The complete lack of experimental evidence concerning the chemical and biological properties of nucleoside-2' and -3' polyphosphates led to the synthesis and characterization of some of these compounds, as reported in this thesis. Since the deoxyribonucleoside-3' polyphosphates were chemically analogous to their 5'-isomers,, the synthesis of deoxycytidine-3' di-, tri- and tetraphosphates and thymidine-3' di-, tri- and tetraphosphates were readily achieved in good yields. The isomeric 2'- and 3'-ribonucleoside polyphosphates were, on the other hand, expected to be much more labile than the corresponding ribonucleoside-5' polyphosphates because of the presence of a cis vicinal hydroxyl group, which facilitates the formation of nucleoside-2',-3' cyclic phosphates. Attempts to synthesize adenosine-3' polyphosphates by way of diacetylated or dipyranylated nucleotide intermediates were without success for the conditions required to remove the protecting groups resulted in concomitant degradation of the pyrophosphate linkages. Investigation of the reaction of adenosine-(2'),3' monophosphate with phosphoramidic acid, as an approach to the synthesis- of adenosine-(2'),3'-polyphosphates, surprisingly revealed that phosphoramidic acid, under certain conditions, not only formed pyrophosphate bonds, as expected, but also esterified free hydroxyl groups. The maximal rate of ester formation occurred in a neutral or mildly alkaline media, with preferential esterification of secondary hydroxyl functions. Attempts to extend this phosphorylation reaction to the synthesis of phospho-diesters were without success as mono- or dialkylated phosphoramidates did not exhibit phosphorylative properties. Although the 2'-and 3'-isomers of adenosine di- and triphosphates were identified as products of the reaction of adenosine-(2'),3' monophosphate with phosphoramidic acid, only adenosine-2' -diphosphate was fully characterized. The latter compound when treated with strong alkali underwent a rearrangement reaction which was unique in the field of nucleotide chemistry. If this alkaline rearrangement is found to be characteristic of all isomeric 2'- and 3'-nucleoside polyphosphates, it will be of considerable practical synthetic value. / Medicine, Faculty of / Biochemistry and Molecular Biology, Department of / Graduate

An attempt has been made to develop a model for predicting the course of an asymmetric alkylation. Thus, by considering the influence of an asymmetric center upon a reaction center located in an adjoining plane, a preferred conformation of the intermediate anion is selected. This conformation is used to predict the stereochemistry of the product. The model correctly predicts the stereochemical result of several reactions known in the literature. The (-) isobornyl and (-) menthyl esters of 2-methylbutyric acid were alkylated with 1-bromobutane in 42% yield. Both of the alkylated esters were reduced with lithium aluminium hydride and the 2-methyl-2-ethylhexan-1-ol isolated by gas-liquid chromatography was shown to be optically inactive. The lack of an observable rotation does not permit a critical evaluation of the proposed model in these instances. The major impurities present in the alkylation of the aforementioned esters, namely the n-butyl ether of the optically active alcohol, have been identified by independent syntheses. / Science, Faculty of / Chemistry, Department of / Graduate

I. Reactions of ∝-Linked Disaccharides Through reaction of specifically substituted maltoses, ∝-glucosidic disaccharide derivatives have been prepared. Catalytic oxidation of benzyl β-maltoside yielded maltobiouronic acid. Tritylation of 1,6-anhydro-β-maltose made possible the preparation of the 6'-0-tosyl ester. Replacement of the tosylate with azide ion followed by reduction and hydrolysis yielded a small amount of 6'-amino-6' deoxy-maltose. Replacement of the tosylate with thiolacetate allowed the preparation of 6'-deoxy-6’-mercapto-maltose. Iodide replacement of the sulphonyl ester followed by reduction gave the 6’-deoxy-1, 6-anhydro derivative which was converted to 6’-deoxy-maltose by acetolysis and deacetylation. A route for the preparation of 4-0-(∝-D-glucopy-ranosyluronic acid)-D-xylose by selective decarboxylation of maltosyldiuronic acid was attempted and found unfeasible. Attempts to prepare 6-substituted maltoses by reaction of benzyl 4',6'-0-benzylidene-β-maltoside with various reagents were unsuccessful. II. Synthesis of the 2,4-Di-0-methyl Tetroses The four isomeric 2,4-di-0-methyl tetroses were prepared by periodate oxidation of known methylated sugars. 2,4-Di-0-methyl-D-and L-erythroses were prepared from 4,6-di-0-methyl-D-glucose and 3,5-di-0-methyl-L-arabinose respectively. 2,4-Di-0-methyl-D-and L-threoses were prepared from 3,5-di-0-methyl-D-xylose and 1,4,6-tri-0-methyl-L-sorbose. The tetroses were characterized as their crystalline 2,4-dinitrophenylhydrazones. The Rf and RG values of the free sugars were recorded in a variety of solvents including a silica gel thin-layer chromatography system. / Science, Faculty of / Chemistry, Department of / Graduate

