Novel tetramic acids via 1,3-dipolar cycloaddition

This Ph.D. thesis has been concerned with the reinvestigation and improvement of the intermolecular 1,3-dipolar cycloaddition strategy using isoxazoles, towards the 3-acyltetramic acids (3-acylpyrrrolidine-2,4-diones) and also the investigation and development of the corresponding intramolecular strategy. A second generation of the intermolecular route was developed previously within our group and we have synthesised a variety of pyrroloisoxazoles, the 'masked' tetramic acids. We have modified and improved both the isoxazole formations and the peptide coupling reactions; we have further developed the chain extension at the isoxazole C-5 (tetramic acid C-3) substituent, testing the aldol-type reaction with some aromatic aldehydes and extending it to aliphatic aldehydes. We have demonstrated the condensation method using a strong base and hydroxyl adducts were obtained. Dehydration has been undertaken to yield the alkenyl C-5 side-chain. Development of the desmethyllaccarin, a derivative of the natural product laccarin, has also been attempted via the intermolecular route. A potential intramolecular route has the reversed sequence from the intermolecular route, by using the N-acylation product produced from an amino acid for the formation of a nitrile oxide and hence our building block pyrroloisoxazole by intramolecular dipolar cycloaddition. We have generated a nitro ketoester compound from the amino acid and investigation on the synthesis of the pyrroloisoxazole has been undertaken.