Preparation and application of D-furanoside-derived phosphoramidites to the enantioselective organic synthesis

Celem pracy była synteza nowej rodziny pochodnych amidofosforynowych zawierających podstawnik D-furanozy oraz wykorzystanie tych związków jako chiralnych ligandów dla atomu metalu przejściowego w wybranych reakcjach asymetrycznych. W pierwszej części moich badań dokonałem kilkuetapowej syntezy odpowiednich II- i III-rzędowych pochodnych amidofosforynowych, dla których materiałem wyjściowym była tania i łatwo dostępna D-ksyloza. Drugą i zasadniczą część mojej rozprawy poświęciłem wykorzystaniu otrzymanych pochodnych D-pentoz jako chiralnych ligandów w dwóch bardzo ważnych reakcjach asymetrycznych: katalizowanej miedzią addycji sprzężonej dietylocynku do α,β-nienasyconych ketonów, oraz katalizowanej palladem reakcji podstawienia allilowego. Głównym założeniem podczas badań nad indukcją asymetryczną było określenie wpływu struktury stosowanych ligandów na indukcję asymetryczną i wydajność chemiczną prowadzonych procesów asymetrycznych. Najwyższe wartości nadmiarów enancjomerycznych (>99% ee) otrzymałem dla substratów zatłoczonych sterycznie tak w reakcjach asymetrycznego podstawienia jak i addycji sprzężonej. Zakończeniem mojej pracy badawczej są dwie wieloetapowe syntezy Boc-γ- oraz Boc-β-aminokwasów o potencjalnej czynności biologicznej. Wyjściowym substratem w obu tych syntezach był bardzo tani i handlowo dostępny trans-chalkon. Kluczowym etapem obu syntez była reakcja alkilowania allilowego, w której wykorzystałem uprzednio otrzymany ligand, otrzymując zaplanowany produkt o wysokiej czystości optycznej.The aim of this work was the synthesis of a new family of phosphoramidite derivatives bearing a D-furanose unit and the application of these compounds as chiral ligands for transition metal-catalyzed asymmetric reactions. The first part of my Thesis was devoted to the multi-step syntheses of appropriate primary and secondary derivative of phosphoramidites for which the starting material was inexpensive and readily available D-xylose. In the second and main part of my dissertation I used thus obtained derivatives of D-pentose as chiral ligands in two very important asymmetric reactions, such as: copper-catalyzed conjugate addition of diethylzinc to α,β-unsaturated ketones as well as a palladium-catalyzed allylic substitution reaction. My research was concentrated on the influence of the structure of the chiral ligands on the enantioselectivity and chemical yield of the conducted asymmetric reactions. I achieved the highest enantiomeric excess values (>99% ee) for sterically demanding substrates for both asymmetric substitution reaction and conjugate addition. The final part of my research deals with two multi-step syntheses of Boc-γ- and Boc-β-amino acids with potential biological activity. As a starting material I choose very cheap and commercially available trans-chalcone. The key step for both syntheses was the asymmetric allylic alkylation reaction performed in the presence of one of previously obtained ligands leading to the desired product of high optical purity

H-Bond Mediated Phase-Transfer Catalysis: Enantioselective Generating of Quaternary Stereogenic Centers in β-Keto Esters

In this work, we would like to present the development of a highly optimized method for generating the quaternary stereogenic centers in β-keto esters. This enantioselective phase-transfer alkylation catalyzed by hybrid Cinchona catalysts allows for the efficient generation of the optically active products with excellent enantioselectivity, using only 1 mol% of the catalyst. The vast majority of phase-transfer catalysts in asymmetric synthesis work by creating ionic pairs with the nucleophile-attacking anionic substrate. Therefore, it is a sensible approach to search for new methodologies capable of introducing functional groups into the precursor’s structure, maintaining high yields and enantiomeric purity

Adjusting the Structure of β-Cyclodextrin to Improve Complexation of Anthraquinone-Derived Drugs

β-Cyclodextrin (CD) derivatives containing an aromatic triazole ring were studied as potential carriers of the following drugs containing an anthraquinone moiety: anthraquinone-2-sulfonic acid (AQ2S); anthraquinone-2-carboxylic acid (AQ2CA); and a common anthracycline, daunorubicin (DNR). UV-Vis and voltammetry measurements were carried out to determine the solubilities and association constants of the complexes formed, and the results revealed the unique properties of the chosen CDs as effective pH-dependent drug complexing agents. The association constants of the drug complexes with the CDs containing a triazole and lipoic acid (βCDLip) or galactosamine (βCDGAL), were significantly larger than that of the native βCD. The AQ2CA and AQ2S drugs were poorly soluble, and their solubilities increased as a result of complex formation with βCDLip and βCDGAL ligands. AQ2CA and AQ2S are negatively charged at pH 7.4. Therefore, they were less prone to form an inclusion complex with the hydrophobic CD cavity than at pH 3 (characteristic of gastric juices) when protonated. The βCDTriazole and βCDGAL ligands were found to form weaker inclusion complexes with the positively charged drug DNR at an acidic pH (pH 5.5) than in a neutral medium (pH 7.4) in which the drug dissociates to its neutral, uncharged form. This pH dependence is favorable for antitumor applications

A General Method for Synthesis of Unclosed Cryptands via H‑Bond Templated Macrocyclization and Subsequent Mild Postfunctionalization

A practical four-step synthesis of a model 26-membered N-Boc-protected macrocycle, starting from commercially available and inexpensive materials, is reported. The crucial macrocyclization step does not require high-dilution conditions and is completed in a short time (8 h). The high yield of macrocyclization (61%) is achieved owing to templation by intramolecular H-bonds and a chloride anion, which both help to adopt a favorable folded conformation of the open-chain intermediate. Finally, mild, selective, and efficient incorporation of intraannular amide function leading to five diversely functionalized unclosed cryptands (UCs) is described