Development of catalytic asymmetric methods employing chiral ketene enolates

This work expands on methodology developed previously in our labs involving the in situ generation of chiral ketene enolates. These methods have been employed in both catalytic asymmetric alpha-halogenation of acid chlorides as well as [4+2] cycloadditions with o-benzoquinones and o-benzoquinoneimides.; The catalytic asymmetric alpha-bromination of acid chlorides has been expanded to yield a wider range of products on more practical scales through the development of a new cinchona alkaloid catalyst and new brominating agents. Mechanistic details of the reaction were also explored through a series of molecular mechanics calculations and cross-over experiments. The similar catalytic asymmetric alpha-chlorination reaction was adapted to a solid phase "column asymmetric catalysis" manifold that is made catalytic by a "flush and flow" technique that regenerates the solid supported reagents.; The catalytic asymmetric [4+2] cycloaddition reaction of o-benzoquinones with ketene enolates gives rise to not only interesting bicyclic products, but importantly to highly optically active alpha-hydroxyesters. The same type of cycloaddition reaction with o-benzoquinone imides leads to benzoxazinones and benzoxazines which are easily converted to a wide range of non-natural alpha-amino acid derivatives, including several that are not easily synthesized using other asymmetric methods. Most notably, all products produced with this method to date have been highly optically active; greater than 99% ee in all cases.