Organocatalysis has rapidly expanded in the last decade to encompass a wide variety of small organic molecules that are capable of either activating substrates or transforming them into more reactive forms. The aim of this study was to develop novel chiral organocatalysts based on the tetrahydroisoquinoline backbone and evaluate them on asymmetric reactions. Three organocatalytic modes of activation have been investigated for C-C bond forming asymmetric reactions. In chapter 2, for the first time organocatalysts bearing a secondary nitrogen within a cyclohexane ring were evaluated in the asymmetric Diels–Alder reaction. These catalysts were tested over a range of dienes and dienophiles and displayed promising chemical conversions of up to 100 % with up to 64 % ee when triflic acid was employed as the cocatalyst. Density functional theory computational studies and 2D NMR spectroscopy were used to determine the structure of the intermediate iminium ion formed between the most efficient catalyst and cinnamaldehyde. Chapter 3 includes a series of novel tetrahydroisoquinoline chiral N-oxide organocatalysts and their evaluation in the asymmetric allylation reaction of aromatic and α-β-unsaturated aldehydes with allyltrichlorosilane. The chiral homoallyl products were obtained with good chemical efficiency (up to 93 % yield) and high enantioselectivity (up to 91 % ee) under mild reaction conditions (23 °C). Chapter 4 is the simple and practical microwave-assisted synthesis of new tetrahydroisquinoline guanidine organocatalysts and their evaluation in the asymmetric Michael addition reaction of malonates and β-ketoesters with nitro-olefins. In addition, a novel microwave assisted procedure of introducing the guanidine unit onto amino amide derivatives is reported. The chiral products were obtained with quantitative chemical efficiency (up to 99 % yield) and excellent enantioselectivity (up to 97 % ee). Chapter 5 is a collection of all X-ray crystal structures that were published from novel compounds synthesized pertaining to Chapters 2-4, it contains 15 published crystal structures while Chapters 3-4 contain 3 other X-ray crystal structures. It should be noted that with the exception of the introduction and Chapter 4 (submitted for publication), the remaining chapters of this thesis have been published in international peer reviewed journals. In the next section (DECLARATION 2 – PUBLICATIONS) a precise description of my contribution to each of the publications/chapters is provided. / Thesis (Ph.D.)-University of KwaZulu-Natal, Westville, 2012.

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.

A series of 88 novel tetrahydroisoquinoline (TIQ) compounds have been synthesised for applications in asymmetric catalysis. Several chiral TIQ ligands, possessing N,O and N,N donor atoms, have been prepared and evaluated for the catalytic asymmetric transfer hydrogenation (ATH) of pro-chiral ketones. The highest selectivity obtained for the asymmetric transfer hydrogenation of acetophenone with the N,O donor atom ligands was >99 % ee at low temperatures in iso-propanol with [Ru(p-cymene)Cl2]2 as a pre-catalyst. The observed enantioselectivity was supported by theoretical calculations using the Jaguar interphase program (Paper I). An enantioselectivity of 70 % was obtained with the ligands possessing the N,N donor atoms with the observation that water played a significant role in the enantioselectivity of the ATH reaction of acetophenone (Paper II). An investigation into the usefulness of the TIQ scaffold with other donor atoms was also undertaken. A series of novel P,N oxazoline ligands were synthesised and coordinated to Iridium BArF. These complexes were screened as chiral catalysts for the high pressure asymmetric hydrogenation of unsymmetrical olefins. The reactions proceeded readily at ambient temperature and provided selectivities of up to >91 % ee with excellent conversion rates (>99 %) for the benchmark reactions. Based upon these favorable results, the ligands providing the best results were further screened on a variety of functionalized and unfunctionalised olefins (Paper III). The success of the TIQ backbone in ATH reactions prompted an investigation into its applications in carbon-carbon (C-C) bond forming reactions. The Henry (nitroaldol) reaction is an important C-C bond forming reaction with the chiral oxazoline class of ligands being widely utilised. A series of novel, chiral TIQ oxazoline ligands were synthesised and complexed to various metals (Cu, Sc, Co, Zn, Ni and Mn). These complexes were screened as chiral catalysts in the asymmetric Henry reaction. The highest enantioselectivity (>77 %) was obtained when Cu(OAc)2was employed as a pre-catalyst and iso-propanol as a solvent (Paper IV). The final chapter deals with carbon-sulphur bond formations facilitated by the conjugate addition of thioglycolate to various chalcones. A series of novel, chiral TIQ N-oxide ligands were synthesised and complexed to lanthanum. The complexes were screened for activity against the benchmark reaction and an enantioselectivity of 81 % was obtained. / Thesis (Ph.D.)-University of KwaZulu-Natal, Westville, 2010.

Thesis (Ph.D.)--Virginia Commonwealth University, 2008. / Title from title-page of electronic thesis. Prepared for: Dept. of Pharmaceutics. Bibliography: leaves 483-511.

Thesis (Ph. D.)--Virginia Commonwealth University, 2008. / Prepared for: Dept. of Pharmaceutics. Bibliography: leaves 483 - 511. Also available online via the Internet.

