Furanoterpene Synthesis via Intramolecular Nitrile Oxide Cycloaddition Reaction: A Total Synthesis of (+)-Menthofuran

Abstract

A fused furan assembling strategy based on an intramolecular [3+2] dipolar cycloaddition reaction of nitrile oxide has been applied to a total synthesis of perfumy furanomonoterpene (+)-menthofuran (1). The key cycloaddition substrates (9) and (12) are easily prepared via straightforward routes starting from (+)-citronellal and these are treated with sodium hypochlorite and p-chlorophenyl isocyanate, respectively. The cycloaddition reactions generate 10:1 mixture of diastereoisomeric isoxazolines (2a) and (2b) in good to excellent yields. The isoxazolines (2a,b) thus obtained are converted to (+) menthofuran (1) by sequential reductive hydrolysis and alkaline hydrolysis (or vice versa) followed by acid treatment of the resulting β,γ-dihydroxy ketone