A number of 3,3'-disubstituted binaphthol-modified allylboronates (<strong>2. 42a-m</strong>) were prepared from the reaction between triallylborane and the corresponding 3,3'-disubstituted binaphthols. These chiral allylboronates could allylate carbonyl compounds to produce chiral homoallylic alcohols in high chemical and optical yields. Chiral ligands were readily recycled through simple acid-base extraction. Among all allylboronates tested, 3,3'-(CF₃)₂-BINOL-modified allylboronate (<strong>2. 42b</strong>) is an especially effective reagent that allows for allylborations of both aldehydes and ketones in high enantioselectivities (up to 98% yield and >99% <em>ee</em>). Reagent <strong>2. 42b</strong> represents one of the best allylation reagents for carbonyl compounds developed thus far. <br /><br /> Allylations of cyclic imines using 3,3'-disubstituted binaphthol-modified allylboronates (<strong>2. 42a-j</strong>) were carried out at low temperature. 3,3'-Bis[3,5-(CF₃)₂-C₆H₃]-binaphthol-modified allylboronate (<strong>2. 42j</strong>) gave the best enantioselectivities (91% <em>ee</em> to >99% <em>ee</em>) in the allylation of a variety of cyclic imines. This methodology represents the first successful enantioselective allylboration of cyclic imines. The versatility of the allylation products (chiral a-allyl cyclic amines) was demonstrated through efficient total syntheses of several naturally occurring alkaloids such as coniine, crispine A and corynantheidol. <br /><br /> 3,3'-Disubstituted binaphthol-modified alkynylboronates (<strong>4. 47a-g</strong>) were synthesized according to a reported procedure. It was found that these chiral alkynylboronates add to <em>N</em>-acylaldimines in an enantioselective manner to produce chiral propargylamides in excellent yields and enantioselectivities. Up to >99% <em>ee</em> could be obtained with 3,3'-diphenyl binaphthol-modified alkynylboronates (<strong>4. 47f</strong>). This represents the first direct asymmetric synthesis of chiral propargylamides. Using this methodology, an antitubulin agent (-)-<em>N</em>-acetylcolchinol (AstraZeneca® ZD6126 phenol) was synthesized in 4 steps from commercially available 3-hydroxybenzaldehyde. <br /><br /> During a study of the asymmetric conjugate alkynylation of enones via chiral alkynylboronates, it was found that achiral dialkyl alkynylboronates could add to enones enantioselectively in the presence of catalytic amounts of chiral bidentate ligands (such as 3,3'-disubstituted binaphthols, diisopropyl tartrate and activated chiral amino acids). A catalytic cycle driven by "ligand-exchange" processes was proposed to rationalize this asymmetric induction. This is the first reported example of an asymmetric reaction that is promoted by a catalytic amount of an exchangeable chiral ligand on the boron reagent. More importantly, we have demonstrated a proof of principle that ligand exchange with boronates can be sufficiently fast that catalytic amounts of chiral ligands can be used to effect high levels of stereoselectivity. This catalytic protocol can potentially be applied to other asymmetric reactions providing the following three requirements are met: (1) the starting achiral boronate does not react with the electrophile (no background reaction); (2) the chiral boronate reacts with the electrophile and (3) ligand exchange or transesterification occurs under the reaction conditions. Potential applications of this principle include asymmetric allylboration, hydroboration, aldol reaction and reduction, just to name a few.

