Levoglucosenone: Bio-Based Platform for Drug Discovery

Levoglucosone (LGO) is a bio-privileged molecule that can be produced on scale from waste biomass. This chiral building block has been converted via well-established chemical processes into previously difficult-to-synthesize building blocks such as enantiopure butenolides, dihydropyrans, substituted cyclopropanes, deoxy-sugars and ribonolactones. LGO is an excellent starting material for the synthesis of biologically active compounds, including those which have anti-cancer, anti-microbial or anti-inflammatory activity. This review will cover the conversion of LGO to biologically active compounds as well as provide future research directions related to this platform molecule

Formation of levoglucosenone and furfural from three different carrageenans via acid-catalyzed pyrolysis in polyethylene glycol

To further develop the potential for carrageenan-use in a seaweed biorefinery, the acid-catalyzed pyrolysis of kappa-, iota- and lambda-carrageenans has been studied in polyethylene glycol (PEG). Using differential scanning calorimetry, it was found that decomposition temperatures for the three polysaccharides were broadened and lowered by 33–60 °C in the presence of H2SO4 and PEG compared to polysaccharide alone. Levoglucosenone (LGO) and furfural were the major products from all polysaccharides with LGO yields of 21.3 mg/gcarr (3.5 mol%), 10.7 mg/gcarr (2.2 mol%) and 3.9 mg/gcarr (1 mol%) and furfural yields of 5.9 mg/gcarr (1.3 mol%), 2.8 mg/gcarr (0.7 mol%) and 1.2 mg/gcarr (0.4 mol%), for kappa-, iota- and lambda-carrageenans, respectively. Total sulfate inversely correlated with the generation of volatile compounds, and the 3,6-anhydro structure may encourage the formation of the major products during the acid-catalyzed pyrolysis of carrageenan in PEG

Oxa-Michael-initiated cascade reactions of levoglucosenone

The reactions of aromatic aldehydes and levoglucosenone promoted by methoxide gives bridged α,β-unsaturated ketones, formed by a series of oxa-Michael-initiated cascade reactions in yields of up to 91% (14 examples). A complex series of equilibria operate during the reaction, and the formation of the bridged species is thermodynamically favored, except in the case of 5-methylfurfural and pyrrole-2-carboxaldehyde. This is the first report detailing this type of aldol/Michael cascade involving oxa-Michael initiation

Enlisting plants in the battle for new antibacterial compounds

A rise in antibacterial drug resistance comes at a time when our once reliable sources of antibacterial natural products, bacteria and fungi, are failing us. The search for new drugs to fight pathogens has led to a range of innovative approaches and includes screening organisms which have developed evolutionary adaptions to prevent bacterial attack. The discovery of antibacterial phytochemicals from plants can be achieved using an activity-guided platform involving biological and chemical pre-screening, compound isolation, structure elucidation, and the direct testing of isolated compounds. Challenges include the clean isolation of natural products, avoiding the rediscovery of known compounds, toxicity, and poor levels of activity

Diastereoselective Weitz-Scheffer epoxidation of levoglucosenone for the synthesis of isolevoglucosenone and derivatives

High-yielding epoxidation conditions for the cellulose pyrolysis product (−)-levoglucosenone (LGO) and 3-aryl derivatives of LGO have been developed. The reaction of LGO with hydrogen peroxide/base is known to give a Baeyer-Villiger reaction, however, it was found that the reactions of LGO or derivatives with tert-butylhydroperoxide/base affords solely epoxides through the Weitz-Scheffer reaction. A critical parameter in the successful isolation of the epoxide from LGO was to avoid all contact with water or alcohols during the reaction and workup. The epoxide products were reacted under Wharton conditions affording allylic alcohols and subsequent oxidation led to isolevoglucosenone or 3-arylisolevoglucosenone derivatives. Previously unreported reactions on isolevoglucosenone were then investigated

Aziridination and aza-Wharton Reactions of Levoglucosenone

Efficient conditions have been developed for the diastereoselective aziridination of the biomass pyrolysis product (−)-levoglucosenone, via the reaction of primary aliphatic amines with 3-iodolevoglucosenone. In contrast to the reactions of aliphatic amines, the use of 4-methoxyaniline resulted in an aza-Michael-initiated dimerisation reaction, and 1,3-diphenylurea gave a 2-imidazolidinone. The aziridine products were transformed using the aza-Wharton reaction, affording novel sulfonamide and amine-substituted 6,8-dioxabicyclo[3.2.1]oct-3-enes with potential as sp3-rich chiral scaffolds

Diterpene and flavonoid constituents of the newly identified Australian species Olearia fulgens

The phytochemistry and antimicrobial activity of the newly identified Australian plant Olearia fulgens A.R.Bean was examined. Antimicrobial TLC bioautography-guided isolation followed by NMR spectroscopy was used to identify the known compounds 8-O-β-D-xylopyranosyl-ent-8β-hydroxylabdan-15-oic acid (1) and pinocembrin (7), and new compounds 8-O-β-D-xylopyranosyl-ent-labdan-8β,15-diol (2) and ent-15-hydroxyclerod-3-en-17-oic acid (4a). Compounds without apparent activity in TLC bioautography included the previously undescribed ent-clerod-3-en-15,17-dioic acid (3a) and ent-cleroda-3,13-dien-15,17-dioic acid (5a), as well as known ent-8β-hydroxylabdan-15-oic acid (6) and penduletin (8). This is the first phytochemical and antibacterial study on this species of Olearia, showing it to be an abundant source of ent-labdanes and ent-clerodanes

Synthesis of a Chiral Auxiliary Family from Levoglucosenone and Evaluation in the Diels–Alder Reaction

A new family of chiral auxiliaries has been developed based on the lignocellulosic biomass pyrolysis product levoglucosenone. A promising single stereoisomer with an alcohol and π-stacking phenyl substituents was prepared in excellent yield in two steps from di­hydrolevoglucosenone without chromatography on >50 g scale. Acrylate esters prepared from the auxiliaries underwent diastereoselective Lewis acid promoted Diels–Alder reactions with cyclopentadiene (­endo/exo 98:2, endo d.r. up to 98:2), dimethylbutadiene (d.r. 93:7), and isoprene (d.r. > 98:2

Sulfuric acid-catalyzed pyrolysis of iota-carrageenan in polyethylene glycol

The use of seaweed polysaccharides for fine chemical synthesis is a promising approach to replace fossil fuelbased feedstocks. In this work, acid-catalyzed pyrolysis of the polysaccharide iota-carrageenan from red seaweed has been studied using differential scanning calorimetry (DSC). DSC shows that sulfuric acid in a polyethylene glycol (PEG) solvent lowers the temperature of the exothermic decomposition peak by ca. 63 ◦C when compared with the pyrolysis of pure polysaccharide. Evolved products from the pyrolysis in a purpose-built glass tube vacuum reactor were analyzed using gas chromatography/mass spectrometry, and showed that levoglucosenone (LGO) and furfural were dominant. Yield of LGO was 12 mg/gIC or 9.0 mol% and of furfural was 2.8 mg/gIC or 2.8 mol% when 2% w/w H2SO4 was used as catalyst

Practical and scalable enantioselective synthesis of (+)-majoranolide from Cyrene

A two-step enantioselective gram scale synthesis of the Persea derived γ-lactones (+)-majoranolide and (+)-majoranolide B has been achieved. The sequence uses the amine promoted crossed condensation of the biorenewable synthon Cyrene with aliphatic aldehydes followed by a Baeyer–Villiger oxidation. Comparison of optical rotation data with the natural products established the absolute configuration of the natural product series, and this work represents the first synthesis of these alkylidene natural products