Evaluation of 99mTc-HYNIC-βAla-Bombesin(7-14) as an agent for pancreas tumor detection in mice

Pancreatic adenocarcinoma is important in oncology because of its high mortality rate. Deaths may be avoided if an early diagnosis could be achieved. Several types of tumors overexpress gastrin-releasing peptide receptors (GRPr), including pancreatic cancer cells. Thus, a radiolabeled peptide derivative of gastrin-releasing peptide (GRP) may be useful as a specific imaging probe. The purpose of the present study was to evaluate the feasibility of using99mTc-HYNIC-βAla-Bombesin(7-14)as an imaging probe for Capan-1 pancreatic adenocarcinoma. Xenographic pancreatic tumor was developed in nude mice and characterized by histopathological analysis. Biodistribution studies and scintigraphic images were carried out in tumor-bearing nude mice. The two methods showed higher uptake by pancreatic tumor when compared to muscle (used as control), and the tumor-to-muscle ratio indicated that99mTc-HYNIC-βAla-Bombesin(7-14)uptake was four-fold higher in tumor cells than in other tissues. Scintigraphic images also showed a clear signal at the tumor site. The present data indicate that99mTc-HYNIC-βAla-Bombesin(7-14)may be useful for the detection of pancreatic adenocarcinoma.

Determination of acrolein, ethanol, volatile acidity, and copper in different samples of sugarcane spirits

Seventy-one samples of sugarcane spirits from small and average size stills produced in the northern and southern Minas Gerais (Brazil) were analyzed for acrolein using HPLC (High Performance Liquid Chromatography). Ethanol and copper concentrations and volatile acidity were also determined according to methods established by the Ministry of Agriculture, Livestock and Supply (MAPA). A total of 9.85% of the samples tested showed levels of acrolein above the legal limits, while the copper concentrations of 21.00% of the samples and the volatile acidity of 8.85% of the samples were higher than the limits established by the Brazilian legislation. The concentration of acrolein varied from 0 to 21.97 mg.100 mL-1 of ethanol. However, no significant difference at 5% of significance was observed between the samples produced in the northern and southern Minas Gerais. The method used for determination of acrolein in sugarcane spirits involved the formation of a derivative with 2,4-dinitrophenylhydrazine (2,4-DNPH) and subsequent analysis by HPLC.

Chemical, biochemical, and microbiological aspects of chitosan quaternary salt as active coating on sliced apples

The biocompatibility of chitosan and chitosan quaternary salt coatings was evaluated for use as edible coatings for sliced apple. Measurement of water loss, color change, and fungal growth appearance were monitored as a function of time. A significant brownish effect was observed on chitosan coated slices, varying greatly from L* = 76.5 and Hue angle = 95.9° (t = 0) to L* = 45.3 and Hue angle = 69.8° (t = 3 days), whilst for TMC coated samples the variation was considerable lower (L* = 74.1; Hue angle = 95.0°) to (L* = 67.0; Hue angle = 83.8°) within the same period. The hydrosoluble derivative N,N,N-trimethylchitosan demonstrated good antifungal activity against P. expansum although highly dependent on the polymer properties such as degree of quaternization. The most efficient formulation was that prepared from derivative having a degree of quaternization of 45%, high solubility, and high viscosity. This formulation restrained fungus spreading up to 30%, while for the control it reached almost 80% of the total assessed surfaces during 7 days of storage.

Fusion of Data from Quadcopter’s Inertial Measurement Unit Using Complementary Filter

A quadcopter is a helicopter with four rotors, which is mechanically simple device, but requires complex electrical control for each motor. Control system needs accurate information about quadcopter’s attitude in order to achieve stable flight. The goal of this bachelor’s thesis was to research how this information could be obtained. Literature review revealed that most of the quadcopters, whose source-code is available, use a complementary filter or some derivative of it to fuse data from a gyroscope, an accelerometer and often also a magnetometer. These sensors combined are called an Inertial Measurement Unit. This thesis focuses on calculating angles from each sensor’s data and fusing these with a complementary filter. On the basis of literature review and measurements using a quadcopter, the proposed filter provides sufficiently accurate attitude data for flight control system. However, a simple complementary filter has one significant drawback – it works reliably only when the quadcopter is hovering or moving at a constant speed. The reason is that an accelerometer can’t be used to measure angles accurately if linear acceleration is present. This problem can be fixed using some derivative of a complementary filter like an adaptive complementary filter or a Kalman filter, which are not covered in this thesis.

