Verruculogen an fumitremorgin A are bioactive alkaloids that contain a unique eight-membered endoperoxide. Although related natural products such as fumitremorgins B and C have been previously synthesized, we report the first synthesis of the more complex, endoperoxide-containing members of this family. A concise route to verruculogen and fumitremorgin A relied not only on a hydroperoxide/indole hemiaminal cyclization, but also on the ability to access the seemingly simple starting material, 6-methoxytryptophan. An iridium-catalyzed C–H borylation/Chan–Lam procedure guided by an N-TIPS group enabled the conversion of a tryptophan derivative into a 6-methoxytryptophan derivative, proving to be a general way to functionalize the C6 position of an N,C3-disubstituted indole for the synthesis of indole-containing natural products and pharmaceuticals.

Taxol® is widely regarded as amongst the most famed natural isolates ever discovered, and has been the subject of innumerable studies in both basic and applied science. Its documented success as an anticancer agent, coupled with early concerns over supply, stimulated a furious worldwide effort from chemists to provide a solution for its preparation through total synthesis. Those pioneering studies proved the feasibility of retrosynthetically-guided access to synthetic Taxol, albeit in minute quantities and with enormous effort. In practice, all medicinal chemistry efforts and eventual commercialization have relied upon natural-(plant material) or biosynthetically-derived (synthetic biology) supplies. Here we show how a complementary divergent synthetic approach that is holistically patterned off of biosynthetic machinery for terpene synthesis can be used to arrive at Taxol®. File list (2) download file view on ChemRxiv Manuscript.pdf (1.42 MiB) download file view on ChemRxiv Supporting Information.pdf (67.60 MiB)

A Nef reaction has been developed that is conducted under mildly basic conditions with molecular oxygen as an oxidant, without the need for metal additives. Whereas nitroalkanes are converted into ketones in good yield, nitroalkenes are transformed into α,β-unsaturated ketones in one-pot by double-bond isomerization followed by the oxygen-mediated Nef reaction. The reaction protocol is both mild and general, and tolerates acid- and base-labile functionality or protecting groups. When oxygen-saturated solvents are employed, the reaction completes within 20 min. Mechanistically, the addition of nitronate ion and molecular oxygen is proposed to proceed initially through a single-electron transfer event, as indicated by radical clock experiments. This ultimately generates a putative 1,1-dioxirane, which reacts further with another nitronate ion to generate the ketone. Involvement of a 1,1-dioxirane is supported by intramolecular trapping experiments with sulfide at the γ-position of the nitro-moiety.