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(sp(2))-N(sp(3)) and O(sp(3))-C(sp(2)); (ii) C(sp(2))-N(sp(3)) and C(sp(3))-C(sp(2)). The metal-free 5-endo-dig oxidative cyclization provided versatile amino 2,3- and 2,5-dihydrofurans bearing the C-5 quaternary carbon. The non-toxicity of all synthesised dihydrofurans was verified via in vitro cell viability assay.