טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentAvidan-Shlomovich Shlomit
SubjectDesign and Analysis in Asymmetric Catalysis
DepartmentDepartment of Chemistry
Supervisor Professor Alex.m Szpilman
Full Thesis textFull thesis text - English Version


Abstract

Chiral compounds are increasingly important, not only in the pharmaceutical industry which produces life-saving drugs but also in other applications, including flavours, fragrances, food additives, and agrochemicals. The development of new methods in enantioselective synthesis is of high interest to scientists in both industry and academia. Asymmetric Catalysis is one of few methods for the synthesis of enanatiopure compounds. This method is an attractive option because of the potential to reduce costs and waste.

In the last decades, significant progress has been made in the development of asymmetric Lewis-acid catalysis. However, the development of efficient chiral catalysts is still one of the most challenging goals.  One of the major limitations is that the catalyst design relies on a low number of molecular interactions through which the substrate bind to the catalyst. These interactions are essential for achieving selectivity by reducing the number of degenerate transition states that could lead to different products.

This thesis describes the study of a new molecular interaction, which was discovered in drug-enzyme complexes and the development of a new method in asymmetric catalysis of aza-Michael addition.

Diederich and Müller discovered in X-ray crystal structures favorable C-F interactions between amide carbonyls in the peptide backbone of enzymes and fluorine substituted inhibitors.  We were interested to use this binding concept in asymmetric catalysis. The favourable interactions between organo-fluorine and carbonyl compound (C-F?C=O, C-F?H-Cα), and the preferred pseudo-orthogonal position in which fluorine approaches the carbonyl plane, led to the assumption that these interactions may play important role in asymmetric catalysis by blocking one of the prochiral faces of the carbonyl. We designed and prepared a series of fluorine containing new type of Ligands. The preparation of these catalysts and its application in catalysis are presented.

β-Amino-ketones are of high importance for the synthesis of drugs as well as natural products. Unfortunately, there are only few catalytic ways to prepare these compounds in an asymmetric fashion. Many of the existing methods require highly functionalized starting material that are prepared through multiple synthetic steps and which may contain nitrogen protecting groups that are difficult to remove. Thus, an asymmetric aza-Michael addition of nitrogen nucleophiles to unsaturated ketones would be a highly desirable for synthetic chemistry.

We have developed a highly practical method for the catalytic asymmetric tetrafluoro-phtalimide protected ketones using Jacobsens Al-µ-oxo-salen complex. The tetrafluoro-phthhalimide (TFP) group is removed under mild conditions and in high yield to afford the free primary amine, without loss of optical purity. The products are formed in up to 89% yield and 96% ee.  The reaction is quite general being tolerant of a wide variety of functional groups

               Mechanistic studies were carried out. The study revealed first order dependence in enone concentrations, second order dependence in catalyst concentrations and pre-equilibrium binding of TFP to the catalyst, Al-µ-oxo-salen. The second order dependence in catalyst concentrations support in dual activation mechanism in which  TFP-catalyst complex reacts with activated enone in the rate determining step to form the product and the free catalyst Al-µ-oxo-salen complex.