The solutions and tunneling properties for a linear potential and an inverted harmonic oscillator in an infinite well

In this work we look at two different 1-dimensional quantum systems. The potentials for these systems are a linear potential in an infinite well and an inverted harmonic oscillator in an infinite well. We will solve the Schrödinger equation for both of these systems and get the energy eigenvalues and eigenfunctions. The solutions are obtained by using the boundary conditions and numerical methods. The motivation for our study comes from experimental background. For the linear potential we have two different boundary conditions. The first one is the so called normal boundary condition in which the wave function goes to zero on the edge of the well. The second condition is called derivative boundary condition in which the derivative of the wave function goes to zero on the edge of the well. The actual solutions are Airy functions. In the case of the inverted oscillator the solutions are parabolic cylinder functions and they are solved only using the normal boundary condition. Both of the potentials are compared with the particle in a box solutions. We will also present figures and tables from which we can see how the solutions look like. The similarities and differences with the particle in a box solution are also shown visually. The figures and calculations are done using mathematical software. We will also compare the linear potential to a case where the infinite wall is only on the left side. For this case we will also show graphical information of the different properties. With the inverted harmonic oscillator we will take a closer look at the quantum mechanical tunneling. We present some of the history of the quantum tunneling theory, its developers and finally we show the Feynman path integral theory. This theory enables us to get the instanton solutions. The instanton solutions are a way to look at the tunneling properties of the quantum system. The results are compared with the solutions of the double-well potential which is very similar to our case as a quantum system. The solutions are obtained using the same methods which makes the comparison relatively easy. All in all we consider and go through some of the stages of the quantum theory. We also look at the different ways to interpret the theory. We also present the special functions that are needed in our solutions, and look at the properties and different relations to other special functions. It is essential to notice that it is possible to use different mathematical formalisms to get the desired result. The quantum theory has been built for over one hundred years and it has different approaches. Different aspects make it possible to look at different things.

Roles of keratins in intestinal health and disease

Intermediate filament keratins (K) play a pivotal role in protein targeting and epithelialcytoprotection from stress as evidenced by keratin mutations predisposing to human liver and skin diseases and possibly inflammatory bowel disease (IBD). The K8-null (K8-/-) mice exhibit colonic phenotype similar to IBD and marked spontaneous colitis, epithelial hyperproliferation, decreased apoptosis, mistargeting of proteins leading to defective ion transport and diarrhea. The K8-heterozygote (K8+/-) mouse colon appears normal but displays a defective sodium (Na+) and chloride (Cl-) transport similar to, but milder than K8-/-. Characterization of K8+/- colon revealed ~50% less keratins (K7, K8, K19, K20) compared to K8 wild type (K8+/+). A similar ~50% decrease was seen in K8+/- mRNA levels as compared to K8+/+, while the mRNA levels for the other keratins were unaltered. K8+/- keratins were arranged in a normal colonic crypt expression pattern, except K7 which was expressed at the top of crypts in contrast to K8+/+. The K8+/- colon showed mild hyperplasia but no signs of inflammation and no resistance to apoptosis. Experimental colitis induced by using different concentrations of dextran sulphate sodium (DSS) showed that K8+/- mice are slightly more sensitive to induced colitis and showed a delayed recovery compared to K8+/+. Hence, the K8+/- mouse with less keratins and without inflammation, provided a novel model to study direct molecular mechanisms of keratins in intestinal homeostasis and ion transport. Different candidate ion transporters for a possible role in altered ion transport seen in the K8-/- and K8+/- mouse colon were evaluated. Besides normal levels of CFTR, PAT-1 and NHE-3, DRA mRNA levels were decreased 3-4-fold and DRA protein nearly entirely lost in K8-/- caecum, distal and proximal colon compared to K8+/+. In K8+/- mice, DRA mRNA levels were unaltered while decreased DRA protein level and patchy distribution was detected particularly in the proximal colon and as compared to K8+/+. DRA was similarly decreased when K8 was knocked-down in Caco-2 cells, confirming that K8 levels modulate DRA levels in an inflammation-independent manner. The dramatic loss of DRA in colon and caecum of K8-/- mice was responsible for the chloride transport defect. The milder ion transport in K8+/- colon might be related to DRA suggesting a role for K8 in regulation of DRA expression and targeting. The current study demonstrates the importance of keratins in stress protection and cell signaling. Furthermore, we have also successfully developed a novel, simple, fast, cost effective, non-invasive in vivo imaging method for the early diagnosis of murine colitis with specificity for both genetic and experimental colitis. The said modality provides continuous measurements of reactive oxygen and nitrogen species (RONS) and minimizes the use of an increased number of experimental animals by using a luminal derivative chemiluminescent probe, L-012 which provides a cost-effective tool to study the level and longitudinal progression of colitis.

