The goal of this PhD research was directed to the isolation and structural elucidation of the secondary metabolites from four species of Durio plants, especially from those growing in the island of Borneo; This island contains most Durio species. The structures of isolated compounds were deduced using state-of-the-art approaches, including 1D and 2D nuclear magnetic resonance (NMR), mass spectrometric (MS) and circular dichroism (CD) analyses. From the bark of the woody species Durio zibethinus Murr. (Bombacaceae), that was collected in Pontianak, a chemically diverse group of oxygenated compounds was obtained. These included caffeoyl triterpenes, lignans and phenylpropanoid derivatives. During this research, one new compound 27-O-cis-caffeoylcylicodiscate was obtained which resulted from a trans to cis isomerization; this process might be caused by acid and light. Two presumed fungal metabolites were also isolated during this study, these possibly arising from fungal (unknown species) contamination of the bark. The relative stereochemistry of 4-hydroxymellein were also established by conversion to it diacetate and measurement of the coupling constant between H-3 and H-4. The absolute configuration was determined by comparison of []D values with those from the literature. Assignment of the 13C NMR spectrum for (+)-(R)-de-O-methyllasiodiplodin was completed using HSQC-TOCSY data. The methanol extract of the bark of Durio kutejensis (Hassk.) Becc. was fractionated and purified by C18-HPLC. Two new caffeoyl pentacyclic triterpenes 3-O-trans-caffeoyl-2-hydroxyolean-12-en-28-oic acid and 3-O-trans-caffeoyl-2-hydroxyurs-12-en-28-oic acid, together with five known compounds were isolated. The known compound fraxidin had previously been obtained from D. zibethinus Murr. The bark of Durio carinatus Mast., a plant species which has non edible fruit was collected in Sambas district, West Kalimantan. Three new lignans, boehmenan X, (-)-(7S,8S)-threo-carolignan X and (-)-(7R,8S)-erythro-carolignan X, and a new caffeoyl triterpene 3-O-cis-caffeoyl betulinic acid, together with three known lignans and one known caffeoyl triterpene, were obtained from the crude MeOH extract. The relative configurations and conformational models of the diastereomers threo- and erythro-carolignan X were determined by the coupling constant data for H-7′ and H-8′ and supported by 2D NMR spectroscopic analysis including NOESY and HSQC-HECADE in CDCl3. However, the magnitude of the coupling constants for both compounds in MeOH-d4 was similar. The stability of the individual conformers was solvent dependent and must be considered for their contribution to the overall conformational equilibria. This stability was determined by steric interactions, dipole repulsion effects and intramolecular hydrogen bonding. The absolute configuration of the two new diastereomers was established by application of circular dichroism (CD) and optical rotation []D measurements. Another Durio plant studied and collected in Bengkayang region, West Kalimantan, was Durio oxleyanus Griff. From the MeOH extract of its bark, two new lignans, (-)-(7S,8S)-threo-carolignan Y and (-)-(7R,8S)-erythro-carolignan Y were isolated using C18-HPLC. The relative stereochemistry of the carolignan Y diastereomers could not be deduced from the coupling constants for H-7′ and H-8′ either in CDCl3 and MeOH-d4, because of the presence of multiple conformers. The conformational model for the diastereomers of carolignan Y was similar to that of threo- and erythro-carolignan X in MeOH-d4. Using 2D NMR spectroscopic methods, including NOESY and HSQC-HECADE, the relative stereochemistry of the threo and erythro isomers of carolignan Y was confirmed. Further, the absolute configuration of threo- and erythro-carolignan Y was explored via analysis of CD spectra and by comparison of experimentally obtained []D values with literature values.

Indiana University-Purdue University Indianapolis (IUPUI) / A version of this thesis was published as: Masters AR, McCoy M, Jones DR, and Desta Z. Stereoselective method to quantify bupropion and its three major metabolites, hydroxybupropion, erythro-dihydrobupropion, and threo-dihydrobupropion using HPLC-MS/MS. J Chromatography B Analyt Technol Biomed Life Sci 1015-1016:201-208, 2016. / Bupropion is a dual dopamine-norepinephrine uptake inhibitor and a nicotine receptor antagonist. Clinically, bupropion is given as a racemate for the management of depression, smoking cessation aid, and for the management of weight. Bupropion has also been targeted as a phenotypic probe of CYP2B6 activity. Bupropion metabolites are formed via oxidation (4-hydroxybupropion) through CYP2B6, and reduction (erythro- and threo-dihydrobupropion) through carbonyl reductases. These metabolites exhibit pharmacological activity, but little is known regarding their stereoselective disposition due to the lack of a chiral assay. A novel reversed phase chiral-HPLC-MS/MS method involving a simple liquid-liquid extraction procedure and a small plasma sample volume (50µL) was developed that allowed simultaneous separation and quantification of enantiomers of bupropion, 4-hydroxybupropion, and those of threo- and erythro-dihydrobupropion in human plasma. This method was successfully implemented to determine the unique stereoselective disposition of bupropion and its metabolites in 15 human volunteers administered a single 100 mg oral dose of racemic bupropion. Significant differences (p<0.05) in the stereoselective metabolism were observed for all of the enantiomers. The highest plasma exposure (AUC0-∞) was (2R, 3R)-4-hydoxybupropion, almost 65 fold higher, than (2S, 3S)-4-hydoxybupropion, and over 32 fold greater than the parent R-bupropion. The second highest plasma exposure was threo-dihydrobupropion A, which was almost 5 fold higher than threo-dihydrobupropion B. (Nomenclature of the enantiomers for erythro- and threo-dihydrobupropion was based on the chromatography of the first eluting peak as “A” and the second eluting peak as “B”.) Threo-dihydrobupropion A and B showed the most significant difference between the racemic and enantiomer profiles. Although the AUC was greater for threo-dihydrobupropion B, threo-dihydrobupropion A had a significantly (p<0.05) higher Cmax. The half-life for threo-dihydrobupropion A and erythro-dihydrobupropion A were the longest for all analytes, which could indicate accumulation in multiple dosing. The importance of this study was, for the first time, to be able to characterize the stereoselective metabolism of bupropion and its three major metabolites. This new method and subsequent pharmacokinetic data should enhance further research into bupropion stereoselective metabolism, drug interactions, and effect. / A version of this thesis was published as: Masters AR, McCoy M, Jones DR, and Desta Z. Stereoselective method to quantify bupropion and its three major metabolites, hydroxybupropion, erythro-dihydrobupropion, and threo-dihydrobupropion using HPLC-MS/MS. J Chromatography B Analyt Technol Biomed Life Sci 1015-1016:201-208, 2016.

