The concept of combining two well established areas of organic chemistry, viz., organosilicon chemistry and the use of chiral auxiliaries, into a viable, alternative method of asymmetric synthesis has only very recently begun to receive attention. At the outset of this investigation, no asymmetric reactions of silyl enol ethers, chiral by virtue of optically active substituents on the silicon, had been reported. A range of novel chiral silyl enol ethers have thus been prepared from a variety of ketones, including pinacolone, cyclohexanone, and α-tetralone, and employing menthol, borneol, and cholesterol as chiral auxiliaries. These preparations have been achieved via several distinct routes, including a novel convergent approach involving the isolation of either the chloro(menthyloxy)dimethylsilane or the (bornyloxy)chlorodimethylsilane. The MS and NMR spectra of these silyl enol ethers were examined in detail and, in the case of the crystalline cholesteryloxy silyl enol ether, the X-ray structure has been determined. The potential of chloroalkoxysilanes to act as general, chiral derivatizing agents has been established by the preparation of diastereomeric silyl acetal mixtures of racemic secondary alcohols (e.g. I-phenylethanol and 2-octanol). The experimental diastereomeric ratios, obtained by GLC and ¹H NMR spectroscopy, approached the expected value of unity, confirming the potential of the alkoxychlorosilanes as chiral probes. The chiral silyl enol ethers have been successfully oxidized to the corresponding α-siloxy ketones employing MCPBA, MMPP, and 2-(phenylsulphonyl)-3-phenyloxaziridine as oxidizing agents and the diastereomeric excesses obtained, which varied from 0 to 16%, indicated some potential for stereochemical control. Alkylation and hydroxyalkylation reactions of the silyl enol ethers have yielded the expected α-iert-butyl and β-hydroxy ketones in good to excellent material yields, with the enantiomeric excesses, as determined by chiral shift reagent studies, reaching 14%. To improve the stereo control in these reactions, attempts have been made to prepare chiral silyl enol ethers with auxiliaries possessing the potential for transition state complex co-ordination in the reactions under consideration. The preparation of such silyl enol ethers, incorporating the proline-derived auxiliaries, N-methyl-2-hydroxymethylpyrrolidine and 2-methoxymethylpyrrolidine met with only limited success. In an alternative approach, three derivatives of 2,3-dihydroxybornane have been prepared. However, two of these auxiliaries, viz., 3-exo-benzyloxy-2-exo-hydroxybornane and 3-exo-(1-methoxyethoxy)-2-exo-hydroxybornane failed to form silyl enol ethers, even under considerably more vigorous conditions than normally employed. The third derivative, 3,3-ethylenedioxy-2-hydroxybornane has been successfully utilized in the preparation of a pinacolone-derived chiral silyl enol ether. Hydroxyalkylation of this compound with benzaldehyde has yielded the β-hydroxyketone with significantly improved enantiomeric excess (26%) and a transition state complex has been proposed to rationalize this improvement.

From Summary: The structural elucidation of condensed tannins, which are considered to consist of C₁₅-flavan units, presents certain difficulties. These tannins occur in extremely complex mixtures, and their isolation is complicated by their susceptibility to oxidative denaturation. Limitations in the formation of significant degradation products add to these problems. Since condensed tannins of black wattle bark yield anthocyanidins on treatment with mineral acids, they are considered to be proanthocyanidin in character. For this reason the initial approach to the investigation of the structures of condensed tannins was by way of the synthesis of novel 7-hydroxyflavan-3,4-diols having a low degree of hydroxyl substitution. Submission of these to modern physical techniques such as nuclear magnetic resonance (n.m.r.) spectroscopy would yield valuable data regarding the chemical shifts and coupling constants of heterocyclic and benzenoid protons which may be used for subsequent work on more highly hydroxylated diols, biflavanols and finally the condensed tannins themselves.

