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Total Synthesis of 7‐Ethyl‐10‐hydroxycamptothecin (SN38) and its Application to the Development of C18‐Functionalized Camptothecin Derivatives
Author(s) -
Yao YuanShan,
Liu JiaLi,
Xi Jie,
Miu Bukeyan,
Liu GuaiSai,
Wang Shaozhong,
Meng Linghua,
Yao ZhuJun
Publication year - 2011
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201101389
Subject(s) - camptothecin , chemistry , combinatorial chemistry , organic chemistry
A new chemical synthesis of SN38, the active metabolite of the camptothecin prodrug irinotecan, has been achieved in 12 steps from simple, commercially available starting materials. A mild and efficient FeCl 3 ‐catalyzed Friedländer condensation was successfully applied to construct the AB ring system. Functionalization of the C ring was accomplished by a vinylogous Mukaiyama reaction of an in situ generated N ‐ acyliminium intermediate with a silyl enol ether. An intramolecular oxa Diels–Alder reaction efficiently constructed the D and E rings in one step. Successive asymmetric dihydroxylation and I 2 ‐based hemiacetal oxidation furnished the stereochemistry of SN38 with high enantiopurity. Utilizing the ABC‐ring intermediate and a functionalized silyl enol ether permitted the synthesis of a number of new C18‐functionalized SN38 derivatives. Several of the novel SN38 derivatives that bore a C10 methoxy group were found to exhibit comparable or more potent inhibitory activity against the proliferation of cancer cells relative to SN38.