Synthesis and properties of some 4H-1, 3, 4 benzothiadiazines /|nby Darko J. Vukov. -- 260 St. Catharines, Ont. : [s. n.],

The work herein has been divided into five sections. In the first section, a new method of converting N-aroyl- hydrazines to hydrazidic halides is described. The second section deals with the products of reaction of hydrazidic halides with thioacetate ion in acetonitrile at room temperature. A number of new acetylthiohydrazides has been isolated together with corresponding hyclrazidic sulphides. Examination of x-ray data for bis-[~ -(2,6- dibromophenylhydrazono) - benZYl] sulphide revealpd the symmetrical structure as the most probable. In the third section, which consists of the three subsections, the synthesis of the 4H-l,3,4 benzothiadiazine ring system has been extended to 4H-l,3,4 benzothiadiazines with substituents in the 5 and 6-positions. Extension of synthesis also involves 4H-l,3,4 benzothiadiazines with mora than one substituent. Nuclear magnetic resonance spectra of 5 and 6 substituted 4H-l,3,4 benzothiadiazines have been ,. recorded. The section ends with a discussion of the mass spectra of some 4H-l.3,4 benzothiadiazines. In the fourth section, which is divided into two sub- -sections, preparation of 7-nitro substituted 4H-l,3,4 benzothiadiazine from N-thiobenzoyl hydrazine and2,4-dinitro -fluorobenzene is found to be satisfactory. Thiohydrazides react with acetic anhydride, in some cases, to give products identical with acetylthiohydrazides obtained from the hydrazidic halides with thioacetate ion at room temperature. In most of the cases thiohydrazides are found to give anomalous products on reaction with acetic anhydride and mechanisms for their formation are discussed. In the fifth section, which forms three subsections, the 4H-l,3,4 benzothiadiazine ring system with a halogen substituent in the 7-position undergoes electrophilic attack preferentially in 5-posi tion. \fuen the 5-posi tion is occupied by a halogen atom, electrophilic substitution occurs at the 7-position of 4H-l,3,4 benzothiadiazine ring system. Substitution at the 4-nitrogen atom in 4H w l,3,4 benzo- -thiadiazine is extremely slow, probably due to delocalisa- -tion of the nitrogen lone pair in the system. Oxidation of 4H-l,3,4 benzothiadiazines occurs at the sulphur atom under relatively mild conditions. t The Appendix deals with the reaction of N-benzoyl-N - -(2,5-dibromophenyl)hydrazine with p-nitrothiophenol~ The proposed p-nitrothiophenoxy - intermediate may undergo benzothiadiazine formation in a proton exchange system.

Synthesis and spectral studies of methyl heterocylic systems

2-Carboxy-2?-methyldiphenyl sulfide was prepared by the Ullmann reaction and cyclodehydrated by sulfuric acid to afford 4-methylthioxanthone. 1-Methylthioxanthone was separated from the reaction mixture obtained upon cyclodehydration of 2-carboxy-3f-methyldiphenyl sulfide. In addition, 1-, 2-, 3- and 4-methylthioxanthone 10,10-dioxides were synthesized by oxidation of the corresponding thioxanthones. o-, m- and p-N-Tolylanthranilic acids were prepared by the Ullmann reaction and used as precursors for the preparation of 1-, 2- and 4- methyl-9-chloroacridine and finally 1-, 2-, 3- and 4-methylacridone. High resolution, 60 MHz PMR spectra were obtained on the four monomethyl isomers of xanthone, thioxanthone, thioxanthone 10,10-dioxide and acridone, and on 1-, 2- and 4-methyl-9-chloroacridine. For some compounds, coupling of all three different aromatic protons to the methyl was observed, two of the couplings typically being smaller than the third. With the large (ortho) coupling being on the order of 0.5 to 1.0 Hz, it was necessary to decouple the aromatic part of the spectrum. The magnitude of the ortho benzylic constant may be related to an incomplete Tr-bond delocalization in the molecules.