Bidentate imidazole-based extractants, 1-octylimidazole-2-aldoxime (OIMOX) and 1-octyl-2-(2′-pyridyl)imidazole (OPIM), along with dinonylnaphthalene sulfonic acid (DNNSA) as a synergist, were investigated as potential selective extractants for Cu²⁺and Ni²⁺ respectively from base metals in a solvent extraction system. The study was extended to evaluate the sorption and separation of Ni²⁺ from other base metals in a solid-solution system using microspherical Merrifield resins and nanofibers functionalized with 2,2′-pyridylimidazole. Copper was effectively separated with OIMOX and DNNSA as extractants from nickel with ΔpH½ ≈1.05 and the extraction order of Cu²⁺ > Ni²⁺ > Zn²⁺ > Cd²⁺> Co²⁺ was achieved as a function of pH. At pH 1.65 the extracted copper, from a synthetic mixture of the base metals reached 90.13(±0.90)%, and through a two-step extraction process 98.22(±0.29)% copper was recovered with negligible nickel and cobalt impurities. Stripping of the copper from the loaded organic phase using TraceSelect sulphuric acid at pH 0.35 yielded 96.60(±0.44)% of the loaded quantity after the second stage of stripping. The separation of Ni²⁺ from the borderline and hard acids; Co²⁺, Cu²⁺, Zn²⁺, Fe2²⁺, Fe²⁺, Mn²⁺, Mg2²⁺ and Ca²⁺ at a pH range of 0.5-3.5 with OPIM and DNNSA was acvieved to the tune of a ΔpH½≈ 1.6 with respect to cobalt from a sulfate and sulfate/chloride media. A three-stage counter-current extraction of Ni²⁺, at the optimized pH of 1.89, from a synthetic mixture of Ni²⁺, Co²⁺ and Cu²⁺, yielded 99.01(±1.79)%. The total co-extracted Cu²⁺ was 48.72(±0.24)% of the original quantity in the mixture, and it was 19.85(±0.28%) for Co²⁺. The co-extracted Cu²⁺ was scrubbed off from the loaded organic phase at pH≈8.5 by using an ammonium buffer, while co-extracted Co²⁺ was selectively and quantitatively stripped with H₂SO₄ at pH 1.64. The total recovery of Ni²⁺ by stripping at pH 0.32 was 94.05(±1.70)%. In the solid-liquid system, Ni²⁺ was separated from Co²⁺, Cu²⁺, and Fe²⁺ with the microspherical resins funtionalised with 2,2′-pyridylimidazole by a separation factor (β) in the range 22-45. Electrospun nanofibers as sorbents yielded high sorption capacity in the range of 0.97 - 1.45 mmol.g⁻¹ for the same metals ions. Thus, 1-octylimidazole-2-aldoxime (OIMOX), and1-octyl-2-(2′-pyridyl)imidazole (OPIM) can be effectively utilized alongside DNNSA as a co-extractant in the separation of Cu²⁺ and Ni²⁺ respectively from base metals in acidic sulfate medium in a solvent extraction process, and the latter as a selective ligand in the solid-liquid separation of Ni²⁺ from Co²⁺, Cu²⁺, and Fe²⁺.

No description available.

Part I. Reduction of the 1-methylpentacyclo [5.4.0.0²,⁶.0³,¹⁰,0⁵,⁹]undecane-8, 11-dione (9) with solid NaBH₄ resulted in highly stereoselective reduction of both C=O groups in the substrate, thereby affording the corresponding endo-8, endo-11-diol (11a). The configuration of 11a was established unequivocally by converting 11a into the corresponding cyclic thiocarbonate ester, 12. Part II. Z-1,2-Di(1'-adamantyl)ethene (14) was synthesized with a high degree of stereoselectively in four steps (Scheme 9 in Chapter 2). E-1,2-di(1'-adamantyl)ethene (15) was synthesized by iodine promoted isomerization of 14. Both structures were established unequivocally via single-crystal X-ray structural analysis. E-1-(exo-8'-Pentacyclo[5.4.0.0²,⁶.0³,¹⁰,0⁵,⁹]undecyl)-2-phenylethylene (16a) was synthesized, and its structure was established via analysis of its 1H, 13C, and 2D COSY NMR spectra. Part III. Reactions of electrophiles, i.e.,:CCl_2, PhSCl, and Br_2, to Z- and E-1,2-di(1'-adamantyl)ethenes (14 and 15, respectively) are described (Scheme 5, 8, 10, and 13 in Chapter 3). Structures of the corresponding products were established unequivocally via analysis of their respective one- and two-dimensional NMR spectra and/or single-crystal X-ray structural analysis. Part IV. An improved asymmetric synthesis of optically active (S)-4-hydroxy-2-cyclohexenone 1 (64%ee, determined via Mosher's method) has been developed (Scheme 5 in Chapter 4). The key step in this synthesis involves the baker's yeast reduction of 13. The absolute configuration of the major product, (S)-1, was established unequivocally via single-crystal X-ray structural analysis of a precursor. The optical purity of the major product 14a (80%de, 67%ee) was established via careful integration of relevant gated-decoupled 13C NMR spectra.

