A facilitated cyclic ether formation and its potential application in solid-phase peptide and organic synthesis

A 'trimethyl lock' system has been known to facilitate lactonization reactions through what has been termed a stereopopulation control mechanism. We have found that a similar trimethyl lock system can also facilitate cyclic ether formation with the concomitant release of a carboxylic acid in the presence of anhydrous tetrabutylammonium fluoride. To study this base- mediated trimethyl lock-facilitated cyclic ether formation, we synthesized fifteen model compounds. All model compounds underwent base-mediated cyclic ether formation in high yields at 0 °C to room temperature (r.t.) with the concomitant release of the attached carboxylate. Such a system potentially could be used for the development of a two-dimensional linker for solid phase peptide and organic synthesis.