Metal-free synthesis of dihydrofuran derivatives as anti-vicinal amino alcohol isosteres

Abstract

Dihydrofuran cores are commonly incorporated into synthetically and pharmacologically significant scaffolds in natural product and drug discovery chemistry. Herein, we report a concise and practical strategy to construct spiro-dihydrofuran and amino dihydrofuran scaffolds as anti-vicinal amino alcohol isosteres. Hypervalent iodine (PhI(OAc)(NTs₂))-mediated C–H activation of alkynes resulted in two-bond formations with one pi bond cleavage: (i) C(sp²)–N(sp³) and O(sp³)–C(sp²); (ii) C(sp²)–N(sp³) and C(sp³)–C(sp²). The metal-free 5-endo-dig oxidative cyclization provided versatile amino 2,3- and 2,5-dihydrofurans bearing the C₅ quaternary carbon. The non-toxicity of all synthesised dihydrofurans was verified via in vitro cell viability assay.