Iron-Carbene Initiated O–H Insertion/Aldol Cascade for the Stereoselective Synthesis of Functionalized Tetrahydrofurans

Abstract

Given its earth abundance, cost-effectiveness, and ecofriendly qualities, iron serves as a promising alternative to precious metals in catalysis. This article presents an iron carbene-initiated cascade approach for synthesizing highly substituted tetrahydrofurans at the gram scale. This cascade reaction utilizes readily accessible β-hydroxyketones and diazo compounds and works with iron catalyst loading as low as 5 mol %. This reaction proceeds through an O−H insertion into diazo-derived iron carbenes, followed by an intramolecular aldol reaction to access functionalized tetrahydrofurans in high yields and diastereoselectivity. The versatile nature of this domino sequence accommodates diverse β-hydroxyketones and diazo compounds, streamlining access to synthetically challenging spiroethers. Furthermore, this cascade process offers a route to enantiopure tetrahydrofurans by utilizing a diazo ester bearing a chiral auxiliary, 8-phenylmenthol. Postmodifications of the tetrahydrofuran product provide access to various analogues, including a medicinally relevant oxetane motif. Density functional theory (DFT) calculations substantiate a stereospecific mechanism wherein the intramolecular aldol reaction proceeds via a fused six-and five-membered iron−oxygen transition-state complex, yielding the contrathermodynamic cis-aldol product.