2, 4-Di-O-methyl-L-erythrose is thought to occur in the hydrolysis and periodate oxidation products of polysaccharides. This sugar has now been synthesized from methyl-L-arabofuranoside by tosylation, methylation, detosylation and periodate oxidation. The free sugar was obtained as a sirup and was characterized by the preparation of a crystalline phenylhydrazone and a crystalline p nitrobenzoate. / Science, Faculty of / Chemistry, Department of / Graduate

It is well established that various partially methylated tetroses and pentoses occur in periodate oxidation products of methylated polysaccharides. To provide reference compounds as a means of identifying some of these sugars 2,3 di-O-methyi-L-threose, 2,3 di-O-methyi-D-erythrose, and 3,4 di-O-methyl-L-xylose have been synthesized. The threose and xylose were synthesized from ∝-methyl-D-glucoside by benzylidene condensation, methyiation, hydrolysis, reduction and periodate oxidation, whereas the erythrose was obtained from D-mannose by a similar sequence of reactions. The sugars were obtained as syrups and were characterized by the preparation of crystalline derivatives. ii. Black Spruce hemicelluloses:- By using different concentrations of alkali three different hemiceiluloses were extracted from black spruce holocellulose. Of these two fractions, the xylan and the glucomannan were purified by fractional precipitation using barium hydroxide solution and Fehling's solution. Previous workers have observed that the xylan fraction was always contaminated by small amounts of galactose. This was also true in the present instance if barium hydroxide alone was used for purification, but when this was followed by two treatments with Fehling's solution the galactose was completely eliminated. This is believed to be the first case of the isolation of such a xylan in a pure state from the hemicelluloses of a coniferous wood. The third fraction - the galactoglucomannan was found to be quite difficult to re-dissolve in alkali and as a result its purification is not quite complete. / Science, Faculty of / Chemistry, Department of / Graduate

Two sequences leading to the total synthesis of several octahydrochrysene derivatives are described; in particular, the synthesis of B-nor-cis-2-methoxy-8α-acetoxy-5-keto-10a-methyl-5,6,7,8,9,10,10a-octahydrochrysene (XL) is achieved. In one sequence an olefinic bond at the 5,6 position of ring B (XXXII) was introduced by reduction of cis-2-methoxy-8α-acetoxy-5-keto-10a-methyl-5,6,6a, 7,8,9,10,lOa-octahydrochrysene (XIV) with sodium borohydride, followed by dehydration with phosphorus pentoxide.Subsequent reaction at the olefinic linkage by osmium tetroxide provided the α-diol (XXX), which upon treatment with periodic acid yielded a hemiacetal (XXXIV). Cyclization on alumina then provided the B-nor internal aldol condensation product (XXXIX). The latter readily underwent / oxidation with Jones' reagent to result in the B-nor-5-keto acetate (XL). In an alternate sequence the cis-2-methoxy-8α-acetoxy-5-keto-5,6,6a,7,8, 9,10, 10a-octahydrochrysene (XIV) is oximinated at the 6-position with isoamyl nitrite and the oxime is converted by acid hydrolysis to a 5,6-diketo-8-hydroxy compound (XLII). An attempt was made to accomplish a benzilic acid rearrangement on the α-diketo compound and the resulting product (XLVII) was subjected to lead tetra-acetate oxidation in the hope that the B-nor-5-keto system (XLVIII) could be obtained. The structures from the last two reactions were only tentatively established. A critical discussion of the n.m.r. data is reserved to a separate section of the thesis. Tentative assignments of all the aromatic protons were made. Of special note is the chemical shift dependence of the proton at C₄ on the substitution at C₅. Configurational and conformational assignments of the ring A/B system were made on the basis of angular methyl and 8β-proton frequencies. / Science, Faculty of / Chemistry, Department of / Graduate

