Skeletal rearrangement of 6,8-dioxabicyclo[3.2.1]octan-4-ols promoted by thionyl chloride or Appel conditions.

A skeletal rearrangement of a series of 6,8-dioxabicyclo[3.2.1]octan-4-ols has been developed using SOCl2 in the presence of pyridine. An oxygen migration from C5 to C4 was observed when the C4 alcohols were treated with SOCl2/pyridine, giving a 2-chloro-3,8-dioxabicyclo[3.2.1]octane ring-system via the chlorosulfite intermediate. Analogous allylic alcohols with endocyclic and exocyclic unsaturations underwent chlorination without rearrangement due to formation of allylic cations. The rearrangement was also demonstrated using Appel conditions, which gave similar results via the alkoxytriphenylphosphonium intermediate. Several reactions of the products were investigated to show the utility of the rearrangement.

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.

Intermolecular Enamine Mizoroki-Heck Reactions on a Bio-Derived Scaffold.

The intramolecular enamine-Mizoroki-Heck reaction allows for the construction of nitrogen-containing heterocycles, although the related intermolecular version is less known. The reactions of enamines derived from Cyrene were investigated under Mizoroki-Heck conditions. An optimization study was used to identify that 1.5 mol % Pd(dba)2 with PCy3 in xylene at reflux temperature gave the highest yield with electron-rich aryl iodides. Arylation occurred predominantly at the C-N center of the enamine, while the diastereoselectivity was dependent on the nitrogen substitution in the enamine.

Desymmetrization and Kinetic Resolution of Endoperoxides Using a Bifunctional Organocatalyst.

Bifunctional thiourea/amine organocatalysts have been used for the desymmetrization of meso-endoperoxides using the Kornblum-DeLaMare reaction, giving 4-hydroxyketones in 78-98% yields with ≤98:2 enantioselectivity. The influence of the catalyst structure, solvent, and temperature was examined. The most promising catalyst was applied to the kinetic resolution of racemic endoperoxides to give enantioenriched materials (≤99:1 er).

Intramolecular Proton-Coupled Hydride Transfers with Relatively Low Activation Barriers.

We report that bifunctional molecules containing hydroxyl and carbonyl functional groups can undergo an effective transfer hydrogenation via an intramolecular proton-coupled hydride transfer (PCHT) mechanism. In this reaction mechanism, a hydride transfer between two carbon atoms is coupled with a proton transfer between two oxygen atoms via a cyclic bond rearrangement transition structure. The coupled transfer of the two hydrogens as Hδ+ and Hδ- is supported by atomic polar tensor charges. The activation energy for the PCHT reaction is strongly dependent on the length of the alkyl chain between the hydroxyl and carbonyl functional groups but relatively weakly dependent on the functional groups attached to the hydroxyl and carbonyl carbons. We investigate the PCHT reaction mechanism using the Gaussian-4 thermochemical protocol and obtain high activation energy barriers (ΔH‡298) of 210.5-228.3 kJ mol-1 for chain lengths of one carbon atom and 160.2-163.9 kJ mol-1 for chain lengths of two carbon atoms. However, for longer chain lengths containing 3-4 carbon atoms, we obtain ΔH‡298 values as low as 101.9 kJ mol-1. Importantly, the hydride transfer between two carbon atoms proceeds without the need for a catalyst or hydride transfer activating agent. These results indicate that the intramolecular PCHT reaction provides an effective avenue for uncatalyzed, metal-free hydride transfers at ambient temperatures.

Oxa-Michael-initiated cascade reactions of levoglucosenone.

The reactions of aromatic aldehydes and levoglucosenone promoted by methoxide gives bridged α,ß-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.

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.

The Diversity of Volatile Compounds in Australia's Semi-Desert Genus Eremophila (Scrophulariaceae).

