It is proposed to develop a new class of Diels-Alder reaction involving cycloaddition of electron-rich alkoxy-substituted 1, 3-dienes with alkymyl-suJlones. This kind of reaction will be investigated in both inter- and intramolecular modes.
In the first part, it is intended to apply this methodology to the synthesis of tether molecules for covalent cross-linking of oligopeptide sequences via the N-termini. It is proposed that these rigidly-oriented peptide sequences will have the requisite geometry to inhibit competitively the homodimerisation of the two domains of HIV-1 protease enzyme. It is this dimerisation which creates the enzyme active site and the catalytic activity essential for the virus replication cycle.
In the second phase of the work it is proposed also to explore the potential of the intramolecular variant of this novel pairing of diene and dienophile for the assembly of the key A-ring sub-unit of the taxol family of potent anti-cancer compounds exemplified by the parent taxol and analogues such as taxotere.