MECHANISM-BASED INACTIVATION OF RIBONUCLEASE-A

The first example of a mechanism-based inhibitor of a phosphodiesteras e is reported. Although the inactivation brought about by the fluoride 4 is not complete, this compound provides a useful starting point for the synthesis of other more potent inhibitors of ribonuclease A, as w ell as inhibitors of other nucleases. In addition, an inexpensive meth od is described for the synthesis of phosphate diesters that cannot be synthesized using standard phosphoramidite methodology. Phosphitylati on of the target alcohol with a dialkyl chlorophosphite, followed by a ctivation of the resulting trialkyl phosphite with It, yields an iodop hosphate. The resulting iodophosphate can then be coupled to a second alcohol, phenol, or enolate to give a phosphate triester, which after subsequent deprotection affords the desired phosphate diester. The nov el phosphorylation chemistry presented should greatly facilitate the s ynthesis of other similar mechanism-based phosphodiesterase inhibitors .