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Leveraging an Allenic Pauson-Khand Reaction to Synthesize 6,12-Guaianolide Analogs with a Tunable α-Methylene-γ-lactam Electrophile

Jackson, Paul A. (2017) Leveraging an Allenic Pauson-Khand Reaction to Synthesize 6,12-Guaianolide Analogs with a Tunable α-Methylene-γ-lactam Electrophile. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Unsaturated amides have emerged as invaluable electrophilic motifs as evidenced by the recent FDA approval of acrylamide-containing drugs, afatinib, ibrutinib, and osimertinib, as treatments for lung and blood cancers. These Michael acceptors represent a class of irreversible, targeted covalent inhibitors that selectively react with a cysteine in the active site of a specific protein. Inspired by these successful drugs, 6,12-guaianolide isosteres equipped with electronically tunable α-methylene-γ-lactams are envisioned as compounds with great potential for exhibiting desired biological activities. The guaianolide family was selected for study because it exhibits an exciting range of biological activities including inhibition of the NF-κB pathway. However, the indiscriminate reactivity of the α-methylene-γ-lactone embedded in many of these natural products raises many concerns. Towards this end, guaianolide isosteres have been prepared using an allenic Pauson-Khand reaction of α-methylene-γ-lactam tethered allene-ynes affording rapid access to the [5,7,5]-ring system characteristic of this class of compounds. In turn, these products are equipped with an unsaturated amide whose electrophilic reactivity is modulated by varying substituents at the lactam nitrogen. The allenic Pauson–Khand precursors were prepared using an allylboration/lactamization reaction to afford the alkynyl functionalized α-methylene-γ-lactam, a heretofore unprecedented transformation utilizing α-imino alkynes. Substituents on the sterically encumbered lactam nitrogen were introduced using Buchwald-Hartwig cross-coupling conditions. Finally, the chemical reactivity of the 6,12-guaianolide isosteres towards biothiols was measured qualitatively and their activity as inhibitors of the NF-κB signaling pathway was demonstrated. The use of allenyl acetates in the allenic Pauson-Khand reaction with α-methylene-γ-lactam tethers was examined to synthesize lactam-containing guaianolide analogs with an α-acyloxy cyclopentenone.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Jackson, Paul A.paj28@pitt.edupaj28
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBrummond, Kay M.kbrummon@pitt.edukbrummon
Committee MemberWilcox, Craig S.daylite@pitt.edudaylite
Committee MemberSmithgall, Thomas E.tsmithga@pitt.edutsmithga
Committee MemberHorne, W. Sethhorne@pitt.eduhorne
Date: 29 September 2017
Date Type: Publication
Defense Date: 3 May 2017
Approval Date: 29 September 2017
Submission Date: 23 August 2017
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 473
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: covalent modifier, electrophile, Michael acceptor, guaianolide, butyrolactone, alpha methylene gamma lactam, natural product, organic synthesis, NF-kappa B,
Date Deposited: 29 Sep 2018 05:00
Last Modified: 29 Sep 2018 05:15


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