Syntheses, Crystal Structures, and Conformations of 10,10-Spiro-Bilirubins

Abstract

Crystal structure determinations of two novel bilirubin analogs with spirocyclohexyl and spirofluorenyl groups at C(10) are reported. Conformation-determining torsion angles and key hydrogen bond distances and angles are compared to those from molecular dynamics calculations, and to the corresponding data from X-ray determinations and molecular dynamics calculations of bilirubin. Like bilirubin, the component dipyrrinones of spirocyclohexyl and spirofluorenyl rubins are present in the bis-lactam form with (Z)-configuration double bonds at C(4) and C(15). Their crystal structures show considerable similarity to that of bilirubin: both pigments adopt a folded, intramolecularly hydrogen-bonded ridge-tile conformation stabilized by six hydrogen bonds. The interplanar angle of the spirocyclohexyl ridge-tile is nearly the same (94°) as that of bilirubin (∼95°), but the interplanar angle of the spirofluorenyl ridge-tile is noticeably smaller (84°). The hydrogen bond distances of both spiro-rubin crystal structures are generally longer by 0.1–0.2A than those in bilirubin. Both new pigments exhibit excellent lipophilicity and, unlike bilirubin, are soluble in methanol.