A number of 3,3'-disubstituted binaphthol-modified allylboronates (<strong>2. 42a-m</strong>) were prepared from the reaction between triallylborane and the corresponding 3,3'-disubstituted binaphthols. These chiral allylboronates could allylate carbonyl compounds to produce chiral homoallylic alcohols in high chemical and optical yields. Chiral ligands were readily recycled through simple acid-base extraction. Among all allylboronates tested, 3,3'-(CF₃)₂-BINOL-modified allylboronate (<strong>2. 42b</strong>) is an especially effective reagent that allows for allylborations of both aldehydes and ketones in high enantioselectivities (up to 98% yield and >99% <em>ee</em>). Reagent <strong>2. 42b</strong> represents one of the best allylation reagents for carbonyl compounds developed thus far. <br /><br /> Allylations of cyclic imines using 3,3'-disubstituted binaphthol-modified allylboronates (<strong>2. 42a-j</strong>) were carried out at low temperature. 3,3'-Bis[3,5-(CF₃)₂-C₆H₃]-binaphthol-modified allylboronate (<strong>2. 42j</strong>) gave the best enantioselectivities (91% <em>ee</em> to >99% <em>ee</em>) in the allylation of a variety of cyclic imines. This methodology represents the first successful enantioselective allylboration of cyclic imines. The versatility of the allylation products (chiral a-allyl cyclic amines) was demonstrated through efficient total syntheses of several naturally occurring alkaloids such as coniine, crispine A and corynantheidol. <br /><br /> 3,3'-Disubstituted binaphthol-modified alkynylboronates (<strong>4. 47a-g</strong>) were synthesized according to a reported procedure. It was found that these chiral alkynylboronates add to <em>N</em>-acylaldimines in an enantioselective manner to produce chiral propargylamides in excellent yields and enantioselectivities. Up to >99% <em>ee</em> could be obtained with 3,3'-diphenyl binaphthol-modified alkynylboronates (<strong>4. 47f</strong>). This represents the first direct asymmetric synthesis of chiral propargylamides. Using this methodology, an antitubulin agent (-)-<em>N</em>-acetylcolchinol (AstraZeneca® ZD6126 phenol) was synthesized in 4 steps from commercially available 3-hydroxybenzaldehyde. <br /><br /> During a study of the asymmetric conjugate alkynylation of enones via chiral alkynylboronates, it was found that achiral dialkyl alkynylboronates could add to enones enantioselectively in the presence of catalytic amounts of chiral bidentate ligands (such as 3,3'-disubstituted binaphthols, diisopropyl tartrate and activated chiral amino acids). A catalytic cycle driven by "ligand-exchange" processes was proposed to rationalize this asymmetric induction. This is the first reported example of an asymmetric reaction that is promoted by a catalytic amount of an exchangeable chiral ligand on the boron reagent. More importantly, we have demonstrated a proof of principle that ligand exchange with boronates can be sufficiently fast that catalytic amounts of chiral ligands can be used to effect high levels of stereoselectivity. This catalytic protocol can potentially be applied to other asymmetric reactions providing the following three requirements are met: (1) the starting achiral boronate does not react with the electrophile (no background reaction); (2) the chiral boronate reacts with the electrophile and (3) ligand exchange or transesterification occurs under the reaction conditions. Potential applications of this principle include asymmetric allylboration, hydroboration, aldol reaction and reduction, just to name a few.

Natural products continue to inspire synthetic chemists to develop novel methodologies to provide efficient and expedient syntheses of the target molecules. Haterumalide NA aroused our interest and prompted development of four differing methodologies. Three of the strategies pursued involved use of B-lactone scaffolds as intermediates. Extensions of the nucleophile catalyzed, aldol-lactonization (NCAL) reaction were also pursued and targeted toward alternative natural product targets. The reactivity of the unexpectedly stable strained spirocycle, spiroepoxy-B- lactone, was explored. Spiroepoxy-B-lactones exhibited a wide range of reactivity, but largely rearranged to tetronic acids. The desired reaction manifold remained inaccessible and led to application of the NCAL process to tetrahydrofuran-fused B-lactones. Several tetrahydrofuran-fused B-lactones were prepared, which displayed low diastereoselectivity. The diastereoselectivity could be somewhat improved in a double diastereoselective NCAL process with varied solvent systems, yet the carbocyclic analogues gave much more promising results. The use of carbocycle-fused !-lactones ultimately culminated in a double diastereoselective NCAL process, and overall led to improvements in diastereoselectivities from 1:1-2 up to >19:1. Further expansion of the substrate scope for the NCAL process was studied for application to bridged tricyclic B- lactones, access to carbocycle-fused y-lactones, and towards development of a dynamic kinetic resolution NCAL process. With our interest aimed at haterumalide NA, a modified Negishi cross coupling between zincates and dichloroolefins was also revisited. The stringent anhydrous reaction conditions led to reexamination of initial leads, which provided user-friendly anhydrous conditions by utilizing commercially available anhydrous solvent. However, application was implemented solely to a simplified model system.

