Amphiphiles are composed of a polar, hydrophilic headgroup and one or more non-polar, hydrophobic tail(s). Hydrated amphiphiles self-organize to form various liquid crystal phases as a function of molecular structure, temperature, concentration, and pressure. Self-supported arrays of self-organized, hydrated amphiphile assemblies include lamellar/vesicles, various normal (Q I) and inverted (QII) cubic phases, and normal (HI) and inverted (HII) hexagonal phases. A bicontinuous cubic liquid crystalline lipid-water phase is one in which the lipid bilayers are arranged in periodic three-dimensional cubic lattice structures. Cubic liquid crystalline nanoparticles prepared from aqueous dispersions of cubic lipid-water phases are kinetically stable in the presence of certain dispersing agents. The ability to incorporate and deliver lipophilic, amphiphilic, and water-soluble molecules in a controlled manner and great biocompatibility of cubic nanoparticles make them excellent candidates for drug delivery applications. Stabilization of the cubic nanoparticles has been achieved through polymerization of the reactive lipids in cubic lipid assemblies. Several QII-forming amphiphiles have been designed and synthesized. Certain compositions of these amphiphiles and water plus cross-linking monomers yield bicontinuous cubic phases, which can be dispersed into cubic nanoparticles in water using Poloxamer 407. These cubic nanoparticles were studied by 2H NMR, Transmission Electron Microscopy, and Scanning Electron Microscopy. The polymerization of the hydrated amphiphiles in the lipid region successfully stabilized the cubic nanoparticles. Selective and simultaneous polymerizations of the reactive groups in regions of different polarity within an inverted bicontinuous cubic phase were achieved via appropriate choice of initiation chemistry. The ability to form stable biocompatible nanoparticles with interpenetrating water channels of high internal surface area provides opportunities for the sequestration and release of relatively large molecules from these novel nanoparticles. Organic light-emitting diodes (LEDs) have attracted much attention because of their academic interests and potential utility of this technology in a wide variety of applications. A more efficient electroluminescent (EL) device requires balanced charge injection and transport of both electrons and holes. Discotic liquid crystalline LEDs are very effective as charge transport and energy transfer conduits, due to the high degree of electron communication between mesogen cores within the columnar packing. Phthalocyanines are well known to form columnar discotic liquid-crystalline mesophases. A novel oxadiazole substituted liquid crystalline phthalocyanine containing hole-transport phthalocyanine moiety as the core and electron-transport oxadiazole moieties on the periphery was designed and synthesized.

Substituted phthalocyanines (Pcs) have been studied intensely for decades as pigments because of their high molar absorptivities, thermal stability, and stability towards light exposure. These materials also show promise as electron and hole transport layers in a variety of device applications such as organic field effect transistors and photovoltaics. This dissertation describes the synthesis of several new phthalocyanines (Pcs) and the fabrication of highly ordered supramolecular assemblies. Efforts to increase the coherence of Pc assemblies have included the incorporation of side chains containing polymerizable and hydrogen bonding moieties. The synthesis of 2,3,9,10,16,17,23,24-octa thioether substituted Pcs was designed to allow the incorporation of diverse thioether side chains. The synthesis is shorter and uses milder conditions than the previous synthetic methods explored in the O'Brien and Armstrong groups. Serendipitously, the thioether linkage allow for chalcogen-chalcogen interactions, increasing the attraction of the Pcs sufficiently to provide for crystal growth. The order of the supramolecular materials has been examined in thin films as well as in solution. The UV-Visible and IR spectroscopic data, Langmuir-Blodgett (LB) film forming behavior, thermotropic properties, and photovoltaic properties are reported for each Pc derivative prepared. Although each compound prepared displays some degree of order, the degree to of this order is controlled by the nature of the side chain. The Pcs exhibit long range ordering on a macroscopic level, as can be seen from polarized optical microscopy, atomic force microscopy, IR, and X-ray diffraction techniques.

