Part A. This thesis describes a new route for the synthesis of dillapiol, a natural synergist, starting with the commercially available sessamol. It has potential for significant scale-up reactions. A key step in our synthesis is the introduction of an oxygen substituent at the C-4 position via an ortho metallation--DMF sequence on suitably protected sessamol followed by a Baeyer Villiger oxidation. The new route allowed us to prepare the first 4-thio, 4-sulfinyl and 4-sulfonyl derivatives of dillapiol. The 4-thio derivatives have been screened for their ability to synergize the light-activated pesticide, alpha-T. Some of the 4-thio derivatives were more active than dillapiol; the 4-sulfinyl and the 4-sulfonyl compounds showed lower synergism with alpha-T than dillapiol. The ability of these compounds to act as drug sparing agents by inhibiting CYP3A4 has also been briefly investigated. In this case the 4-sulfonyl derivatives were found to be potent in inhibiting CYP3A4 with IC50 values in micro molar range.* Part B. The synthesis of trichiliasterone B was completed starting from an androsterone intermediate (16-ethylenedioxypregnan-3-one) prepared earlier by Hantos. It involved converting the 3-keto functionality of the Hantos intermediate into a 2-keto-3beta-hydroxy arrangement. This was accomplished via preparation and thermolysis of 3beta-acetoxy-2alpha,3alpha-epoxy-16-ethylenedioxypregnane followed by treatment with basic alumina.* Four ester derivatives of 3beta-hydroxyandrost-17(20)-en-16-one were prepared and sent for screening as potential anti-cancer agents based on the concept that the alpha,beta-unsaturated ketone should act as a potential Michael acceptor. Promising activity was found towards in vitro tests against the human leukemia cell line.* *Please refer to dissertation for diagrams.

The synthesis of a novel family of acetylenic cyclophanes via Pd, Cu and Zn catalyzed cross-coupling reactions is described. The cyclophanes were constructed in good yields and X-ray crystal analysis revealed a twisted helical geometry. The nature of the geometry and the ability to complex solvent molecules within the lattice varied upon the number of acetylenic linkages present. Functionalized cyclophanes bearing long alkyl chains based on the helical structures 191 and 213 were also synthesized with potential as novel liquid crystals. Cyclophane 280 showed LC-like behavior when melting was observed under a polarized light microscope. Intramolecular cyclization of paracyclophanes was observed and resulted in cyclophanes, 192 and 203. X-ray crystallographic analysis of the carboxylic acid derivative, 203 revealed the strained nature of the butadiyne bridge. The triple bonds were distorted with bond angles of 163.7° and 163.5°. A novel method for the synthesis of diynes and tetraynes using an in situ desilylation/dimerization procedure was developed but was unsuccessful in producing linear hexaynes. Attempted dimerization of 281 for the synthesis of 282 failed due to a competing intramolecular producing 283. Derivative 307 revealed another highly strained butadiyne bridge possessing bond angles of 164.1° and 153.4°. Metacyclophanes with a termini separation of approximately between 7.8 and 10 A did not undergo intramolecular cyclization. A sequential coupling procedure involving a double dimerization of acetylenes produced traces of the desired cyclophane 282 and no competing intramolecular cyclization products were observed. Progress towards 327, a structural isomer of 282, using an alternative sequential coupling protocol involving a double Sonogashira cyclization is detailed. Attempts to prepare acetylenic cyclophanes bearing metaphenyl/acetylene linkages are described. Initial investigations into the incorporation of thiophenes to acetylenic cyclophanes were thwarted by the instability of the precursor, 372.* *Please refer to dissertation for diagram.

A synthetic route to N-alkylated 2-vinylazetidines is presented, and highly regioselective methods for the palladium(0)-catalyzed insertion of heterocumulenes into these substrates have been established, employing a Pd(OAc)2/PPh3 catalyst system under very mild conditions. An assortment of tetrahydro-pyrimidin-2-ones, tetrahydro-pyrimidin-2-imines, and [1,3]thiazinan-2-imines have been acquired in reactions with isocyanates, diarylcarbodiimides, and arylisothiocyanates. Unoptimized results in reactions with ketenes and ketenimines indicate a variety of carbon electrophiles could be used for the insertion and suggest great potential for these methods in organic synthesis. The steric and electronic influence of substituents on either the azetidine or carbodiimide has established maximal characteristics of substrates suitable for the insertion. Two conformational isomers result from insertion of o-tolylisocyanate into a variety of 2-vinylazetidines, indicating that enhanced congestion about the heterocycle creates an energy barrier at room temperature and inhibits ring flexibility. Stereochemical and regiochemical evidence support a likely catalytic cycle that involves the formation of a pi-allylpalladium intermediate as the active species for insertion and an equilibrium between a kinetic and thermodynamic product. An asymmetric procedure for the synthesis of optically active products could not be established, which suggests a more complex catalytic cycle.

