Synthesis of Enantioenriched (Poly)Fluorinated Building Blocks, 2,2-Disubstituted Pyrrolidines and [7,7]Paracyclophanes

Citation

Goldstein, Elizabeth Lee (2020) Synthesis of Enantioenriched (Poly)Fluorinated Building Blocks, 2,2-Disubstituted Pyrrolidines and [7,7]Paracyclophanes. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/hks0-tg22. https://resolver.caltech.edu/CaltechTHESIS:06042020-213305750

Abstract

The Stoltz group, and moreover the synthetic community at large, has long been interested in the synthesis of enantioenriched compounds with interesting biological activities. This thesis presents three projects unified in an attempt to access compounds with relevance to the medicinal chemistry and natural products communities, encompassing reaction development, synthetic strategy and natural product synthesis.

A general method for the enantioselective synthesis of carbo- and heterocyclic carbonyl compounds bearing fluorinated α-tetrasubstituted stereocenters using palladium-catalyzed allylic alkylation is described. These fluorinated, stereochemically rich building blocks hold potential value in medicinal chemistry and are prepared using an orthogonal and enantioselective approach into such chiral moieties compared to traditional approaches, often without the use of electrophilic fluorinating reagents.

The synthesis of a variety of enantioenriched 2,2-disubstituted pyrrolidines is described. A stereogenic quaternary center is first formed utilizing an asymmetric allylic alkylation reaction of a benzyloxy imide, which can then be reduced to a chiral hydroxamic acid. This compound can then undergo a thermal "Spino" ring contraction to afford a carbamate protected 2,2-disubstituted pyrrolidine stereospecifically, allowing access to new molecules that could be useful in the medicinal chemistry community.

Finally, we have developed a synthesis of an enaptioenriched [7,7]paracyclophane compound using sequential C-H functionalization reactions, including selective Rh-catalyzed C-H insertion reactions developed by the Davies group at Emory University. Investigations are currently ongoing into potential antimicrobial activity of different [7,7]paracyclophanes and the total synthesis of naturally occurring [7,7]paracyclophanes.

Thesis Files