Synthesis of novel pentacyclo-undecane chiral ligands for application in asymmetric catalysis

Thesis (M.Sc.) - University of KwaZulu-Natal, Westville, 2008.There is enormous interest in the design and development of efficient chiral ligands for asymmetric catalysis, as a result, this field has become one of the most popular areas of research in organic chemistry. This project involved the investigation of the novel chiral pentacyclo-undecane (PCU) diol 54a, PCU bisimine 87 and PCU bis(oxazoline) 100 type ligands. The PCU diol ligand was synthesized, but proved to be difficult to obtain enantiomerically pure which hindered further investigation into this type of ligand. The PCU bisimine ligand 87 was synthesized. However due to its instability it was not further pursued. Synthesis of the PCU bis(oxazoline) ligand 100 was successful. This ligand was complexed to various metal salts and its efficiency as a chiral Lewis acid catalyst was evaluated on the asymmetric Diels-Alder reaction between 3-acryloyloxazolidin- 2-one 52 and cyclopentadiene 33. The anhydrous magnesium perchlorate ligand complex emerged as the best catalyst providing the endo-cycloadduct product 53 in 81 % enantiomeric excess at -40 oC. Optimizations of the possible conformations of the magnesium complex of ligand 100 with the substrate 52 were performed using Density Functional Theory (DFT) calculations. The more energetically favoured complex conformation was established. The Re-face of the dienophile which was less hindered produced the product consistent with the experimentally observed product 16. Based on the calculated bond lengths from the computational model binding of the ether oxygen on the PCU moiety to magnesium was observed. All the novel compounds were fully characterized using NMR, IR and mass spectroscopy as the main tools

Synthesis and evaluation of novel tetrahydroisoquinoline organocatalysts in asymmetric catalysis.

Thesis (Ph.D.)-University of KwaZulu-Natal, Westville, 2012.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.This is a thesis in which the chapters are written as a set of discrete research papers, with an Overall Introduction and Final Discussion. Typically these chapters will have been published in internationally recognized, peer-reviewed journals

Methyl 1-cyclo­hexyl-6,7-dimeth­oxy-3,4-dihydro­isoquinoline-3-carboxyl­ate

There are two independent mol­ecules in the asymmetric unit of the title compound, C19H25NO4. A single C—H⋯π inter­action and various inter­molecular contacts (2.65–2.83 Å) link the independent mol­ecules in the crystal structure. The N-containing six-membered ring assumes a twisted half-boat conformation

(1S,3S)-Methyl 6,7-dimeth­oxy-1-phenyl-1,2,3,4-tetra­hydro­isoquinoline-3-carboxyl­ate

In the title compound, C19H21NO4, an organocatalyst with a tetra­hydro­isoquinoline backbone, the heterocyclic ring assumes a half-boat conformation. The dihedral angle between the aromatic rings is 82.93 (8)°. In the crystal, mol­ecules are linked via N—H⋯O and C—H⋯O hydrogen bonds, forming a layer parallel to (10)

(1S,3S)-Methyl 2-benzyl-6,7-dimeth­oxy-1-phenyl-1,2,3,4-tetra­hydro­isoquinoline-3-carboxyl­ate

In the title compound, C26H27NO4, the heterocyclic ring assumes a half-chair conformation and inter­molecular C—H⋯O inter­actions help to construct the three-dimensional network within the crystal packing

(3S)-2-Benzyl-3-carb­oxy-1,2,3,4-tetra­hydro­isoquinolinium chloride monohydrate

In the title compound, C17H18NO2 +·Cl−·H2O, a precursor to novel asymmetric catalysts, the N-containing six-membered ring of the tetra­hydro­quinolinium unit assumes a half-boat conformation. In the crystal, inter­molecular O—H⋯O, O—H⋯Cl, N—H⋯Cl and C—H⋯O hydrogen bonds and C—H⋯π inter­actions link the mol­ecules into a three-dimensional network

(1R,3S)-Methyl 6,7-dimeth­oxy-1-(4-meth­oxy­phen­yl)-1,2,3,4-tetra­hydro­isoquinoline-3-carboxyl­ate

The title compound, C20H23NO5, is the third in a series of tetra­hydoisoquinoline (TIQ) compounds that are precursors to novel chiral catalysts. The N-containing six-membered ring assumes a half-boat conformation. No hydrogen bonding is observed in the crystal structure

(S)-N-Benzyl-2-methyl-1,2,3,4-tetra­hydro­isoquinoline-3-carboxamide

The structure of the title compound, C18H20N2O, at 173 K has hexa­gonal (P61) symmetry. The N-containing six-membered ring assumes a half-chair conformation. In the crystal, inter­molecular N—H⋯O hydrogen bonding via the amide groups cross-link the mol­ecules along the a axis. The absolute configuration was confirmed by 2D NMR studies

(S)-Methyl 3-(3,4-dimeth­oxy­phen­yl)-2-[2-(diphenyl­phosphan­yl)benzamido]­propano­ate

Mol­ecules of the title compound, C31H30NO5P, show a sttagered conformation about the C—C bond joining the dimeth­oxy­benzene group to the chiral centre, with the dimeth­oxy­benzene ring gauche to the amide group and anti to the ester group. In the crystal, weak inter­molecular N—H⋯O and C—H⋯O hydrogen bonds form layers parallel to (110)

(S)-2-Benzyl-N-(2,6-diisopropyl­phen­yl)-1,2,3,4-tetra­hydro­isoquinoline-3-carboxamide

The asymmetric unit of the title compound, C29H34N2O, contains two mol­ecules in which the N-containing six-membered rings assume different conformations viz. half-chair and envelope. Inter­molecular N—H⋯O hydrogen bonding via the amide groups cross-link the mol­ecules in the crystal structure