Synthesis of nanoporous materials for preconcentration and determination of trace elements by ICP-AES ; Investigation and elimination of the memory effects of mercury, gold, silver and boron in ICP-AES

Nanoporous materials with large surface area and well-ordered pore structure have been synthesized. Thiol groups were grafted on the materials' surface to make heavy metal ion pre-concentration media. The adsorption properties ofthe materials were explored. Mercury, gold and silver can be strongly adsorbed by these materials, even in the presence of alkaline earth metal ion. Though the materials can adsorb other heavy metal ions such as lead and copper, they show differential adsorption ability when several ions are present in solution. The adsorption sequence is: mercury> == silver> copper » lead and cadmium. In the second part of this work, the memory effects of mercury, gold, silver and boron were investigated. The addition of 2% L-cysteine and 1% thiourea eliminates the problems of the three metal ions completely. The wash-out time for mercury dropped from more than 20 minutes to 18 seconds, and the wash-out time for gold decreased from more than 30 minutes to 49 seconds. The memory effect of boron can be reduced by the use of mannitol.

Synthetic studies on prostaglandins: "synthesis of a new thia-PGEI analog"

A PGE1 analog, namely (±)-trans-2-(6'-carbomethoxyhexyl)-3- (E-3"-thia-1 "-octene)-4-hydroxycyclopentanone 71, has been prepared for the first time. Towards the synthesis of this compound, several synthetic approaches aimed at the preparation of the required acetylenic and E-halovinylic sulfides as building blocks were investigated. Among all the methods examined, it appeared evident that the best route to ethynyl n.pentyl sulfide 81 is via a double dehydrohalogenation of the corresponding 1,2-dibromoethyl sulfide with sodium amide in liquid ammonia. In addition, the isomerically pure E-2-iodoethenyl n.pentyl sulfide 85 is conveniently prepared in high yield and stereoselectivity by hydrozirconation-iodination of the terminal ethynyl sulfide 81. The classical hydroalumination and hydroboration reactions for the preparation of vinyl halides from alkynes gave only small yields when applied as methods towards the synthesis of 85 . The building block 2-(6'-carbomethoxyhexyl)-4-hydroxy-2- cyclopentenone (±)-1 carrying the upper side-chain of prostaglandin E 1 was prepared by a step-wise synthesis involving transformations of compounds possessing the required carbocyclic framework (see scheme 27). The synthesis proved to be convenient and gave a good overall yield of (±)-1 which was protected as the TH P-derivative 37 or the siloxy derivative 38. With the required building blocks 81 and 37 in hand, the target 1S-thia-PGE1 analog (±)-71 was prepared via the in situ higher cuprate formation-conjugate addition reaction. This method proved to be convenient and stereospecific. The standard cuprate method, involving an organocuprate reagent generated from an isolated vinyl iodide, did not work well in our case and gave a complicated mixture of products. The target compound will be submitted for assessment of bio log ical activity.

Chemical synthesis of glycosylated oligoribonucleotides for siRNA development

In this study, an efficient methodology for the preparation of carbohydrate-RNA conjugates was established, which involved the use of 3,4~diethoxy-3-cyclobutene-l,2- dione (diethyl squarate) as the linking reagent. First, a glycan moiety containing an amino group reacted with diethyl squarate to form an activated glycan, which further reacted with an amino modified oligoribonucleotide to form a glycoconjugate under slightly basic conditions. The effect of glycosylation on the stability of RNA molecules was evaluated on two glycoconjugates, monomannosyl UlO-mer and dimannosyl UlO-mer. In the synthesis of aromatic fluorescent ribosides, perbenzylated ribofuranosyl pyrene and phenanthrene were synthesized from perbenzylated ribolactone. Deprotection of benzyl-protected ribofuranosyl phenanthrene and pyrene by boron tribromide gave ribofuranosyl phenanthrene and ribopyranosyl pyrene, respectively. UV/vis and fluorescent properties of the ribosides were characterized.

Evolutionary synthesis of stochastic gene network models using feature-based search spaces

A feature-based fitness function is applied in a genetic programming system to synthesize stochastic gene regulatory network models whose behaviour is defined by a time course of protein expression levels. Typically, when targeting time series data, the fitness function is based on a sum-of-errors involving the values of the fluctuating signal. While this approach is successful in many instances, its performance can deteriorate in the presence of noise. This thesis explores a fitness measure determined from a set of statistical features characterizing the time series' sequence of values, rather than the actual values themselves. Through a series of experiments involving symbolic regression with added noise and gene regulatory network models based on the stochastic 'if-calculus, it is shown to successfully target oscillating and non-oscillating signals. This practical and versatile fitness function offers an alternate approach, worthy of consideration for use in algorithms that evaluate noisy or stochastic behaviour.