The first part of this thesis describes a sequence which provides a total synthesis of cleavamine (23) and catharanthine (12). Dihydrocatharanthinol (76) obtained by lithium aluminum hydride reduction of dihydrocatharanthine (34) was converted to its tosylate derivative. The latter intermediate upon heating in benzene containing two equivalents of triethylamine underwent an interesting fragmentation reaction to provide a seco-diene (78) containing the cleavamine ring system. Reaction of this diene with osmium tetroxide provided a tetrol (96) which could be converted to cleavamine on the one hand and the C₄-functionalized cleavamine derivatives on the other. Thus treatment of the tetrol with sodium borohydride allowed the hydrogenolysis of the carbinol amine function and provided a triol (97). The vicinal diol present in 97 was cleaved by means of periodate and the resultant 2-acylindole chromophore was further converted by borohydride to a 4,18-dihydroxy dihydrocleavamine derivative (99). Reductive removal of the C₁₈ hydroxyl function by means of lithium aluminum hydride provided isovelbanamine (100). Acid catalyzed dehydration of the latter yielded cleavamine (23) while isomerization under aqueous acidic conditions provided velbanamine (22). To complete the total synthesis of catharanthine (12), cleavamine was reacted with t-butyl hypochlorite and the resultant chloroindolenine was then subjected to nucleophilic attack by cyanide ion to provide 18ϐ-cyanocleavamine. Basic hydrolysis of the nitrile function followed by esterification provided 18ϐ-carbomethoxycleavamine (60). This compound upon reaction with mercuric acetate was cyclized to catharanthine. The second part of this thesis establishes the utility of both the chloroindolenine and the C₁₈-hydroxy analogues of the cleavamine systems to the synthesis of dimeric compounds structurally similar to the natural dimeric alkaloids. Treatment of either of these analogues with vindoline under mild acidic conditions yielded the appropriate dimers containing the indole and dihydroindole units present in vincaleukoblastine. The dimerization reaction was shown to be stereospecific and led in each case to the same stereochemistry at C₁₈, of the resulting dimers / Science, Faculty of / Chemistry, Department of / Graduate

This thesis describes work leading to the completion of a total synthesis of the sesquiterpenoids (±)-prezizanol (188) and (±)-prezizaene (6). The known alcohol 128 was transformed, in three steps, into the endo-monochloride 156. The commercially available alcohol 129 was converted, in a two step sequence, into the vinyl iodide 127. Palladium catalyzed coupling of the vinyl iodide 127 with an organozinc compound derived from the chloride 156 provided the bicyclo[3.1.0]hexane 165. The bicyclo[3.1.0]hexane 165 was elaborated, in three steps, into the ester 172. Treatment of this ester with lithium diisopropylamide, followed by kinetic protonation of the resultant enolate anion, provided the endo-(1-alkenyl)-bicyclo[3.1.0]hex-2-ene 123, which cleanly underwent a Cope rearrangement to provide the bicyclo[3.2.1]octadiene 121. An attempt to cleanly synthesize 121 via the Cope rearrangement of the exo-(1-alkenyl)bicyclo-[3.1.0]hex-2-ene 122 was unsuccessful. A six step sequence was used to synthesize the mixture of silyl ethers 186 and 187 (88:12, respectively) from the bicyclo[3.2.1]octadiene 121. (±)-Prezizanol (188) was prepared, in a series of seven steps, from the silyl ether 186. Dehydration of (±)-prezizanol (188) provided (±)-prezizaene (6) in 2.2% overall yield from the alcohol 128. [Formula Omitted] / Science, Faculty of / Chemistry, Department of / Graduate

