title: Structures of two isomeric bicyclic derivatives of 4-hydroperoxyisophosphamide.
abstract: Crystal structure determinations of C4-oxygen-substituted cytotoxic derivatives of the anticancer drug cyclophosphamide have all found the oxygen to be in the axial position, suggesting an inherent stability for this geometry. Recently, two isomeric bicyclic derivatives of 4-hydroperoxyisophosphamide (cyclized cis- and trans-HPIPA) have been obtained for which NMR coupling constants imply that the trans isomer has the C4-oxygen substituent in the equatorial position. Crystal structure determinations of both bicyclic compounds have now been performed. They show that the cis isomer has phosphoryl oxygen and C4-peroxy group both axial, similar to the conformation of the uncyclized HPIPA precursor and to the expectation based on NMR data; the trans isomer, however, has a phosphoryl oxygen equatorial, C4-peroxy group axial conformation, similar to its uncyclized HPIPA precursor but opposite in conformation at both positions to the NMR-based inferences. The oxazaphosphorinane ring in each isomer has a half-chair conformation, with the trans isomer probably flipping between two equally probable half-chairs; this disorder may account for the observed differences in the NMR C4-hydrogen coupling constants in the two isomers. The peroxy-containing ring adopts a chair conformation in both molecules.
mesh_terms: D003460:Crystallization; D003520:Cyclophosphamide / Q000031:analogs & derivatives*; D007069:Ifosfamide / Q000031:analogs & derivatives*; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular
chemical_list: C012353:hydroperoxyisophosphamide; D003520:Cyclophosphamide; D007069:Ifosfamide