Enantiodivergent chemoenzymatic synthesis of Balanol and approaches to the synthesis of (+)-Codine

The present thesis reviews the development of a formal enantiodivergent synthesis of the (+)- and (-)-isomers of balanol. This approach commences from a cis-dihydrodiol derived from the enzymatic dihydroxylation of bromobenzene. The stereochemistry of the diol is used to direct the synthesis of two different aziridines, each used in the formal synthesis of one enantiomer of balanol. Also described are several enantioselective approaches to (+ )-codeine. Each strategy begins with the enzymatic dihydroxylation of p-bromoethylbenzene and involves a Mitsunobu inversion and intramolecular Heck reaction as key steps.

Two enantiodivergent syntheses of balanol and the chemoenzymatic synthesis of oseltamivir

The present thesis outlines our latest findings on the reactivity of the Burgess reagent with oxiranes. Structural, mechanistic, and computational studies are presented. Included is the development of a (-)-menthyl version of the Burgess reagent and its application to the synthesis of enantiomerically pure ~-amino alcohols. This methodology has been exploited in the formal enantiodivergent synthesis of the (+)- and (-)-isomers of balanol. Also described is a second generation approach to both balanol enantiomers; each commencmg with the chemoenzymatic dihydroxylation of bromobenzene. This study also describes the steric and functional limitations of the toluene dioxygenase-mediated oxidation of benzoate esters. The metabolite derived from ethyl benzoate was employed in a formal synthesis of oseltamivir. Finally, several synthetic approaches to oseltamivir and its analogs are presented, each proceeding through a different vinyl aziridine derived from bromobenzene and ethyl benzoate.

Stereoselective synthesis of 5-substituted pyrrolo[1,2-c]imidazol-3-ones. Access to aldosterone synthase inhibitors and chiral precatalysts

Compounds containing the pyrrolidine moiety are key substructures of compounds with biological activity and organocatalysts. In particular, annulated chiral pyrrolidines with alpha stereogenic centers have aldostereone synthase inhibition activity. In addition, 5-substituted pyrroloimidazol(in)ium salts precursors to N-heterocyclic carbene (NHC) precatalysts are rare due to a lack of convenient synthetic routes to access them. In this thesis is described a rapid synthesis of NHC precursors and a possible route to 5-substituted pyrroloimidazole biologically active compounds. The method involves the preparation of chiral saturated and achiral unsaturated pyrrolo[I,2- c]imidazol-3-ones from N-Cbz-protected t-Butyl proline carboxamide. The resulting starting materials may be used to prepare the target chiral annulated imidazol(in)ium products by a two-step sequence involving first stereoselective lithiation-substitution, followed by POCh induced salt formation.

Stereoselective synthesis of substituted hexahydro-3a,4a-diazacyclopentaphenanthren-4-ones and aminoferrocenes

This thesis explored the development of several methodologies for the stereoselective construction of ligand frameworks and some of their applications. The first segment concerns the application of an enantioselective lithiation at an Sp3_ hybridized position adjacent to nitrogen by means of the widely used and typically highly effective enantioselective lithiation with ( -)-sparteine. This investigation was intended to develop a method to install chirality into a system that would be converted into a family of diaminoylidenes for use as phosphine mimics in transition metal catalysis or as nucleophilic reagents. Molecular modeling of the system revealed some key interactions between the substrate and (-)-sparteine that provided general insight into the diamine's mode of action and should lend some predictive value to its future applications. The second portion focuses on the development of methods to access 1,2- disubstituted aminoferrocenes, an underexplored class of metallocenes possessing planar chirality. Two routes were examined involving a diastereoselective and an enantioselective pathway, where the latter method made use of the first BF3-mediated lithiation-substitution to install planar chirality. Key derivatives such as 1,2- aminophosphines, made readily accessible by the new route, were evaluated as ligands for Pd(II), Pt(II) and Ir(I). These complexes show activity in a number of transformations with both achiral and prochiral substrates. Optimization experiments were conducted to prepare enantiomerically enriched 2-substituted-I-aminoferrocenes by direct asymmetric lithiation of BF3-coordinated tertiary aminoferrocenes. A predictive computational model describing the transition state of this reaction was developed in collaboration with Professor Travis Dudding's group (Department of Chemistry, Brock University). The predicted stereochemistry of the process was confirmed by single-crystal X-ray analysis of a 2-phosphino-l-dimethylaminoferrocene derivative. Enantiomerically pure samples of the aminophosphine ligands derived from this new process have given promising preliminary results in the enantioselective hydrogenation of prochiral alkenes and warrant further stUdy in metal-mediated catalysis.

