Configurational Reassignment and Improved Preparation of the Competitive IL-6 Receptor Antagonist 20R21R-Epoxyresibufogenin-3-formate

摘要

20R,21R-Epoxyresibufogenin-3-formate (>1) and 20S,21S-epoxyresibufogenin-3-formate (>2) were synthesized from commercial resibufogenin (>3) using known procedures. The major product (>1) was dextrorotatory, as was the major product from the reported synthesis of epoxyresibufogenin-3-formate; however, the literature (+)-compound was assigned the 20S,21S-configuration based on NMR data. We have now unequivocally determined, using single-crystal X-ray structure analyses of the major and minor products of the synthesis and of their derivatives, that the major product from the synthesis was (+)-20R,21R-epoxyresibufogenin-3-formate (>1). Our minor synthetic product was determined to have the (-)-20S,21S-configuration (>2). The (+)-20R,21R-compound >1 has been found to have high affinity for the IL-6 receptor and to act as an IL-6 antagonist. A greatly improved synthesis of >1 was achieved through oxidation of preformed resibufogenin-3-formate. This has enabled us to prepare, from the very expensive commercial resibufogenin, considerably larger quantities of >1, the only known non-peptide small molecule IL-6 antagonist.