The work described in this study aims to investigate methods that will improve a lengthy synthetic pathway in the synthesis of the P57 cymarose moiety, and to examine the conformational structure of certain glycosides in order to shed light on the problematic stereochemical issues surrounding the formation of the cymarose glycosyl donor. The cymarose moiety forms part of the trisaccharide derivative present in P57, an appetite suppressant molecule. Modification of reaction steps in the conversion of the stereochemistry at C-3 of a previously reported synthesis of the P57 cymarose moiety was carried out. The first step was the selective oxidation of D-glucal using Pd/C in the presence of acetonitrile. These reaction conditions are more appropriate for the oxidation step to avoid decomposition of the formed molecules. Successive protection of the free OH groups was followed by NaBH4 reduction under stereo-controlled conditions, influenced by CeCl3•7H2O. However, the reduced product could not be isolated from the starting material and this led to ambiguous results when attempting to confirm whether the conversion of the stereochemistry at C-3 had occurred or not. The effect of reaction conditions, such as change in reaction temperature, during the preparation of the cymarose glycosyl donor was studied in order to find suitable reaction conditions to produce α,β-allo derivatives with high stereoselectivity. Compared to the reported synthetic method, this set-up gave improved yields with, unfortunately, similar or slightly lower selectivity to the formation of α-altro:α,β-allo derivative. Examination of the conformational structure of the allal derivative, in order to understand the mechanism at work during the placement of the directing group at C-2, was carried out using molecular modelling. The mechanistic implications of this very short study are discussed and it provides some insights into the likely pathway of the iodination reaction and its selectivity in particular, to the D-allose system.

A sequence leading to the total synthesis of certain derivatives in the 11, 12-seco (see XXIV) and 5, 6-seco hydro-chrysene (see XXXI) series is described. The synthesis employs in its initial stages the Robinson-Mannich base reaction and the Michael condensation reaction to construct the parent tetracyclic skeleton. Condensation of 6-methoxy-2-tetralone with 1-diethylamino-3-pentanone methiodide produced an isomeric mixture of tricyclic ketones. This mixture was then condensed with methyl vinyl ketone to yield a tetracyclic ketol (XII) which in turn was converted to the tetracyclic ketone (XIII) by reaction with sodium methoxide. By appropriate modifications, this latter substance may then be utilized for the synthesis of a variety of hydrochrysene analogues. Oxidation of trans-anti-trans-2-methoxy-8β-acetoxy-10a -methyl-4b, 5, 6, 6a, 7, 8, 9, 10, 10a, 10b, 11, 12-dodecahydrochrysene (XVI) with t-butyl chromate solution gave not only the 12-keto derivative (XIX), but the 5-keto octahydrochrysene analogue (XX) as well as small amounts of the octahydrochrysene (XVII) and the hexahydrochrysene analogue (XVIII). The olefinic bond at the 11, 12 position of ring C (XXII) was introduced by reduction of the 12-keto derivative (XIX) with sodium borohydride, followed by dehydration with phosphorus pentoxide. Subsequent ozonization of XXII yielded the dialde-hyde (XXIV). The olefinic bond at the 5, 6 position of ring B (XVIII) was introduced by the same procedure as in the ring C series. This hexahydrochrysene analogue (XVIII) was reacted with osmium tetroxide to provide the diol (XXVI), which upon treatment with periodic acid yielded the aldol condensation product directly without isolation of the dialdehyde. Nuclear magnetic resonance (n. m. r.) spectroscopy was found to be a powerful tool for the purpose of the characterization of these rather complex molecules. / Science, Faculty of / Chemistry, Department of / Graduate

