SYNTHESIS OF MANZAMINE A VIA NOVEL DIELS-ALDER REACTION

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The proposed research concerns the development of a convergent asymmetric total synthesis of manzamine A. The range of cytotoxic and antibacterial activity, as well as the formidable structural challenges of the various manzamines, warrant the development of a convergent asymmetric synthesis amenable to analogue studies. The key feature of the proposed synthesis is a novel intramolecular macrocyclic Diels-Alder reaction of an alpha,beta-unsaturated amidine and an electron rich diene. Asymmetry is induced by the use of an enantiomerically pure bicyclic amidine obtained in 4 steps from a readily available L-serine derivative. The initial grant period (3-4 months) will be spent on an intermolecular variation of this key reaction. The diene and dienophile used will closely resemble those proposed in the total synthesis. Optimized conditions in the intermolecular case should be easily modified for the intramolecular reaction. The remainder of the grant period will be devoted towards the synthesis of manzamine A. Convergence is maintained by independent synthesis of the diene and dienophile. Coupling and subsequent cyclization result in the isoquinoline core of manzamine A with the intact 13-membered azacine. The functionality necessary for introduction of the C and E rings also serve as the stereocontrol element in the Diels-Alder cycloaddition, thereby eliminating the removal of chiral auxiliary. The introduction of the beta-carboline moiety and can be achieved by known chemistry. The synthesis should allow easy access into the manzamine skeleton and be amenable to systematic variations; an attribute particularly attractive for analogue studies.