School of Chemistry - Theses

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Type: Masters Coursework thesis × End date: 2018 × Subject: organic chemistry × Author: Robertson, Angus ×

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    It’s hip to be square: a cyclobutene diester approach to alkyl citrate natural products
    Robertson, Angus ( 2018)
    This thesis features an enatiospecfic synthesis of a key alkyl citrate retron that was leveraged in the total syntheses of squalene synthase inhibitors (-)-CJ-13,982, (-)-CJ-13,981 and (-)-L-731,120 (featured in Org. Let. 2018, 20, 4255–4258). This key retron was prepared in 7 linear steps, requiring only 4 purification, with a 40% yield from (S)-(+)-γ-hydroxymethy-γ-butyrolactone. The synthesis highlights the application of a formal [2+2] cycloaddition and a remarkable acid-mediated rearrangement sequence to furnish the correct stereochemistry and oxidation level of the citrate moiety. This thesis demonstrates the shortest enantiospecifc total synthesis of (-)-CJ-13,981 to date, via the use of this key citrate retron, affording this natural product in 7.7% total yield over 10 steps. Efforts towards the squalene synthase inhibitor (-)-L-731,120 and the viridiofungins, a family of serine palmitoyl transferase inhibitors that have activity inhibiting hepatitis C replication, are also featured.