More than a curiosity in the field of steroid derivatives, the 17-membered macrocycle 1 was obtained from a more rigid ansa-steroid. Compound 1 serves as a prototype of a template with differentiable functional groups, which can be used in the synthesis of libraries of novel macrocycles.

Mehr als nur eine interessante Kuriosität auf dem Gebiet der Steroidderivate ist der 17-gliedrige Makrocyclus 1, der als konformativ flexiblere Struktur aus einem Ansa-Steroid erhalten wurde. 1 dient als Prototyp eines Templates mit differenzierbaren funktionellen Gruppen, welches zur Synthese von Substanzbibliotheken neuer Makrocyclen verwendet werden kann.

All four diasteromeric 16,17-diols in the 3-methoxy-13α-estra-1,3,5(10)-triene series have been synthesized. The trans-diols 1 and 2 can be obtained by hydroborating the 17-enol acetate 6 (61%, ratio 27:73, preferred α attack). OsO4 dihydroxylation of the olefin 7 yielded the cis-diols 3 and 4 (ratio 13:87). The dihydroxylation proceeds with preference for β attack caused by a C-ring twist-boat form of 7. The conformations of the diols 2 and 4, the 17-benzyl-17-hydroxy compounds 9 and 10 (obtained by Grignard reaction), and the 16α-bromo-17β-hydroxy compound 8 were determined by X-ray analysis and by 1H NMR spectroscopy in solution. Some compounds, in spite of a 17β-hydroxy group, had a conformation with a ring C chair form (4, 8, 9) caused by intermolecular interaction in the solid state. The rest of the compounds studied here (2, 10) possessed a conformation with a ring C twist-boat form, which has been also found for all 17β-substituted compounds in solution. The preferred conformation of the D-ring with 17β-substituents seems to be the 16β-envelope form or near this form, but the existence of the 16α-envelope form (inversion of the ring D) for some compounds showed great variance in the conformation of ring D, which is substituent dependent.

Aiming towards spiroketal-modified artificial cephalostatin molecules, two orthogonal approaches were investigated. First, the introduction of 17-O-functionality into hecogenin derivatives with a closed spiroketal moiety was accomplished by different remote-oxidation procedures. These allowed the synthesis of tetradecacyclic artificial cephalostatin molecules with improved tumor-inhibiting properties. Second, a novel reduction-oxidation pathway for spiroketal opening in sapogenins was discovered, which should provide the basis for a broad access towards spiroketal-modified building blocks for cephalostatins.