Sähkönmyyntiyhtiöiden riskienhallinnan haasteet ja kehittäminen

Diplomityön tavoitteena on esitellä sähkökaupan ja erityisesti sähköyhtiöiden kokemia sähkönmyynnin riskejä sekä kuvata sähkönmyyntiin liittyvää riskienhallinnan problematiikkaa. Tarkastelun näkökulmana on tietojärjestelmien ja saatavissa olevan tiedon hyödyntäminen energiayhtiöiden riskienhallinnassa. Toinen päätavoitteista on tutkia, kuinka saatavilla olevaa tiedon hyödyntämistä voidaan kehittää sähkönmyynnin hinnoittelussa sekä suojausten suunnittelussa. Työ toteutettiin työskentelemällä asiantuntijana energia-alaan keskittyneessä ohjelmistoyrityksessä sekä haastattelemalla yhdeksän suomalaisen sähkönmyyntiyhtiön henkilöitä riskienhallinnan haasteiden sekä tietojärjestelmien näkökulmasta. Saatavilla olevien tietojen nykyistä parempi hyödyntäminen ja automatisointi voivat auttaa pienentämään yhtiöiden riskitasoa ja parantaa menestymisen edellytyksiä sähkönmyynnin vähittäismarkkinoilla. Lisäksi kulloiseenkin markkinatilanteeseen sopivat sähkön hankintahinnan suojausstrategiat sekä monipuoliset dynaamiset hinnoittelumallit auttavat pienentämään yhtiön kokemia riskejä tai niiden vaikutuksia. Näiden hyödyntäminen vaatii laajaa ymmärrystä sähkö- ja johdannaismarkkinoiden toiminnasta sekä usein myös nykyisten tietojärjestelmien kehittämistä. Tulevaisuudessa yhä yleistyvä hajautettu tuotanto sekä kysynnän jousto asettavat tietojärjestelmille uusia vaatimuksia, jotka toteutuessaan mahdollistavat uudenlaisten palveluiden käyttöönoton sekä voivat tuoda tilaa myös alan uusille toimijoille. Työssä käsitellään energiayhtiöiden kokemia riskejä sähkönmyynnin näkökulmasta, esitellään alan yleisimmät riskit sekä keinot ja työkalut niiltä suojautumiseen. Työn lopuksi tarkastellaan sähkönmyynnin ja –hankinnan oleellisimpia prosesseja riskienhallinnan kehittämisen näkökulmasta.

The solutions and tunneling properties for a linear potential and an inverted harmonic oscillator in an infinite well

In this work we look at two different 1-dimensional quantum systems. The potentials for these systems are a linear potential in an infinite well and an inverted harmonic oscillator in an infinite well. We will solve the Schrödinger equation for both of these systems and get the energy eigenvalues and eigenfunctions. The solutions are obtained by using the boundary conditions and numerical methods. The motivation for our study comes from experimental background. For the linear potential we have two different boundary conditions. The first one is the so called normal boundary condition in which the wave function goes to zero on the edge of the well. The second condition is called derivative boundary condition in which the derivative of the wave function goes to zero on the edge of the well. The actual solutions are Airy functions. In the case of the inverted oscillator the solutions are parabolic cylinder functions and they are solved only using the normal boundary condition. Both of the potentials are compared with the particle in a box solutions. We will also present figures and tables from which we can see how the solutions look like. The similarities and differences with the particle in a box solution are also shown visually. The figures and calculations are done using mathematical software. We will also compare the linear potential to a case where the infinite wall is only on the left side. For this case we will also show graphical information of the different properties. With the inverted harmonic oscillator we will take a closer look at the quantum mechanical tunneling. We present some of the history of the quantum tunneling theory, its developers and finally we show the Feynman path integral theory. This theory enables us to get the instanton solutions. The instanton solutions are a way to look at the tunneling properties of the quantum system. The results are compared with the solutions of the double-well potential which is very similar to our case as a quantum system. The solutions are obtained using the same methods which makes the comparison relatively easy. All in all we consider and go through some of the stages of the quantum theory. We also look at the different ways to interpret the theory. We also present the special functions that are needed in our solutions, and look at the properties and different relations to other special functions. It is essential to notice that it is possible to use different mathematical formalisms to get the desired result. The quantum theory has been built for over one hundred years and it has different approaches. Different aspects make it possible to look at different things.