Magnesium-mediated carbometallation has been employed as a route to a diverse range of organic synthons. The original carbometallation procedure has been optimized by a solvent study, which indicates that cyclohexane can be used in most cases, to improve the yields and consistency of the reaction. A wide-range of polysubstituted furans (232) were obtained when the reaction intermediate (144) was quenched with either dimethylformamide or benzonitrile. The use of carbon dioxide as an electrophile, provided a short (two-steps) synthesis of the Merck anti-inflammatory drug, Vioxx RTM (231). The reaction was also extended to a direct one-step synthesis of the ene-diyne chromophore (186). Additional research afforded a versatile route from 144 to dienophiles for intramolecular Diels-Alder reactions. An expedient route to the Taxol A/B-ring system (329) was developed. This ring system underwent a facile enone accelerated Cope rearrangement to generate a bicylco[2.2.2]octanone ring system (330). Finally, the dienophiles prepared from the carbomagnesiation reaction were employed as key steps in the preparation of tether controlled intramolecular Diels-Alder reactions. The reactions were shown to be more facile when cis-isopropylidene acetals ( 386) were employed in the tether. The trans-isopropylidene acetal tether (385b) was also prepared for a direct comparison. As anticipated the cycloaddition occurred at a much slower rate.* *Please refer to dissertation for diagrams.

A study of heterocyclic formation by cycloaddition reactions has been made utilizing 2-vinyloxiranes, 2-vinyloxetanes, o-iodophenols and o-iodoanilines with heterocumulenes in the presence of a palladium catalyst. Cycloaddition reactions of 2-vinyloxiranes with carbodiimides using Pd2(dba)3·CHCl3 and TolBINAP in THF, at ambient temperature, afforded 4-vinyl-1, 3-oxazolidin-2-imines in 70--99% yields and in up to 95% ee. The stereoselectivity is strongly influenced by the structure of the chiral phosphine ligands and substrates as well as by the reaction conditions. Reaction of 2-vinyloxiranes with isocyanates using the same catalyst system afforded 4-vinyl-1, 3-oxazolidin-2-ones in high yields but no greater than 50% ee under identical conditions. The cycloaddition reactions of 2-vinyloxiranes with unsymmetrical carbodiimides catalyzed by palladium(0) complexes gave two isomers of 4-vinyl-1, 3-oxazolidin-2-imine derivatives in excellent total isolated yields. Highly enantioselective cycloadducts (up to >99% ee) were formed by using TolBINAP as the chiral phosphine ligand, in THF at ambient temperatures. 4-Vinyl-1, 3-oxazine-2-imines were obtained in fine yields by the reaction of 2-vinyloxetanes with carbodiimides catalyzed by Pd2(dba) 3·CHCl3 and bidentate phosphine ligands (dppe or dppp). When isocyanates were utilized in the reaction, moderate to good yields of 4-vinyl-1, 3-oxazine-2-ones were achieved. Palladium catalyzed cycloaddition of fused-bicyclic vinyloxetanes with heterocumulenes proceeds in a highly stereoselective fashion affording only the cis-3-aza-1-oxo-9-vinyl[4.4.0]decane derivatives. Benzo[e]-1,3-oxazin-2-imine-4-ones were synthesized regioselectively by cyclocarbonylation of o-iodophenols with carbodiimides in the presence of a catalytic amount of palladium catalyst and 1,4-bis (diphenylphosphino) butane under CO pressure. Product yields are dependent on the nature of the substrate, catalyst, solvent, and base as well as phosphine ligand. Benzo[e]-1,3-oxazin-2,4-diones were obtained in good-excellent yields using the same procedure, and a 1:2 ratio of o-iodophenol: isocyanate. Pyrido[3,2-e]-1,3-oxazin-4-ones were isolated in fine yield using 2-hydroxy-3-iodopyridine. A catalyst system comprising palladium acetate-bidentate phosphine is effective for the cyclocarbonylation of o-iodoanilines with heterocumulenes to give the corresponding 4(3H)-quinazohn-4-one derivatives in good yields. Utilizing o-iodoanilines with isocyanates, carbodiimides and ketenimines for the reaction afforded 2,4-(1 H,3H)-quinazolinediones, 2-amino-4(3H)-quinazolinones and 2-alkyl-4(3H)-quinazolinones, respectively. In the last Chapter, a study on the one-pot reaction of o-iodoanilines with acid chlorides and carbon monoxide showed that in the presence of a palladium catalyst and a base, the pharmaceutically important compounds, 2-substituted-4 H-3,1-benzoxazin-4-ones, could be isolated in high yields.