Melanocortin receptors (MC1R-MC5R) belong to the G-protein coupled receptor superfamily. The interactions of peptide hormones (ACTH, alpha-, beta- and gamma-MSH) with the melanocortin receptors regulate multiple physiological functions in the human body. Pharmacological studies of the melanocortin receptors have revealed very broad biological effects including pigmentation, steroidogenesis, energy homeostasis, thermoregulation, anti-inflammation, nerve regeneration, sexual behavior, feeding behavior and memory, and others. Due to the lack of selectivity of the endogenous ligands (except ACTH) the exact biological roles of the melanocortin receptor subtypes have not been fully elucidated. The objectives of our research are the design and synthesis of new, selective and potent ligands for the melanocortin receptor subtypes to help elucidate their biological functions. Since the three-dimensional structures of the melanocortin receptors and their endogenous ligands are unknown, receptor structure-based design has not been applied. We have chosen a "classical" ligand-based design with the primary structure of an endogenous ligand, gamma-MSH, as a starting point. Our design strategy is to gain high selectivity and potency by fixing the spatial structure of this very flexible peptide ligand in hopes that we can induce the bioactive conformation. We have examined two strategies to constrain the peptide backbone. The first approach is based on global constraint of the peptides by cyclization. A group of 36 cyclic peptides has been synthesized using thioether bond formation as a cyclization step. Macrocyclic peptide ligands varied from 15- to 30-membered rings. The truncated sequence of gamma-MSH has been applied in the cyclic series. In the second strategy we have introduced a local constraint into the peptide backbone similar to a reverse turn structure. We have made a very radical change in ligand conformation by peptide complexation with a transition metal in different positions of the sequence. In this approach we have conserved all amino acid residues of gamma-MSH. All novel modified peptides have been synthesized by solid phase methodology. Preliminary biological studies indicate that we have identified very selective and potent ligands.

Glycosphingolipids (GSLs) have been found to be involved in a myriad of cellular function, including the following: cell-cell communication, cell adhesion and proliferation, neuronal growth and repair, immune response and tumor progression (metastasis). To study the cellular effects of GSL depletion, Radin developed the first known inhibitors of the enzyme responsible for the initial glycosylation of the lipid portion (ceramide) of the glycosphingolipid. This inhibitor, PDMP (1-phenyl 2-decanoyl amino 3-morpholino 1-propanol), not only suppresses the initial glycosylation, but also inhibits the formation of all preceding glycosphingolipids and causes the accumulation of ceramide, an active participant in cellular apoptosis (or programmed cell death). Using a developed procedure, PDMP analogues with truncations about the aromatic region were synthesized. Aromatic PDMP analogues were more potent than the lead compound when tested against isolated embryonic cells from the Manduca sexta. Later procedures developed allowed for the manufacturing of head group analogue, which allowed for the generation of a water-soluble PDMP analogue. A new synthetic protocol, using a commercially available advanced intermediate, permitted the production of enantiomerically pure PDMP in five steps with an overall yield of 50%. As these compounds gain more medicinal attention, we hope to use PDMP and analogues, combined with the Manduca sexta as a model system, to gain a greater understanding of GSL functionality and cellular malfunctions---including cancer metastasis.

A paradigm and theoretical model for the design and construction of acentric crystalline solids is presented. In theory, molecular assembly in a predetermined arrangement will result for molecules that possess and participate in three chemically and geometrically orthogonal intermolecular interactions. A class of piperazinediones was designed to possess such orthogonal recognition elements and may provide an appropriate scaffold for the rational design of molecular building blocks for construction of acentric crystals. The topography and conformational rigidity of this scaffold limit packing options, which facilitate prediction of crystal structures from consideration of readily identified forces associated with three orthogonal recognition elements. Recognition elements can be introduced and modified by changing the functional groups on the scaffold via chemical synthesis. Structural variability facilitates exploration and exploitation of these molecules. A family of organic molecules that satisfy many of the conditions of the theoretical model is described and evaluated on the basis of their design, synthesis, and characterization.

