The nikkomycins and neopolyoxins are a group of nucleoside dipeptides produced during the fermentation of Streptomyces tendae or cacaoi var asoensis. These natural products are competitive chitin synthetase inhibitors in both fungal and insect tissue culture assays. This activity is extremely high and thus the nikkomycin-neopolyoxin group are very potent antifungal and insecticidal agents. We shall seek to develop novel methodology for the concise total synthesis of these important molecules. The condensation reaction of 5-hyroxypyridine-2-carboxaldehyde with 1-t-butylimino-1-lithio-oxy-2-(N-lithio-oxy-lithioamino)-2-butene will be used as a key step in the highly stereoslective synthesis of the N-terminal amino-acid unit. In addition, we shall introduce the use of phenylthio-nitromethane for the conversion of aldehydes into alpha-amino-acids with control of stereochemistry. This reaction will be applied to the conversion of uridine into all of the nucleoside amino-acid units. All synthetic nikkomycins and intermediates will be evaluated for inhibition of chitin synthetase. It is our intention in this work to clarify the mode of action of these biologically active compounds and to develop chemistry for the synthesis of more active analogs.
| Barrett, A G; Doubleday, W W; Gross, T et al. (2000) Total synthesis of antifungal natural products. Ernst Schering Res Found Workshop :149-81 |
