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

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.