The scope of microwave induced synthesis of various cyclic compounds was investigated and considerably expanded. The advantages of this synthetic method were clearly demonstrated when compared to conventional heating methods of organic synthesis. The exposure of organic compounds to continual Ultraviolet (UV) radiation damages the materials and reduces their chemical and physical properties and in most cases irreversibly and this is not only a concern for industry but for consumers as well. Particularly prevalent are incidences of skin cancer now linked to UV radiation. Research efforts are directed towards finding cheap and efficient UV-absorbers to protect such light sensitive materials. Phenyl salicylates and hydroxybenzophenones constitute families of UV-absorber compounds, and this has necessitated this research. The condensation of differently substituted phenols with salicylic acid, catalyzed by either phosphoric acid (PPA), POCl3/ZnCl2 or ZnCl2 afforded the anticipated phenolic type UV -absorber molecules such as phenyl salicylate, 4-hydroxyphenyl-2-hydroxybenzoate, 2,3-dihydroxyphenyl-2-hydroxyphenylbenzoate, 3-hydroxyphenyl-2-hydroxybenzoate, (2,4-dihydroxyphenyl)(2-hydroxyphenyl)methanone, (2,3-dihydroxyphenyl)(2-hydroxyphenyl) methanone and 1,3-dihydroxyxanthone. PPA proved to be a more efficient catalyst for the condensation of salicylic acid with phenol, hydroquinone, pyrogallol and catechol while POCl3/ZnCl2 gave higher yields for resorcinol and phloroglucinol. In all cases, ZnCl2 alone did not show significant yield enhancement. The second part of this research work describes a convenient one-pot synthesis of NMethyl-2-pyrrolidone (NMP) an important industrial solvent by a conventional heating process and by microwave irradiation. The intermediate N-Methyl-hydroxybutyramide formed from the exothermic reaction of =-butyrolactone with aqueous monomethylamine, underwent an intramolecular condensation reaction catalyzed by highly active copper powder to form the anticipated product in very good yields.

 A palladium-catalyzed oxidative cascade cyclization reaction has been developed to prepare pyrrolizidine and indolizidine derivatives from simple aliphatic alkenyl amides 2.1ak in one step in moderate to good yields, using Pd(TFA)2 as the catalyst and molecular oxygen (1 atm) as a green oxidant. This cascade cyclization can also proceed for ring-containing unsaturated amides 2.1ln to afford azatricyclic systems. Palladium(II)-catalyzed dehydrohalogenation cascade cyclization reactions have been developed to synthesize polycyclic pyrrolizidine derivatives from iodoalkenylanilides 4.1ai in satisfactory to excellent yields under mild conditions. This reaction produces two stereocenters in one step and only one single diastereomer was obtained in the cyclization of 4.1. The reaction is proposed to proceed through an organopalladium(IV) species, formed by oxidative addition after the aminopalladation. This organopalladium(IV) species then undergoes reductive elimination to give the cyclized product. This cyclization is a fast and efficient way to construct natural alkaloids that contain pyrrolizidine or indolizidine cores. / published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

The previously unreported 3-methyltetrahydrothiophene I-oxide (<u>1</u>) and 3-methyl-2, 5-dihydrothiophene I-oxide (<u>2</u>) have been prepared by oxidation of the corresponding sulfides. The structure of these unsymmetric sulfoxides was established by chemical and physical methods. Nuclear magnetic resonance analyses have provided significant information concerning some stereochemical aspects of these molecules. In the case of <u>1</u>. which has four possible configurations, both <u>cis</u> and <u>trans</u> isomers were shown to exist in the synthetic material. A study on the temperature dependence of the nuclear magnetic resonance spectrum of <u>2</u> between -34° and 100°, suggested little or no association of a dimeric nature between molecules of this unsaturated sulfoxide. The rapid and clean reduction of <u>2</u> to the corresponding sulfide was carried out using hydriodic acid and detected by gas chromatographic analysis. The partial base catalyzed isomerization of <u>2</u> to 3-methyl-4, 5- dihydrothiophene 1-oxide (<u>13</u>) was carried out in sodium hydroxide solution and detected by gas chromatographic analysis of the reduced products. Maximum isomerization occurred after 96 hours when <u>2</u> and <u>13</u> were present in a ratio of 1.78:1 respectively. This finding is similar to the previously observed isomerization of the corresponding sulfone, but is in contrast to the lack of isomerization of the olefinic bond of the related 2, 5-dihydrothiophene l-oxide. A plausible mechanism has been proposed for this interesting isomerization of <u>2</u>. Sulfoxide <u>1</u> was reacted with various Grignard reagents and shown to undergo a substitution reaction at the α-carbon atoms. Predominant reaction occurred at position-5 of <u>1</u> and binary sulfide mixtures composed of 2-substituted-4-methyl- and 2-substituted-3-methyltetrahydrothiophenes were obtained in yields ranging from 17-31%. The ratio of isomeric sulfides ranged from 1.50:1, in the case of phenylmagnesium bromide, to 8.09:1 when using neopentylmagnesium chloride. The binary sulfide mixtures were desulfurized and the hydrocarbon products were identified. In this manner, the structure and composition of the components of the sulfide mixtures was established. Preparative-scale gas chromatography was used to separate two binary sulfide mixtures. Desulfurization of the individual sulfides led to the discovery of isomerization reactions which occurred during desulfurization. By-products of the Grignard reaction were identified as 3-methyltetrahydrothiophene, 3-methyl-2, 3- and 3-methyl-4, 5-dihydrothiophene, and, in some cases the alkene and alcohol derived from the Grignard reagent. A reaction pathway, by which these products and by-products may conceivably be formed has been proposed. Results of the reaction of the unsaturated sulfoxide <u>2</u> with Grignard reagents were quite different than with sulfoxide <u>1</u>. Sulfoxide <u>2</u> underwent reaction at the sulfur atom with a subsequent cleavage of the ring yielding single dienyl sulfides. These novel compounds were formed by a stereospecific ring cleavage of <u>2</u>, a reaction similar to that previously observed with the corresponding sulfone. The dienyl sulfides, 1-phenylthio- and 1-n-propylthio-2-methyl-1, 3-butadiene, were isolated in good yield and characterized by their spectral properties and by conversion to known compounds. The only detectable by-product of this reaction was a trace amount of 3-methyltetrahydrothiophene. A mechanism, consistant with the data obtained, has been suggested. / Ph. D.

