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.''

Aryl hydroxamic acid analogues as potential therapeutic agents /

A new synthetic pathway to analogues of the aglucones of naturally occurring cyclic hydroxamic acids (2,4-dihydroxy-l,4-benzoxazin-3-ones) has been developed. The new pathway involves the coupling of substituted nitrophenols wdth /-propyl-abromo- O-methoxymethylglycolate. These materials were reductively cyclised to reveal the hydroxamic acid functionality. Removal of the C-2 0-methoxymethyl protecting group was achieved chemoselectively using boron trichloride. The analogue 7-methoxy-2,4-dihydroxy-l,4-benzoxazin-3-one (DIMBOA) was assayed with papain and a semilog plot of activity of papain in the presence of excess DIMBOA was found to be linear. A single exponential equation was suggested as the model for kinetic analysis. '^ Nuclear magnetic resonance (NMR) spectra of a couple of hydroxamates were acquired as reference standards for future mechanistic studies of these compounds as thiol protease inhibitors. A 10% '^-labeled sample ofDIMBOA was also prepared for future mechanistic studies using NMR techniques.

Synthesis of chiral homoallylic alcohols and phthalans through the asymmetric allylation of carbonyl compounds /

The implementation of chiral centres within biologically active compounds has been a perplexing yet motivational force in chemistry. This work presents the attempted formation of a concurrent or sequential tandem catalyzed methodology of enantioselective nucleophilic addition and electrophilic cyclization. The 2'- arylalkynyl- aldehyde, ketone, and imine substrates used within were adeptly chosen with a dually activated structure; 1) for nucleophilic addition to the electrophilic substituents; and 2) for carbophilic activation of the alkyne substituent to undergo cyclization. To accomplish the nucleophilic addition, two distinct allylation methodologies were pursued: (/?)-BINOL catalyzed-allylboration and (5)- BINAP-AgF catalyzed-allylsilylation. BINAP catalyzed enantioselective allylation of 2'-arylalkynyl-aldehydes, to form chiral homoallylic alcohols, was successful. Homoallylic alcohols were isolated with high enantio-purity (>80%), which then underwent sequential cyclization to form chiral allylic phthalans, in moderate yields. An application of this methodology towards the construction of biologically active compounds was included with the partial synthesis of the natural product and H. pylori inhibitor, (+)-Spirolaxine methyl ether.

Synthesis of isotope-labelled methoxypyrazine compounds as internal standards and quantitative determination of aroma methoxypyrazines in water and wines by solid-phase extraction with isotope dilution-GC-MS /

An efficient way of synthesizing the deuterium labelled analogues of three methoxypyrazine compounds: 2-d3-methoxy-3-isopropylpyrazine, 2-d3-methoxy-3- isobutylpyrazine, and 2-d3-methoxy-3-secbutylpyrazine, has been developed. To confirm that the deuterium labels had been incorporated into the expected positions in the molecules synthesized, the relevant characterization by NMR, HRMS and GC/MS analysis was conducted. Another part of this work involved quantitative determination of methoxypyrazines in water and wines. Solid-phase extraction (SPE) proved to be a suitable means for the sample separation and concentration prior to GC/MS analysis.Such factors as the presence of ethanol, salt, and acid have been investigated which can influence the recovery by SPE for the pyrazines from the water matrix. Significantly, in this work comparatively simple fractional distillation was attempted to replace the conventional steam distillation for pre-concentrating a sample with a relatively large volume prior to SPE. Finally, a real wine sample spiked with the relevant isotope-labelled methoxypyrazines was quantitatively analyzed, revealing that the wine with 10 beetles per litre contained 138 ppt of 2-methoxy-3-isopropylpyrazine. Interestingly, we have also found that 2-methoxy-3-secbutylpyrazine exhibits an extremely low detection limit in GC/MS analysis compared with the detection limit of the other two methoxypyrazines: 2- methoxy-3-isopropylpyrazine and 2-methoxy-3-isobutylpyrazine.

