Development of New Strategies for the Incorporation of Small Strained Heterocycles.

The first part of this thesis describes the development of new methods for the introduction of an oxetane and azetidine ring into heterocycles of interest for medicinal chemistry. Small ring heterocycles are of value to medicinal chemists because they have the opportunity to bind to receptor residues whilst contributing relatively little to overall molecular weight.
We have developed a new method for the introduction of an oxetane ring in the C4 position of sydnones and describe their utilization in the development of oxetanyl-substituted pyrazole compounds. In addition, the intramolecular cycloaddition of propargyl ether derivatives allows a small family of spiro-oxetane pyrazoles to be prepared. Finally, the further functionalization of a 3-bromo spiro-oxetane pyrazole can be exploited to provide a range of polycyclic heterocycles.
We have also explored the direct coupling of small ring heterocycles. The synthesis of oxetane and azetidine boronic acids under copper catalysis is first presented. Unfortunately, these substrates were found to be unreactive to Suzuki-Miyaura cross-coupling and conjugate addition to enone derivatives. However, we report the successful preparation of the sodium sulfinate salts of azetidine and oxetane and their introduction in the positions C2 and C3 of indoles. The application of this methodology to the synthesis of analogues of a marketed pharmaceutical is also described.
The second part of this thesis describes the investigation of the scope of a mild cycloaddition of 2-pyrones and potassium alkynyl trifluoroborates in the presence of a Lewis acid.