No description available.

Obtaining enantiomerically pure compounds is of major importance in modern organic chemistry, and this PhD thesis outlines new advances made in this area. Two new enantioselective synthetic methodologies have been designed using isothiourea based- organocatalysts. A brief introduction to the recent literature involving this catalyst architecture is presented. Then, the results of the structure-activity relationship study carried out on a range of isothiourea catalysts for the kinetic resolution of (±)-1-naphthylethanol 16 is described. Chiral isothiourea HBTM 2.1 58 was identified as the optimum catalyst and was further employed in the resolution of a range of secondary alcohols. Good levels of conversion (c~50%) and selectivity (S up to 100) were achieved delivering alcohols in high levels of enantioselectivity (up to 98% ee). The synthetic utility of this process was subsequently demonstrated through isolation of a range of enantiopure alcohols (>99% ee) on a preparative scale, using low catalyst loading of HBTM 2.1 (0.10 mol%). Secondly, a new organocatalytic asymmetric transformation involving the generation of a C1-ammonium enolate using isothiourea is described. An intramolecular Michael addition-lactonisation (IMAL) of enone-acid substrates was developed using (‒)-tetramisole 37 as a catalyst. The generality of this protocol was probed via structural variation of the enone-acid substrates, providing a range of highly functionalised syn-polycyclic carbo- and heterocycles in excellent yields, diastereo- and enantioselectivities (up to 99% yield, 99 : 1 dr and 99% ee). Whilst investigating this process, we discovered that using cinchona alkaloid derivatives as catalysts gave preferential access to the diastereomeric anti-products. Therefore, a range of anti-dihydrobenzofurans was synthesised from readily available starting materials in good yield and stereoselectivities (up to 73%, 20 : 80 dr and 99% ee) using OTMS-quinidine catalyst. These two complementary synthetic strategies allowed facile and controllable access to both syn- and anti-diasteroisomers of a product in high enantioselectivity via judicious choice of catalyst. Subsequently, two telescoped procedures combining the synthesis of the enone-acid through olefination and asymmetric functionalisation were designed, giving rapid access to stereodefined pyrrolidines in high levels of diastereo- and enantioselectivitiy (up to 99 : 1 dr and 99% ee). The last part of this thesis describes preliminary studies toward the development of a doubly diastereoselective intramolecular Michael addition-lactonisation process, opening new avenues for the construction of complex molecular architectures.

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

Nature has gifted peptides as important modulators in the human body, but these types of molecules often have not been favored when we were looking for therapeutic agents. The poor bioavailability, fast degradation and until recent high manufacturing costs of some bioactive peptides lowered their potential usage in the health industry. Under these circumstances, unnatural amino acids were developed as indispensible tools providing enormous support to peptide science. By incorporating proper unnatural amino acids into a peptide or protein, we now can significantly improve peptide's or protein's half-life, cell permeability, bio-distribution, etc. In addition, their potency and receptor/acceptor selectivity could also be enhanced. Site-specific modifications of peptides and proteins under physiological conditions with the use of unnatural amino acids also have been made easier with the advance of biotechnology. Therefore, my research described in this dissertation contributes to the efforts in the development of novel unnatural amino acids. In particular, I have focused on novel methods in the synthesis of anti beta-functionalized gamma,delta-unsaturated amino acids. These amino acids have special interests in peptide chemistry: they can provide conformational constraints to the peptide 3D structures; the beta-functionalization allows the introduction of pharmaceutically interesting side chain groups; and the terminal double bond which is orthogonal to peptide synthesis provides access to further chemical modifications. Two general methodologies for the synthesis of both racemic and optically active anti beta-functionalized gamma,delta--unsaturated amino acids were developed by using the thio-Claisen rearrangement (TCR) reaction. Excellent diastereoselectivies and enantioselectivities were obtained when C2-symmetric chiral auxiliaries were selected to control the stereochemistry outcome. The mechanism and the scope of the TCR reaction were also studied, showing unique advantages in the preparation of these biological interesting amino acids.Another effort of developing angiotensin II type 1 (AT1) receptor biased peptide ligands is also documented in this dissertation. The AT1 receptor is a 7-transmembrane G-protein coupled receptor, which recent researches have shown could be activated through a beta-arrestins only, but G-protein independent, pathway. We synthesized 12 analogs of Sar1,Ile4,Ile8-AngII (SII), and tested them in biological assays, and obtained valuable information for further "perfect" biased ligands design.

