Glycolic Acid Scaffolds

As part of their ongoing investigation into the synthesis of stereochemically complex molecules, researchers in the Johnson Group, as reported in Journal of Organic Chemistry, report the addition of α-angelica lactone to β-halo-α-ketoesters.

This diastereoselective reaction is catalyzed by commercially available quinidine to yield a fully substituted glycolic acid scaffold with three contiguous stereocenters. A subsequent diastereoselective hydrogenation provides an additional stereocenter within the molecule. Previous additions of α-angelica lactone to a variety of electrophiles have been conducted. However, the Johnson Group researchers observe unusual regioselectivity in their reaction manifold. Few examples of α-angelica lactone acting as a nucleophile at the α-position have been reported prior to their studies. In all cases, the lactone adds to the α-ketoester regioselectively at the α-position, with no observation of γ-nucleophilic trapping. The Johnson Group believes this divergence arises from the more demanding steric environment imposed by the β-ketoester than previously employed electrophiles. Pleasingly, this reaction is tolerant of electron-rich aryl-, electron-poor aryl-, and alkyl-substitution. Both chlorine and bromine can serve as the halogen in the substrate.

The Johnson Group believes that quinidine is an efficient catalyst for this reaction because of its ability to properly orient the furanyl oxygen and carbonyl oxygen via hydrogen bonding. Future directions for this work include investigations into the regioselectivity phenomenon and an expanded study of more complex α-angelica lactone nucleophiles. Applications of this methodology and development of an asymmetric variant are ongoing in the Johnson laboratory.