Tuulivoimaliiketoimintaan liittyviä epävarmuustekijöitä

Diplomityön tavoitteena oli selvittää tuulivoimatuotannon epäsymmetrisyyden vaikutuksia liiketoiminnalle. Tarkastelun kohteena oli tuotetun energian sekä tuulivoimatuotannosta maksettavan korvauksen keskinäinen epäsymmetria. Työssä asiaa tarkasteltiin esimerkki tuulivoimalaitoksen avulla. Tarkastelujaksoksi työssä rajattiin ajanjakso 2014 tammikuusta vuoden 2015 kesäkuuhun. Tämän lisäksi työssä perehdyttiin tuotetun sähkön hinnan suojausstrategioihin, tuotannon häviötekijöihin sekä tasesähkön aiheuttamien kustannusten kehitykseen. Työn tulosten perusteella tuulivoimaliiketoiminta tulee kokemaan epävakauden lisääntymistä. Tuulivoimatuotannon epävarmuus johtuu heikosta pitkän aikavälin ennustettavuudesta, joka koostuu aikaisemmin mainituista tuotannon ja sähkön markkinahinnan välisestä epäsymmetrisyydestä. Työssä käsitellään tuulivoimatuotannon ajallista vaihtelua, joka ilmentää hyvin tuulivoimatuotannon perimmäistä olemusta. Työn lopputuloksena saatiin kuvaus tuotantojen ajallisesta jakautuneisuudesta, joiden pohjalta yritys voi suunnitella suojausstrategioita työssä esiteltyjen johdannaistuotteiden avulla. Edellisten loppupäätelmien lisäksi työssä perehdyttiin häviöiden sekä tasesähkökustannusten taloudellisiin vaikutuksiin sekä kehityssuuntiin tulevaisuudessa.

Viologen based electroactive polymers and composites for durable electrochromic systems

Electrochromism, the phenomenon of reversible color change induced by a small electric charge, forms the basis for operation of several devices including mirrors, displays and smart windows. Although, the history of electrochromism dates back to the 19th century, only the last quarter of the 20th century has its considerable scientific and technological impact. The commercial applications of electrochromics (ECs) are rather limited, besides top selling EC anti-glare mirrors by Gentex Corporation and airplane windows by Boeing, which made a huge commercial success and exposed the potential of EC materials for future glass industry. It is evident from their patents that viologens (salts of 4,4ʹ-bipyridilium) were the major active EC component for most of these marketed devices, signifying the motivation of this thesis focusing on EC viologens. Among the family of electrochromes, viologens have been utilized in electrochromic devices (ECDs) for a while, due to its intensely colored radical cation formation induced by applying a small cathodic potential. Viologens can be synthesized as oligomer or in the polymeric form or as functionality to conjugated polymers. In this thesis, polyviologens (PVs) were synthesized starting from cyanopyridinium (CNP) based monomer precursors. Reductive coupling of cross-connected cyano groups yields viologen and polyviologen under successive electropolymerization using for example the cyclic voltammetry (CV) technique. For further development, a polyviologen-graphene composite system was fabricated, focusing at the stability of the PV electrochrome without sacrificing its excellent EC properties. High electrical conductivity, high surface area offered by graphene sheets together with its non-covalent interactions and synergism with PV significantly improved the electrochrome durability in the composite matrix. The work thereby continued in developing a CNP functionalized thiophene derivative and its copolymer for possible utilization of viologen in the copolymer blend. Furthermore, the viologen functionalized thiophene derivative was synthesized and electropolymerized in order to explore enhancement in the EC contrast and overall EC performance. The findings suggest that such electroactive viologen/polyviologen systems and their nanostructured composite films as well as viologen functionalized conjugated polymers, can be potentially applied as an active EC material in future ECDs aiming at durable device performances.