<p> The reactions of methyllithium and phenyllithium with the iminium chloride, [(2R,3S)-2,3-dihydroxy-3-(6,7 -dimethoxy-3,4-dihydroisoquinolin-1-yl)]propionate hydrochloride, 34 as a means of preparing enantiomerically pure compounds are described. These reactions afford a single product in high yield. The nmr spectra of the products, 1-(1 ,2,3-trihydroxy-3,3-dimethylpropyl)-1 ,2,3,4-tetrahydro-6,7 -dimethoxy-1- methylisoquinoline 54 and 1-( 1,2,3-trihydroxy-3,3-diphenylpropyl)-1,2,3,4-tetrahydro-6,7- dimethoxy-1-phenylisoquinoline 62, are discussed and an explanation is given to account for the diastereoselectivity of the reaction. By this method, enantiomerically pure compounds bearing a quaternary centre at C-1 of the tetrahydroisoquinoline system may be prepared. Oxidative degradation of the hydroxylated side chain of compound 62 has led to the preparation of several other new compounds. </p> <p> The usefulness of the t-butoxycarbonyl group as a selective protecting group for nitrogen in the preparation of 2-t-butyloxycarbonyl-1,2,3,4-tetrahydro-1-(1,2,3- trihydroxy-3,3-dimethylpropyl)-6,7-dimethoxy-1-methylisoquinoline 59 is described. It has advantages over the ethoxycarbonyl group in that it not only selectively protects the amino group but also is easy to remove by short treatment with trifluoroacetic acid and water at room temperature. Treatment of 59 with sodium periodate afforded the aldehyde, 1-formyl-2-t-butyloxycarbonyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline, 60. An attempted oxidation of the aldehyde 60 to the acid is also described. </p> <p> A review of recent methods of inducing chirality at C-1 of the tetrahydroisoquinoline system is given in the Introduction. </p> / Thesis / Master of Science (MSc)

No description available.

Isoquinoline alkaloids and analogs play an important role in today's pharmaceutical industry. The need to synthesize single stereoisomers of these alkaloids is important. Many times only a single stereoisomer exhibits the desired activity, while other stereoisomers of the alkaloid exhibit undesired side effects. The stereoselective synthesis of 1, 1-disubstituted 1,2,3,4- tetrahydroisoquinolines using Reissert compound chemistry containing chiral acyl auxiliaries was studied with the ultimate goal of synthesizing spirobenzylisoquinoline alkaloids. / Ph. D.

This thesis is concerned with the development of methodology for the regioselective ring-opening of aziridines and aziridinium intermediates and its subsequent application to the asymmetric synthesis of &beta;-substituted-&alpha;-amino acids and 1,2,3,4-tetrahydroisoquinolines. Chapter 1 introduces methods for the formation of aziridines and aziridinium ions and focusses on their utility as intermediates in synthesis. Chapter 2 describes studies into the synthesis of aziridines from enantiopure &alpha;-hydroxy-&beta;-amino esters and their subsequent conversion to the corresponding &beta;-hydroxy-&alpha;-amino acids via either a regioselective ring-opening with Cl₃CCO₂H, or a rearrangement promoted by Cl3CCO2H. Application of this procedure to both syn- and anti-configured substrates enabled the syntheses of (S,S)-allo-threonine, (2R,3S)-threonine, (R,R)-3-hydroxyphenylalanine and (2S,3R)-3-hydroxyphenylalanine. Chapter 3 details attempts to truncate the synthesis described in Chapter 2 by investigating the synthesis of enantiopure anti-&beta;-hydroxy-&alpha;-amino acids via the intermediacy of aziridinium ions. These studies culminated in the development of a regioselective and stereospecific one-pot aziridinium formation and ring-opening protocol, leading to the synthesis of a range of C(3)-aryl and C(3)-alkyl substituted anti-&beta;-hydroxy-&alpha;-amino acids. Chapter 4 discusses the conversion of enantiopure anti-&alpha;-hydroxy-&beta;-amino esters to anti-&beta;-fluoro-&alpha;-amino esters via the regioselective and stereospecific ring-opening of an aziridinium intermediates in situ. The subsequent development of a one-pot deprotection strategy leads to a concise and expedient synthesis of anti-&beta;-fluorophenylalanines. The extension of this methodology to access a representative anti-&alpha;,&beta;-diamino acid is also demonstrated. Chapter 5 describes the development of a one-pot diastereoselective rearrangement of enantiopure &alpha;-hydroxy-&beta;-amino esters to 1,2,3,4-tetrahydroisoquinolines. The substrate scope of this reaction manifold is examined and application to the asymmetric synthesis of enantiopure 1,2,3,4-tetrahydroisoquinolines also discussed. Chapter 6 contains full experimental procedures and characterisation data for all compounds synthesised in Chapters 2, 3, 4 and 5.

Les potentiels daction neuronaux sont suivis dune post-hyperpolarisation qui est médiée par les canaux K+ Ca2+-dépendant de faible conductance (canaux SK). Cette post-hyperpolarisation joue un rôle important dans la régulation de lexcitabilité neuronale et les agents modulant lamplitude cette post-hyperpolarisation possèdent un intérêt thérapeutique potentiel (schizophrénie, maladie de Parkinson, maladie dAlzheimer, épilepsie,). Dans un premier temps, cette étude pharmacochimique de la N-méthyl-laudanosine (NML) a permis de mettre en évidence un composé tertiaire possédant une affinité significative vis-à-vis des canaux SK. Cette observation a initié la recherche de bloqueurs non quaternaires des canaux SK. Dans cette seconde partie, deux groupes de composés ont été préparés et testés. Dune part, des bis-isoquinoliniums ont montré des affinités 50 x plus élevées que celle de la NML. Dautre part, la préparation et la résolution de bis-1,2,3,4-tétrahydroisoquinoléines a permis dobtenir un stéréoisomère 4 x plus affin que la NML. Ce composé tertiaire a été caractérisé sur le plan chimique et physico-chimique (cristallographie RX, lipophilie et pKas) et étudié dans un modèle comportemental chez le rat. Sur base des premiers résultats comportementaux, un effet central a effectivement été observé.