Biotransformation of polycylic aromatic compounds by fungi and an investigation into the oxidation of alkylbenzenes by Mortierella isabellina NRRL 1757

Incubations of several polycyclic heteroaromatic compounds and two polycyclic aromatic hydrocarbons with a series of common fungi have been performed. The fungi Cunninghamella elegans ATCC 26269, Rhizopus arrhizus ATCC 11145, and Mortierella isabellina NRRL 1757 were studied in this regard. Of the aza heteroaromatics, only dibenzopyrrole gave a ring hydroxylated product following the incubation with C. elegans. From the thio heteroaromatics studied, dibenzothiophene was metabolized by all the three fungi and thioxanthone by C. elegans and M. isabellina giving sulfones and sulphoxides. Thiochromanone was metabolized stereoselectively to the corresponding sulphoxide by C. elegans. Methyl substituted thioxanthones on incubation with C. elegans produced oxidative products, arising from S -oxidation and hydroxylation at the methyl group. Of the cyclic ketones studied, only fluorenone was reduced to hydroxyfluorene and this metabolism is compared with that reported with cytochrome P-450 monooxygenases of hepatic microsomes. A series of para-substituted ethylbenzenes has been transformed stereoselectively to the 1-phenylethanols by incubation with M. isabellina. Comparisons of the enantiomeric purities obtained from products with their respective para substituent of the same steric size but different electronic properties indicate that the stereoselectivity of hydroxylation at benzylic carbon may be susceptible to electron donating or withdrawing factors in some cases, but that observation is not va lid in all the comparisons. The stereochemistry of the reaction is discussed in terms of three possible steps, ethylbenzene ---) 1-phenylethanol ---) acetophenone ---) 1-phenylethanol. This metabolic pathway could account for the inconsistencies observed in the comparisons of optical purities and electronic character of para substituents. Furthermore, formation of 2-phenylethanol (in some cases), l-(p-acetylphenyl)ethanol from p-diethylbenzene, and N-acetylation of p-ethylaniline was observed. n-Propylbenzene was also converted to optically active 1-phenylpropanol. Acetophenone, p-ethylacetophenone, and o(,~,~-trifluoroacetophenone were transformed to 1-phenylethanol, l-(p-ethylphenyl)ethanol, and 1-phenyl-2,2,2-trifluoroethanol, respectively, with high chemical and excellent optical yields. The 13 C NMR spectra of several substrates and metabolic products have been reported and assigned for the first time.

Fast atom bombardment and electron impact mass spectrometry studies of some aryltin compounds and ferrocenes

Both El MS and FAB MS behavior of two groups of compounds, aryltin and ferrocene compounds, have been studied. For the aryltin compounds, the effect of substituent group position, substituent group type and ligand type on the El spectra have been explored in the El MS studies. The fragmentation mechanism has been investigated under El with linked scans, such as fragment ion scans(BJE), parent ion scans(B2JE) and constant neutral radical loss scans(B2(1-E)JE2). In the FAB MS studies, matrix optimization experiments have been carried out. The positive ion FAB MS studies focused on the effect of substituent group position, substituent group type and ligand type on the spectra. The fragmentation mechanisms of all the samples under positive ion FAB have been studied by means of the linked scans. The CA positive ion FAB fragmentation studies were also carried out for a typical sample. Negative ion FAB experiments of all the compounds have been done. And finally, the comparison of the El MS and FAB MS has been made. For ferrocenes, the studies concentrated on the fragmentation mechanism of each compound under El with linked scan techniques in the first field-free region and the applicability of positive/negative ion FAB MS to this group of compounds. The fragmentation mechanisms under positive ion FAB of those ferrocenes which can give positive ion FAB MS spectra were studied with the linked scan techniques. The CA +ve F AB fragmentation studies were carried out for a typical sample. Comparison of the E1 MS and FAB MS has been made.

