Synthesis, stereochemistry and antitumor activity of 4-hydroperoxyisophosphamide (NSC-227114) and related compounds.

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Abstract
4-Hydroperoxyisophosphamide and its analogs were synthesized by ozonolysis reactions of O-(3-butenyl)-N,N''-bis(2-chloroethyl)phosphorodiamidate and related O-(3-butenyl)phosphoramidates. An acid-catalyzed isomerization of 4-hydroperoxyisophosphamide proceeded with inversion of its P configuration giving 2-epi-4-hydroperoxyisophosphamide. Both isomers readily afforded C4-substituted isophosphamide derivatives by reactions with nucleophilic agents and acid. L1210 mouse antileukemic activities were tested for the isomers and some analogs revealing that the C4-hydroperoxylation of isophosphamide resulted in a marked enhancement of its activity and the inverted stereochemistry of an alkylating functionality at the P atom is also effective in promoting antitumor action as an alternative activated species of isophosphamide.

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