Date of Award

Summer 8-19-2022

Level of Access Assigned by Author

Open-Access Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor

Matthew Brichacek

Second Committee Member

Alice E. Bruce

Third Committee Member

Barbara J. W. Cole

Additional Committee Members

William M. Gramlich

Michael Kienzler

Abstract

HIV is among the leading causes of death worldwide resulting in over 1 million deaths annually according to the World Health Organization. Despite advances in the treatment of HIV, eradicating this pathogen remains a top priority in the medical and scientific communities. EM2487 is a natural product produced by Streptomyces sp. Mer-2487 that possesses promising activity against HIV. Specifically, EM2487 is a potent and selective inhibitor of HIV replication in both acutely and chronically infected cells. The observed HIV activity is hypothesized to be the result of targeting the Tat-TAR (trans-activation response) element which activates RNA polymerase II at the stage of transcriptional elongation. EM2487 has a unique structure that poses two important synthetic challenges: 1) The stereochemical relationships of the complex pseudosaccharide core, and 2) The synthesis of the rare bisphosphoramidate in EM2487. First, the stereochemical relationships of the complex pseudosaccharide core were not elucidated during the isolation due to the significant line broadening of the NMR spectra and must be determined by total synthesis. Toward this goal, Achmatowicz reaction of furfuryl alcohol followed by rearrangement of the pyranone into a cyclopentenone provided the core pseudosaccharide in 30% yield over three steps. Bromination, Stille coupling, and phosphoramidite coupling produced the protected EM2487 pseudosaccharide. Finally, global deprotection using trifluoroacetic acid and boron trichloride provided an isomeric mixture of the target pseudosaccharide (trans and cis) in two steps overall yield of 30%. Chemical correlation experiments were used to determine the trans relationship between the hydroxyl groups in EM2487. In addition to approaches towards the pseudosaccharide, the synthesis of the rare bisphosphoramidate in EM2487 will be described. In addition to resolving the structure of EM2487, novel analogues with improved potency could be pursued by discovering an efficient synthesis scheme.

Download

Share