Investigation of the composition of linear alkylbenzenes with emphasis on the identification and quantitation of some trace compounds using GS/MS system in both electron impact and chemical ionization modes

Linear alkylbenzenes, LAB, formed by the Alel3 or HF catalyzed alkylation of benzene are common raw materials for surfactant manufacture. Normally they are sulphonated using S03 or oleum to give the corresponding linear alkylbenzene sulphonates In >95 % yield. As concern has grown about the environmental impact of surfactants,' questions have been raised about the trace levels of unreacted raw materials, linear alkylbenzenes and minor impurities present in them. With the advent of modem analytical instruments and techniques, namely GCIMS, the opportunity has arisen to identify the exact nature of these impurities and to determine the actual levels of them present in the commercial linear ,alkylbenzenes. The object of the proposed study was to separate, identify and quantify major and minor components (1-10%) in commercial linear alkylbenzenes. The focus of this study was on the structure elucidation and determination of impurities and on the qualitative determination of them in all analyzed linear alkylbenzene samples. A gas chromatography/mass spectrometry, (GCIMS) study was performed o~ five samples from the same manufacturer (different production dates) and then it was followed by the analyses of ten commercial linear alkylbenzenes from four different suppliers. All the major components, namely linear alkylbenzene isomers, followed the same elution pattern with the 2-phenyl isomer eluting last. The individual isomers were identified by interpretation of their electron impact and chemical ionization mass spectra. The percent isomer distribution was found to be different from sample to sample. Average molecular weights were calculated using two methods, GC and GCIMS, and compared with the results reported on the Certificate of Analyses (C.O.A.) provided by the manufacturers of commercial linear alkylbenzenes. The GC results in most cases agreed with the reported values, whereas GC/MS results were significantly lower, between 0.41 and 3.29 amu. The minor components, impurities such as branched alkylbenzenes and dialkyltetralins eluted according to their molecular weights. Their fragmentation patterns were studied using electron impact ionization mode and their molecular weight ions confirmed by a 'soft ionization technique', chemical ionization. The level of impurities present i~ the analyzed commercial linear alkylbenzenes was expressed as the percent of the total sample weight, as well as, in mg/g. The percent of impurities was observed to vary between 4.5 % and 16.8 % with the highest being in sample "I". Quantitation (mg/g) of impurities such as branched alkylbenzenes and dialkyltetralins was done using cis/trans-l,4,6,7-tetramethyltetralin as an internal standard. Samples were analyzed using .GC/MS system operating under full scan and single ion monitoring data acquisition modes. The latter data acquisition mode, which offers higher sensitivity, was used to analyze all samples under investigation for presence of linear dialkyltetralins. Dialkyltetralins were reported quantitatively, whereas branched alkylbenzenes were reported semi-qualitatively. The GC/MS method that was developed during the course of this study allowed identification of some other trace impurities present in commercial LABs. Compounds such as non-linear dialkyltetralins, dialkylindanes, diphenylalkanes and alkylnaphthalenes were identified but their detailed structure elucidation and the quantitation was beyond the scope of this study. However, further investigation of these compounds will be the subject of a future study.

NMR studies of mixed tetrahaloborates and some related boron trihalide complexes /|nGary John Schrobilgen. -- 260 St. Catharines, Ont. : [s. n.],

Nuclear magnetic resonance spectroscopy has been used to study donor-acceptor complexes of boron trifluoride with several ureas, tetramethylthiourea, tetramethylselenourea, and tetramethylquanidine as well as adducts of tetramethyl- -urea with BF2Cl, BFC1 2 , and BC1 3 - A large number of mixed tetrahaloborate ions, including some of the ternary ones such as BF2CIBr-,have been obtained by ligand exchange reactions and studied by NMR techniques. The bonding in these ions is of the same inherent interest as the bonding in the isoelectronic tetrahalomethanes which have been the subject of many detailed studies and have been involved in a controversy concerning the existence of and the nature of "fluorine hyperconjugation" or C-F P1T- Pn bonding_ Ligand exchange reactions also gave rise to the difluoroboron cation, (TMU)20BF2+o The difluoroboron cation has been observed in solutions of TMU-BF3 , and has been proposed as a possible intermediate for fluorine exchange reactions in BF3 adducts.

