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.

Two novel types of elegant three-component reactions of stable isochromenylium tetrafluoroborates (ICTBs) have been developed under mild metal-free conditions in this work. Mechanistically, these reactions are commonly initiated by a [4+2]-cycloaddition between the non-classical isochromenylium diene and the aldehyde–enol, and terminated by the following addition of weak nucleophiles, including nitriles or the second equivalent of aldehydes, in a one-pot fashion. The developed methodologies exhibit excellent chemoselectivity, regioselectivity, and diastereoselectivity, and provide a new convenient access to functionalized dihydronaphthalenes and tetrahydronaphthalenes.

An efficient total synthesis of (S)-14-azacamptothecin has been accomplished in 10 steps and 56 % overall yield from 5H-pyrano[4,3-d]pyrimidine 8. A mild Hendrickson reagent-triggered intramolecular cascade cyclization, a highly enantioselective dihydroxylation, and an efficient palladium-catalyzed transformation of an O-allyl into N-allyl group are the key steps in the synthesis. This work provides a much higher overall yield than the previous achievement and shows sound flexibility for the further applications that will lead to new bioactive analogues.