Australia's endemic desert shrubs are commonly aromatic, with chemically diverse terpenes and phenylpropanoids in their headspace profiles. Species from the genus Eremophila (Scrophulariaceae ex. Myoporaceae) are the most common, with 215 recognised taxa and many more that have not yet been described, widely spread across the arid parts of the Australian continent. Over the years, our research team has collected multiple specimens as part of a survey to investigate the chemical diversity of the genus and create leads for further scientific enquiry. In the current study, the diversity of volatile compounds is studied using hydrodistilled essential oils and leaf solvent extracts from 30 taxa. Several rare terpenes and iridoids were detected in chemical profiles widely across the genus, and three previously undescribed sesquiterpenes were isolated and are assigned by 2D NMR-E-11(12)-dehydroisodendrolasin, Z-11-hydroxyisodendrolasin and 10-hydroxydihydro-α-humulene acetate. Multiple sampling from Eremophila longifolia, Eremophila arbuscular, Eremophila latrobei, Eremophila deserti, Eremophila sturtii, Eremophila oppositifolia and Eremophila alternifolia coneys that species in Eremophila are highly chemovariable. However, taxa are generally grouped according to the expression of (1) furanosesquiterpenes, (2) iridoids or oxides, (3) mixtures of 1 and 2, (4) phenylpropanoids, (5) non-furanoid terpenes, (6) mixtures of 4 and 5, and less commonly (7) mixtures of 1 and 5. Furthermore, GC-MS analysis of solvent-extracted leaves taken from cultivated specimens conveys that many heavier 'volatiles' with lower vapour pressure are not detected in hydrodistilled essential oils and have therefore been neglected in past chemical studies. Hence, our data reiterate that chemical studies of the genus Eremophila will continue to describe new metabolites and that taxon determination has limited predictive value for the chemical composition.

Prostanthera (Lamiaceae) as a 'Cradle of Incense': Chemophenetics of Rare Essential Oils from Both New and Forgotten Australian 'Mint Bush' Species.

The highly aromatic Australian mint bushes from the genus Prostanthera Labill. produce a high yield of essential oil on hydrodistillation. Together with its rich history, horticultural potential, iconic flowers, and aromatic leaves, it achieves high ornamental and culinary value. Species in the genus express highly diverse and chemically unique essential oils that demonstrate intra- and inter-specific patterns that have inspired taxonomic reinterpretation for over a hundred years. Previous studies have conveyed that phenoplastic expression of volatiles creates chemotypes within taxa, adding complexity to chemophenetic exploration. The current study chemically characterised essential oils from 64 highly aromatic specimens, representative of 25 taxa, giving yields as high as >2% g/g. The chemical profiles of essential oils are diverse, but generally include 1,8-cineole and signatory compounds such as sesquiterpene oxides, caryophyllene oxide, kessane and cis-dihydroagarofuran; sesquiterpene alcohols, globulol, epiglobulol, maaliol, prostantherol, spathulenol and ledol; and monoterpene derivatives of common scaffolds, borneol, bornyl acetate, bornanone, linalool and linalyl acetate. As in previous studies, analysis of chemical data confirms that the chemistry strongly agrees with taxonomic classifications. Importantly, as in classical taxonomy, the current chemical study complemented morphological analysis but conveys chemovariation, obscuring the taxonomic agreement. Nevertheless, variation within taxa may be due to environmental factors, meaning that cultivation of species in gardens will create different chemical profiles as compared to those published here.

New Labdanes with Antimicrobial and Acaricidal Activity: Terpenes of Callitris and Widdringtonia (Cupressaceae).

In spite of the evidence for antimicrobial and acaricidal effects in ethnobotanical reports of Callitris and Widdringtonia, the diterpene acids from Widdringtonia have never been described and no comparison to the Australian clade sister genus Callitris has been made. The critically endangered South African Clanwilliam cedar, Widdringtonia wallichii (syn. W. cedarbergensis), of the Cederberg Mountains was once prized for its enduring fragrant timbers and an essential oil that gives an aroma comparable to better known Mediterranean cedars, predominantly comprised by widdrol, cedrol, and thujopsene. In South Africa, two other 'cedars' are known, which are called W. nodiflora and W. schwarzii, but, until now, their chemical similarity to W. wallichii has not been investigated. Much like Widdringtonia, Callitris was once prized for its termite resistant timbers and an 'earthy' essential oil, but predominantly guaiol. The current study demonstrates that the essential oils were similar across all three species of Widdringtonia and two known non-volatile diterpene acids were identified in leaves: the pimaradiene sandaracopimaric acid (1) and the labdane Z-communic acid (2) with a lower yield of the E-isomer (3). Additionally, in the leaves of the three species, the structures of five new antimicrobial labdanes were assigned: 12-hydroxy-8R,17-epoxy-isocommunic acid (4), 8S-formyl-isocommunic acid (5), 8R,17-epoxy-isocommunic acid (6), 8R-17R-epoxy-E-communic acid (7), and 8R-17-epoxy-E-communic acid (8). Australian Callitris columellaris (syn. C. glaucophylla) also produced 1 and its isomer isopimaric acid, pisiferal (9), and pisiferic acid (10) from its leaves. Callitris endlicheri (Parl.) F.M.Bailey yielded isoozic acid (11) as the only major diterpene. Diterpenes 4-6, pisiferic acid (10), spathulenol, and guaiol (12) demonstrated antimicrobial and acaricidal activity.

