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Abraham Ustoyev

Posted on October 19, 2022


Date - October 19, 2022
1:00 pm - 2:00 pm


Public PhD Defense
Department of Chemistry & Biochemistry
UNC Greensboro
Croatt Research Laboratory
Title: Towards the Total Synthesis of Ambuic Acid for the Production of Analogues as Therapeutic Agents for Methicillin-Resistant Staphylococcus Aureus


Ambuic acid is a natural product derived from the fungus Pestalotiopsis microspora. The synthetic and therapeutic interest of ambuic acid spans from its complex epoxyquinol scaffold that allows it to inhibit the conserved quorum sensing pathway of pathogenic Gram-positive bacteria, including methicillin resistant Staphylococcus aureus (MRSA). Quorum sensing is a process by which bacteria secrete signaling molecules to reach a bacterial cell density that ultimately leads to infection. To date, ambuic acid is the only known inhibitor of Accessory gene regulator B (AgrB), a transmembrane protein responsible for releasing autoinducing peptides (AIP) that regulate intercellular quorum sensing. The objective is to synthesize analogues of ambuic acid for structure-activity relationships to ultimately obtain more active compounds against the quorum sensing pathway of MRSA. These analogues are targeted through semi-synthesis using ambuic acid isolated from the fungus P. microspora, and primarily through total synthesis. Two synthetic routes are explored, with each providing potential for efficient access to a variety of analogues. The first route incorporates two aromatic Claisen rearrangements to reveal the two side chains of ambuic acid, with the first rearrangement regioselective for the more sterically congested isomer. This process served advantageous for completing the functionality of one side chain of ambuic acid before installing the second, functionally different side chain. The second route involved screening a variety of olefination methods, including a Wittig, Still-Gennari, and Ando olefination to prepare a Z trisubstituted system. The Ando process was most successful in providing this system to set the stage for a relay enyne ring closing metathesis. This research describes our efforts towards acquiring ambuic acid analogues through our semi-synthetic and total synthetic approaches.

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