Total synthesis of 7-ethyl-10-hydroxycamptothecin (SN38) and its application to the development of C18-functionalized camptothecin derivatives

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 FeCl₃‐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 I₂‐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.