No description available.

<p> In four separate experiments, DL-[5-3H]/DL-[5-14C]ornithine, L-[5-3H]/DL- [5- 14C]ornithine, D-[5-3H]/DL- [5- 14C]ornithine and L-[2-3H]/L-[5- 14c]ornithine were administered to intact tobacco plants (Nicotiana tabacum). Nicotine, ornithine and proline were isolated in each of these experiments. In another experiment, R-[1-2H][l ,4-14C] putrescine was administered to intact tobacco plants and nicotine was isolated. The results of these experiments are consistent with the accepted mode of biosynthesis of nicotine from ornithine via putrescine (1,4-diaminobutane), N-methylputrescine, N-methyl-4-aminobutanal and N- methyl-1-pyrrolinium ion. The 3H:14c ratios of nicotine, the distribution of tritium within nicotine as established by chemical degradation and the distribution of deuterium within nicotine as established by 2H NMR are interpreted as showing that L-ornithine is the preferred enantiomer for nicotine biosynthesis, that the decarboxylation of L-ornithine to yield putrescine proceeds with retention of configuration at the reaction site, and that the oxidation of N-methylputrescine to N-methyl-4-aminobutanal proceeds with loss of the 4(S)hydrogen. </p> <p> Contrary to earlier reports, ornithine isolated in the 3H, 14C experiments had a changed 3:14c ratio from the ornithine which was fed. These results are interpreted as showing that L-ornithine is metabolised more rapidly than is D-ornithine in the tobacco plant. </p> <p> In all 3H, 14c experiments, proline was found to contain at least a small amount of tritium. In particular, when L-[2- 3H]/L-[5-14C] ornithine served as substrate, proline was found to contain 40 + 1% of the tritium, relative to 14C, that had been present in the feeding material. This result is interpreted as showing that, contrary to earlier reports, L-ornithine can be converted into proline via either a-keto-s-aminovaleric acid or glutamic semialdehyde. Together with the 3H: 14C ratios of proline in the other experiments, the results of this work are interpreted as showing that, when DL-ornithine serves as the substrate for proline biosynthesis in tobacco, 88 + 1% of the proline arises from D-ornithine via a-oxidation, 7 + 1% of the proline comes from L-ornithine via a-oxidation and 5 + 1% of the proline is produced from L-ornithine via s-oxidation. </p> / Thesis / Master of Science (MS)

Synthetic cathinones, commonly referred to as “bath salts”, are a subgroup of novel psychoactive substances that have seen a dramatic rise in abuse worldwide over the past decade. These compounds are synthesized by clandestine drug manufacturers using basic medicinal chemistry techniques, and marketed as “legal high” alternatives to illicit psychostimulants (ie. cocaine and MDMA). Two of the most common synthetic cathinones since the emergence of this class of drugs are 4-methylmethcathinone (mephedrone, MEPH) and 3,4-methylenedioxypyrovalerone (MDPV). The novelty of these compounds in the illicit drug marketplace has limited the current understanding of synthetic cathinone neuropharmacology. Our studies, as outlined in this dissertation, aimed to further characterize the neuropharmacology of MEPH and MDPV, specifically evaluating the contributions of stereospecific mechanisms in the monoaminergic systems, as well as the role of the glutamatergic system in mitigating reward, reinforcement, and relapse to drug seeking. We first evaluated MEPH’s ability to produce behavioral sensitization (detailed in Chapter 2), a hallmark behavior of psychostimulants involving repeated, intermittent drug administration, followed by a period of drug abstinence, and a subsequent drug challenge. This evaluation of MEPH’s ability to produce behavioral sensitization was conducted across multiple treatment and dosing paradigms, withdrawal time point intervals, and drug administration contexts. A 7-day, variable-dose administration paradigm (Days 1+7= 15 mg/kg, Days 2-6= 30 mg/kg) and a 5-day, constant-dose administration paradigm (15 mg/kg) both induced enhancement of repetitive movements (i.e. stereotypy), but not ambulatory activity, during a challenge dose following 10 days of drug abstinence. Additionally, with the 7-day variable-dose design, sensitization of repetitive movements was observed following a shorter (2-day) abstinence interval, and before the initiation of MEPH abstinence on Day 7 of MEPH treatment. This sensitization