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15
demand of organofluorine compounds it is not surprising that the need for new
methods and fluorinating reagents is increasing rapidly.
Many natural products and biologically active molecules contain various
heterocycles as well as amino acid functionalities that are important for the
observed biological activities. However, there exist few simple and direct methods
to incorporate fluorine into these systems. In fact, one could argue that some of
these fluorinated compounds have not been studied for their potential use as drug
candidates because they are not easily accessible. In that respect, our research in
this area has allowed us to develop novel methodologies to introduce fluorine and
fluorinated moieties (trifluoromethyl, difluoromethyl and monofluoromethyl
groups) to a variety of heterocycles as well as provide access to fluorinated amino
acids precursors, not only in a manner that is simple, but also that is efficient.
In addition, vinyl fluorides are an important class of compounds both from
a synthetic as well as a biological point of view. While there are many ways to
make them, there are very few methods that are simple and stereoselective. We
have developed a novel methodology that enables not only easy but stereoselective
access to these peptide isosteres. Thus, the work covered in this thesis aims to
provide not only new but also efficient methodology to introduce fluorine and
fluorinated moieties to a variety of small molecules that have important
applications both as fine chemicals as well as in medicinal chemistry.
Object Description
| Title | Synthesis of organofluorine compounds via Lewis/Bronsted acid and base catalysed reactions and related chemistry |
| Author | Vaghoo, Habiba Ebrahim |
| Author email | vaghoo@usc.edu; vaghoo@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program |
Chemistry vinyl fluorides |
| School | College of Letters, Arts and Sciences |
| Date defended/completed | 2008-06-24 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-10-31 |
| Advisor (committee member) |
Olah, George A. Shing, Katherine S. |
| Abstract | This dissertation describes the development of new and practical methodologies for the synthesis of a broad variety of fluorinated heterocycles and vinyl fluorides via acid and base catalysis, respectively. It also describes efficient cyanosilylation of carbonyl compounds using a variety of nucleophilic catalysts.; Chapter 1 explores the rich history of fluorine and its compounds. Important milestones that have made a significant contribution to the field of chemistry are highlighted with emphasis on fluorine's role in medicinal chemistry. Methods to introduce fluorine are also included in this chapter.; Chapter 2 deals with the use of gallium (III) triflate as a versatile Lewis acid for the synthesis of different fluorinated heterocycles and α-aminonitriles. The condensation-cyclization reactions of various aromatic amino derivatives with fluorinated ketones to afford the corresponding fluorinated benzimidazolines, benzothiazolines, benzoxazolines, and dihydrobenzoxazinones, as well as fluorinated 1, 5 benzodiazepines and quinoxaline derivatives is described. Also included in this chapter are the syntheses of α-aminonitriles and their fluorinated analogs via the multicomponent Strecker reaction using gallium (III) triflate. Monofluoro-, difluoro-, or trifluoromethyl groups have been incorporated into both heterocycles and the α-aminonitrile products by varying the nature of the fluorinated ketones.; In Chapter 3, Nafion^®-H, a perfluoroalkanesulfonic acid resin, is shown to be a suitable solid acid catalyst with high selectivity and catalytic activity for the one-pot synthesis of fluorinated heterocycles. The Nafion-H mediated reactions are easily achieved under mild conditions in high yields and purity. Monofluoro, difluoro and trifluoromethylated derivatives can be prepared and its advantage as a solid superacid is highlighted by the recyclability studies.; Chapter 4 describes a new approach for the stereoselective synthesis of vinyl fluorides using α-substituted fluoro(phenylsulfonyl)methane derivatives under mildly basic reaction conditions. A variety of fluorovinyl sulfones as well as α-fluoro-α,β-unsaturated carbonyls can be synthesized to afford the E-isomer.; Finally, in Chapter 5, cyanosilylation of aldehydes and ketones using various nucleophilic catalysts under mild conditions is portrayed. Use of dimethylformamide (DMF) as solvent, afforded the trimethylsilylated cyanohydrins in good to excellent yields. K2CO3 and (MeO)2P(O)(O^-)(N^+Bu4)3 have been employed as the nucleophilic catalysts for the cyanosilylation using trimethylsilyl cyanide (TMSCN). |
| Keyword | fluorine chemistry; fluorinated heterocycles; fluorinated aminonitriles; cyanosilylation |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m1729 |
| Contributing entity | University of Southern California |
| Rights | Vaghoo, Habiba Ebrahim |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | cisadmin@lib.usc.edu |
| Filename | etd-Vaghoo-2053 |
| Archival file | uscthesesreloadpub_Volume44/etd-Vaghoo-2053.pdf |
Description
| Title | Page 29 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | 15 demand of organofluorine compounds it is not surprising that the need for new methods and fluorinating reagents is increasing rapidly. Many natural products and biologically active molecules contain various heterocycles as well as amino acid functionalities that are important for the observed biological activities. However, there exist few simple and direct methods to incorporate fluorine into these systems. In fact, one could argue that some of these fluorinated compounds have not been studied for their potential use as drug candidates because they are not easily accessible. In that respect, our research in this area has allowed us to develop novel methodologies to introduce fluorine and fluorinated moieties (trifluoromethyl, difluoromethyl and monofluoromethyl groups) to a variety of heterocycles as well as provide access to fluorinated amino acids precursors, not only in a manner that is simple, but also that is efficient. In addition, vinyl fluorides are an important class of compounds both from a synthetic as well as a biological point of view. While there are many ways to make them, there are very few methods that are simple and stereoselective. We have developed a novel methodology that enables not only easy but stereoselective access to these peptide isosteres. Thus, the work covered in this thesis aims to provide not only new but also efficient methodology to introduce fluorine and fluorinated moieties to a variety of small molecules that have important applications both as fine chemicals as well as in medicinal chemistry. |