The ozonization of 7-ketocholesteryl acetate has yielded 5-keto-5, 7-seco-6-nor-3-cholesten-7-oic acid, an intermediate useful in the preparation of 6-azacholestane. Catalytic hydrogenation converted this intermediate to 5-keto-5,7-seco-6-norcholestan-7-oic acid which, upon treatment with benzyl amine, gave N-benzyl-6-aza-4-cholesten-7-one. Catalytic reduction of this enol-lactam yielded N-benzyl-6-azacholestan-7-one which was reduced with lithium aluminum hydride to N-benzyl-6-azacholestane. The generality of this route was shown when it was applied to compounds of the androstane series. Ozonization of 3β,17β-dihydroxy-5-androsten-7-one diacetate gave 17β-hydroxy-5-keto-5,7-seco-6-nor-3-androsten-7-oic acid which was hydrogenated catalytically to 17β-hydroxy-5-keto-5,7-seco-6-norandrostan-7-oic acid. This saturated acid ring—closed with benzyl amine to yield 17β-hydroxy-N-benzyl-6-aza-4-androsten-7-one. Catalytic hydrogenation of this enol-lactam gave 17β-hydroxy~N-benzyl-6-azandrostan-7-one which was reduced with lithium aluminum hydride to N-benzyl-6-azaandrostan-17β-ol. A mild chromic acid oxidation converted the alcohol to the keto compound, N-benzyl-6-azaandrostan-17-one. / Science, Faculty of / Chemistry, Department of / Graduate

Certain aromatically substituted phenyl vinyl ethers were prepared by means of a two-step synthesis involving first, the synthesis of the corresponding beta-chlorophenetole derivative and subsequently treating this compound with flake potassium hydroxide to yield the vinyl ether. The beta-chlorophenetole derivatives prepared were: ortho-methyl-, meta-methyl-, para-methyl-, ortho-methoxy-, para-methoxy-, ortho-chloro-, and ortho-phenyl-beta-chlorophenetole. The vinyl ethers prepared were: phenyl, ortho-methyl-, meta-methyl-, and para-methyl-phenyl vinyl ether. Allyl phenyl ether was also prepared. The polymeric properties of these ethers were investigated. 2-aminovanillin was prepared from vanillin and its condensations with anthranilic acid, ortho-toluidine, ortho-phenylenediamine, and ortho-aminophenol were attempted. Diagnostic derivatives of 2-aminovanillin were also prepared: 2-acetaminovanillin, 2-aminovanillin phenylhydrazone, 2-aminovanillin 2,4-dinitrophenylhydrazone. / Science, Faculty of / Chemistry, Department of / Graduate

The synthesis of 2:3-benzo-1,1-dimethyl-1-silacyclo-hex-2-ene has been reported. This compound was prepared by the simultaneous addition of 3-(o-bromophenyl)-propyl bromide and dichlorodimethylsilane to excess magnesium in tetra-hydrofuran. The six-membered ring organosilicon compound was readily brominated by N-bromosuccinimide to give the 4-derivative. Attempts were then made to synthesize the 4-cyano and the 4-carboxylate derivatives from this bromination product. Experimental data are also given for an attempted preparation of 2:3-benzo-4-(2-dimethylaminoethoxy)-1,1-dimethyl-1-silacyclohex-2-ene. / Pharmaceutical Sciences, Faculty of / Graduate