In the first part of this thesis, the construction of the novel bifunctional proline-(1R,2R)-2-aminoDMAP organocatalyst backbone is described. Target compound has both Lewis base and Br&oslash / nsted acid catalaphoric sites. The Lewis base site is synthesized via selective mono-N-pyridilization of trans-(1R,2R)-cyclohexane-1,2-diamine by Cu catalysis and Br&oslash / nsted acid site is subsequently introduced by anchoring L-proline unit. In the second part, catalytic activities of organocatalysts are tested in asymmetric Michael addition reaction between a cyclic 1,3-dicarbonyl compound 4-hydroxycoumarin and various &alpha / ,&beta / -unsaturated ketones to afford optically active warfarin as anticoagulants, in one step. Reaction parameters such as solvent, temperature, equivalency, and cocatalyst were screened. Enantiomeric excess value (ee) up to 72% is attained.

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

The main focus of this thesis lies on transition metal-catalyzed hydrogen transfer reactions. In the first part of the thesis, the mechanism for racemization of sec-alcohols with a ruthenium complex, Ru(CO)2Cl(η5-C5Ph5) was studied. The reaction between 5-hexen-2-ol and Ru(CO)2(Ot-Bu)(η5-C5Ph5) was studied with the aim to elucidate the origin of the slow racemization observed for this sec-alcohol. Two diastereomers of an alkoxycarbonyl complex, which has the double bond coordinated to ruthenium, were characterized by NMR and in situ FT-IR spectroscopy. The observed inhibition of the rate of racemization for substrates with double bonds provided further confirmation of the importance of a free coordination site on ruthenium for β-hydride elimination. Furthermore, we observed that CO exchange, monitored by 13C NMR using 13CO, occurs with both the precatalyst, Ru(CO)2Cl(η5-C5Ph5), and the active catalytic intermediate, Ru(CO)2(Ot-Bu)(η5-C5Ph5). It was also found that added CO has an inhibitory effect on the rate of racemization of (S)-1-phenylethanol. Both these observations provide strong support for reversible CO dissociation as a key step in the racemization mechanism. In the second part of this thesis, Ru(CO)2Cl(η5-C5Ph5) was combined with an enzymatic resolution catalyzed by a lipase, leading to several efficient dynamic kinetic resolutions (DKR). DKR of exocyclic allylic alcohols afforded the corresponding acetates in high yields and with excellent enantiomeric excess (ee). The products were utilized as synthetic precursors for α-substituted ketones and lactones. DKR of a wide range of homoallylic alcohols afforded the products in good to high yields and with high ee. The homoallylic acetates were transformed into 5,6-dihydropyran-2-ones in a short reaction sequence. Furthermore, DKR of a wide range of aromatic β-chloroalcohols afforded the products in high yields and with excellent ee. The β-chloro acetates were further transformed into chiral epoxides. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 5: Mansucript.</p>