Reactions of polyhalogenated aromatic compounds and related ethers with metal/ammonia solutions

This work contains the results of a series of reduction studies on polyhalogenated aromatic compounds and related ethers using alkali metals in liquid ammonia. In general, polychlorobenzenes were reduced to t he parent aromatic hydrocarbon or to 1 ,4-cyc1ohexadiene, and dipheny1ethers were cleaved to the aroma tic hydrocarbon and a phenol. Chlorinated dipheny1ethers were r eductive1y dechlorinated in the process. For example, 4-chlorodipheny1- ether gave benzene and phenol. Pentach1orobenzene and certain tetrachlorobenzenes disproportionated to a fair degree during the reduction process if no added proton source was present. The disproportionation was attributed to a build-up of amide ion. Addition of ethanol completely suppressed the formation of any disproportionation products. In the reductions of certain dipheny1ethers , the reduction of one or both of the dipheny1ether rings occurred, along with the normal cleavage. This was more prevalent when lithium was the metal used . As a Sidelight, certain chloropheno1s were readily dechlorinated. In light of these results, the reductive detoxification of the chlorinated dibenzo-1,4-dioxins seems possible with alkali metals in l iquid ammonia.

Some aspects of the chemistry of Reissert compounds / |nDurga Prasad Aysola. -- 260 St. Catharines [Ont. : s. n.],

1-(0- and m-Ohlorobenzoyl)isoquinolines have been synthesized by two routes involving Reissert compounds. One route involves condensation of 2-benzoyl-l,2-dihydroisoquinaldonitrile with the appropriate chlorobenzaldehyde and the second involves rearrangement of the appropriate Z-(chlorobenzoyl)-l,Z-dihydroisoquinaldonitrile under basic conditions. The action of potassamide in anhydrous liquid ammonia on both ketones gave unexpectedly N-(l-isoquinolyl)benzamide (67) as the major product and the use of dibenzo-18-crown-6-ether 98% substantially improved the yd..e.ld in the case of l-chloroketone. This amide (67) exhibits unusual hydrogen bonding. 1-(o-chlorobenzoyl)-6,7-dimethoxyisoquinoline (79) was prepared in very s,amll quantities by the route involving condensation of 2-benzoyll, Z-dihydro-6,7-dimethoxyisoquinaldonitrile with o-chlorobenzaldehyde. The poor yields are due to the instability of the anion of 2-benzoyl1, Z-dihydro-6,7-dimethoxyisoquinaldonitrile. Attempted preparation of the ketone (79) by rearrangement of 2-(o-chlorobenzoyl)-l,2-dihydro6,7- dimethoxyisoquinaldonitrile under basic conditions yielded the start~ng material (Reissert compound) and 6,7-dimethoxyisoquinoline. The action of potassamide in anhydrous liquid ammonia on l-(o-bromo-4,5-dimethoxybenzoyl)isoquinoline (85), which was prepared by the route involving the condensation of 2-benzoyl-l,4-dihydroisoquinaldonitrile with o-bromo-4,5-dimethoxybenzaldehyde, gave two products, which have not yet been identified. The ketone (85) and its precursors are interest~ng in that their 20 eV and 70 eV mass spectra do not show molecular ions.

Some aspects of the chemistry of 1, 3, 4 - Thiadiazolium salts and related compounds

