DEVELOPMENT OF NEW METHODS FOR THE SYNTHESIS OF DIHYDROPYRANS AND TETRAHYDROPYRANS

This thesis detail attempts to develop a procedure, based on the Maitland-Japp reaction, for the formation of functionalised tetrahydropyran (THP) rings. Previous work in the Clarke group has focused on the development of the Maitland-Japp reaction, but it produced mixtures of diastereomeric THPs. The work described in this thesis details the stereocontrolled synthesis of functionalised 2,6-cis- and 2,6-trans-THP rings from dihydropyran (DHP) rings, as well as the synthesis of 3,3,6-trisubstituted THP rings. The formation of 2,6-cis THP rings was achieved by the addition of hydride nucleophiles to C2-substituted DHPs, and trapping with carbon electrophiles. Treatment of 2H-DHPs with carbon nucleophiles led to the formation of 2, 6-trans THP rings. Reduction of 2H-DHPs with L-Selectride® produce the 3,6-disubstituted THP rings, while trapping of the intermediate enolate with carbon electrophiles give formation of 3,3,6-trisubstituted THP rings. The development of a successful method for the synthesis of functionalised THP rings led to a synthesis of the A-ring of Lasonolide A and Diospongin B

A Maitland–Japp inspired synthesis of dihydropyran-4-ones and their stereoselective conversion to functionalised tetrahydropyran-4-ones

The Maitland–Japp reaction has been extended to the synthesis of highly functionalised dihydropyran-4-ones. These dihydropyran-4-ones can in turn be converted stereoselectively into tetrahydropyran-4-ones with tertiary and quaternary stereocentres via the one-pot addition of hydride or carbon nucleophiles and trapping with carbon electrophiles. The utility of this method is demonstrated by providing access to the functionalised tetrahydropyran units present in a component of the Civet fragrance and the anticancer polyketide lasonolide A

Synthesis of 2,6-trans- and 3,3,6-Trisubstituted Tetrahydropyran-4-ones from Maitland-Japp Derived 2H-Dihydropyran-4-ones: A Total Synthesis of Diospongin B

6-Substituted-2H-dihydropyran-4-one products of the Maitland-Japp reaction have been converted into tetrahydropyrans containing uncommon substitution patterns. Treatment of 6-substituted-2H-dihydropyran-4-ones with carbon nucleophiles led to the formation of tetrahydropyran rings with the 2,6-trans-stereochemical arrangement. Reaction of the same 6-substituted-2H-dihydropyran-4-ones with l-Selectride led to the formation of 3,6-disubstituted tetrahydropyran rings, while trapping of the intermediate enolate with carbon electrophiles in turn led to the formation 3,3,6-trisubstituted tetrahydropyran rings. The relative stereochemical configuration of the new substituents was controlled by the stereoelectronic preference for pseudo-axial addition of the nucleophile and trapping of the enolate from the opposite face. Application of these methods led to a synthesis of the potent anti-osteoporotic diarylheptanoid natural product diospongin B

Chemical constituents and biological activities of calophyllum nodusum vesque and calophyllum gracilipes merr

