Convergent Synthesis of Trisubstituted Tetrahydrofurans via Bis-Thermally Reactive 1,5-Diene-Tert-Butyl Carbonates.
Cascade reactions (also known as domino- or tandem reactions) are an efficient strategy for generating molecular complexity. We report that synergizing the thermal reactivity of 3,3-dicyano-1,5-dienes and tert-butyl carbonates result in stereospecific 2,3,4-trisubstituted tetrahydrofuran synthesis. While substituted tetrahydrofurans can be challenging to synthesize, this discovery converts readily available 1,5-dienes derived from aldehydes, malononitrile, and cis-buten-1,4-diol into complex tetrahydrofurans via a process involving thermal Cope rearrangement, Boc-deprotection, and oxy-Michael addition. Described herein includes background related to the discovery, optimization and scope, and representative functional group interconversion chemistry for the scaffolds.