Tandem reactions have been proven to be powerful methods for creating new types of carbon-carbon bonds in organic synthesis. One such type of reaction is the oxy-Cope/ene reaction of 1,2-divinylcyclohexanols. This reaction has been shown to be a highly diastereoselective method for creating polycyclic compounds with tertiary alcohols at a ring junction. Unfortunately, in many of the previously reported cases, undesired retroene products were also observed.* A new method has been developed that increases the ratio of oxy-Cope/ene with respect to retroene product that involves the use of DBU as a co-solvent in this reaction. This methodology was applied to intermediate 109 (readily obtainable from (+)-limonene) as a key step in the total synthesis of (+)-Arteannuin M (128), a potential drug for the treatment of malaria.* *Please refer to dissertation for diagrams.

Rhodium complex, [Rh2(PPh3)4(mu-OH) 2] containing bridging hydroxo ligands, smoothly reacts with [HM(CO) 3Cp] (M = Cr, Mo, W) to afford the corresponding heterobimetallic complexes, [(Ph3P)2Rh(mu-CO)2M(CO)Cp]. The reaction of [Pd2L2(Ph)2(mu-OH) 2] with an equimolar amount of [HM(CO)3Cp] gives the organometallic hydroxo clusters [L2Pd2(Ph)2(mu-OH)(mu-CO) 2(mu3-CO)MCP] in high yield. These reactions can be regarded as the neutralization of an acidic transition metal hydride by a basic transition metal hydroxide. The structure of the Pd2Cr cluster was determined by single crystal X-ray diffraction study. The trinuclear hydroxo clusters are stable in the solid state but slowly decompose in solution, the decomposition path being strongly dependent on the nature of M. Facile and selective decomposition of the Pd2W hydroxo complex resulted in the formation of [Pd2(PPh3)2(Ph)2(mu-OH) 2], biphenyl, and the tetranuclear Pd2W2 cluster. Similar tetranuclear clusters were obtained in high yield when the palladium hydroxo dimers were neutralized with excess [HM(CO)3CP] or [HM(CO) 3Cp*]. However these reactions proceed by a different pathway involving Ph/H exchange process, and resulted in the formation of benzene and [PhM(CO) 3Cp] or [PhM(CO)3Cp*], respectively. Labeling experiments suggested that the H atoms of the hydrido and hydroxo ligands underwent an exchange which was faster than the neutralization and the concomitant formation of the metal-metal bond. Infrared and NMR studies show that the structures of the trinuclear hydroxo clusters were more rigid than those of the tetranuclear species. Tetranuclear complexes containing three different metals, Pd 2MoW and Pd2CrW were prepared and characterized. The reaction of [Rh(CO)(PPh3)2Cl] with the sodium salt of (1S, 2R, 5S)-menthol (NaOMent) cleanly affords chiral rhodium carbonyl alkoxo complex, [Rh(CO)(PPh3)2OMent], which was characterized by single crystal X-ray diffraction. The similar reaction of [Rh(PPh3) 3Cl] with NaOMent leads to the formation of [Rh(PPh 3)3H], apparently due to fast decomposition of the intermediate rhodium phosphine alkoxo complex via beta-H elimination. The reaction of [Rh(PPh3)3Cl] with NaOAr in toluene cleanly affords the corresponding aryloxo complexes [Rh(PPh3) 3(OAr)] (4.1). In solution 4.1 exists in equilibrium with PPh3 and the corresponding [Rh(PPh3)2(pi-OAr)] (4.2) The addition of HOAr shifts the equilibrium completely toward the corresponding adducts 4.2 · 2HOAr due to hydrogen bonding between the oxygen atom of the pi-coordinated OAr ligand and two molecules of HOAr. (Abstract shortened by UMI.)

This thesis describes the different synthetic routes carried out towards a dendritic catalyst. Various dendrimers were investigated as possible starting points for the exterior portion of the catalyst. These dendrimers were synthesised as well as their modified versions. The attachment of a phosphine-containing moiety was thought to be crucial for high activity of these catalysts, in the hydroformylation of olefins. Different methods were investigated to affect the incorporation of a bis-phosphine. The tetra-phosphine, 4,5-bis(bis[{diphenyl-phosphanyl}methyl]aminomethyl)-2,2-dimethyl-[1,3]dioxolane, and the bis-phosphine, N,N'-Bis-(2-benzyloxyethyl)- N,N'-bis[(diphenylphosphanyl)methyl]-ethane-1,2-diamine, were both synthesised and their rhodium(I) complexes were used successfully in the hydroformylation of m different olefins. Suggested pathways to bring together these exterior and interior pieces were then investigated. During the synthesis of one of the core units a phosphine oxide compound, (diphenylphosphinoyl)phenyl-methanol was prepared. This compound is an excellent ligand in rhodium-catalysed hydroformylation reactions. As the phosphine oxide contained a chiral centre, it was resolved and employed in the enantioselecove hyrdoformylation reactions of olefinic substrates.

