Biomimetic Synthesis of Mitchellenes B-H from the Abundant Biological Precursor 14-Hydroxy-6,12-muuroloadien-15-oic Acid

Abstract

A step-economic biomimetic synthesis of mitchellenes B-H found in <i>Eremophila sturtii</i> has been achieved. Starting from the putative muurolane biological precursor, redox isomerization of the allylic alcohol gave an epimeric mixture of aldehydes, which could be used as a handle for cyclization onto the C6 position, using Bu₃SnH-mediated radical cyclization or NHC-catalyzed Stetter reaction. The NHC-mediated approach was superior as the epimeric mixture underwent a dynamic kinetic resolution during the reaction, and reduction of the mixture with NaBH₄ selectively formed the mitchellene ring system in 56% yield for the three steps. In the campaign to obtain the acid-starting material, two new natural products, mitchellene H and a muurolane aldehyde, were isolated. Synthetic procedures to access this family of natural products will enable further studies on their biological properties.