Applications of isothioureas in organocatalysis : kinetic resolution of secondary alcohols and intramolecular Michael addition-lactonisation
Abstract
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.
Type
Thesis, PhD Doctor of Philosophy
Rights
Embargo Date: Print and electronic copy restricted until 6th December 2015
Embargo Reason: Thesis restricted in accordance with University regulations
Collections
Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.