As part of a program directed toward the synthesis of novel glycosyl transferase inhibitors possessing a sugar-CH₂-SO₂-CH₂-SO₂-CH₂-nucleoside structure, β-C-glycoside sulfones have been prepared with high stereoselectivity. Both glucose and fucose derivatives were prepared. Sulfur incorporation was achieved by free radical addition of thiolacetic acid to exocyclic glycals. As part of a program directed toward the preparation of amide-linked sialic acid oligomers, a strategy was developed for the synthesis of sialic acid derivatives possessing either a free amine or a free acid functionality. Solution phase coupling of these monomers using standard peptide coupling techniques resulted in the synthesis of (1 → 5)-amide linked sialic acid dimers. As part of a program directed toward the identification of novel helical structures, the solution phase conformation of the polylactone of colominic acid was examined by NMR and molecular modeling. The two structures generated from molecular modeling that were consistent with the NOE data were both helical.

The usefulness of glycosyl iodides in carbohydrate chemistry has been demonstrated. Both anionic and neutral nucleophiles have been shown to react readily with glycosyl iodides as the glycosyl donor. High yields and stereoselectivity were obtained along with short reaction times. Anionic nucleophiles gave β glycosides selectively, whereas neutral nucleophiles gave α glycosides in the presence of tetrabutylammonium iodide. Initial investigation of the applicability of these glycosidation conditions to solid phase oligosaccharide synthesis has been accomplished.

Small cycloalkanones with adjacent fused cyclopropane rings are excellent substrates for highly diastereoselective (α'-alkylations of enolates derived from these systems. Diastereoselectivity can be attributed to steric interactions between the cyclopropane endo methylene hydrogen and the incoming electrophile, since this atom shields the face of the enolate cis to the cyclopropane. Monoalkylation of enolates derived from bicyclo[3.1.0]hexan-2-one, bicyclo[4.1.0]heptan-2-one and bicyclo[5.1.0]octan-2-one with general electrophiles resulted in the corresponding 3-alkylated cyclopropyl ketone derivatives in synthetically useful yields. Diastereoselectivities for these systems ranged from 4:1 for six-membered cyclopropyl ketones to >20:1 for five- and seven-membered cyclopropyl ketones. Enolates derived from these 3-alkylated cyclopropyl ketones exhibited similar diastereoselectivities and yields to give the corresponding 3,3-dialkylated derivatives when alkylated with similar electrophiles. The relative stereochemistry of alkylation was determined to be trans to the cyclopropane through analysis of anisotropic shielding interactions between alkyl side chains containing phenyl rings and the endo protons on the cyclopropane carbon. This relative stereochemistry can be controlled by the sequence of alkylation, since reversal in the alkylative steps results in an inversion at the newly formed quaternary center. Synthesis of tricyclic enones was carried out through application of this (α'-alkylation methodology using electrophiles that could later be modified to give the corresponding 1,3- and 1,4-cyclopropyl diketones. Cyclization of these diketone intermediates through intramolecular aldol condensations resulted in a series of tricyclic enones whose ring junction relative stereochemistry is controlled through correct ordering of electrophiles in the alkylation steps. The result is a broadly applicable toolbox of annulated materials that can be applied towards the synthesis of natural products containing fused five- and six-membered rings with a defined stereochemistry at the ring junction.

