Synthesis of Tetrahydrofurans from Aldehydes and Cyclopropanes

Key words

tetrahydrofurans - [3+2] cycloaddition - Lewis acid catalysis

Significance

The synthesis of cis-2,5-disubstituted tetrahydrofurans via Lewis acid catalyzed [3+2] cycloaddition of cyclopropanes with aldehydes is described. Treatment of racemic 2-aryl-cyclopropanes 1 with a range of aldehydes 2 using Sn(OTf)₂ as catalyst led to cis-substituted tetrahydrofurans 3 in good to excellent yield, with excellent diastereoselectivity in most cases. Extensive screening of Lewis acids was carried out to obtain the optimized conditions. A broad range of functional groups are tolerated and optically active tetrahydrofurans 6 may be obtained from enantiopure cyclopropane 4 without the need for a chiral ligand control. Inversion of the stereocenter was observed during this process. The scope of the reaction was extended to accommodate the reaction of vinylcyclopropanes 7 with both aldehydes and ketones 8 to give tetra­hydrofurans 9, also in high yield and diastereoselectivity.

Comment

The tetrahydrofuran structure is found in a variety of biologically active compounds. Cycloadditions provide a particularly attractive route to the tetrahydrofuran core due to high convergence and atom economy. The current method represents an efficient one-pot procedure. Further modification of the products by decarboxylation and ozonolysis was also demonstrated. The starting cyclopropanes were easily prepared from ­benzaldehydes and diethyl malonate via Knoevenagel condensation followed by treatment with di­methyloxosulfonium methylide. Evidence for a mechanism involving an unusual stereospecific ion pair mechanism where the aldehyde acts as a nucleophile with malonate as the nucleofuge was obtained.