Synthesis and evaluation of novel tetrahydroisoquinoline organocatalysts in asymmetric catalysis.
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Date
2012
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Abstract
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.
Description
Thesis (Ph.D.)-University of KwaZulu-Natal, Westville, 2012.
Keywords
Tetrahydroisoquinolines., Catalysis., Theses--Pharmacy and pharmacology.