טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentHaitman Ilana
SubjectCatalytic Asymmetric Synthesis of Quaternary Alpha-fluorine
Carbonyl Compounds
DepartmentDepartment of Chemistry
Supervisor Professor Mark Gandelman
Full Thesis textFull thesis text - English Version


Abstract

The natural abundance of organofluorine compounds is scarce since only a dozen such naturally occurring molecules have been discovered. However, the biosynthesis of these natural organofluorine compounds has been investigated and continues to attract considerable interest, due to their popularity within the pharmaceutical and agrochemical industries.

There are several specific reasons to make use of fluorine compounds, including size similarity with hydrogen, dramatic electronic effect on neighbouring groups, enhanced lipophilicity, increased stability, resistance to metabolic transformation and better bioavailability. Moreover, it was shown that substitution of a fluorine atom for a hydrogen atom at the α-positions in the 2-aryl-2-fluoropropanoic acids prohibits the unwanted epimerization of the fluorinated analogue of non-steroidal anti-inflammatory drugs, which converts them from the biologically active chiral forms to less active epimerized forms in vivo. Investigation of effective and selective methods for the introduction of a fluorine atom at the α-positions can dramatically increase the pharmacokinetic properties of those types of drugs.

We decided to concentrate on construction of stereogenic quaternary carbon center featuring a fluorine atom via cross coupling reactions. For this purpose, our goal was to start with racemic mixtures of geminal fluoro-halo-alkanes as substrate, and be employing chiral catalyst produce the desired enantioenrich product.

By employing Negishi cross-coupling in order to produce quaternary fluorinated stereocenter showed that the production of the desired product is problematic due to kinetic problems and the sole product that can be produced is the homocoupled product.

By employing the more robust Stille cross-coupling which employs less nucleophilic transmetallating agent, we have shown that we can construct quaternary fluorinated center via palladium-catalyzed allylation in mild conditions, unfortunately applying enantioselective synthesis torn out to be problematic.

However by employing Hiyama cross-coupling we have shown that we can successfully construct quaternary fluorinated center in enantioselective manner, nevertheless more optimization of the reaction condition could be investigated in order to enhance the enantioselectivity of the reaction.