Chiral heterocycles from intramolecular 1,3-dipolar cycloadditions.

The project was concerned with investigating the synthesis of novel enantiomerically pure heterocyclic compounds of various ring size via an intramolecular 1,3-dipolar cycloaddition reaction.The thesis begins with a general introduction to asymmetric synthesis and to 1,3-dipolar cycloadditions in chapters 1 and 2. The synthetic work described in the remaining chapters utilized the chiral template approach. Cheap readily available materials, namely aspartic acid and glucose, were used as building blocks to form suitable nitrile oxide or nitrone (1,3-dipoles) precursors for the 1,3-dipolar cycloaddition reaction. These precursors needed to contain a vinyl ether functionality (dihydrofuran or dihydropyran) for the regioselectivity of the intramolecular cycloaddition. [chemical formula] The synthetic route to pyrrolidines from aspartic acid was not successful due to the inability to alkylate the various derivatives of 3(S)-amino-y-butyrolactone. The synthesis of nitrile oxide and nitrone precursors for the six and eight membered heterocyclic system was unsuccessful whereas the synthesis of the precursors for the five and seven membered heterocyclic systems was successful. The nitrone precursor for the seven membered ring system did not cyclise possibly due to the extra rigidity which had been introduced into the molecule, whereas the nitrile oxide and nitrone precursors to the five membered ring system cyclised to form respectively a Delta2-isoxazoline and an isoxazolidine as single stereoisomers.The cleavage of the Delta2-isoxazoline and isoxazolidine produced was further investigated. It was found that the cycloadducts exhibited extra stability which was believed to be due to the oxygen in the adjoining ring. The Delta2-isoxazoline could not be cleaved under a range of conditions but the isoxazolidine was successfully cleaved and modified to form a functionalised tetrahydrofuran.An alternative synthesis of pyrrolidines was carried out, starting from glucose. A 3-aminoglucose derivative was prepared which underwent further reactions to give a nitrone which cyclised to an isoxazolidine as a potential precursor to functionalised pyrrolidines. A brief preliminary study of the cleavage of this system was unsuccessful.The final chapter gives details of the experimental procedures used.