Synthetic approaches to syn-diol containing biologically active compounds /

The deoxy derivative of pancratistatin 1.10 was prepared in good yield through the use of a [4+2] Diels-Alder cycloaddition and Bischler-Napieralski cyclization approach. The Bischler-Napieralski cyclization was shown to yield two additional side products 2.9, 2.10, however, under slightly modified hydrolysis conditions, the tetracyclic product 2.11 was obtained exclusively in greater than 84% yield. Initial screening of the di-hydroxylatgd derivative, and the other complementary pair analogue 1.10' previously prepared in our laboratories gave interesting results. Both of these compounds were shown to exhibit cytostatic activity; the mono-alcohol was marginally active while the di-hydroxylated analogue proved to be more potent although one to two magnitudes less potent than pancratistatin itself Human tumour cell line assay results indicated that the di-hydroxylated derivative exhibited selective cytotoxic inhibition in the following cell lines: non-small cell lung cancer line NCI-H226 (ED50 - 0.65 ^g/mL), leukemia cell lines CCRF-CEM (ED30 = 0.55 Hg/mL) and HL-60(TB) (ED50 = 0.89^ig/mL). Our results demonstrated that the pharmacophore is not a mono-alcohol, and that the minimum pharmacophore contains the hydroxyl group at the C4 position in addition to either, or both, of the hydroxyl groups present at C2 and C3.' The minimum pharmacophore has been narrowed to only three possibilities which are current synthetic targets in several research groups. The controlled Grignard addition to the tartaric acid derived bis-Weinreb amide 1.25 afforded a direct entry to a host of 1,4-diflferentiated tartaric acid derived intermediates (2.12-2.18). This potentially usefiil methodology was demonstrated through the efficient synthesis of the naturally occurring lactone 2.23, which bears the inherent syn-dio\ subunit. Based on this result, a similar approach to the synthesis of syn-dio\ bearing natural products looks very promising? A direct 2,3-diol desymmetrization method using TIPS-triflate was shown to be effective on the selective differentiation of Z,-methyl tartrate (and diisopropyl tartrate). The mono-silyl-protected intermediates 2.31 also proved to be useful when they were selectively differentiated at the 1,4-carboxyl position (2.35, 2.36) through the use of a borohydride reducing agent. Furthermore, the mono-silyl-protected derivative underwent periodate cleavage affording two synthetically useful a,P-unsaturated esters 2.43, 2.44, with one of esters being obtained via a silyl-migration method.''

Enantiodivergent chemoenzymatic synthesis of codeine

The present thesis describes our latest results in the chemistry of morphine alkaloids. An enantiodivergent synthesis of codeine utilizing a cis-cyclohexadiene diol derived from microbial whole cell oxidation of ~-bromoethylbenzene,as starting material is discussed. The total synthesis of (+)-codeine in 14 steps featuring a Mitsunobu inversion and two intramolecular Heck cyclizations is presented. Investigation of a regioselective nucleophilic opening of a homochiral vinyl oxirane, which led to a total synthesis of the natural isomer of codeine, is detailed. Furthermore, described herein are novel methodologies designed for the transformation of naturally occurring opiates into medicinally relevant derivatives. Two studies on the conversion of thebaine into the commercially available analgesic hydrocodone, two novel ·transition metal catalyzed N-demethylation procedures for opioids, and the development of a catalytic protocol for N-demethylation and Nacylation of morphine and tropane alkaloids are presented. In addition, reactions of a menthol-based version of the Burgess reagent with epoxides are discussed. The synthetic utility of this novel chiral derivative of the Burgess reagent was demonstrated by an enantiodivergent formal total synthesis of balanol. ii

Investigations towards the synthesis of isotope labelled analogues of tocopherols and tocotrienols /