<p>Numerous methodologies for efficient formation of carbon-nitrogen bonds have been developed over the decades due to the widespread importance of nitrogen containing compounds in pharmaceuticals and bulk commercial chemicals. Among many methods, hydroamination, especially, has attracted enormous attention because of its atom-economical characteristic to synthesize amine moieties. As a result, numerous publications have been reported relating the hydroamination reaction using various metal catalysts. However, the hydroamination of unactivated alkenes still remains a challenge task because of the low reactivity of the CC double bond. Recent development of superior gold(I) catalysis in many organic transformations stimulated us to develop efficient gold(I)-catalyzed methods for enantioselective intra- and intermolecular hydroamination of unactivated alkenes. </p><p>A gold(I)-catalyzed system for enantioselective intramolecular hydroamination of unactivated alkenes has been developed. For the effective gold(I)-catalyzed method, various gold(I)-catalysts have been synthesized and tested. Among the catalysts, bis(gold) complexes containing an axially chiral bis(phosphine) ligand catalyze the enantioselective intramolecular hydroamination of unactivated alkenes with carboxamide derivatives, most effectively. The method was effective for both carbamates and ureas to form pyrrolidine derivatives with up to 85 % ee.</p><p>The first enantioselective intermolecular hydroamination of unactivated alkenes was realized by a gold(I)-catalyzed method. The gold(I) catalyst system adds cyclic ureas to unactivated 1-alkenes to produce corresponding enantiomerically enriched hydroamination product in good yield with enantioselectivity up to 78 % ee. </p><p>Polymer-embedded ligands have been synthesized to demonstrate proofs of concepts for fluxional mechanocatalysis. We applied a certain shear stress using a rheometer in the course of palladium-catalyzed asymmetric allylic alkylation to examine catalytic reactivity change under the mechanical force.</p> / Dissertation

Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2004. / Includes bibliographical references (leaves 206-216). Also available in electronic version. Access restricted to campus users.

The health benefits of fish oil supplementations have been proven to be effective by several studies which are discussed in this thesis. It was found that these compounds had potent anti-inflammatory properties and since then has prompted much research into the use of these compounds as potential treatments for chronic inflammation based diseases, where the overuse of current anti-inflammatory drugs cause many problems with undesired side-effects. The aim of this research is to study the bioactivity of resolvin E1 and various analogues, and to determine a novel route towards resolvin E1 natural product so that bioactivity tests may be conducted in comparison of synthetically produced resolvin E1 and naturally extracted resolvin E1. The initial aim of this research was to develop a range of analogues of a fragment of Resolvin E1. This was so that a series of compounds could be produced with various R groups to identify any structure-activity relationships for this part of the natural product. There is one stereocentre in this fragment of resolvin E1 and it was decided that a racemic version of these compounds would be tested for bioactivity, and if any of the compounds had significant anti-inflammatory properties then the R and S versions could be separated, allowing for the testing of both enantiomers to determine which gave the most potent anti-inflammatory response. This led to the creation of several novel fragments and their biological testing. The secondary aim of the project was to complete the total synthesis of the resolvin E1 natural product. We devised a novel route towards resolvin E1 which used MIDA boronate protecting group to introduce a fixed trans double bond which was useful in a compound with multiple alkene systems. Resolvin E1 also contains three stereocentres, the synthesis from the fragment work was recycled to begin the synthesis, and made use of 1,2:5,6-di-O-isopropylidene-D-mannitol and Noyori s catalyst to setup the stereocentres. The use of new MIDA-boronate moieties were also explored in order to develop a new, efficient synthesis toward resolvin E1.

The work presented in this thesis involves new transformations of azacycles, focusing on the introduction of functionality &alpha;-to N. &alpha;-C-H functionalisation on an azetidine has been a long-standing challenge, with N-protecting/activating groups that work well in the higher and lower azacyclic systems not viable. A recent breakthrough in the Hodgson group showed the rarely used N-thiopivaloyl group was effective for &alpha;-deprotonation– electrophile trapping on azetidines, but was not without limitations concerning harsh removal conditions and scope for further substitutions. This thesis describes efforts to overcome these issues by development of a new protecting/activating group for N, t-butoxythiocarbonyl (Botc).