was observed in both context-independent and context-dependent dosing schedules. A lower dose of MEPH (5 mg/kg) in the 5-day constant dose paradigm produced no sensitization of repetitive movements following 10 days of abstinence. Lastly, in all sensitization paradigms employed, no sensitization of ambulatory activity was observed. These data indicate that MEPH produces preferential sensitization of repetitive movements across multiple treatment paradigms, preferentially over ambulatory activity. Our findings suggest that MEPH is a unique stimulant displaying weak sensitizing properties with both amphetamine-like properties, as well as distinctive properties relative to both amphetamine and cocaine. Abusers of synthetic cathinones are often polydrug abusers who seek out compounds like MEPH as a replacement for other psychostimulants that are commonly detected on drug screenings. We investigated interactions of MEPH with cocaine (COC) and methamphetamine (METH), specifically testing the hypothesis that prior MEPH exposure enhances the locomotor-stimulant effects of COC and METH, and vice versa (detailed in Chapter 3). For cocaine experiments, rats were conditioned with saline, cocaine (15 mg/kg), or MEPH (15 mg/kg) for 5 days were given a cocaine challenge (15 mg/kg) after 10 days of drug abstinence. For METH experiments, rats conditioned with saline, METH (2 mg/kg), or MEPH (15 mg/kg) were given a METH challenge (2.0 mg/kg) after 10 days of drug absence. Cocaine challenge produced greater locomotor activity in rats conditioned with cocaine or MEPH than those conditioned with saline. METH challenge produced greater locomotor activity in METH-conditioned rats than saline-conditioned rats; however, locomotor activity in rats conditioned with MEPH or saline and then challenged with METH (0.5 or 2.0 mg/kg) was not significantly different. The locomotor response to MEPH (15 mg/kg) was not significantly affected by conditioning with cocaine (15 mg/kg) or METH (0.5, 2 mg/kg). The present demonstration that cocaine-induced locomotor activation is enhanced by prior MEPH exposure suggests that MEPH cross-sensitizes to cocaine and increases cocaine-evoked locomotor activity. Interestingly, MEPH cross-sensitization was not bidirectional and did not extend to METH, suggesting that the phenomenon is sensitive to specific psychostimulants. Similar to other cathinone and amphetamine-related compounds, MEPH has a chiral center at its alpha carbon, and exists stably as two enantiomers. To further explore enantiomer-specific MEPH neuropharmacology, individual MEPH enantiomers R-MEPH and S-MEPH were examined for their behavioral and neurochemical effects (detailed in Chapter 4). We analyzed both enantiomers in rat brain synaptosome neurotransmitter release assays and investigated each MEPH enantiomer for their acute ambulatory activity and repetitive movements, ability to produce behavioral sensitization, and rewarding properties. Both enantiomers displayed similar potency as substrates (i.e. releasers) at dopamine transporters, but R-MEPH was much less potent than S-MEPH at serotonin (5-HT) transporters. Locomotor activity was evaluated after acute administration of each enantiomer, with R-MEPH producing greater repetitive movements than S-MEPH across multiple doses. Pretreatment with the 5-HT2C antagonist SB242084 significantly increased S-MEPH locomotor activity, indicating 5-HT receptor activation is involved in suppressing S-MEPH locomotor activation. In repeated drug administration paradigms, R-MEPH, but not S-MEPH, produced sensitization of repetitive movements. R-MEPH also produced a conditioned place preference whereas S-MEPH produced no place preference at the doses tested. Lastly, R-MEPH and S-MEPH produced biphasic profiles in an assay of intracranial self-stimulation (ICSS), but R-MEPH produced greater ICSS facilitation than S-MEPH. Our data were the first to demonstrate stereospecific effects of MEPH enantiomers and suggests that the predominant dopaminergic actions of R-MEPH (i.e. the lack of serotonergic actions) render this stereoisomer more stimulant-like when compared to S-MEPH. Following the increased clinical presence of MDPV over MEPH in the United States, and reports from abusers detailing intense cravings to re-dose during drug administration sessions, our studies shifted focus onto the neuropharmacology of MDPV. The first investigation of