1.[1,2]-SIGMATROPIC REARRANGEMENT OF BENZYLIC AMMONIUMY LIDS - 2. CATALYTIC SP3-SP3 FUNCTIONALISATION OF SULFONAMIDES - 3. ANNULATION OF ARYNES IN THE SYNTHESIS OF SULTAMS

The first chapter in this thesis describes research on the asymmetric [1,2]-sigmatropic rearrangement of benzylic ammonium ylids. Our group previousely developed method showing that DMSO as solvent, and BTPP as base, in the presence of 5Å molecular sieves, dramatically improves the yield of the reaction. Hence, we applied the developed the method using8-(–)-phenylmenthol and (2S)-camphorsultam as chiral auxiliaries.

In the second chapter, a new application of Pd-catalysed allylation is reported. This enabled the synthesis of (30)of branched sp3-functionalised sulfonamides, a compound class for which few reported methods exist. By reacting benzyl sulfonamides with allylic acetates in the presence of Pd0 catalysts and a base, at room temperature, direct allylation was efficiently performed, yielding products that are analogues of structural motifs seen in biologically active small molecules. The reaction was performed under mild conditions and could be applied to nanomolar sigma-receptor binders, thus enabling a late-stage functionalisation and efficient expansion of drug-like chemical space.

The third chapter described a synthesis of benzosultam without recourse to transition-metal catalysis, or stoichiometric amounts of organometallic building blocks. Iodomethane sulfonylamide adds to benzyne (generated using fluoride sources), and then the formed intermediate undergos an intramolecular cyclisation to afford sultam. Using this method that procceds under simple reaction conditions, (11) benzosultams were synthesised in modest yield.