A synthesis of cephalostatin 1

Abstract A synthesis of cephalostatin 1 from hecogenin is described in detail. The gram-scale synthesis of south part features a Baeyer–Villiger oxidation of hecogenin to 16,20-diol, a selective oxidation of C16 OH with Dess–Martin periodinane, a Rh(I)-catalyzed C15 C16 double bond shift to C14 C15 position, and a Hg(OAc) 2 -mediated spiroketal formation from cyclic enol ethers with alkenyl side chain at 2-position. Key transformations in the synthesis of north part, also on gram scale, include an abnormal Baeyer–Villiger oxidation of hecogenin to the corresponding dinorcholanic lactone, where a catalytic amount of iodine acts as a traceless and catalytic switch, an umpolung of steroidal 22-aldehyde to forge C22 C23 bond with good stereochemical control, a cascade spiroketal-forming process to establish DEF rings in one operation, and a selective oxidation of C3 OH. There are also other noteworthy transformations that, although not used in our final route, are valuable and could be applied to other syntheses, including: intra- or intermolecular S N 2′ processes of C14-heteroatom-substituted C15 C16 alkenes, an unprecedented rearrangement of β-adduct of D-ring dienes and singlet oxygen, a chelation-controlled methylallylation of C23 aldehyde, and so on.