MDPV evaluated the effects of non-contingent MDPV administration on the glutamate system (detailed in Chapter 5). To date, all pharmacological studies on MDPV have focused on monoaminegic systems, leaving a critical void in the literature. The glutamate system has been extensively studied with psychostimulants with similar monoamine mechanisms to MDPV, and glutamatergic dysregulation is an underlying component in behavioral sensitization and relapse to drug seeking. Two important regulators of glutamate homeostasis are the enzyme glutamate carboxypeptidase II (GCPII) and the glutamate transporter subtype 1 (GLT-1), which contribute to the synthesis and extrasynaptic reuptake of glutamate, respectively. Ceftriaxone (CEF), a beta-lactam activator at the glutamate transporter subtype 1 (GLT-1), has shown preclinical promise in attenuating the rewarding and reinforcing properties of cocaine. We provide the first investigation of the effects of MDPV on GLT-1 and GCPII expression in the reward center, and the role of GLT-1 in MDPV behavior. MDPV effects on GLT-1 and GCPII expression at multiple withdrawal time points following MDPV or saline administration in a 7-day variable-dose paradigm via Western blot. Compared to saline controls, MDPV-treated rats had decreased expression of GLT-1 from Withdrawal Day 2 to Withdrawal Day 10 in the nucleus accumbens, while no changes in GLT-1 expression were observed in the prefrontal cortex. GCPII expression was decreased in MDPV treated rats compared to saline controls at Withdrawal Day 0 in the nucleus accumbens, as well as Withdrawal Day 0 to 10 in the prefrontal cortex. The effects of repeated CEF treatment on acute MDPV locomotor activity was also evaluated across multiple doses of MDPV, and no differences were observed. To evaluate behavioral sensitization, MDPV or saline was administered to rats in a 7-day variable-dose paradigm. Rats in the CEF group received CEF (200 mg/kg IP) for four days prior to MDPV treatment, and received CEF 30 minutes prior to each MDPV injection. Following 10 days of MDPV abstinence, a challenge dose (0.5 mg/kg MDPV) was administered and locomotor activity was recorded. Sensitization of repetitive movements was observed with repeated administration of MDPV, and this sensitization was attenuated in rats pretreated with CEF. MDPV’s reward was evaluated using a 4-day conditioned place preference model. MDPV (2.0 mg/kg IP) produced significant place preference compared to saline, and this effect was attenuated with pretreatment with CEF. These data indicate that repeated MDPV exposure decreases GLT-1 and GCPII expression in the mesolimbic reward center, and that pharmacological activation of GLT-1 may be a viable target for developing therapeutics to attenuate the rewarding effects MDPV. To further expand on the role of GLT-1 in MDPV abuse liability, CEF and the cysteine-glutamate antiporter (xCT) substrate N-acetylcysteine (NAcetyl) were evaluated in operant intravenous self-administration (IVSA) models, including fixed-ratio 1 (FR-1) self-administration and reinstatement to drug seeking (detailed in Chapter 6). The first experiment assessed CEF and NAcetyl treatment when administered after MDPV IVSA had cease (i.e. during extinction procedures). Rats were trained to self-administer MDPV (0.056 mg/kg/infusion) in daily 2 hours sessions for 14 days, during which ultrasonic vocalizations (USVs) were recorded. Following acquisition of MDPV self-administration, rats were pretreated daily with either saline, CEF (200 mg/kg) or NAcetyl (100 mg/kg) 30 minutes prior to extinction procedures for 10 days. One day after extinction, rats underwent cue-induced reinstatement procedures in the absence of CEF/NAcetyl, followed 24 hours later by a cue+MDPV-primed reinstatement procedures, where a non-contingent MDPV injection (0.5 mg/kg) was administered immediately prior to the reinstatement session. Neither CEF nor NAcetyl altered the rate of extinction of MDPV drug seeking, nor did either treatment attenuate cue- or cue+MDPV-primed reinstatement. After observing no differences in treatment with CEF or NAcetyl during extinction of MDPV drug seeking, our second experiment explored CEF and NAcetyl against the acquisition of MDPV self-administration, as well as the effects of CEF and NAcetyl administered throughout acquisition on reinstatement. Rats were treated with either saline, CEF (200 mg/kg) or