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- Title
- ALLENYL ESTER BUILDING BLOCKS: THEIR APPLICATION TO THE SYNTHESIS OF BRIDGED BICYCLIC COMPOUNDS AND UTILITY AS PRENUCLEOPHILES IN THE DIASTEREOSELECTIVE FORMATION OF ALL-CARBON QUATERNARY ALDOL PRODUCTS.
- Creator
- Maki, Samantha, Lepore, Salvatore, Florida Atlantic University, Department of Chemistry and Biochemistry, Charles E. Schmidt College of Science
- Abstract/Description
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The present dissertation will be largely focused on the synthesis of various [3.2.1] bridged bicycles using allenyl esters. Chapter one will present the importance of various [3.n.1] bridged bicycles in medicinal chemistry. A three-step synthetic route will then be described on how to produce a small library of [3.n.1] bridged bicycles using allenyl esters in an annulation reaction. The [3.n.1] bicyclic diketones can then undergo Grob fragmentation to deliver highly functionalized medium...
Show moreThe present dissertation will be largely focused on the synthesis of various [3.2.1] bridged bicycles using allenyl esters. Chapter one will present the importance of various [3.n.1] bridged bicycles in medicinal chemistry. A three-step synthetic route will then be described on how to produce a small library of [3.n.1] bridged bicycles using allenyl esters in an annulation reaction. The [3.n.1] bicyclic diketones can then undergo Grob fragmentation to deliver highly functionalized medium sized rings. Studies towards the total synthesis of vitisinol D, a highly functionalized [3.2.1] bridged bicycle will be discussed. In chapter two, synthesis knowledge gleamed from chapter one will be used to create a model route to form simplified versions of vitisinol D, called resveramorphs. These resveramorphs are structurally similar to resveratrol but possess rigid three-dimensional configuration desired in drug design. The synthetic route to create a variety of resveramorphs will be reported. The sub-nanomolar results of various resveramorph compounds in a Drosophila melanogaster neural tissue model under oxidative stress will be reported. Chapter three will focus on the use of allenyl esters as prenucleophiles to produce triply diastereoselective β-hydroxy esters containing all carbon α-quaternary centers. The challenges in the opitmization of this novel reaction will be described. The relative stereochemistry of the β-hydroxy ester products will be presented using various techniques including X-ray crystallography, 1D NMR, 2D NMR, and force field calculations (MM2). A closed transition state mechanism will be proposed to describe the diastereoselectivity that is observed in the reaction. Additionally, a short indanone synthesis will be shown as a potential application for this novel reaction.
Show less - Date Issued
- 2019
- PURL
- http://purl.flvc.org/fau/fd/FA00013391
- Subject Headings
- Bicyclic compounds, Esters, Diastereoisomers
- Format
- Document (PDF)
- Title
- Synthesis and Bioactivity Investigation of Bridged Bicyclic Compounds and a Mechanistic Investigation of a Propargyl Hydrazine Cycloaddition Catalyzed by an Ammonium Salt.
- Creator
- St.Germain, Elijah, Lepore, Salvatore D., Florida Atlantic University, Charles E. Schmidt College of Science, Department of Chemistry and Biochemistry
- Abstract/Description
-
We report the development of a general route to the synthesis of [4.3.1], [3.3.1], an especially [3.2.1] bicyclic compounds structurally related to vitisinol D, a natural product. This allows for diastereoselective synthesis of bicyclic compounds with five adjacent chiral centers. This route was employed in a preliminary SAR investigation into the neuroprotectant effect of small molecules in an in vivo experiment measuring the degree of restorative effect of synaptic transmission in the...
Show moreWe report the development of a general route to the synthesis of [4.3.1], [3.3.1], an especially [3.2.1] bicyclic compounds structurally related to vitisinol D, a natural product. This allows for diastereoselective synthesis of bicyclic compounds with five adjacent chiral centers. This route was employed in a preliminary SAR investigation into the neuroprotectant effect of small molecules in an in vivo experiment measuring the degree of restorative effect of synaptic transmission in the neuromuscular junction of Drosophila melanogaster larvae under acute oxidative stress. One of the compounds exhibited intriguing potential as a neuroprotectant and outperformed resveratrol in restoring synaptic function under oxidative stress. The hypothesis that bridged bicyclic compounds may hold promise as drug scaffolds due to their conformational rigidity and ability to orient functional appendages in unique orientations is developed. The second focus is a mechanistic investigation into a tetrabutylammoniumcatalyzed cycloaddition as evidence of a novel ammonium-alkyne interaction. A carbamate nitrogen adds to a non-conjugated carbon–carbon triple bond under the action of an ammonium catalyst leading to a cyclic product. Studies in homogeneous systems suggest that the ammonium agent facilitates cyclitive nitrogen–carbon bond formation through a cation–π interaction with the alkyne unit. Using Raman spectroscopy, this cation–π interaction is directly observed for the first time. DFT modeling elucidated the mechanistic factors in this cycloaddition. A teaching experiment was developed based on this mechanistic investigation. Control experiments were employed to demonstrate the testing of two alternative mechanistic hypotheses. Cyclization reactions were performed with a soluble base (sodium phenoxide) with and without tetrabutylammonium bromide under homogeneous conditions. Students observed that ammonium salt accelerates the reaction. They were encouraged to develop a testable hypothesis for the role of the ammonium salt in the cyclization mechanism: typical phase transfer or other. IR spectroscopy was used to directly observe a dose dependent shift of the alkyne stretching mode due to a cation−π interaction. Undergraduates were able to employ the scientific method on a contemporary system and see how data are generated and interpreted to adjudicate between rival hypotheses in a way that emulates authentic and current research in a lab setting.
Show less - Date Issued
- 2018
- PURL
- http://purl.flvc.org/fau/fd/FA00013100
- Subject Headings
- Bicyclic compounds., Ammonium salts., Cycloaddition Reaction.
- Format
- Document (PDF)
- Title
- DIASTEREOSELECTIVE ADDITION OF H-PHOSPHINATES TO ALKENYL KETONES UNDER PHASE-TRANSFER CONDITIONS AND SYNTHESIS OF BRIDGED BICYCLIC COMPOUNDS FOR BIOLOGICAL EVALUATION.
- Creator
- Yadavalli, Krishna Prasad, Lepore, Salvatore D., Florida Atlantic University, Department of Chemistry and Biochemistry, Charles E. Schmidt College of Science
- Abstract/Description
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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...
Show moreIn 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.
Show less - Date Issued
- 2022
- PURL
- http://purl.flvc.org/fau/fd/FA00014015
- Subject Headings
- Bridged bicyclic compounds, Chemistry, Organic, Organic compounds--Synthesis
- Format
- Document (PDF)