Ring -expansion carbonylation of epoxides: development of new catalysts for improved regio- and stereocontrol
Mulzer, Michael Franz
Carbon monoxide is arguably one of the most important feedstocks in organic synthesis because it enables the introduction of valuable functional groups in often a mild, efficient, and economical manner. Utilization of this building block in hydroformylation reactions or ring-expansion carbonylation reactions of heterocycles gives rise to value added-products. One transformation of particular importance is the carbonylation of epoxides to ?-lactones. ?-Lactones are a highly versatile set of compounds that can undergo numerous reactions in often a benign and economical fashion, thus giving rise to small molecules such as aldol-type compounds, and polymers such as polyesters. The use of catalysts of the form [Lewis acid]+[Co(CO)4]- have streamlined the synthesis of ?-lactones to a point where implementation on an industrial scale seems feasible. Nonetheless, challenges remain in the conversion of epoxides to ?-lactones using these catalysts. Regioselectivity in the carbonylation of cis- or trans-disubstituted epoxides, and enantioselectivity in general are two largely unsolved synthetic hurdles in this regard and await further exploration. The work presented herein introduces new catalyst design strategies, and implements them in an effort to address these remaining challenges. The result are four new carbonylation catalysts that enable the highly regioselective synthesis of ?-lactones starting from cis- or trans-disubstituted epoxides. The value of the resulting products, and the fact that regioselective ring-opening reactions of disubstituted epoxides have been a long-standing challenge in the field of organic synthesis make this study relevant on both a practical as well as an academic level. In addition to the four catalysts introduced for improved regioselectivity, two more catalysts were synthesized and found to be competent for the formation of highly enantioenriched ?-lactones starting from meso or racemic epoxides. Given the scarcity of catalysts that can affect similar transformations with equally high selectivities, this represents another important step forward in the field of ring-expansion carbonylation reactions. Lastly, the use of carbon monoxide in a more streamlined synthesis of a pharmaceutically relevant class of compounds called ampakines is explored. This new methodology underlines once more the synthetic potential that rests in this building block.
Ganem, Bruce; Lewis, Chad; Chirik, Paul
Doctor of Philosophy, Chemistry and Chemical Biology
Doctor of Philosophy
dissertation or thesis