NAcetyl (100 mg/kg) daily for 10 days prior to the start of acquisition of MDPV IVSA. Rats continued saline/CEF/NAcetyl daily treatment 30 minutes prior to acquisition of MDPV self-administration for 14 days. After acquisition, rats underwent 10 days of extinction procedures in a drug-free state and reinstatement procedures identical to the first experiment. Pretreatment with CEF, but not NAcetyl, resulted in significantly less active lever presses and reinforcers throughout acquisition, as well as an increase in latency of active lever pressing (i.e. an increase in time spent between reinforcers) during the early load-up phase across the second week of acquisition. Neither treatment was efficacious in attenuating cue- or cue+MDPV-primed relapse to MDPV seeking. Further characterization of the rewarding and reinforcing properties of MDPV were performed during cocaine self-administration by quantifying positive affective ultrasonic vocalizations (USVs) in rats self-administering MDPV versus cocaine. After rats acquired IVSA, rats self-administering MDPV (0.056 mg/kg/infusion) produced a greater calling rate and slower decay of 50 kHz calls per infusion, compared to cocaine (0.56 mg/kg/infusion). Latency to active lever pressing was lower in MDPV rats compared to cocaine, indicating that rats self-administering MDPV wait a smaller amount of time between doses than cocaine. In summary, the experiments described in this dissertation aimed to highlight various aspects of the neuropharmacology of MEPH and MDPV; two pharmacologically distinct synthetic cathinones that are both commonly abused and serve as a pharmacological template for the development of second generation synthetic cathinones. MEPH produces locomotor behaviors similar to that of pharmacologically similar psychostimulants, as well as bi-phasic cross-sensitization with cocaine. Locomotor and reward behaviors observed with MEPH administration are stereospecific, with the R-enantiomer of MEPH possessing the more dopaminergic and stimulant like profile. Repeated MDPV administration and withdrawal induces depletions in GLT-1 and GCPII in the reward center, and pharmacologically targeting GLT-1 with CEF attenuates MDPV sensitization, reward, and reinforcement. Despite evaluating CEF and NAcetyl in multiple paradigms of administration, neither compound was found to be efficacious in attenuating relapse to MDPV seeking. MDPV self-administration produces a greater positive affective status, compared to cocaine, throughout the latter parts of acquisition of IVSA. These studies have identified crucial differences in the behavioral profile and neuroadaptations expressed during and after MDPV versus cocaine. In conclusion, our studies have expanded the neuropharmacology knowledge base of these two synthetic cathinones, MEPH and MDPV, and provide a strong foundation for future investigations into the neuropharmacology of this constantly-evolving class of drugs. The stereoselectivity of MEPH enantiomers towards the more rewarding R- enantiomer, compared to the S- enantiomer possessing a more serotonergic and less stimulant-like profile indicates that the change in steric orientation around the chiral carbon at MEPH is critically involved in dopaminergic and rewarding activity. This observation may be useful in the development of future pharmacotherapies aimed at targeting pathologies with a mixed monoaminergic substrate activity, similar to the cathinone bupropion. Additionally, our studies with MDPV have identified MDPV as a highly reinforcing and rewarding psychostimulant, with notable potency differences compared to cocaine. While our efforts to attenuate reinstatement of MDPV-seeking the promising compounds CEF and NAcetyl were unsuccessful, the lack of efficacy in these reinstatement studies continue to underlie the importance of investigating pharmacotherapies against MDPV reinstatement. The conclusions in this dissertation should be used as foundation for future studies investigating both MEPH and MDPV, as well as second-generation cathinones that continue to emerge as the problem of novel psychoactive substances evolves and persists. / Pharmacology

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemistry, 1978 / Vita. / Includes bibliographical references. / Ph. D. / Ph. D. Massachusetts Institute of Technology, Department of Chemistry

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy