The oxidative, intermolecular homo- and cross-coupling of phenols has been an area of intense interest over the last decade. Despite this, the intramolecular coupling of unactivated C-H and C-C positions in tethered bisphenols to form complex molecular architectures remains a challenge to synthetic organic chemists. Inspired by prior work within our group, a simple, bench-stable vanadium(V)-oxo catalyst was developed for the intramolecular oxidative coupling of simple tethered phenols to form phenol-dienone products with a newly generated quaternary center. This mild reaction is catalytic in vanadium, utilizing oxygen as a co-oxidant, and demonstrates broad scope in substitution type and pattern on the tethered phenol rings. Given the prevalence of the phenol-dienone motif in natural products and related compounds, this method was applied to the syntheses of four biologically relevant molecules. Most notably, <i>N</i>-(ethoxycarbonyl)-5'-hydroxynorreticuline was oxidized catalytically to its corresponding salutaridine derivative, a chemical transformation which is biomimetic to the key oxidative coupling step in the biosynthesis of morphine. This newly developed intramolecular coupling reaction proceeds in good yield with catalytic quantities of vanadium and offers a mild, operationally simple alternative to similar reported transformations.

Vanadium-catalyzed intramolecular coupling of tethered phenols: Formation of phenol-dienone products

ACS Fall 2020 Virtual Meeting

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