Biomimetic Synthesis of Mitchellenes B-H from the Abundant Biological Precursor 14-Hydroxy-6,12-muuroloadien-15-oic Acid.

A step-economic biomimetic synthesis of mitchellenes B-H found in Eremophila sturtii has been achieved. Starting from the putative muurolane biological precursor, redox isomerization of the allylic alcohol gave an epimeric mixture of aldehydes, which could be used as a handle for cyclization onto the C6 position, using Bu3SnH-mediated radical cyclization or NHC-catalyzed Stetter reaction. The NHC-mediated approach was superior as the epimeric mixture underwent a dynamic kinetic resolution during the reaction, and reduction of the mixture with NaBH4 selectively formed the mitchellene ring system in 56% yield for the three steps. In the campaign to obtain the acid-starting material, two new natural products, mitchellene H and a muurolane aldehyde, were isolated. Synthetic procedures to access this family of natural products will enable further studies on their biological properties.

Revision of the Phytochemistry of Eremophila sturtii and E. mitchellii.

Eremophila sturtii and E. mitchellii are found in the arid and temperate regions of Australia and, because of their similar appearances, are often confused. Previous phytochemical investigations have described mitchellene sesquiterpenes (1-5) reported from E. mitchellii but are here demonstrated to be from E. sturtii. A previous study that described serrulatic acids (16 and 17) from a species reported as E. sturtii actually used E. mitchellii. In addition, two new C-15 modified analogues, mitchellenes F (14) and G (15), were isolated from E. sturtii. The absolute configuration of 14 was determined with the first X-ray structure of a compound with the mitchellene skeleton.

Serrulatic acid diastereomers identified from an antibacterial survey of Eremophila.

In an age of growing antimicrobial resistance, new antibacterial agents are desperately needed. A rapid antibacterial and phytochemical survey was designed to screen for antibacterial leads in plants. The survey was applied to over 90 Australian native plants from the genus Eremophila, revealing Eremophila complanata and E. nivea×E. drummondii as active against Gram positive bacteria. Thin layer chromatography with bioautography, flash chromatography and nuclear magnetic resonance led to the isolation and identification of two diastereomeric serrulatic acids. A single stereoisomer of 7,8,16-trihydroxyserrulat-19-oic acid has been previously described as its methyl ester. This paper describes the NMR of both serrulatic acids epimeric at C15 and their methyl esters, and demonstrates their Gram positive antibacterial activity. It is the first time that stereoisomers of this serrulatic acid have been found together in some Eremophila species. Further characterization of E. complanata additionally found an abundance of α-selinene and ß-selinene. The study validates a rapid survey approach to finding antibacterial phytochemicals.

Support for a Dioxyallyl Cation in the Mechanism Leading to (-)-Levoglucosenone.

Levoglucosenone (LGO) is the major product formed when cellulose is pyrolyzed in the presence of acid at temperatures between 170 and 350 °C. The current intense interest in biomass conversion has led to a number of reports on its preparation; however, there is still uncertainty on the mechanism leading to LGO. We propose a new mechanism which involves a C2-C1 hydride shift followed by intramolecular trapping of a dioxyallyl cation. The reaction has been modeled using DFT calculations from the known LGO precursors levoglucosan and 1,4:3,6-dianhydro-α-D-glucopyranose to a common intermediate with calculated barriers of 10.6 and 13.5 kcal·mol-1, respectively. A discussion of the literature on the formation of LGO from late pathway intermediates is also provided.

Chemo-Enzymatic Synthesis of Chiral Epoxides Ethyl and Methyl (S)-3-(Oxiran-2-yl)propanoates from Renewable Levoglucosenone: An Access to Enantiopure (S)-Dairy Lactone.

Chiral epoxides-such as ethyl and methyl (S)-3-(oxiran-2-yl)propanoates ((S)-1a/1b)-are valuable precursors in many chemical syntheses. Until recently, these compounds were synthesized from glutamic acid in four steps (deamination, reduction, tosylation and epoxide formation) in low to moderate overall yield (20%-50%). Moreover, this procedure requires some harmful reagents such as sodium nitrite ((eco)toxic) and borane (carcinogen). Herein, starting from levoglucosenone (LGO), a biobased chiral compound obtained through the flash pyrolysis of acidified cellulose, we propose a safer and more sustainable chemo-enzymatic synthetic pathway involving lipase-mediated Baeyer-Villiger oxidation, palladium-catalyzed hydrogenation, tosylation and treatment with sodium ethoxide/methoxide as key steps. This route afforded ethyl and methyl (S)-3-(oxiran-2-yl)propanoates in 57% overall yield, respectively. To demonstrate the potentiality of this new synthetic pathway from LGO, the synthesis of high value-added (S)-dairy lactone was undertaken from these epoxides and provided the target in 37% overall yield from LGO.