An A value of 3.7 kcal/mole was determined for the (η⁵-cyclopentadienyl) iron (II) dicarbonyl group by variable temperature ¹H NMR spectroscopic studies on cis-4-phenyl-1-(η⁵-cyclopentadienyl) iron (II) dicarbonyl cyclohexane. This is the first determination of the A value of a group with a transition metal directly attached to a cyclohexane ring. The energy of activation (-ΔG‡) for ring inversion of cis-4-phenyl-1-(η⁵-cyclopentadienyl) iron (II) dicarbonyl cyclohexane was calculated to be 9.4 kcal/mol. The stereospecific synthesis of cis- and trans-4-phenyl-1-(η⁵-cyclopentadienyl) iron (II) dicarbonyl cyclohexane, cis- and trans-4-tert-butyl-1-(η⁵-cyclopentadienyl) iron (II) dicarbonyl cyclohexane and the X-ray crystal structure of cis-4-tert-butyl-1-(η⁵-cyclopentadienyl) iron (II) dicarbonyl cyclohexane are reported. The multistep stereospecific synthesis of the redox active adenine analog (S)-ferrocenyl-4-aminopyrimidine is reported. This redox active system will be incorporated into oligonucleotides to study the electron transfer through the molecular π-stack system of DNA in future studies. This synthesis used a chiral metalation to synthesize α-aminoferrocenenitrile. t-Butylcarbamate as the metalation-directing group gave a low yield of the 1,2-disubstituted ferrocene. N,N-diisopropylcarboxamide as the metalation-directing group using a chiral base gave moderate yields of 1,2-disubstituted ferrocene derivatives. However, standard hydrolytic methods failed to hydrolyze the diisopropylamide grouping in these 1,2-disubstituted ferrocene derivatives. A new method was developed to convert the amide functionality of N,N-diisopropylferrocenecarboxamide to ester functionality using Me₃O⁺BF₄⁻, NaOMe and an acidic workup. Unfortunately, when this condition was applied to iodo-N,N-diisopropylferrocenecarboxamide and amino-N,N-diisopropylferrocenecarboxamide, only starting materials and N',N'-dimethylamino-N,N-diisopropylferrocenecarboxamide were obtained, respectively. A chiral acetal as the metalation-directing group was used to give stereoselectively (S)-α-carbomethoxyferrocenecarboxaldehyde after the hydrolysis of the acetal group. The aldehyde was then converted to the nitrile, and the ester group was converted to an amino group to give (S)-α-aminoferrocenenitrile. In a two step sequence, (S)-α-aminoferrocenenitrile was reacted with HC(OMe)₃ and gaseous ammonia to give (S)-α-ferrocenyl-4-aminopyrimidine.

The oxidation potentials and electrooxidation mechanism of 3,6-di substituted-1,2-dichalcogenins was investigated by cyclic voltammetry. An EC mechanism was found experimentally and the basis for the chemical step was found computationally to be a change in the planarity of the ring on electron transfer. Photoelectron spectra were obtained of 3,6-disubstituted-1,2-dichalcogenins a different ionizing photon energies. The interpretation of the photoelectron spectra was assisted by computational simulation. A narrow ionization band was found, and was assigned as the sulfur-sulfur σ orbital by computation and comparison of ionization cross-sections. Computational simulation of the excited state determined that this orbital is paired with a low-energy σ* orbital. Electronic transitions to the σ* orbital were found to be common in disulfides, and the low energy of the σ* orbital in 1,2-dichalcogenins causes their unusual color. The computed geometry of the excited state, coupled with ¹H NMR and ⁷⁷Se NMR data, also provided evidence of the limited anti-aromaticity of 1,2-dithiins. A systematic study of the α-deprotonation of dialkyl sulfides was made with Lochmann's/Schlosser's base. The products were analyzed by GC/MS, and the extent of both deprotonation and decomposition was assessed. Mechanisms of decomposition were evaluated. 4-tert-Butylthiane was alpha-deprotonated and stannylated in good yield, in a 38:1 cis:trans ratio. The oxidation potentials of various α-stannylated dialkyl sulfides were analyzed by cyclic voltammetry. The dependence of oxidation and ionization potential on the C-S-C-Sn dihedral angle was investigated computationally, and was found to obey a Karplus-Barfield-type relationship, with an ionization potential minimum near 90°. The computational predictions were borne out in the oxidation potential of cis-2-trimethylstannyl-4-tert-butylthiane (1.17 V), which was found to be slightly lower than the underivatized sulfide but much higher than other alpha-stannylated sulfides due to the 180°C-S-C-Sn dihedral angle. Various computational techniques were used to find evidence of the cyclic interaction of p-type lone pair orbitals in tetrathiatetraasterane. The neutral species and the radical cation were computationally predicted to be possess the same symmetry (D₄(h)) and cyclic interaction of sulfur lone pair orbitals, but oxidation to the dication was predicted to break a carbon-carbon bond.