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A synthesis of cephalostatin 1

Author:
Shi, Yong, Xiao, Qing, Lan, Quan, Wang, Da-Hai, Jia, Lan-Qi, Tang, Xiao-Hu, Zhou, Tao, Li, Min, Tian, Wei-Sheng
Source:
Tetrahedron 2019 v.75 no.12 pp. 1722-1738
ISSN:
0040-4020
Subject:
aldehydes, alkenes, chemical bonding, chemical structure, enol ethers, iodine, mercury, oxidation, singlet oxygen, stereochemistry
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 C16OH with Dess–Martin periodinane, a Rh(I)-catalyzed C15C16 double bond shift to C14C15 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 C22C23 bond with good stereochemical control, a cascade spiroketal-forming process to establish DEF rings in one operation, and a selective oxidation of C3OH. 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 SN2′ processes of C14-heteroatom-substituted C15C16 alkenes, an unprecedented rearrangement of β-adduct of D-ring dienes and singlet oxygen, a chelation-controlled methylallylation of C23 aldehyde, and so on.
Agid:
6232099