α-Epimerisation has been found to be absent in the reactions of threo-1,2-diphenyl-1-propyltrimethylammonium ion and its -2-d₁ analogue with t-butoxide ion in t-butyl alcohol at 30ºC. The formation of trans-α-methylstilbene, cis-α-methylstilbene and threo-N,N-dimthyl-1,2-diphenyl-1-propylamine has been associated with anti-elimination, syn-elimination and with nucleophilic substitution at a N-methyl carbon atom, respectively, and interpreted in terms of structural and medium features of the reactions. The β-hydrogen isotope effects for anti- and syn-elimination have been associated with reactant-like and product-like transition states, respectively, for these reaction modes. / Thesis / Master of Science (MSc)

The thesis entitled “Chemistry of Tetrathiomolybdate: Applications in Organic Synthesis” is divided in to six chapters Chapter 1: Synthesis of -amino disulfides, cystines and their direct incorporation into peptides mediated by tetrathiomolybdate In this chapter, we report a simple method for direct access to β-amino disulfides by regioselective ring opening of sulfamidates with benzyltriethylammonium tetrathiomolybdate [BnEt3N]2MoS4. The versatility of this reaction has been shown by preparing a number of β-amino disulfides having different N-protecting groups and the stability of these protecting groups under the reaction conditions has been evaluated. This methodology is also extended to the synthesis and direct incorporation cystine and 3, 3′-dimethyl cystine derivatives into peptides. Chapter 2: Unusual reactivity of tetrathiomolybdate: A new entry to the synthesis of b-aminothiols In this chapter, we disclose a simple and highly efficient method for the synthesis of β and γ-amino thiols via regioselective ring opening of sulfamidates with tetrathiomolybdate 1. The scope and generality of this methodology has been exemplified by synthesizing a carbohydrate derived β-aminothiol. This methodology has also been extended to the synthesis of isocysteine derivatives in optically pure form. Chapter 3: Part 1: Synthesis of β-aminodiselenides via sequential one-pot, multistep reactions mediated by tetrathiomolybdate In this chapter, we have demonstrated that a variety of N-alkyl-β-aminodiselenides can be synthesized in high yield from appropriate sulfamidates under mild reaction conditions using potassium selenocyanate and tetrathiomolybdate [BnEt3N]2MoS4 via a sequential one-pot multistep process. The compatibility of different protecting groups under the reaction conditions has been discussed. Chapter: 3 Part 2: Synthesis of unnatural seleno amino acids and their direct incorporation into peptides In this chapter, we have demonstrated the first and general method for the synthesis of selenocystine, 3, 3'-dialkylselenocystine, isoselenocystine and their direct incorporation into peptides using a one-pot multistep reaction strategy mediated by tetrathiomolybdate. Chapter 4: Synthesis and functionalization of cysteine, selenocysteine and their derivatives via the formation of unsymmetrical disulfide and sulfur-selenium bond. In this chapter, we present a novel one-pot multi component strategy for the synthesis and functionalization of cysteine, selenocysteine and their derivatives via unsymmetrical disulfides and sulfur-selenium bond formation. Chapter 5: Part 1: A novel method for the synthesis of thioacetates employing benzyltriethylammonium tetrathiomolybdate and acetic anhydride In this chapter, we report a simple and efficient methodology for the synthesis of thioacetates using benzyltriethylammonium tetrathiomolybdate [BnEt3N]2MoS4 and acetic anhydride as the key reagents, starting from alkyl halides in a multi step, tandem reaction process. The application of this methodology for the synthesis of orthogonally protected cysteine derivatives and anomeric β-thioglycosides has also been demonstrated. Chapter 5: Part 2: One-pot synthesis of β-aminothioacetates using benzyltriethyl-ammonium tetrathiomolybdate and acetic anhydride. In this chapter, we have demonstrated a simple and efficient method for the synthesis of β-amino thioacetates and pseudo thioinositol derivatives, via ring opening of aziridines and aziridino epoxides using tetrathiomolybdate 1 and acetic anhydride as key reagents. Chapter 6: Simple and efficient synthesis of allo and threo-3, 3'-dimethylcystine derivatives in optically pure form In this chapter, we have presented a simple and efficient methodology for the synthesis of allo-3,3'-dimethylcystine and threo-3,3'-dimethylcystine derivatives in optically pure form using L-threonine as the chiral pool and benzyltriethylammonium tetrathiomolybdate 1 as the key reagent. (For structural formula pl see the pdf file)