No description available.

Several tetrahydroisoquinoline (TIQ) diamine derivatives were prepared for use as ligands in asymmetric transfer hydrogenation (ATH) of acetophenone of which 17 intermediates and the eight target ligands were novel compounds. The initial design followed that of Noyori, who presented the efficiency of his monotosylated diamine in ATH. A series of eight novel secondary amine derivatives (78a-g and 88) were prepared with substituents that influenced the electronics and the sterics of and around the nitrogen donor. Ligand 71 was shown to have no activity for the ATH of acetophenone. It was apparent from experimental observations that a balance between the electronic and steric characteristics of the substituent was necessary to facilitate activity. It was found that ligand 78d possessing a benzyl group, had the greatest activity (81 % conv.). The greatest selectivity was obtained with ligand 78f (77 % ee) having a chiral phenylmethyl substituent. It was discovered in the case of the active diamine ligands that an optimised 1500 equivalents of water was required in order to demonstrate any enantioselectivity. The exact role of the water has never been ascertained, although there are many publications in which the effect of water has been examined. The most active metal precursor was also investigated and [RhCl2(Cp*)]2 was found to be the best for these TIQ diamine ligands in the specified model reactions. This work has recently been accepted for publication and has established criteria for further rational design on this system. / Thesis (M.Sc.)-University of KwaZulu-Natal, Westville, 2010.

No description available.

Leung, Chi Yin. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 81-89). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts also in Chinese.

O presente trabalho descreve o uso de carboidratos como materiais de partida para a preparação de catalisadores quirais e também de substratos quirais. Primeiramente estudos envolvendo a aplicação de amino álcoois derivados de carboidratos na arilação assimétrica de aldeídos, usando ácidos arilborônicos como fontes de grupos arila transferíveis, revelaram que um ligante preparado a partir da D-xilose mostrou-se bastante eficiente e conduziu aos produtos em excelentes rendimentos e altos excessos enantioméricos. Posteriormente a arilação de aldeídos derivados de carboidratos é descrita. Em alguns casos diastereosseletividades maiores que 20:1 foram observadas e a metodologia foi aplicada a síntese total da 7-epi-goniofufurona e análogos. / The work described herein is centered on the use of carbohydrates as starting materials for the synthesis of chiral ligands and chiral sugar-derivatives. Initially, chiral amino alcohols were studied as ligands for the asymmetric arylation of aldehydes using aryl boronic acids as the source of transferable aryl groups. We found that a chiral ligand derived from D-xylose was very efficient and the desired products were obtained in excellent yields and enantiomeric excesses. In addition, the arylation of sugar-based aldehydes was also studied. In many cases, excellent diastereoselectivities of >20:1 were achieved and the methodology was employed in the total synthesis of 7-epi-goniofufurone and analogues.

Luk To. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (leaves 115-123). / Abstracts in English and Chinese. / Contents --- p.i / Acknowledgement --- p.ii / Abstract --- p.iii / Abbreviation --- p.vi / Chapter 1. --- Introduction --- p.1 / Chapter 1-1 --- Background --- p.1 / Chapter 1-2 --- Sharpless Epoxidation --- p.2 / Chapter 1-3 --- Mn-Salen Complexes for Epoxidation --- p.4 / Chapter 1-4 --- Oxaziridinium Salts --- p.6 / Chapter 1-5 --- Dioxiranes --- p.9 / Chapter 1-6 --- Asymmetric Epoxidation by Dioxirane --- p.12 / Chapter 2. --- Results and Discussion --- p.31 / Chapter 2-1 --- Epoxidation of trαns-disubstituted and trisubstituted alkenes catalyzed by L-αrαbino-4-uloses --- p.31 / Chapter 2-2 --- Epoxidation of cis-alkenes catalyzed by L-arabino-4-uloses --- p.47 / Chapter 2-3 --- Epoxidation of alkenes catalyzed by new L-arabino-4-uloses --- p.55 / Chapter 3. --- Conclusion --- p.77 / Chapter 4. --- Experimental Section --- p.80 / Chapter 5. --- References --- p.115 / Chapter 6. --- Appendix --- p.124