The Synthesis of Imidazole Fatty Acid Conjugates as Inhibitors of Apoptosis

Ionizing radiation is known to initiate apoptosis in mammalian cells by causing the transformation of cytochrome c into a peroxidase, which results in the specific peroxidation of the mitochondrial phospholipid cardiolipin. Here we report the design and synthesis of 8 imidazole fatty acid derivatives that bind to the cyt c:CL complex and inhibit the peroxidase activity required for the initiation of apoptosis. We postulate that imidazole acts as a sixth ligand to the haem iron and stops the interaction with H2O2. Two mitochondrially directed analogues (3-hydroxypropyl)triphenylphosphonium esters) of 12-imidazole-stearic acid and 12-imidazole-oleic acid not only were demonstrated to be peroxidase inhibitors in vitro, but were also extraordinarily effective in protecting mice from lethal doses (9 Gy) of ionization radiation. We studied the structure activity relationship to a group of triphenyl phosphonium derivatives containing imidazole at different positions on the fatty acid chain, and observed that the C8-imidazole stearate analogue had marginally better activity than the others. But overall, the structure activity result were remarkable “flat” with all compounds prepared having rather similar inhibitory strength. We also synthesized carnitine mono and di-esters of 12-imidazole fatty acids but full biological data is not yet available for these compounds.

Chemoenzymatic Synthesis of ent-Neopinone

The present thesis describes the chemoenzymatic synthesis of ent-neopinone. The total synthesis of neopinone was accomplished in 14 steps from B-bromoethylbenzene. The synthesis began with a microbial oxidation of bromobenzene by Escherichia coli JM109(pDTG601) and features a Heck reaction, aldol condensation and a 1,6-conjugate addition.

SYNTHESIS OF CYCLIC AZOBENZENE ANALOGUES FOR INCORPORATION INTO OLIGONUCLEOTIDES, PEPTIDES AND POLYMERS

(A) In recent years, considerable amount of effort has contributed towards enhancing our understanding of the new photoswitch, cyclic azobenzene, particularly from the theoretical point of view. However, the challenging part with this system was poor efficiency of its synthesis from 2,2’- dinitrodibenzyl and lack of effective methods for further modification which would be useful to incorporate this system into biomolecules as a photoswitch. We report the synthesis of cyclic azobenzene and analogues from 2,2’-dinitrodibenzyl, which would allow for further incorporation of this cyclic azobenzene into biomolecules. Reaction of 2,2’-dinitrodibenzyl with zinc metal powder in the presence of triethylammonium formate buffer (pH-9.5) gave a cyclic azoxybenzene, 11,12-dihydrodibenzo[c,g][1,2]diazocine-5-oxide. The latter compound was converted into cyclic azobenzene analogues (bromo-, chloro-, cyano-, and carboxyl) through subsequent transformations. The carboxylic acid analogue was reacted with D-threoninol to give the corresponding amide, which readily undergoes photo-isomerization upon illumination with light. Upon illumination with light at 400 nm, approximately 70% of cis- isomer of amide was isomerized to trans- isomer. It was observed that cis- to trans- isomerization reached the maximum steady state of light transmission after approximately 40 min, whereas the trans- to cis- isomerization approximately acquired in 2 h to regain full recovery of light transmission. Cyclic azobenzene phosphoramidite was synthesized from DMT-protected D-threoninol linked cyclic azobenzene. (B) In recent years, there has been considerable interest invested towards the synthesis of azobenzene analogues for incorporation into proteins. Among the many azobenzene analogues, the synthesis of bi-functional cyclic azobenzene analogues for the incorporation into proteins is relatively new. In this thesis, we report the synthesis of a cyclic azobenzene biscarboxylic acid from 4-(bromomethyl)benzonitrile. (C) Azobenzene has been widely used in the field of polymer science to study the surface morphology and surface properties of polymers. In this thesis, we report the incorporation of cyclic azobenzene into a commercial polymer 2- (hydroxyethyl)methacrylate. Samples collected after 24 h from the reaction solution showed approximately 9% of incorporation of cyclic azobenzene into polymer compared to samples collected after 10 h, which showed approximately 6% incorporation.