The work described in this thesis has been divided into seven sections. The first section involves the preparation of N'-acyl-N'-arylN- benzothiohydrazides by the acylation of N'-aryl-N-benzothiohydrazides and is followed by a brief discussion of their possible conformation in solution. The second section deals with the preparation of 1,3,4-thiadiazolium salts by the action of perchloric acid/acetic anhydride on N'-acylN'- aryl-N-benzothiohydrazides and also by the reaction of N'-arylN- benzothiohydrazides with nitriles in an acidic medium. The preparation of 2-methylthio-I,3,4-thiadiazolium methosulfate by methylating the corresponding thione is also described. The third section deals with the reaction of 2-phenyl- and 2-methyl-I,3,4-thiadiazolium salts with alcohols in the presence of base. The stability and spectra of these compounds are discussed. Treatment of the 2-methyl-I,3,4-thiadiazolium salt with base was found to give rise to a dimeric anhydrobase and evidence supporting its structure is given. The anhydrobase could be trapped by a variety of acylating and thioacylating agents before dimerization occurred. In the fourth section, the reaction of N'-acyl-N'-aryl-N-benzothiohydrazides with a variety of acid anhydrides is described. These compounds were found to be identical with those obtained by acylating the anhydrobase. The mass spectral fragmentation of these compounds is described and the anomolous product obtained upon thiobenzoylation of 3-methyl-l-phenyl-pyrazal-5-one is also discussed. The fifth section deals with thioacyl derivatives of the anhydrobase which were prepared by the action of phosphorus pentasulfide upon the oxygen analogues and also obtained as the major product of the reaction of thioacetic acid with compounds related to N'-aryl-N-benzothiohydrazides. The mass spectra and p.m.r. spectra of these compounds are discussed. In the sixth section, the reaction of the 2-methylthio-l,3,4- thiadiazolium salt with active methylene compounds to give acyl and diacyl derivatives of the anhydrobase is described. Some aspects of these compounds are discussed. The seventh section describes the synthesis of ncyanine~' type dyes incorporating the l,3,4-thiadiazole ring and their spectra are briefly discussed.

Studies of tetrahedral haloboron cations of pyridines and aliphatic tertiary amines

The preparation of the haloboron cations D2BF2 + and DD'BF 2+, where D=R3N or a pyridine, has been systematically . 19 11 studied uS1ng F and B n.m.r. Both types of amines form numerous difluoroboron cations by heavy halogen displacement from D.BF 2X (X=CI,Br) adducts. Previously, D.BFX2 (X=CI,Br) adducts of aliphatic tertiary amines were unreactive towards cation formation. However, with the more-reactive pyridines, D.BFX 2 adducts formed new monofluoroboron cations D2BFX+ In non-fluorinated D.BX Y3 systems for n -n both pyridines and R3N, haloboron cations of type D2BX2 + and D2BXY+ can be similarly prepared. FAB-MS studies of ionic salts of our haloboron cations resulted in m/z peaks characteristic of D2 BX2 + and its f ragmentation products. These results s upport our n.m.r. solution s t u d ies. Pairwise interaction n . m.r . parameters for tetrahedral boron halide species were def i ned, then used to assist confirmation of our haloboron cations.

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.

The satellite band patterns in the near ultraviolet absorption spectra of isotopic compounds of acetaldehyde

The 3700 A - 3000 A absorption spectra of CH3CHO and its isotopic compounds such as CH3CDO, CD3CHO and CD3CDO were studied in the gas phase at room temperature and low temperatures. The low resolution spectra of the compounds were recorded by a 1.5 m Baush and Lomb grating spectrograph. The high resolution spectra were recorded by a Ebert spectrograph with the Echelle grating and the holographic grating separately. The multiple reflection cells were used to achieve the long path length. The pressure-path length used for the absorption spectrum of CH 3CHO was up to 100 mm Hg )( 91 . 43mo The emission spectrum and the excitation spectrum of CH3CHO were also recorded in this research. The calculated satellite band patterns \vhich were ob-tailied by the method of Lewis were used to compare with the observed near UV absorption spectrum of acetaldehyde. These calculated satellite band patterns belonged to two cases: namely, the barriers-in-phase case and the barriers- out-of-phase case. Each of the calculated patterns corresponded to a stable conformation of acetaldehyde in the excited state . The comparisons showed that the patterns in the observed absorption spectra corresponded to the H-H eclipsed conformations of acetaldehyde in the excited state . The least squares fitting analysis showed that the barrier heights in the excited state were higher than in the ground state. Finally, the isotopic shifts for the isotopic compounds of acetaldehyde were compared to the compounds with the similar deuterium substitution.