TOTAL SYNTHESIS OF TIRANDAMYCIN AND STREPTOLYDIGIN

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This proposal outlines a strategy for the total synthesis of tirandamycin and streptolydigin in optically active form. Tirandamycin and Streptolydigin are members of the 3-enoyl tetramic acid family of metabolites isolated from various strains of Streptomyces. Streptolydigin has been shown to selectively inhibit terminal deoxynucleotidyl transferase (TDT), an enzyme present in large quantities in leukemic lymphoblasts, but not in normal leucocytes. TDT is believed to play a crucial role in the cellular metabolism of these cancer cells. It is possible that stretolydigin/tirandamycin or an analogue of these natural products will prove effective in the treatment of various leukemias. Tirandamycin and streptolydigin also display antimicrobial activity by inhibiting bacterial DNA-directed RNA polymerase. These compounds are especially effective in arresting the growth of anaerobic bacteria which are responsible for pelvic and abdominal infections. The synthetic strategy outlined in the proposal would yield optically active tirandamycin or streptolydigin in approximately 20 steps by a convergent route and would have sufficient generality that a diversity of structural analogues could be readily prepared for testing as antileukemic or antimicrobial agents.