Isothiourea-mediated synthesis of functionalised heterocycles Article Swipe

The research outlined in this thesis describes methodologies for the synthesis of
\nfunctionalised heterocycles through the use of C1-ammonium enolate catalysis utilising
\nisothiourea organocatalysts.
\n
\nChapter 2: Initial work demonstrated a DHPB-mediated Michael addition-lactamisation/PhSH elimination/N- to O-sulfonyl transfer one-pot cascade for the synthesis of
\n2,4,6-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%)
\nwith the functionalisation of the incorporated sulfonate group examined through various
\nderivatisations.
\n
\nChapter 3: The established isothiourea-mediated pyridine methodology was expanded
\ninto the synthesis of 2,3- and 2,3,5-substituted pyridine 6-tosylates through a three-stage
\nMichael addition-lactamisation, S-oxidation-sulfoxide elimination and N- to O-sulfonyl transfer
\nprotocol. Using (phenylthio)acetic acids and 2-N-tosyliminoacrylates a range of pyridine
\nproducts were provided in moderate to good yield over the three-stage process (44-72%).
\nDerivatisation of the installed sulfonate group allowed access into 2,3-, 2,3,5-, 2,3,6 and 2,3,5,6-substituted pyridines.
\n
\nChapter 4: Subsequent studies expanded the scope of dihydropyranone and
\ndihydropyridinone products accessible through isothiourea-catalysis using 2-aroyl acrylates or
\n2-N-tosyliminoacrylates in an enantioselective Michael addition-cyclisation process. It was
\ndiscovered 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
\ndihydropyranone products, while carboxylic acids can be used with 2-N-tosyliminoacrylates,
\nproviding dihydropyridinones in high enantioselectivity (typically >90% ee).
\n
\nChapter 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
\nof the CCl₃ group providing a range of diesters and diamides in high diastereo- and
\nenantioselectivity (up to 95:5 and up to >99% ee).
\n
\nChapter 6: The pyrrolizine core is present in many biologically relevant molecules. It
\nwas demonstrated that an isothiourea-catalysed enantioselective Michael addition-lactonisation/ring opening process gives access to these important molecules with exquisite
\ndiastereo- and enantioselectivity (typically >95:5 dr and >99% ee). A novel synthetic route into
\nthe synthesis of the pyrrole enone-acid substrates was established, hence making the overall
\nmethodology more efficient and reproducible. Computational studies are provided to compliment the synthetic studies with investigations into the origin of the high stereocontrol
\nobserved in this process.
\n
\nChapter 7: Saccharin-derived Michael acceptors have been shown as useful substrates
\nin isothiourea-catalysis. (2R,3S)-HyperBTM catalyses the Michael addition-lactamisation of
\ncarboxylic acids and saccharin-derived Michael acceptors to give 8,9-dihydro-7H
\nbenzo[4,5]isothiazolo[2,3-a]pyridin-7-one 5,5-dioxides in good to excellent stereocontrol
\n(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
\nelimination process giving access to the corresponding 1,2-benzoisothiazolopyridone 1,1-dioxide heterocycle in a chromatography-free procedure.