Antineoplastic agents. 511. Direct phosphorylation of phenpanstatin and pancratistatin

Selective phosphorylation of phenpanstatin (3a) with tetrabutylammonium dihydrogen phosphate and dicyclohexylcarbodiimide in pyridine followed by cation-exchange chromatographic procedures was found to provide an efficient route to a new series (3b-3d) of promising 3,4-O-cyclic phosphate prodrugs designated phenpanstatin phosphates. Application of analogous reaction conditions to pancratistatin (1a) led to a mixture of monophosphate derivatives where sodium pancratistatin 4-O-phosphate (4a) was isolated and the structure confirmed by X-ray crystallography. Modification of the reaction conditions allowed direct phosphorylation of pancratistatin followed by cation-exchange chromatography to afford sodium pancratistatin 3,4-O-cyclic phosphate (5a), which was selected for preclinical development.