentration. 406,407Caprylic acid can be produced by de novo synthesis from bio-engineered yeast or E. coli strains [408][409][410] or by anaerobic microbial fermentation from ethanol and acetate via chain elongation. 411,412auric acid is converted to the ketene thioacetal 259 which is subjected to a tandem Mukaiyama aldol-lactonization with aldehyde 257 to form the b-lactone ring.For the synthesis of 257, methyl caprylate is converted to octanal (254) 413 followed by enantioselective addition of an allyl group, protection and ozonolysis.Aer desilylation, N-formyl glycine was attached by a Mitsunobu reaction to furnish (À)-panclicin D ((À)-261).The use of little functionalized starting materials for the formation of this interesting natural product makes this synthesis remarkable.
2.4.2.3.(+)-Prosophylline and (+)-prospinine.The antibiotic piperidine alkaloids (+)-prosophylline ((+)-272) 414 and (+)-prosopinine ((+)-273) 415,416 were synthesized by Helmchen et al. via an iridium-catalyzed allylic substitution (Scheme 42). 417,418This key reaction was used twice during the synthesis to introduce and modify the required stereochemistry.The rst application of this methodology was the conversion of the trityl-protected carbonate 262 available from dimethyl fumarate 419 to allylic amine 264.Dimethyl fumarate can be obtained from malic acid or furfural (207), [420][421][422] both available from cellulose.Aer epoxidation, Grignard reaction and cross metathesis with a biscarbonate likewise accessible from dimethyl fumarate, the nitrogen was deprotected to enable the ring closure, while the free hydroxy group was protected.Both diastereomers from the epoxidation reaction were convergently converted to the same threo-amino aclohol 267 with the desired conguration.Again, allylic substitution with both enantiomers of the chiral ligand (L2) led to the respective piperidine diastereomers 271a, b with excellent ee and high dr which is the result of extensive optimization studies.Nprotection, olen metathesis with dodec-1-en-10-one ( 275), hydrogenation and Cbz-removal led to the desired natural products 272 and 273.Ketone 275 423 is produced from the cross metathesis product of methyl oleate (274) with ethylene. 275his synthesis is characterized by the use of powerful methodology for the catalytic introduction of chiral information in combination with the utilization of various sustainable carbon sources to produce two alkaloids through a common precursor.
The antiproliferative isocarbostyril alkaloid pancratistatin (288) 438,439 was synthesized by Alonso et al. 440 from 277 and the xylochemical vanillin (4).The correct stereochemistry is established by the organocatalyzed reaction of 277 with nitroenal 283 441 during which ve stereocenters are formed (Scheme 44).Nitro group reduction, carbamate formation and reduction of the keto group gave the precursor 286 for the Bischler-Napieralski reaction, aer which global deprotection led to (+)-pancratistatin ((+)-288).2-Nitroethanol can be considered a xylochemical since it is produced from nitromethane (itself available in a single operation from methanol) 442 and formaldehyde. 443The presented approach is very straightforward and uses renewable inexpensive starting materials as well as simple synthetic methods.botryolide E (297) 444 is an excellent example of the combination of a biomass-derived chiral precursor (isopropylideneglyceraldehyde ( 289)), other renewables-derived simple building blocks and organocatalysis for the formation of a variety of natural products (Scheme 45).Like dihydroxyacetone, glyceraldehyde can be generated from glycerol, e.g. by aerial oxidation over platinum catalysts, 386 or directly by fermentation of carbohydrate biomass. 445Proline-catalyzed aldol reaction of acetonide-protected aldehyde 289 and acetone led to the respective b-hydroxy ketone 290 in excellent de which was protected with a TBDPS group.Before the cumene process was introduced, acetone was produced by Weizmann's acetone-butanol-ethanol (ABE) fermentation of carbohydrates through Clostridium acetobutylicum. 446Another source of acetone is the pyrolysis and dry distillation of wood and therefore it is considered a xylochemical. 290,291Reduction, PMBprotection and acetonide cleavage led to the pivotal intermediate 291 and all four natural products that were mentioned earlier were synthesized from this anti-diastereomer.For the synthesis of ophiocerins A and C (300 and 295), the secondary hydroxy group was converted into a leaving group and the synepoxy alcohol 293 was formed by nucleophilic substitution.For 300, the inversion of alcohol, epoxide opening, acetonide protection, Lemiuex-Johnson oxidation and reduction were performed.Trimethylsulfonium iodide was used for the olen synthesis from epoxide 293 (available from dimethylsulde and iodomethane, 447 both methanol-derived).Aer PMB cleavage, the primary alcohol was converted into a leaving group and the tetrahydropyran ring was closed by nucleophilic substitution.Final acetonide cleavage furnished (À)-ophiocerin A ((À)-300).Ophiocerin C (295) was synthesized by essentially the same sequence except that no inversion was conducted and that PMB deprotection was performed prior to olen cleavage by ozonolysis to obtain a suitable intermediate for the synthesis of botryolide E (297).Likewise, ophiocerin B (292) was prepared via the respective anti-epoxy alcohol (sequence not shown).
