Progress toward the Total Synthesis of Lymphostins: Preparation of a Functionalized Tetrahydropyrrolo[4,3,2-de]quinoline and Unusual Oxidative DimerizationClick to copy article linkArticle link copied!
- Grant S. SeilerGrant S. SeilerCenter for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, La Jolla, California 92093, United StatesDepartment of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United StatesMore by Grant S. Seiler
- Chambers C. Hughes*Chambers C. Hughes*E-mail: [email protected]Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, La Jolla, California 92093, United StatesMore by Chambers C. Hughes
Abstract
The lymphostins are a family of closely related pyrrolo[4,3,2-de]quinoline natural products produced by Streptomyces and Salinispora actinobacteria. Neolymphostin A was recently shown to strongly inhibit phosphoinositide 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) in a covalent manner via conjugation to a catalytic lysine residue in the ATP-binding pocket of the enzymes, making this metabolite the first reported covalent kinase inhibitor from a bacterium. A flexible and efficient synthetic route toward these alkaloids would allow for improvements in their solubility, stability, and selectivity and help to deliver a viable drug candidate. We have since established a short synthesis to methyl 8-bromo-1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline-4-carboxylate via a conjugate addition/intramolecular Ullman reaction sequence. However, attempts to oxidize this intermediate to the pyrrolo[4,3,2-de]quinoline characteristic of the lymphostins resulted in formation of either a 2-oxo-1,2-dihydropyrrolo[4,3,2-de]quinoline or an unusual N,C-linked tetrahydropyrroloquinoline-pyrroloquinoline heterodimer. We expect that key modifications to the tetrahydropyrroloquinoline intermediate prior to oxidation should prevent these side reactions and pave the way for the completion of the synthesis.
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