Isothiourea-mediated synthesis of functionalised heterocycles
Abstract
The research outlined in this thesis describes methodologies for the synthesis of
functionalised heterocycles through the use of C1-ammonium enolate catalysis utilising
isothiourea organocatalysts.
Chapter 2: Initial work demonstrated a DHPB-mediated Michael addition-lactamisation/PhSH elimination/N- to O-sulfonyl transfer one-pot cascade for the synthesis of
2,4,6-substituted pyridine sulfonates. Applying (phenylthio)acetic acid and a range of a,ß-unsaturated ketimines, pyridine sulfonates were obtained in moderate to good yield (40-69%)
with the functionalisation of the incorporated sulfonate group examined through various
derivatisations.
Chapter 3: The established isothiourea-mediated pyridine methodology was expanded
into the synthesis of 2,3- and 2,3,5-substituted pyridine 6-tosylates through a three-stage
Michael addition-lactamisation, S-oxidation-sulfoxide elimination and N- to O-sulfonyl transfer
protocol. Using (phenylthio)acetic acids and 2-N-tosyliminoacrylates a range of pyridine
products were provided in moderate to good yield over the three-stage process (44-72%).
Derivatisation of the installed sulfonate group allowed access into 2,3-, 2,3,5-, 2,3,6 and 2,3,5,6-substituted pyridines.
Chapter 4: Subsequent studies expanded the scope of dihydropyranone and
dihydropyridinone products accessible through isothiourea-catalysis using 2-aroyl acrylates or
2-N-tosyliminoacrylates in an enantioselective Michael addition-cyclisation process. It was
discovered that the use of homoanhydride enolate precursors was necessary when applying 2-aroyl acrylates to ensure high enantioselectivity (up to 99%) and reproducibility of the
dihydropyranone products, while carboxylic acids can be used with 2-N-tosyliminoacrylates,
providing dihydropyridinones in high enantioselectivity (typically >90% ee).
Chapter 5: Enantioselective Michael addition-lactonisation of 2-aryl and 2-alkenylacetic acids and a,ß-unsaturated trichloromethyl ketones, catalysed by (2S,3R)-HyperBTM was shown to give dihydropyranones with subsequent ring opening and substitution
of the CCl₃ group providing a range of diesters and diamides in high diastereo- and
enantioselectivity (up to 95:5 and up to >99% ee).
Chapter 6: The pyrrolizine core is present in many biologically relevant molecules. It
was demonstrated that an isothiourea-catalysed enantioselective Michael addition-lactonisation/ring opening process gives access to these important molecules with exquisite
diastereo- and enantioselectivity (typically >95:5 dr and >99% ee). A novel synthetic route into
the synthesis of the pyrrole enone-acid substrates was established, hence making the overall
methodology more efficient and reproducible. Computational studies are provided to compliment the synthetic studies with investigations into the origin of the high stereocontrol
observed in this process.
Chapter 7: Saccharin-derived Michael acceptors have been shown as useful substrates
in isothiourea-catalysis. (2R,3S)-HyperBTM catalyses the Michael addition-lactamisation of
carboxylic acids and saccharin-derived Michael acceptors to give 8,9-dihydro-7H
benzo[4,5]isothiazolo[2,3-a]pyridin-7-one 5,5-dioxides in good to excellent stereocontrol
(80:20->95:5 dr and 71->99% ee). Furthermore, these Michael acceptors can be utilised with 1-(1H-imidazol-1-yl)-2-(phenylthio)ethan-1-one in a Michael addition-lactamisation/PhSH
elimination process giving access to the corresponding 1,2-benzoisothiazolopyridone 1,1-dioxide heterocycle in a chromatography-free procedure.
Type
Thesis, PhD Doctor of Philosophy
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