Abstract not available

The synthetic studies include the synthesis of the cyclic siloxydiyne, 3,3,5,5,8,8,10,10-octamethyl-4,9-dioxa-3,5,8,10-tetrasilacyclodeca-1,6- diyne [VI] and its novel iron carbonyl complex. In the preparation of [VI] by HBr promoted condensation of bis (methoxydimethylsilyl) acetylene, a minor product, a cyclic trimer was always formed along with the major product [VI]. No evidence of an equilibrium between the trimerization product and the dimerization product was found. Compound [VI] can react with iron carbonyl reagents to produce a novel binuclear iron complex of trimethylenemethane [VII] in very low yield either in a thermal or photo-reaction. The key step proposed by us in the formation of [VII] is a I,2-silyl shift in a complexed bis (silyl) acetylene to form a vinylidene intermediate. Experiments aimed at isolating this intermediate were not successful.

Tetrahydrofuran (THF) and tetrahydropyran (THP) rings are commonly found in a wide range of natural products and biologically active compounds. In total synthesis, the formation of THF/THP motifs is often the key step but existing methods often involve numerous steps and low overall efficiencies. Part one of this thesis details the development of a practical method for the synthesis of THF rings by the controlled mono-addition/cyclisation of organolithium species to C2-symmetric diepoxides (Scheme A-1). This method can also be applied to the synthesis of bis-THF rings from triepoxides and has potential applications in more complex cascade reactions. A similar cyclisation process providing THF rings from epoxyaldehydes is also described. Part two of this thesis details our efforts towards the synthesis of the marine macrolide neopeltolide. Wright and co-workers reported the isolation of neopeltolide 211 from a deep-water sponge of the family neopeltidae off the north coast of Jamaica. The structure, which was assigned by NMR and HRMS studies and reassigned by total synthesis, contains a 14-membered macrolactone, a 2,6-cis THP ring and an unsaturated oxazole side-chain. Chapter four describes the synthesis of the C2-C8 and C9-C16 fragments (Scheme A-2). Chapter five details our initial attempts in the coupling of subunits 268 and 320, as well as a revised synthetic strategy that allowed us to successfully couple C2-C9 alkyne 347 with C10-C16 aldehyde 348 and the preparation of an advanced intermediate 364 (Scheme A-3).

The oxidation of simple benzene derivatives by a mutant of Pseudomonas putida, called 39-D, produces cis-arenediols (1). The diols are enantiomerically pure and can be used as synthons for the preparation of a variety of interesting compounds because of their stereochemistry and the special array of functional groups. See: Figure 1 cis -Toluenedio] (2) served as a chiral intermediate in an efficient synthesis of enone (3). which has been used to attain prostaglandin Fra and Neplanocin A. The same diol (2) was transformed into both enantiomers of a terpene synthon (4). See: Figures 2, 3, 4 Oxidative functionalization of cis-chlorobenzenediol (5) afforded intermediates suitable for transformation into L-erythrose (6), conduritol C (7), dihydroconduritol C (8) and aminoconduntol F-4 (9). See: Figures 5, 6, 7, 8 The application of this versatile synthetic protocol culminated in an approach to kifunensine (10), an important glycosidase inhibitor, which was approached according to the following retrosynthetic analysis: See: Figures 10, 11, 12, 5, 14, 13 A detailed study of the nucleophilic opening of epoxide 13 was carried out in order to better understand the parameters of the diastereoselective functionalization of arenediols. Details are provided for the oxidative functionalization of chlorobenzenediol (5), the key compound in all of the projects discussed. / Ph. D.