Mechanism-Based Inactivation of Ribonuclease A

The first example of a mechanism-based inhibitor of a phosphodiesterase 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 well as inhibitors of other nucleases. In addition, an inexpensive method is described for the synthesis of phosphate diesters that cannot be synthesized using standard phosphoramidite methodology. Phosphitylation of the target alcohol with a dialkyl chlorophosphite, followed by activation of the resulting trialkyl phosphite with I₂, yields an iodophosphate. 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 novel phosphorylation chemistry presented should greatly facilitate the synthesis of other similar mechanism-based phosphodiesterase inhibitors.