A study involving both the applications of internuclear double resonance (INDOR) spectroscopy and the synthesis of carbohydrates containing organometallic substrates was undertaken. The thesis is divided into two sections to facilitate discussion. The first section involves an evaluation of homonuclear and heteronuclear INDOR as a tool for spectral analysis. Homonuclear INDOR studies of carbohydrate derivatives such as 2-deoxy-a-D-arabino-hexo-pyranose(l), sucrose octaacetate(2) and D-ribose(3) have shown this technique to be extremely effective for analysing multi-line spectra having hidden transitions. Within certain power-level ranges, the resolution of the INDOR responses is comparable to that of the normal proton spectra. Heteronuclear INDOR spectra were obtained indirectly by monitoring specific transitions in the proton spectra while irradiating the appropriate heteronuclear frequency. In this manner, the methoxy-methyl ¹³C INDOR shift of a number of anomeric gluco- and xylo-pyranoside derivatives were measured. The ¹³C shifts of the α anomers were found to be ca. 2 ppm to high field of the β anomer. This difference is more diagnostic than the small 0.1 ppm variation between two methoxy-methyl anomers in the ¹H n.m.r. spectra. Such diagnostic differences were not found for the acetoxy-methyl ¹³C shifts of anomeric sugar acetate derivatives. Other heteronuclear INDOR spectra were readily obtained for organo-metallic compounds such as trimethylphosphite(15), trimethyltin chloride (16), bromosilane(17) and tetramethyl lead(18). The second section of the thesis deals with the synthesis of some phosphorus and organometallic derivatives of monosaccharides. Treatment of various primary O-tosyl sugar derivatives with lithium diphenyl-phosphine reagent ,19, gave, in ca. 70% yields, such products as diphenyl {1,2 :3,5-di-0-methylene-α-D-glucofuranose} 6-C-phosphine oxide(20b), diphenyl {methyl 2,3,4-tri-0-acetyl-α-D-glucopyranoside} 6-C-phosphine oxide(21b) and diphenyl {l,2:3,4-di-0-isopropylidene-α-D-galactopyranose} 6-C-phosphine oxide(22b). The facile preparation of 22b is rather unique because of the known resistance of the O-tosyl group of the sugar reactant toward nucleophilic displacement. Diphenyl {3,6-anhydro-l,2-0-isopropylidene-α-L-idofuranose} 5-C-phosphine oxide(24b) was obtained in 31% yield via nucleophilic displacement of the corresponding 5-0-mesyl derivative using 19_. This typified the much lower yields obtained from secondary sulphonyl displacements. Other secondary sugar diphenyl-phosphine oxide derivatives were prepared in 50-70% yields from the opening of sugar epoxides with 19_. Notably, the scission of the epoxide bond of methyl 2,3-anhydro-3-L-ribopyranoside(29) gave diphenyl ^methyl 2,4-0-acetyl-B-L-xylopyranosidej. 3-C-phosphine oxide(30). The product was found to favour the conformation in which all the major substituents are axial. The ³¹P chemical shifts for all the sugar diphenylphosphine oxide , derivatives were measured using the INDOR technique. These shifts provided confirmation that the products were phosphine oxides. It was further shown by use of ³¹P decoupling that ³JpH ranges of 6.6-11.8 Hz and 22-33 Hz for 60° and 180° dihedral angles respectively, were present in these products. These couplings are similar to those reported for, vicinal P-H couplings in hydroxy phosphonate derivatives. Preliminary experiments, undertaken to evaluate the effectiveness of other organometallics such as lithium triphenyltin(33), lithium tri-phenyllead(34) and lithium triphenylsilane (35) , showed 33 to be an effective reagent for displacing primary O-tosylates and opening epoxides of sugar derivatives. Both 34 and 35 gave poor yields when used to displace the 0-tosylate group of 20b. Generally, organometallic species were shown to provide a viable means of synthesizing novel sugar derivatives. / Science, Faculty of / Chemistry, Department of / Graduate

This thesis describes the syntheses of the molecules 11-aza-pentacyclo[6.2.1.0²՚⁷. 0⁴,⁹.0⁵, ¹⁰]decane (28) and 4,5-dimethyl-11-aza-pentacyclo [6.2.1 .0²,⁷. 0⁴,⁹.0⁵,¹⁰ ] decane (29). Owing to their structural similarities to 1-aminoadamantane (an anti-viral and anti-Parkinson's disease agent), they might possess activities against influenza viruses and/or Parkinson' disease. The key intermediates involved were the two cage ketols namely, 10-exo-hydroxytetracyclo-[5.3.0.0²,⁶.0⁴,⁹]decan-3-one (33a) and 6,7-dimethyl-10-exo-hydroxytetracyclo [5.3.0. 0²,⁶.0⁴,⁹]decan-3-one (33b) which were prepared via a three-step sequence starting from p-benzoquinone , 1,3-butadiene and 2,3-dimethyl-1,3-butadiene respectively. The incorporation of the required nitrogen atoms was done by transforming the ketone groups of compound 33a and 33b into the corresponding oxime and oxime ether. Generation of the amine functional groups and building of the nitrogen bridges were achieved in a single step by reduction of the oxime derivatives employing aluminium hydride as the reducing agent. The syntheses of compound (28) and (29) were therefore accomplished via a five-step reaction sequence (scheme III) starting from p-benzonquinone and the corresponding butadienes. / Science, Faculty of / Chemistry, Department of / Graduate

D.Phil. (Chemistry) / Please refer to full text to view abstract

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemistry, 1976 / Vita. / Includes bibliographical references. / Ph. D. / Ph. D. Massachusetts Institute of Technology, Department of Chemistry

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