In order to further understand fundamental carbohydrate-protein interactions as well as to supply carbohydrate clusters of high affinity, glycoconjugates with differing carbohydrate densities, conformations, and interglycosidic spacings were prepared. A series of multivalent alpha-sialosides were scaffolded onto gallic acid-based dendrimers; and calix[4]arenes. Carbohydrate residues involved in the syntheses of glycoconjugates were all prepared stereoselectively in high yields from phase transfer catalysis (PTC) reaction. These carbohydrate ligands were coupled to the dendritic and calixarene cores through nucleophilic displacement of chlorides by thioglycosides. The conjugation strategy employed herein lead to the study of different chemoselective deprotection of thioacetate glycosides. The methods studied involved, (i) hydrazinium acetate in DMF (one- & two-pot reactions) and (ii) sodium methoxide in MeOH at low temperature (Zemplen conditions). Solid phase synthesis on Wang resin was used to construct the first dendritic athiosialosides. The design of these hyperbranched clusters was based on L-lysine core structures using established Fmoc protecting group and benzotriazolyl activated ester coupling procedures. Chain extension of the lysyl amino groups with chloroacetylglycylglycine active ester allowed introduction of the required functionality necessary for the coupling to an alpha-thiosialoside derivative. The synthesis of hyperbranched glycodendrimers containing sialic acid residues having 3n in valency, is also described. Gallic acid as trivalent core and oligoethylene glycol derivatives as hydrophilic spacers were used to scaffold the dendritic backbones. alpha-Thiosialoside derivative was conjugated onto N-chloroacetylated dendritic precursors by nucleophilic substitution to afford tri- and nona-valent sialodendrimers. The synthesis of glycocalix[4]arenes was then effected since these glycoconjugates have an extra advantage over chemically well-defined glycodendrimers. They possess the ability to form drug inclusion complexes. p-Tert-butylcalix[4]arene was transformed into its tetraethyl ester. This opened the way to the formation of the acid chloride which was treated with excess mono-Boc-1,4-butanediamine or mono-Boc-1,6-hexanedianiine used as spacer arms. alpha-Thiosialoside derivative was covalently attached to the calix[4]arenes by nucleophilic substitution on the cone-shaped tetra-N-chloroacetylated calix[4]arenes. The glyco-calix[4]arenes were liberated from their protecting groups to afford biologically active clusters where sialic acid is the ligand. A different tetravalent sialocalixarene was synthesized following a convergent approach. Tetraacyl chloride calix[4]arene derivative was reacted by peptide coupling with an aminosialoside having a long spacer arm. Finally, octavalent dendritic sialocalix[4]arene was then synthesized from a tetraamino, calix[4]arene and N-bromoacetylated sialoside derivatives. Both reagents have built-in spacer arms which allowed for an efficient double N-alkylation reaction. Binding studies via turbidimetric analysis confirmed the ability of the glycodendrimers and glycocalix[4]arenes to cross-link and precipitate appropriate lectins (WGA and LFA).

The kinetics for the 5-exo cyclizations of secondary alkyl radicals onto various imine acceptors (alkyl-, aryl-, benzoylhydrazones, oxime ethers, etc) have been determined. The preparation of a series of halo C=N containing "bis imine" systems (182 a--i ) for use in kinetic studies has been described. The rate constants have been established by competitive "internal radical clock" type cyclizations on the basis of the known rate constants for alkene and N,N-diphenylhydrazone systems. In refluxing benzene the rate constants for these 5-exo cyclizations fall within the range of 4 x 107 to 16 x 107 s-1 depending on the electron withdrawing capacity of the imine acceptor. These rate constants are approximately 200 times faster than those for the corresponding 5-exo cyclizations onto alkenes. The fastest rate constants were observed for the N,N-diphenylhydrazones and N-benzoylhydrazones. N,N-Diphenylhydrazones were further employed in the formation of nitrogen containing bicyclic systems via tandem radical cyclizations. Tandem products were obtained for 5,5- and 6,5-bicyclic systems. Attempted synthesis of 5,6- and 6,6-bicyclic systems via tandem cyclizations resulted only in the formation of monocylized products 284 and 285 respectively. A new chiral auxiliary 327 was synthesized for use in the study of asymmetric induction in radical cyclizations in the presence of chiral auxiliaries in systems such as 328b. In search of "taxoid mimics" with less functionality and better therapeutic profile as compared to the anti cancer drug "Taxol", small taxol like compounds 350 and 351 were synthesized and their biological activity was evaluated.