Vitamin E is considered as the most effective lipophilic chain breaking antioxidant. a-Tocopherol and its analogues have been studied thoroughly with regards to its biokinetics and bioavailabily. Deuterated tocopherols have been synthesized and utilized in such studies. Tocotrienols are arousing more and more interest because of their high efficiency as antioxidants. However, to date, there is no effective synthetic method reported for deuterated tocotrienols. This thesis is focused on the investigation of the synthetic methods of deuterated tocotrienols and their analogues: 5-trideuteromethyl-a-tocotrienol, 5- trideuteromethyl-p-tocotrienol, tocotrienol acetate, silyl tocotrienol ether, etc. Several synthetic procedures for the preparation of poly-deuterated tocopherols are known. Mainly the deuterium is introduced by use of labelled formaldehyde and deuterated hydrogen chloride under Lewis acid catalysis. However, these methods are not effective in tocotrienols due to exchange of protons for deuterium at other sites under the acidic conditions. We developed several different approaches to generate polydeuterated tocotrienols by using both morpholinomethylation followed by reduction with NaCNBDs as deuterated reducing reagents and transmetalation strategy. The 5-trideuteromethyl-a-tocotrienol was finally obtained in a satisfactory yield of 60%. In addition, this thesis also discussed the study of structural comparison and the chemical property difference of tocopherols and tocotrienols, which provides hints to explain the reactivity difference of them towards oxidation at the C3-C4 positions.Furthermore, the methodology of halogenation and dehydrohalogenation of tocotrienol was explored to prepare a hexaene tocotrienol derivative as a florescent reporter of tocopherol.

Localization and functional characterization of iridoid biosynthetic genes in Catharanthus roseus /

Catharanthus roseus is the sole biological source of the medicinal compounds vinblastine and vincristine. These chemotherapeutic compounds are produced in the aerial organs of the plant, however they accumulate in small amounts constituting only about 0.0002% of the fresh weight of the leaf. Their limited biological supply and high economical value makes its biosynthesis important to study. Vinblastine and vincristine are dimeric monoterpene indole alkaloids, which consists of two monomers vindoline and catharanthine. The monoterpene indole alkaloids (MIA's) contain a monoterpene moiety which is derived from the iridoid secologanin and an indole moiety tryptamine derived from the amino acid tryptophan. The biosynthesis of the monoterpene indole alkaloids has been localized to at least three cell types namely, the epidermis, the laticifer and the internal phloem assisted parenchyma. Carborundum abrasion (CA) technique was developed to selectively harvest epidermis enriched plant material. This technique can be used to harvest metabolites, protein or RNA. Sequencing of an expressed sequence tagged (EST) library from epidermis enriched mRNA demonstrated that this cell type is active in synthesizing a variety of secondary metabolites namely, flavonoids, lipids, triterpenes and monoterpene indole alkaloids. Virtually all of the known genes involved in monterpene indole alkaloid biosynthesis were sequenced from this library.This EST library is a source for many candidate genes involved in MIA biosynthesis. A contig derived from 12 EST's had high similarity (E'^') to a salicylic acid methyltransferase. Cloning and functional characterization of this gene revealed that it was the carboxyl methyltransferase imethyltransferase (LAMT). In planta characterization of LAMT revealed that it has a 10- fold enrichment in the leaf epidermis as compared to the whole leaf specific activity. Characterization of the recombinant enzyme revealed that vLAMT has a narrow substate specificity as it only accepts loganic acid (100%) and secologanic acid (10%) as substrates. rLAMT has a high Km value for its substrate loganic acid (14.76 mM) and shows strong product inhibition for loganin (Kj 215 |iM). The strong product inhibition and low affinity for its substrate may suggest why the iridoid moiety is the limiting factor in monoterpene indole alkaloid biosynthesis. Metabolite profiling of C. roseus organs shows that secologanin accumulates within these organs and constitutues 0.07- 0.45% of the fresh weight; however loganin does not accumulate within these organs suggesting that the product inhibition of loganin with LAMT is not physiologically relevant. The limiting factor to iridoid and MIA biosynthesis seems to be related to the spatial separation of secologanin and the MIA pathway, although secologanin is synthesized in the epidermis, only 2-5% of the total secologanin is found in the epidermis while the remaining secologanin is found within the leaf body inaccessable to alkaloid biosynthesis. These studies emphasize the biochemical specialization of the epidermis for the production of secondary metabolites. The epidermal cells synthesize metabolites that are sequestered within the plant and metabolites that are secreted to the leaf surface. The secreted metabolites comprise the epidermome, a layer separating the plant from its environment.