Synthesis, Catalysis and Stoichiometric Reactivity of Mo Imido Complexes

The syntheses, catalytic reactivity and mechanistic investigations of novel Mo(IV) and Mo(VI) imido systems is presented. Attempts at preparing mixed bis(imido) Mo(IV) complexes of the type (RN)(R′N)Mo(PMe3)n (n = 2 or 3) derived from the mono(imido) complexes (RN)Mo(PMe3)3(X)2 (R = tBu (1) or Ar (2); X = Cl2 or HCl, Ar=2,6-iPr2C6H3) are also described. The addition of lithiated silylamides to 1 or 2 results in the unexpected formation of the C-H activated cyclometallated complexes (RN)Mo(PMe3)2(η2-CH2PMe2)(X) (R = Ar, X = H (3); R = tBu, X = Cl (4)). Complexes 3 and 4 were used in the activation of R′E-H bonds (E = Si, B, C, O, P; R′ = alkyl or aryl), which typically give products of addition across the M-C bond of the type (RN)Mo(PMe3)3(ER′)(X) (4). In the case of 2,6-dimethylphenol, subsequent heating of 4 (R = Ar, R′ = 2,6-Me2C6H3, E = O) to 50 °C results in C-H activation to give the cyclometallated complex (ArN)Mo(PMe3)3(κ2-O,C-OPh(Me)CH2) (5). An alternative approach was developed in synthesizing the mixed imido complex (ArN)(tBuN)Mo(PMe3)(η2-C2H4) (6) through EtMgBr reduction of (ArN)(tBuN)MoCl2(DME) in the presence of PMe3. Complex 6 reacts with various hydro- and chlorosilanes to give β-agostic silylamido complexes and in one case, when Me2SiHCl is the silane, leads to the silanimine complex (tBuN)Mo(η2-SiMe2-NAr)(Et)(η2-C2H4) (7). Mechanistic studies on the formation of the Mo(VI) tris(silyl) complex (tBuN)Mo(SiHPh)(H){(μ-NtBu)(SiHPh)}(PMe3)2 (8) were done from the addition of three equivalents of PhSiH3 to (tBuN)Mo(PMe3)(η2-C2H4), resulting in identification of β- and γ-agostic SiH…Mo intermediates. The reactivity of complex 8 towards ethylene and nitriles was studied. In both cases coupling of unsaturated substrates with the Mo-Si bond of the metalacycle was observed. In the case of nitriles, insertion into the 4-membered disilaazamolybdacycle results in complexes of the type (tBuN)Mo{(κ2-Si,C-SiHPh-NtBu-SiHPh-N=C(R)}(PMe3)2. Catalytic hydrosilylation of carbonyls mediated by the β-agostic silylamido complex (ArN)2Mo(η3-NtBu-SiMe2-H)(H) (9) was investigated. Stoichiometric reactions with organic substrates showed that catalysis with 9 does not proceed via the conventional insertion of substrate into the Mo-H bond.

Racemic and Enantioselective Total Syntheses of Mosquito Oviposition Pheromone from a Naturally Available Unsaturated Fatty Acid

The unnatural threo-6-acetoxy-5-hexadecanolide and the natural mosquito oviposition pheromone erythro-6-acetoxy-5-hexadecanolide were synthesized in a diastereodivergent fashion in 44% and 33% overall yield respectively from 5-bromovaleric acid and undecanal. The key step utilized a chemoenzymatic epoxidation-lactonization of a naturally available fatty acid to form the 6-hydroxy-5-hexadecanolide core.17 The epoxidation strategy was later adapted to allow for an asymmetric synthesis. Shi epoxidation afforded highly enantioenriched (5R, 6R)-6-hydroxyhexadecanolide (er = 10) in 70 % overall yield. Other derivatives of the chiral ketone catalyst were also screened. Finally, attempts were made to obtain the correct stereochemistry at C(6) of the target with a dynamic kinetic transformation using lipase and a transfer hydrogenation catalyst. Epimerization of the lactol with the transfer hydrogenation catalyst was successful, but lipase mediated reactions halted at <10 % conversion.