Comparing and Taming the Reactivity of Lithiated Oxetanes and Tetrahydrofurans: Concepts and Applications

Among saturated oxygen heterocycles, both oxetane and tetrahydrofuran derivatives are important scaffolds in a broad array of biologically active natural compounds (1). However, while increasing attention has recently been paid to the regio- and stereoselective construction of these ring motifs and new reactivity discover, direct functionalization processes remain extremely rare (2). In addition, conventional strong organolithium bases are long-lasting known to promote, in the case of oxetanes, both nucleophilic substitution reactions at C-2 in competition with alpha-lithiation, and reverse [3+2] cycloadditions for tetrahydrofurans. The occurrence of such competing reaction pathways and fragmentation reactions has most likely discouraged the use of these heterocycles as starting materials in organic synthesis for many years. In this communication, we report and compare the protocols found for a direct regioselective lithiation-electrophile interception of both aryloxetanes (3) and aryltetrahydrofurans. The role played by aggregation, the nature of the solvent, and the presence of co-solvents in coaxing alpha-lithiated intermediates to react as nucleophiles (thereby suppressing their intrinsic carbene-like character) while keeping their cycloanionic structure intact, will be discussed. The ability to effect ortho metallation reactions together with mechanistic, stereochemical aspects, and synthetic applications will be tackled as well.