Direct Ketone-to-2 H -ChromyneConversion Enabling Alkyne-Ene Reactions and Synthetic Entry intothe Nyingchinoid Natural Products

Abstract Cyclohexynes are highly strained intermediates that are largely underexplored compared with benzynes, their aromatic counterparts. Known strategies toward generating cyclohexynes include accessing precursors with specific functionalities such as silyl alkenyl triflates, alkenyl halides, alkenyl pseudohalides, diazirines, carbene precursors, or diacyl peroxides, among others. Ultimately, the stepwise buildup of these starting materials and the transient nature of cyclohexynes have led to their synthetic utility being limited to specific classes of reactions, including cycloadditions and nucleophilic trapping. Within this class of strained cycloalkynes, oxacyclohexynes are even more understudied and significantly fewer strategies for their generation exist. Here, we show that 2H-chromynes can be directly accessed from ketones, one of the most abundant and easy-to-install functional groups. The in situ formed 2H-chromynes undergo a subsequent alkyne-ene reaction, an unprecedented mode of reactivity for this strained intermediate. Mechanistic investigations reveal the bifunctional role of phenyl triflimide as both a triflating reagent and a base scavenger. The cyclopentachromene products obtained map onto multiple natural products, including nyingchinoid C, which has yet to be synthesized. To demonstrate the utility of this method, we applied the developed chromyne-ene reaction to a concise total synthesis of nyingchinoid C. The work presented herein highlights an alternative strategy toward generating strained cyclic alkynes and expands their synthetic utility.