The family Guttiferae includes some of the well known and important trees in Malaysia. The Calophyllum belongs to the family Guttiferae is the largest genus and locally known as ‘bitangor’. In this investigation the dried stem bark of Calophyllum nodusum and dried stem bark together with dry leaf Calophyllum gracilipes were phytochemically studied and screened for their biological activities. The stem bark of Calophyllum nodusum, stem bark and dried leaf of Calophyllum gracilipes were collected form Sabah, East Malaysia and identified by the Department of Forestry in Sandakan. The extracts were separated by various chromatographic techniques including column chromatography, chromatotron and preparative thin layer chromatography. The compounds were analysed by using MS, NMR, IR and UV techniques. Based on interpretation of these spectral data and comparison with literature reports, the structures of the new and known compounds were established. The crude extracts and pure isolated compounds from all plants were screened for free radical scavenging activity by using 1, 2-Diphenyl-2-picrylhydrayl (DPPH) assay, cytotoxic activity by tetrazolium salt (MTT) assay and antibacterial activity using disc diffusion assay. Seven compounds were isolated from the Calophyllum nodusum. From the hexane extract four known triterpenes were isolated and identified as friedelin (95), lupeol (96), stigmasterol (99) and betulinic acid (100). A new xanthone was isolated from the chloroform extract and identified as nodusuxanthone (110). Another new xanthone, trapezifolixanthone A (112) was also obtained from the methanol extract together with a known compound 4, 5-dihydroxy-2,3-dimethoxyxanthone (111). Chromatogarphic separation of the extracts of stem bark and dried leaf of Calophyllum gracilipes afforded three compounds. From the hexane stem bark and dried leaf extract, similar compounds as in the hexane extract of Calophyllum nodusum were isolated. From the chloroform stem bark extract, two known compounds were isolated and identified as zeyloxanthanone (93) and trapezifolixanthone (79). Similar chromatographic separation procedure for the methanol extract of dried leaf led to a new xanthone, gracixanthone (113). The free radical scavenging activity of the plant extracts and pure isolated compounds were carried out using 1, 2-diphenyl-2-picrylhydrayl (DPPH). However, none of the crude extracts of both plant species gave positive test results while theM methanol extracts of Calophyllum nodusum showed moderate activity (IC50 < 182.86 μg/mL). Similarly, all the compounds also displayed negative scavenging activity on DPPH assay. One of the isolated compounds, zeyloxanthanone (93) exhibited excellent cytotoxic activity against four cell lines, human prostate (PC-3), colon (HCT-116), breast (MCF-7) and mouse Macrophages (RAW 264.7) cells with IC50 values ranging from 3.6-4.5 μM. The results for the antimicrobial tests using disc diffusion assay indicated that the methanol extract of Calophyllum nodusum showed 3 mm inhbition zone against Salmonella typhimurium bacteria and the chloroform extract of Calophyllum gracilipes showed 2 mm and 2 mm inihibition zone towards Salmonella typhimurium and Escherichia coli bacteria respectively. The disc diffusion assay was further tested on isolated compounds. Trapezifolixanthone A (112) showed moderate inhibition activity towards Staphylococcus bacteria with 4 mm inhibition zone and moderate activity against Salmonella typhimurium with 5 mm. Both trapezifolixanthone (79) and zeyloxanthonone (93) exhibited medium inhibition activity against some of the microbes tested

Xanthones from calophyllum gracilipes and their cytotoxic activity

Extraction and chromatographic isolation of the hexane, chloroform and methanol extracts of stem bark of Calophyllum gracilipes has led to the isolation of a new xanthone, gracixanthone (1) and the known zeyloxanthanone (2) and trapezifolixanthone (3) together with three common sterols, namely stigmasterol, friedelin and lupeol. The structures of the compounds were elucidated and established by spectroscopic analysis and compared with the spectral data from literature. The cytotoxicity of the compounds was evaluated and zeyloxanthanone (2) exhibited strong activity towards five cell lines with IC50 values ranging at 8.00-26.00 μΜ

A review on biological properties and synthetic methodologies of Diarylpentadienones

Medicinal chemists have continuously shown interest in new curcuminoid derivatives, diarylpentadienones, owing to their enhanced stability feature and easy preparation using a one-pot synthesis. Thus far, methods such as Claisen-Schmidt condensation and Julia- Kocienski olefination have been utilised for the synthesis of these compounds. Diarylpentadienones possess a high potential as a chemical source for designing and developing new and effective drugs for the treatment of diseases, including inflammation, cancer, and malaria. In brief, this review article focuses on the broad pharmacological applications and the summary of the structure-activity relationship of molecules, which can be employed to further explore the structure of diarylpentadienone. The current methodological developments towards the synthesis of diarylpentadienones are also discussed

Metabolite Characterization and Correlations with Antioxidant and Wound Healing Properties of Oil Palm (Elaeis guineensis Jacq.) Leaflets via 1H-NMR-Based Metabolomics Approach