Starting from the olen 294, botryolide E was synthesized by ester synthesis, ozonolysis and the Still-Gennari modication of the Horner reaction to obtain E-olen 296.The required phosphonate can be produced from an a-haloacetic acid derivative and is therefore accessible by fermentation of carbohydrates through acetic acid. 347,448,449Acid catalyzed acetonide cleavage and lactone formation produced (À)-297.
The use of simple bio-based starting materials and pivotal intermediates for the stereochemically exible synthesis of natural products are notable key features of this work.

Terpenes
Terpenes represent abundant and renewable, inexpensive and versatile chiral starting materials and were employed in natural product synthesis ever since. 80,450[453][454] 2.5.1.Valorization of terpene feedstock.6][457] Terpenes are hydrocarbon compounds usually containing one or more C]C-double bonds and having a limited degree of oxygenation.They can be divided into subgroups named aer their carbon count, since isoprene units containing ve C-atoms are the biosynthetic precursors of all terpenes: 452 the monoterpenes (C 10 ), the sesquiterpenes (C 15 ), the diterpenes (C 20 ), etc.They also differ in the arrangement of the isoprenoid units (acylic, mono-or polycyclic) and in their oxidation state (Scheme 46).Despite the enormous advances in asymmetric synthesis in the 20 th century, terpenes are still widely used as chiral starting materials. 458Furthermore, they can be useful as potential fuels, 459 agents for the chemical communication of plants, avor enhancement and pesticides, 460,461 or as a source of chirality in catalysts. 81he major sources of monoterpenes are turpentine oil (a waste product of paper pulp industry, contains mainly aand bpinene), 462 and citrus oil (contains mainly (+)-limonene), 463 a coproduct of citrus juice production. 4525][466] For further information about sources of terpenes, their use in total synthesis and utilization as chiral building blocks, the reader may be referred to the literature. 80,450,452heme 48 Synthesis of (+)-grandisol ((+)-315) from (À)-carvone ((À)-302).
sequence and a NaBH 4 reduction yielding alcohol 316.The C-4 methine position was oxidized under Suárez conditions to afford ether 317.Oxidation with in situ-generated RuO 4 , Riley oxidation and treatment with L-selectride led to the tetracyclic enol lactone 318.The latter was transformed via DMDOoxidation to an a-hydroxyketone, bond reorganization by heating in triuorotoluene, selective reduction of the a-ketol group using Me 4 NBH(OAc) 3 and treatment with acid to furnish the dlactone 319.(À)-Majucin ((À)-320) was obtained via an enolate oxidation using Vedejs' MoOPH reagent, subsequent epimerization via Ru-catalyzed transfer hydrogenation and nal dihydroxylation.
