Enantio- and diastereoselective small ring formation

Abstract

Small rings are useful reactive building blocks. Three membered rings have a large amount of strain and can be opened or rearranged to form more complex molecules. Our group has been active in the areas of catalytic asymmetric epoxidation and zinc mediated cyclopropanation.

Epoxidation of nitrogen-containing olefins was studied using the fructose-derived chiral ketone catalyst developed in our laboratory. A number of methods for preventing nitrogen oxidation were surveyed, showing that electron-poor nitrogens are compatible with dioxirane-mediated epoxidation. The epoxides were obtained in good optical purity and yield. These simple epoxides could be cyclized to form a hydroxy nitrogen heterocycles with little or no loss of enantiomeric excess. This method is complementary to other catalytic asymmetric epoxidation reactions, and is able to tolerate a variety of nitrogen-containing substituents.

Desymmetrization of cyclic dienes was studied. Symmetrical cyclic dienes with a prochiral directing group were epoxidized using the fructose-derived catalyst. Initial enantioselectivities and yields were good. If the reaction was continued a kinetic resolution occurred improving the enantiopurity of the mono epoxide. Very few catalytic reactions have shown the ability to perform this two step process. Symmetrical cyclic dienes without a prochiral-directing group were also found to be suitable substrates for this desymmetrization-kinetic resolution procedure. The change in ee of the mono epoxides with conversion to the bis epoxide can be explained using a simple transition state model based on sterics. These results provide further validation of the transition state model developed in our group.

The use of zinc carbenoids to cyclopropanate electron rich olefins has been known for some time. In the interest of gaining further understanding of the reactivity of these zinc species for application to chiral cyclopropanation reactions, ligand effects were studied. Both the electronic and steric properties of the ligand on zinc affect the rate of cyclopropanation. A very reactive cyclopropanation reagent was developed using trifluoroacetic acid as the ligand. Variation of the leaving group on the carbenoid carbon produced a number of new carbenoid precursors which were able to cyclopropanate olefins with trifluoroacetic acid as the ligand on zinc. These new carbenoid precursors open up the opportunity for chiral Lewis acid or chiral leaving group controlled asymmetric cyclopropanation.