An aryne route to aporphine alkaloids and related topics / |nIjaz Ahmad Chanda. -- 260 St. Catharines, Ont. : [s. n.],

This research was directed towards the investigation and development of an aryne route to the syntheses of aporphi ne and dibenzopyrrocolinium (dibenzoindolizinium) alkaloids and to the stability of the latter under the conditions used for aryne formation. The work c an be divided into three main sections . i) - Synthesis of Glaucine 6-Bromo-3,4-dimethoxyphenylacetic acid, prepared by the action of bromine i n acetic acid on3,4-dimethoxyphenylacetic a cid, was converted into its acid chloride by t he action of thionyl chloride. This on treatment with 3,4- dimethoxyphenylethylamine pr ovided N-(3, 4-dimethoxyphenylethyl)- 2-(2-bromo-4,S-dimethoxyphenyl)-acetamide which on dehydration with phosphoryl chloride (Bischler Napieralski reaction) in dry benzene afforded l -(2-bromo-4,S-dimethoxybenzyl)- 3,4-dihydro-6,7-dimethoxyisoquinoline, isolated as hydrochl oride. A new method o f destroying the excess of phosphoryl chloride was developed which proved to be quite useful. Methylation of the dihydroisoquinoline'with methyl iodide in methanol , and subsequent reduction with sodium borohydride provided (±)-6-bromolaudanosine. Act ion of potassamide or sodamide in anhydrous liquid ammonia on (±)-6-bromolaudanosine yielded the corresponding amino derivative along with other products. Diazotization and ring closure of (±)-6-aminolaudanosine then a f forded (±)-glaucine which was isolated as methiodide. ii) - Intramolecular Capture of Aryne During Glaucine Synthesis, and Subsequent Reactions . This section deals with the by-products formed under the conditions of the aryne stage of t he glaucine synthesis. The crude product, obtained in the reaction of potassamide or sodamide in liquid ammonia on (±)-6-bromolaudanosine, was s eparated by chromatography, Three products were separated and identified. a ) - 5,6-Dimethoxy-2-( 3,4-dimethoxy-6-ethylphenyl)-lmethylindole. Two mechanisms are proposed for the formation of this interesting product. This compound also was prepared by the action of potassamide in l,iquid ammonia on 5,6 ,l2,l2atetrahydro- 2,3,9,lO-tetramethoxy-7-methyldibenz[b,g]indolizinium i odide . b) - 5,6-Dimethoxy-2-(3,4-dimethoxy-6-vinylphenyl)-lmethylindoline. Its formation represented a new method of Hofmann degradation . Further confirmation of structure was done by performing the normal Hofmann reaction on 5, 6,12,12a-tetrahydro -2/3,9,lO-tetramethoxy ~7-methyldibe nz[ b,g]indolizinium iodide. The indoline prepared i n this way was identical in all respects with that prepared above . c) - 1- (2-amino-4,5-dimethoxybenzyl ) -l,2,3,4-tetrahydro-2- methyl-6,7-dimethoxyisoquinoline, was converted t o glaucine as stated in section 1 . iii) - Attempt:,ed Sxnthesis of Liriodenine Piperonal was converted into 3,4-methylenedioxyinitrostyrene which on reduction with lithium aluminium hydride provided 3,4-methylenedioxyphenylethylamine. The method of extraction after the reduction was improved t o some extent. The amine on condensation with m-chlorophenylacetyl chloride, prepared by the action of oxalyl chloride on 3,4-methylenedioxyphenylacetic acid, provided N-[ ~ -(3,4-methylenedioxyphenyl)- e thyl)-3-chlorophenylacetamide. This on dehydration with phosphoryl chloride in dry benzene followed by air oxidation afforded l-(3-chlorobenzoyl)-6,7-methylenedioxyi soquinoline. This compound on r eaction with potassamide in liquid ammonia afforded a crude product from which. one product was separated by chromatography i n a pure condition . This yellow compound analysed as,c17Hl ON2021 and was t he main product i n the reaction ; a t entative structure is proposed. A second compound, not obtained in pure condition, was submitted to Pschorr reaction in the hope of obtaining liriodenine, but without success.