Oil palm (Elaeis guineensis Jacq.) leaflets (OPLs) are one of the major agricultural by-products generated from the massive cultivation of Malaysian palm oil. This biomass is also reported to be of potential value based on its health-improving effects. By employing proton nuclear magnetic resonance (1H-NMR) spectroscopy combined with multivariate data analysis (MVDA), the metabolite profile of OPLs was characterized and correlated with their antioxidant and wound healing properties. Principal component analysis (PCA) classified four varieties of extracts, prepared using solvents ranging from polar to medium polarity, into three distinct clusters. Cumulatively, six flavonoids, eight organic acids, four carbohydrates, and an amine were identified from the solvent extracts. The more polar extracts, such as, the ethyl acetate-methanol, absolute methanol, and methanol-water, were richer in phytochemicals. Based on partial least square (PLS) analysis, the constituents in these extracts, such as (+)-catechin, (&minus;)-epicatechin, orientin, isoorientin, vitexin, and isovitexin, were strongly correlated with the measured antioxidant activities, comprising ferric reducing antioxidant power (FRAP), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and nitric oxide (NO) free radical scavenging activities, as well as with cell proliferation and migration activities. This study has provided crucial evidence on the importance of these natural antioxidant compounds on the wound healing properties of OPL

Palladium and copper catalyzed Sonogashira cross coupling has been an excellent methodology for C-C bond formation for 17 years: a review

Sonogashira coupling involves coupling of vinyl/aryl halides with terminal acetylenes catalyzed by transition metals, especially palladium and copper. This is a well known reaction in organic synthesis and plays a role in sp2-sp C-C bond formations. This cross coupling was used in synthesis of natural products, biologically active molecules, heterocycles, dendrimers, conjugated polymers and organic complexes. This review paper focuses on developments in the palladium and copper catalyzed Sonogashira cross coupling achieved in recent years concerning substrates, different catalyst systems and reaction conditions

Combination of Molecular Networking and LC-MS/MS Profiling in Investigating the Interrelationships between the Antioxidant and Antimicrobial Properties of Curculigo latifolia

Curculigo is a potent plant with a variety of traditional uses, such as anti-oxidant, anti-diabetic, anti-tumor, anti-bacterial, anti-cancer, anti-osteoporosis, and wound-healing. The comprehensive profiling of the Curculigolatifolia metabolome was carried out by generating a molecular network (MN) from Liquid Chromatography–Tandem Mass Spectrometry (LC-MS/MS) data to profile the methanol extract and correlating them with their antioxidant (2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH), total phenolic contents (TPC), and β-carotene) and antimicrobial (disk-diffusion agar method, minimum inhibitory concentration (MIC), and minimum bactericidal concentration (MBC)) properties. The antioxidant capacity was observed to be significantly higher in the rhizome crude extract, with 18.10 ± 0.91 µg/mL DPPH activity, and a β-carotene bleaching result of 35.20%. For the antimicrobial activity, the leaf crude extract exhibited a strong Staphylococcus aureus and Salmonella choleraesuis (8–15 ± 3.0 mm) inhibition in the disk-diffusion agar. The leaf extract also exhibited maximum antibacterial activity against S. aureus (MIC = ±0.25 mg/mL, MBC = ±0.25 mg/mL) and S. choleraesuis (MIC = ±0.25 mg/mL, MBC = ±0.25 mg/mL). LC-MS/MS analysis and MN revealed norlignans and phenolic glycosides as major metabolites in the rhizome and leaf extracts of the negative mode (M − H)−. Fourteen known compounds were identified, and three unknown compounds were putatively identified in the rhizome extract, while ten known compounds and six unknown compounds were putatively identified in the leaf extract

Two new xanthones from Calophyllum nodusum (Guttiferae)

The air-dried powdered stem bark of Calophyllum nodusum (Guttiferea) collected from Sandakan (Sabah, Malaysia), was extracted sequentially with hexane, chloroform and methanol. The solvents were removed by rotary evaporator to give dark viscous extracts. Detailed and repeated chromatographic separation of the extracts lead to isolation of two new xanthones, identified as nodusuxanthone (1a) and trapezifolixanthone A (2). Other common terpenoids such as betulinic acid, lupeol, stigmasterol and friedelin were also isolated from the extracts and identified. The structures of the compounds were established by detailed spectral analysis and comparison with previously reported data