The major theme of the work described in this thesis is concerned with the preparation of the β-trimethylstannyl enoates 53, 54 and 55, and their utilization in annulation processes. Treatment of the enol triflates 88, 91 and 92 with the cuprate reagent 56 produces compounds 53, 54 and 55, respectively, in good yields. Base promoted alkylation of the enoates 53 and 54 with 3-iodo-1-chloropropane provides the products 111 and 119. Under similar reaction conditions, 55 was alkylated with 1,4-dibromobutane and 1,5-dibromopentane to give 132 and 136. By employing standard reactions, 111, 119, 132 and 136 were converted into 113, 123, 134 and 141, respectively. Treatment of 113, 123, 134 and 141 with methyllithium in THF, in the presence of HMPA, led to the formation of the substituted bicycle[4.3.0]nonenes 114, 124 and 128, and the bicyclo[5.3.0]decene 142, respectively. The annulation method described above was applied successfully to the synthesis of the sesquiterpenoid (±)-chiloscyphone (151) and its isomer (±)-S-epi-chilos-cyphone (203). Thus, reaction of compounds 182 and 183, which were derived from 54 and the alkylating agent 178, with methyllithium in THF-HMPA provided the key bicyclic intermediates 184 and 190, respectively. These two compounds were subsequently transformed into 151 and 203. The sesquiterpenoid eremofukinone, whose structure was proposed as 204, was synthesized by exploiting the annulation method described earlier. Treatment of compound 228, which was produced from 54 and the dibromide 223, with methyllithium in 1,2-dimethoxyethane afforded the key intermediate 229 along with the diene 230. Suitable chemical manipulations converted 229 into 204. On comparing the ¹H nmr spectra of 204 and eremofukinone, substantial differences were noticed. Since compound 204 was constructed by an unambiguous route, it was concluded that the original structural proposal for eremofukinone is in error. [Formula Omitted] / Science, Faculty of / Chemistry, Department of / Graduate

A number of conjugates of carbohydrates were prepared. Metal conjugates were synthesized in two different ways. Firstly, chelate coordination complexes were synthesized by forming salicylaldimine ligands derived from combinations of amino sugars [methyl-3,4,6-tri-0-acetyl-2-amino-2-deoxy-β-D-glucopyranoside, 1,3,4,6-tetra-0-acetyl-2-amino-2-deoxy-β-D-glucopyranose or 2-amino-2-deoxy-a,β-D-glucopyranose (glucosamine)] and either salicylaldehyde or 3-formyl-2-hydroxy-benzoic acid with subsequent complexation of these to copper (II) , cobalt (II), and zinc (II). A number of physical techniques were used to characterize these complexes including esr spectroscopy, visible absorption spectroscopy, mass spectrometry, nmr spectroscopy and magnetic susceptibility measurements. From the data provided by these techniques the copper-sugar complexes derived from salicylaldehyde were found in general to have the usual bis-bidentate structure. The copper complex derived from the amino-glycoside and 3-formyl-2-hydroxy-benzoic acid was found to be binuclear in structure containing two sugar moieties and two copper atoms. The second approach to forming metal sugar conjugates consisted of synthesizing organometallic π-complexes: ferrocenyl-sugar conjugates. A variety of organic- and water-soluble compounds were formed by reaction of amino, hydroxyl, or thio sugar groups with suitably substituted ferrocene derivatives. Thus organic soluble products were obtained from combinations of the sugars [l,3,4,6-tetra-0-acetyl-2-amino-2-deoxy- β-D-glucopyranose, l-thio-2,3,4,6-tetra-0-acetyl-β-D-glucopyranose, 1,2,5,6-di-0_-isopropylidene-α-D-glucofuranose and 1,2,3,4-di-o-isopropylidene-α-D-galactopyranose] with 1 - and 1,1'-ferrocenecarbonyl chlorides, N,N-dimethylaminomethylferrocene methiodide, (1-hydroxymethylferrocene)-p-toluenesulphonate and 2,4-dichloro-6-(1-hydroxymethylferrocene)-s-triazine. Water soluble products were prepared by deacetylation of some of the above compounds and by condensation of ferrocene carboxaldehyde with glucosamine to form the corresponding Schiff's base. Proton spin-lattice relaxation rates were used to assign the substituted cyclopentadienyl rings and to determine the relative spinning rates of the substituted and unsubstituted cyclopentadienyl rings. The chemistry of cyanuric chloride (2,4,6-trichloro-s-triazine), as a general means of derivatizing carbohydrates was also investigated. Thus, metals, hydrophobic alkyl groups and nitroxide spin labels were attached in various combinations to carbohydrates. A number of monosaccharide derivatives were formed including model glycolipids and a number of polysaccharides, cellulose, agarose, Sephadex, guar gum, xanthan gum and starch were spin labelled using this chemistry. For polysaccharides, information such as extent of derivatization, evidence for a covalent bond, environment of the triazine unit and the distance between triazine units was obtained. This chemistry was also extended to derivatize Bovine Serum Albumin, microporous glass beads and aluminum oxide. / Science, Faculty of / Chemistry, Department of / Graduate