Overall, 13 oxidations were employed while three reduction steps were necessary to achieve the correct oxidation state and for stereochemical adjustments.Favorable aspects in the light of "green" chemistry are the use of a photocatalyzed reaction, and of green solvents (acetone, H 2 O, MeOH), yet undesired solvents like CCl 4 or PhCF 3 also occur.
synthesis commenced with catalyzed hydration of the enone moiety, followed by an oxidative C]C-cleavage.An aldol lactonization afforded bicyclic b-lactone 347, which was then reduced to the corresponding diol, subjected to a one-pot tosylation/bromination sequence and a subsequent acylation reaction to furnish ester 348.Treatment with base and iodomethane formed two C-C-bonds in a single operation, affording d-lactone 349.With in situ-formed allyllithium, a conversion into a ring-opened b,g-unsaturated ketone was performed and an olen isomerization/RCM sequence led to cycloheptenone 350.Aer reduction and cyclopropanation, the natural product (+)-omphadiol ((+)-351) was obtained.Diiodomethane is available from iodoform, 509 the latter being a product of the wellknown reaction from ethanol with I 2 in alkaline medium. 300he synthesis proceeds in a highly efficient manner, using onepot, sequential and tandem processes, and avoids the use of protecting groups.
2.5.2.12.(+)-Cubitene.Lindel et al. reported an enantioselective total synthesis of the diterpene (+)-cubitene ((+)-373). 524+)-Carvone ((+)-302) was reacted rst with aldehyde 368 and subsequently O-phosphorylated to furnish allyl phosphate 369 (Scheme 58).525 By treating the latter with SmI 2 , an intramolecular coupling reaction afforded an [8.2.2]-bicyclic compound, which was converted into an acyloin and subsequently reduced to diol 370.The latter was cleaved with H 5 IO 6 , followed by an oxidation under Pinnick conditions, affording macrocycle 371.Subsequently, 371 was subjected to a Wittig reaction, followed by deprotection and an oxidation of the hydroxyl group under Parikh-Doering conditions promoting a decarboxylation to ultimately form ketone 372.A three-step sequence, comprising a reduction of the keto group, silylation of the resulting hydroxy group and an allylic deoxygenation using Li/EtNH 2 , afforded the natural product (+)-cubitene ((+)-373).524,526 Aldehyde 368 is available from natural geraniol via an allylic oxidation.479,527,528 2.6. Misellaneous Since natural products can be very complex molecules and the total synthesis oen is already challenging, the construction of the entire carbon framework from bio-based starting materials may constitute a considerable challenge.In addition, it is not always possible to adhere to green synthetic methods and guidelines throughout the entire sequence so that conventional methodology has to be employed where the available ecofriendly alternatives failed.An efficient step in the right direction is the synthesis of fragments and to build at least as much as possible from biomass derived starting materials.
2.6.1.L-Rednose-containing antibiotics.A concise example is the L-rednose (L-204) building block synthesized by Sperry and coworkers from 3A5AF (203) (Scheme 32). 342It is part of the complex tetracycline-type natural products rudolphomycin (374), 529,530 aclacinomycin X (375), 11-hydroxyaclacinomycin X (376) 531,532 as well as saquayamycins H (377) and I (378) 533,534 which have not been synthesized so far (Schemes 59 and 60).A viable synthesis of an advanced intermediate like 204 based on eco-friendly methods and starting materials already constitutes a signicant progress in the total synthesis of these compounds.
The eco-friendliness of this route is quite favorable regarding the carbon efficiency.Furthermore, almost every carbon atom introduced into the molecule during the synthesis is retained (except for the triuoroethyl and methyl groups), further increasing the carbon efficiency.Further circumstantial protecting group operations are completely avoided.
Aer benzyl protection, 114 was transformed into the monocyclic trichloracetimidate 389, which was reacted with the dimethyl D-malate-derived building block 390 in a Schmidt glycosylation.Both ester groups were saponied and subsequent ring forming esterication furnished 393.
This approach makes exemplary use of enantiopure biobased starting materials to furnish a pivotal building block for the syntheses of fairly complex natural products, but is hampered by extensive protecting group usage well known from carbohydrate chemistry. 554.6.4.(AE)-Lasiodiplodin from Cashew Nut Shell Liquid (CNSL).A highly promising renewable feedstock, although rather unusual for natural product synthesis, is cashew nut shell liquid, a waste product of the cashew nut production and is the cold ethanol extract of the waste shells.It contains in up to 95% the three phenolic compounds anacardic acid (395), cardanol (396) and cardol (397) which all carry a C 15 chain with one to three double bonds (Scheme 63). 5557][558][559] The for natural product synthesis, the long alkyl/alkenyl chain is rather impractical but CNSL has found numerous applications in fuel research, 560 polymer chemistry, [561][562][563] synthesis of ne chemicals [564][565][566] and for the synthesis of functional materials like surfactants 567,568 and UV absorbers. 116,569agalhães and dos Santos 570 managed to utilize CNSLderived cardol (397) for the synthesis of antileukemic lasiodiplodin (402). 571,572Acetyl protected cardol was subjected to ozonolysis and following reductive treatment to yield a truncated alcohol (Scheme 64).
