Search

This work encompasses the synthesis, analysis, and optimization of [3.2.1] all-carbon bridged bicyclic compounds, known as resveramorphs (RVM), Studies were conducted using a Caenorhabditis elegans model, where RVMs were tested for antiseizure capabilities. In both applications, RVMs proved potent with activities in the sub-nanomolar level in one case. A structure-activity relationship (SAR) was hypothesized for the identification of the pharmacophore. The six to seven step synthesis route towards the RVM analogues is discussed in further detail. The bicyclization of the RVMs is achieved through a reductive aldol reaction. The reaction suffers from selectivity issues leading to multiple bicyclic products. By following a one-factor-at-a-time (OFAT) methodology, attempts at optimization for this reaction were made, however, despite important gains, the overall yields of the bicyclic product remain low. Other products from this reaction have been used to understand the reaction mechanism, which will be the basis for future efforts to further optimize this key step., 2023, Includes bibliography., Degree granted: Thesis (MS)--Florida Atlantic University, 2023., Collection: FAU Electronic Theses and Dissertations Collection

In the present dissertation, we discuss the development of a stereoselective method for the production of phosphorus compounds that utilizes a phospha-Michael addition reaction. Separately, the design and synthesis of compounds that contain an all-carbon bridged bicyclic scaffold is reported; these compounds were used in initial SAR studies in different in vivo models. In Chapter one is presented a mechanistic framework to develop a highly diastereoselective method catalyzed by phase transfer chemistry leading to phosphinate compounds. In this method, phosphinate nucleophiles were added to various alkenyl ketones as Michael acceptors using crown ethers as phase transfer agents to obtain highly diastereoselective products with the generation of a carbon-based quaternary centers. A closed transition state mechanism is proposed to describe the diastereoselectivity observed in the reactions that is consistent with product outcome as established by X-ray crystallography. Analysis using the 31P NMR technique is also reported to ascertain the diastereomeric ratios in product formation. Using products obtained with the newly developed method, we disclose for the first time a novel phospha-heterocycle with high control of stereochemistry. Relative stereochemistry of the phosphorus containing heterocycle was reported using 2D NMR analysis. In Chapter two focus is placed on the use of acrylates as Michael acceptors in both the diastereoselective and enantioselective studies of phospha-Michael addition. In the asymmetric method development, screening of various chiral catalysts and development of HPLC method to quantify the enantiopurity of products obtained under reaction conditions are reported. The role of crown ether catalysts towards diastereoselectivity is reported., 2022, Includes bibliography., Degree granted: Dissertation (Ph.D.)--Florida Atlantic University, 2022., Collection: FAU Electronic Theses and Dissertations Collection

Summary: The present thesis will be largely focused on identifying and understanding the scope and mechanistic details associated with the tetrabutylammonium fluoride (TBAF) mediated cyclization of alkynyl hydrazines and (O)-hydroxylamines. Also, the synthesis of 2-(2-carboxyethyl)-4-methyl-5-propylfuran-3-carboxylic acid (CMPF) and its analogs will be discussed along with an analysis of their effects on insulin secretion. Chapter 1 will present the importance of developing isoxazoline and pyrazoline type heterocycles given that they are continually demonstrated to possess a variety of biological activities. Further, the scope of the reaction in terms of functional group tolerability, scalability and mild conditions will be shown. To expand the importance of this work, a route to access non-racemic heterocycles is also noted. With the heterocycles in hand, new methods were developed to generate more complex frameworks in the form of a novel one pot deprotection/functionalization reaction. Chapter 2 will focus on mechanistic investigations of the cyclization. From the initial discovery of the reaction, its actual mechanism was unknown and a main point of interest. What appeared unusual is that a nucleophilic attack occurs on an unactivated triple bond. Given the identity of the products, a reasonable proposal was a 5-endo-dig type cyclization. However, such a pathway would result in the generation of a vinyl anion intermediate which is well known to be of very high energy and it would seem unlikely to occur under mild conditions. Various trapping experiments were used to demonstrate that the vinyl anion forms and a 5-endo-dig-cyclization is the operative mechanism. Chapter 3 analyzes the importance of the tetrabutylammonium fluoride reagent. During optimization studies, it became clear that this base is the ideal reagent to facilitate the cyclization although other bases can also enable the transformation at much slower rates. Addition of non-basic ammonium salt addi, 2017, Includes bibliography., Degree granted: Dissertation (Ph.D.)--Florida Atlantic University, 2017., Collection: FAU Electronic Theses and Dissertations Collection

