Stereoselective Preparation of Enantiopure Abasic Nucleosides and 4-Nitroisoxazoles
Chapter 1. Stereoselective preparation of enantiopure abasic nucleosides
The synthesis of artificial oligonucleotides capable of forming stable complexes with divalent Cu2+ ions and, by virtue of that, replacing the hydrogen-bonded natural base pairing in DNA has been recently reported. Based on these findings, a strategy for the development of novel C-nucleosides analogues bearing functional groups able to complex divalent metal ions, therefore avoiding the need of the natural nucleobase for the formation of a DNA double helix, has been devised. Here we describe the preparation of modified nucleosides, prepared from a cheap and readily available starting material (i.e. deoxyribose), which possess additional functional groups for the complexation of divalent metal ions. Biological tests to evaluate the ability of forming an artificial DNA double helix through the employment of the automated oligonucleotide synthesis are also reported.
Chapter 2. Asymmetric Michael addition of C- and N- nucleophiles to isoxazoles
3-Methyl-4-Nitro-styrylisoxazole has been reported as an excellent Michael acceptor in the reaction with enolisable pronucleophiles, allowing the generation of a wide variety of Michael adducts. Here we report the development of an enantioselective Michael addition reaction between 3-methyl-4-nitro-styrylisoxazole and C- and N-nucleophiles. A thorough screen of reaction conditions development, including a screening of chiral catalysts, bases and organic solvents under phase-transfer catalysis conditions was performed. Next, the phase-transfer catalysed Michael addition of nitromethane to 3- methyl-4-nitro-styrylisoxazole has been investigated for the development of the enantioselective synthesis of a useful precursor of a commercially available drug.
Chapter 3. ¹H NMR titration experiment
Next, an investigation aimed at the identification of the role of the quaternary ammonium salt and the hydroxyl group in the cinchona alkaloid-mediated Michael addition reaction of nitromethane to 3-methyl-4-nitro-styrylisoxazole has been performed. In order to determine whether an efficient catalyst-substrate coordination and concomitant activation was taking place during the Michael addition of nitromethane to the substrate, ¹H NMR titration experiments have been performed to identify the formation of a catalyst-styryilsoxazole complex.
First SupervisorProfessor Mauro Adamo
CommentsA thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2012.
Published CitationBellini G. Stereoselective Preparation of Enantiopure Abasic Nucleosides and 4-Nitroisoxazoles. [PhD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2012.
- Doctor of Philosophy (PhD)