Aer saponication of the acetates, formylation was performed by means of a Gattermann reaction and the p-hydroxy group was benzylated to furnish aldehyde 399.The second aromatic hydroxy group was converted to the methyl ether and aldehyde oxidation was achieved under Pinnick conditions.The respective carboxylic acid was O-alkylated with iodomethane and the remaining primary hydroxy group was oxidized to an aldehyde, which was subjected to a Grignard reaction with methylmagnesium iodide to yield secondary alcohol 401.Aer saponication and macrolactone formation through the action of 2-chloro-1-methylpyridinium iodide (CMPI), the benzyl group was cleaved to furnish racemic lasiodiplodin.
Although this very concise approach makes formidable use of this particular starting material, it also demonstrates an issue when used for total synthesis: The C 15 moiety oen has to be truncated so that a non-negligible part of the molecule (in this case about one third) is not retained in the desired nal product.Therefore, the carbon and atom efficiency is decreased however, the C 7 -fragment split off may e.g.nd application in the synthesis of the fragrance jasmin aldehyde. 573

Future challenges and outlook
The use of fossil carbon sources as the basis of the vast majority of current activities in synthetic organic chemistry is only rarely questioned by practitioners and scholars.Nevertheless, the current discussion on the necessity of CO 2 reduction and the of the doubtlessly nite underground deposits of fossil carbon brings up interesting challenges for current and future chemists.Atom awareness among the chemical community, i.e. the knowledge of the origin of the matter that we deal with in our work, certainly leaves some room for improvement.As outlined in the Introduction, chemists were never shy to accept new challenges, e.g. to utilize the seemingly unattractive, black and smelly coal tar to produce beautiful dyestuffs or life-saving drugs.The combination of starting materials from renewable feedstocks with eco-friendly solvents, reagents, and methodologies as well as a reduced energy consumption can ultimately lead to processes with minimal impact on our ecosystem.Therefore, existing methods, synthetic routes and processes need to be revisited constantly.A big part of whether or how quickly those concepts will be applied on a large scale is dependent on the economic competitiveness.
Furthermore, the conception of bio-based starting materials has also reached other organic chemical elds like pharmaceutical and agrochemistry.The synthesis of the anti-ulcer drug ranitidine 574 and the insecticide prothrin from CMF (120) 575 as well as the synthesis of norfenefrine and fenoprofen from cashew nut shell liquid-derived cardanol 576 are pioneering examples of this development.
8][579][580] This could particularly inuence natural product synthesis, a eld in which the extensive use of protecting group transformations is commonplace.Atom-and step-efficiency of synthetic routes could be signicantly increased if alternative methods for achieving selectivity can be employed instead.

Conflicts of interest
There are no conicts of interest to declare.
)) or by oxidation and O-demethylation (taiwaniaquinone A (57), Scheme 13).Quinols B 59 and D 60 were obtained from the silyl enol ether derived from intermediate 54.Via a sequence of Saegusa-Ito oxidation, demethylation and oxidation, quinol D 60 was furnished.Subjecting the silyl enol ether of 54 to dihydroxylation conditions, a demethylation and an oxidation reaction led to quinol B 59 (Scheme 14).
Ozonolysis and acetal hydrolysis gave key tricarbonyl intermediate 197a in the lactol form 197b, which was subjected to triple reductive amination.During this reaction only 5% of the undesired C8aepimer was formed.Global deprotection furnished enantiopure (+)-castanospermine ((+)-198) with a high yield of 22% over nine steps starting from 194.

Scheme 33
Scheme 33 Schematic synthesis of terminal olefins 206 and 208 for the synthesis of rhizochanilin C (217).