Summary: We report here the development of a Lewis acid catalyzed method for the dehydrative coupling of cyclic alcohols and nitriles to form amides with retention of configuration. By contrast, the formation of amides by nitrile trapping of carbocations (Ritter reaction) usually affords racemic product. The present reaction was accomplished by first converting alcohol starting materials to their corresponding chlorosulfites in situ. Even after an extensive search, only copper (II) salts were able to produce the desired conversion of these chlorosulfites to amides though with low catalytic turnover. Improving the turnover without deteriorating the stereochemical outcome was eventually accomplished by a careful selection of the reagent addition sequence and through the removal of gaseous byproducts. This Ritter-like coupling reaction proceeds in good yields with secondary cyclic alcohols under mild conditions. The stereochemical outcome likely due to fast nucleophilic capture of a non-planar carbocations (hyperconjomers) stabilized by ring hyperconjugation., 2014, Includes bibliography., Degree granted: Dissertation (Ph.D.)--Florida Atlantic University, 2014., Collection: FAU Electronic Theses and Dissertations Collection

Summary: The synthesis and reactivity of Nucleophile Assisting Leaving Groups was studied in order to assess the rate enhancement of nucleophilic substitution reactions. Various Nucleophile Assisting leaving groups were synthesized, all of them containing a coordinating arm positioned ortho to an electrophilic center on a benzene ring. The various coordinating arms had novel geometries and binding properties. Their reactivity was studied with a variety of metal salts and the kinetics of the reactions was studied with 1H-NMR spectroscopy. This method provided a quantitative measurement of the rate enhancement observed in the substitution reactions from the rate constants obtained. In the case of certain crown ether-containing substrates, NMR experiments suggest that the mechanism of substitution proceeds in two steps, the first being a pre-coordination of the metal salt with the coordinating arm, followed by a conversion of the complex to products., Thesis (M.S.)--Florida Atlantic University, 2006., Charles E. Schmidt College of Science, Collection: FAU Electronic Theses and Dissertations Collection

Summary: We report the development of a novel hetero-Diels-Alder reaction involving the use of allenyl carbonyls as heterodienes. We have described the synthesis of a variety of allenyl carbonyls via a base promoted and manganese mediated isomerization of alkynyl carbonyls for use in methodology studies. In our model studies, a variety of enamines were utilized effectively as dienophiles to form "hydrolyzed" Diels-Alder adducts while investigating optimal reaction conditions. Initial studies towards the synthesis of an allenyl ester tethered to an aldehyde for an eventual application in an intramolecular Diels-Alder reaction were performed. Possible mechanisms were proposed while computational studies were performed in attempt to rationalize product selectivity., Charles E. Schmidt College of Science, Thesis (M.S.)--Florida Atlantic University, 2005., Collection: FAU Electronic Theses and Dissertations Collection

Summary: The conversion of alkynyl carbonyls to allenyl carbonyls via manganese mediated coordinations followed by a based-catalyzed isomerization was carried out using a range of chiral and achiral amine bases. In this work we employed HPLC equipped with a chiral column to determine the enantiomeric excess. Deuterium labeling experiments suggested that the alkyne/allene rearrangement reaction involved an intermediate cumenolate. We also demonstrated that the reaction required a ligand on manganese for an amine base to be used catalytically. Phosphines were tested as a possible ligand because they are neutral two electron donors that binds to transition metals through their lone pairs. It was observed that the rate of the reaction decreased from 24hr to 3hr by use of phosphine as a ligand. It was also confirmed that amine base with pKa lower then DBU (pKa = 13.6) would not carry out the isomerization. Chiral amidine and chiral DBU derivatives were synthesized to carry out the isomerization enantioselectively. Alkoxy base were also used in isomerization that demonstrated enantioselectivity., Charles E. Schmidt College of Science, Degree granted: Thesis (M.S.)--Florida Atlantic University, 2004., Collection: FAU Electronic Theses and Dissertations Collection

Summary: Carbohydrate recognition is one of the most sophisticated recognition processes in biological systems, mediating many important aspects of cell-cell recognition, such as inflammation, cell differentiation, and metastasis. Consequently, lectin-glycan interactions have been intensively studied in order to mimic their actions for potential bioanalytical and biomedical applications. Galectins, a class of ß-galactoside-specific animal lectins, have been strongly implicated in inflammation and cancer. Galectin-3 is involved in carbohydrate-mediated metastatic cell heterotypic and homotypic adhesion via interaction with Thomsen-Friedenreich (TF) antigen on cancer-associated MUC1. However, the precise mechanism by which galectin-3 recognizes TF antigen is poorly understood. Our thermodynamic studies have shown that the presentation of the carbohydrate ligand by MUC1-based peptide scaffolds can have a major impact on recognition, and may facilitate the design of more potent and specific galectin-3 inhibitors that can be used as novel chemical tools in dissecting the precise role of galectin-3 in cancer and inflammatory diseases. Another lectin, odorranalectin (OL), has been recently identified from Odorrana grahami skin secretions as the smallest cyclic peptide lectin, has a particular selectivity for L-fucose and very low toxicity and immunogenicity, rendering OL an excellent candidate for drug delivery to targeted sites, such as: (1) tumor-associated fucosylated antigens implicated in the pathogenesis of several cancers, for overcoming the nonspecificity of most anticancer agents; (2) the olfactory epithelium of nasal mucosa for enhanced delivery of peptide-based drugs to the brain., 2015, Includes bibliography., Dissertation (Ph.D.)--Florida Atlantic University, 2015.