α- i β- fluorowane aminofosfoniany – synteza oraz właściwości
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2014-06-18
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α- and β- fluorinated aminophosphonates – synthesis and properties
Abstract
Chemia fluorowanych aminofosfonianów jest stosunkowo nowym obszarem badań, intensywnie rozwijanym na przestrzeni ostatnich trzech dekad. Unikatowe właściwości fluorowanych aminofosfonianów spowodowały, iż wiele z tych związków wykazuje aktywności przeciwnowotworowe, przeciwbakteryjne, przeciwwirusowe, owadobójcze czy przeciwgrzybicze. Także ich pochodne ‒ fluorowane kwasy aminofosfonowe znalazły zastosowanie jako inhibitory wielu enzymów. Celem niniejszej pracy było opracowanie metod syntezy oraz określenie struktury nowych fluorowanych aminofosfonianów. W toku badań otrzymano serię β-fluoro-α-aminofosfonianów. Związki te zsyntetyzowano w wyniku nukleofilowego fluorowania serii β-amino-α-hydroksyfosfonianów, stosując dietyloaminotrifluorek siarki (DAST) jako odczynnik fluorujący. W ramach badań opracowano również stereoselektywną metodę syntezy (E)-α-fluorowinylofosfonianów z wykorzystaniem reakcji Hornera-Wadswortha-Emmonsa. Pochodne te posłużyły jako substraty w syntezie serii α-fluoro-γ-aminofosfonianów. Otrzymane β-fluoro-α-aminofosfoniany oraz α-fluoro-γ-aminofosfoniany poszerzają grupę dotychczas znanych w literaturze analogów fluorowanych aminofosfonianów. Pochodne te stanowią użyteczne bloki budulcowe w syntezie cząsteczek o potencjalnej aktywności biologicznej.
Aminophosphonates and aminophosphonic acids are important substrates in the study of biochemical processes. They have found a wide range of applications as enzyme inhibitors, agrochemicals and pharmaceuticals in the areas of biological and medicinal chemistry. Due to the unique properties of fluorine atom, such as high electronegativity and electron density, its presence in aminophosphonates’ moiety can influence chemical reactivity, biological activity, metabolic stability, chemical bonding ability and solubility. Recently, special interest has been focused on synthesis of fluorinated aminophosphonates due to their promising applications in the fields of bioorganic chemistry. Many of these compounds exhibit antitumor, antibacterial and antifungal activities. In this dissertation neighbouring group participation during DAST-mediated fluorination of series of β-amino-α-hydroxyphosphonates has been studied. This is the first example of direct access to various β-fluoro-α-aminophosphonates. In addition stereoselective synthesis of (E)-α-fluorovinylphosphonates was presented. These compounds were converted to series of α-fluorinated-γ-aminophosphonates. β-Fluoro-α-aminophosphonates as well as α-fluorinated-γ-aminophosphonates can be used as convenient precursors (“building blocks”) in the preparation of medicinally important analogs.
Aminophosphonates and aminophosphonic acids are important substrates in the study of biochemical processes. They have found a wide range of applications as enzyme inhibitors, agrochemicals and pharmaceuticals in the areas of biological and medicinal chemistry. Due to the unique properties of fluorine atom, such as high electronegativity and electron density, its presence in aminophosphonates’ moiety can influence chemical reactivity, biological activity, metabolic stability, chemical bonding ability and solubility. Recently, special interest has been focused on synthesis of fluorinated aminophosphonates due to their promising applications in the fields of bioorganic chemistry. Many of these compounds exhibit antitumor, antibacterial and antifungal activities. In this dissertation neighbouring group participation during DAST-mediated fluorination of series of β-amino-α-hydroxyphosphonates has been studied. This is the first example of direct access to various β-fluoro-α-aminophosphonates. In addition stereoselective synthesis of (E)-α-fluorovinylphosphonates was presented. These compounds were converted to series of α-fluorinated-γ-aminophosphonates. β-Fluoro-α-aminophosphonates as well as α-fluorinated-γ-aminophosphonates can be used as convenient precursors (“building blocks”) in the preparation of medicinally important analogs.
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Wydział Chemii
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Keywords
fluorowanie, fluorination, aminofosfoniany, aminophophonates, DAST, Reakcja Hornera–Wadswortha–Emmonsa, Horner–Wadsworth–Emmons reaction