Total Synthesis of Gracilioether F: Development and Application of Lewis Acid Promoted Ketene–Alkene [2+2] Cycloadditions and Late‐Stage CH Oxidation

Abstract

The first synthesis of gracilioether F, a polyketide natural product with an unusual tricyclic core and five contiguous stereocenters, is described. Key steps of the synthesis include a Lewis acid promoted ketene-alkene [2+2] cycloaddition and a late-stage carboxylic acid directed C(sp(3) )H oxidation. The synthesis requires only eight steps from norbornadiene.

Lewis acid-promoted [2 + 2] cycloadditions of alkenes with aryl ketenes

“…5 In our initial installment, we developed a method for cycloaddition of “stable” disubstituted ketenes (Scheme 2a). 5a In these reactions the ketene is fully generated prior to addition of alkene and Lewis acid.…”

“…5 In our initial installment, we developed a method for cycloaddition of “stable” disubstituted ketenes (Scheme 2a). 5a In these reactions the ketene is fully generated prior to addition of alkene and Lewis acid. To extend the utility of this method towards use of unstable ketenes, like monosubstitued aryl ketenes, a new protocol was developed as pregeneration of the ketene was not possible.…”

“…5c In this reaction, because mono- substituted ketenes undergo dimerization, the ketene needed to be generated in situ at low concentrations. This was achieved by slow addition of acid chloride 1 to a solution of Lewis acid, i -Pr NEt, and alkene 2 .…”

“…This was achieved by slow addition of acid chloride 1 to a solution of Lewis acid, i -Pr NEt, and alkene 2 . 5b …”

“…5c The optimization of the test reaction is outlined in Table 1. We found that the dropwise addition of a solution of acid chloride 6 to a mixture of alkene, base, and Lewis acid at −78 °C then warming to −45 °C was critical to success for formation of cyclobutanone 8 .…”