Synthesis of enantiopure cyclopropyl esters from (-)-levoglucosenone.

The biorenewable chiral synthon (-)-levoglucosenone has been converted to enantiopure cyclopropyl esters using the base-promoted carbocyclisation of 4,5-epoxyvalerates. This protocol was applied to the enantiospecific synthesis of the GABAc receptor agonist (1R,2R)-trans-2-aminomethylcyclopropanecarboxylic acid ((-)-TAMP) and its enantiomer. The process was also extended to generate 1,1,2- and 1,2,3-trisubstituted cyclopropanes resulting in a formal synthesis of the selective glutamate receptor antagonist PCCG-4.

Keeping it simple: lessons from the golden era of antibiotic discovery.

Bacteria are becoming increasingly resistant to currently used antibiotics. At the same time, little progress has been made in discovering new antibacterial drugs to combat resistant organisms. History teaches us that 'high tech' target-based complex methods are not synonymous with success and a return to simple, systematic screening of natural products against bacteria from traditional and novel resources holds our greatest hope of success.

The Iridoid Myodesert-1-ene and Elemol/Eudesmol are found in Distinct Chemotypes of the Australian Aboriginal Medicinal Plant Eremophila dalyana (Scrophulariaceae).

The strongly aromatic Australian desert species Eremophila dalyana is an Aboriginal medicinal plant that continues to be used today in Central Australia in the treatment of respiratory complaints and Sarcoptes scabiei infestation. Using hydrodistillation of aerial parts of the plant, the new natural product myodesert-l- ene was isolated in two disjunct populations at up to 98% of the volatiles present in the hydrodistilled oils. Weak antimicrobial activities were observed for whole oils and myodesert-l-ene. Activities in the hydrodistilled oil were attributed to the antimicrobial sesquiterpenes elemol and eudesmol which showed good activity when isolated and were relatively abundant in the chemotype used medicinally. The biogenesis of myodesert-l-ene from iridodial is proposed.

Synthesis, Formulation, and Adjuvanticity of Monodesmosidic Saponins with Olenanolic Acid, Hederagenin and Gypsogenin Aglycones, and some C-28 Ester Derivatives.

In an attempt to discover a new synthetic vaccine adjuvant, the glycosylation of hederagenin, gypsogenin, and oleanolic acid acceptors with di- and trisaccharide donors to generate a range of mimics of natural product QS-21 was carried out. The saponins were formulated with phosphatidylcholine and cholesterol, and the structures analyzed by transmission electron microscopy. 3-O-(Manp(1→3)Glcp)hederagenin was found to produce numerous ring-like micelles when formulated, while C-28 choline ester derivatives preferred self-assembly and did not interact with the liposomes. When alone and in the presence of cholesterol and phospholipid, the choline ester derivatives produced nanocrystalline rods or helical micelles. The effects of modifying sugar stereochemistry and the aglycone on the immunostimulatory effects of the saponins was then evaluated using the activation markers MHC class II and CD86 in murine bone marrow dendritic cells. The most active saponin, 3-O-(Manp(1→3)Glcp)hederagenin, was stimulatory at high concentrations in cell culture, but this did not translate to strong responses in vivo.

Synthesis of allo- and epi-inositol via the NHC-catalyzed carbocyclization of carbohydrate-derived dialdehydes.

A synthesis of carbocyclic sugars from carbohydrate-derived dialdehydes using organocatalysis has been developed. Sorbitol, mannitol, and galactitol were converted via 1,6-tritylation, perbenzylation or permethylation, detritylation, and Swern oxidation into 2,3,4,5-tetra-O-alkyl-dialdoses that were cyclized via the benzoin reaction promoted by a triazolium carbene. Manno- and galacto-configured dialdehydes gave predominantly single inosose stereoisomers in up to 75% yield if the mixture was acetylated prior to isolation while the gluco-dialdehyde afforded a mixture of three stereoisomers in 61% overall yield. The inososes were stereospecifically reduced using sodium borohydride and then deprotected to give allo- and epi-inositol in good yield that confirmed the structural and stereochemical assignments.