Synthesis of medium-ring nitrogen heterocycles and their application to diverse scaffold assembly

Wood, Russell J. H. (2021). Synthesis of medium-ring nitrogen heterocycles and their application to diverse scaffold assembly. University of Birmingham. Ph.D.

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Medium ring-containing scaffolds have been shown to display a broad range of biological activity and yet are under-represented within approved pharmaceuticals. Diversity-oriented synthesis (DOS) is a methodology by which multiple compounds can be efficiently synthesised in a diversity-driven approach.

Combining both DOS and medium-ring methodology, a 10-membered ring containing an alkene, an amine and a ketone, was identified as a key intermediate for the synthesis of a library of scaffolds. The synthesis of the 10-membered ring in which the amine is protected as a tosylsulfonamide is described. The synthesis was accomplished in 34% overall yield over seven steps, utilising a key Cope-type rearrangement to enable synthesis of the ring. Conformational analysis and the crystal structure demonstrated that the ring sat preferentially in a chair-chair-chair conformation, although other conformations were accessible at room temperature. External nucleophilic addition into the ketone proved challenging, with only reduction successfully providing an alcohol product. A decalol scaffold was generated via an intramolecular Prins or ene type cyclisation. Epoxidation of the alkene, followed by treatment with a Lewis acid generated a diketone, which could be further transformed into a range of 5,7-fused rings, albeit with poor diastereoselectivity. Treatment of the epoxide with a Brønsted acid gave an enol ether embedded within a rare [5,3,1]-bicyclic framework, which could be reversibly transformed into the methyl acetal by further treatment with a Brønsted acid and methanol. Treatment of the methyl acetal with an acid and a nucleophile generated a variety of different bicyclic ether scaffolds.

Deprotection of the tosylsulfonamide functionality was unsuccessful. Use of the alloc protecting group proved more successful and optimisation of the alloc removal step is described. All of the previous scaffolds were accessed using this alternative amine protecting group. Cheminformatic analysis guided the identification of three key scaffolds which were decorated \(\textit{in silico}\) with a selection of 45 compounds identified for synthesis. A library of 15 decalol derivatives and eight bicyclic ether derivatives was synthesised. A Paternò-Büchi reaction on the free amine produced an oxetane scaffold albeit in low yield, which was successfully derivatised. Overall, 30 compounds representing 26 different Murcko scaffolds have been synthesised and submitted to an in-house compound library – future investigations of further scaffold development are discussed.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
Licence: All rights reserved
College/Faculty: Colleges (2008 onwards) > College of Engineering & Physical Sciences
School or Department: School of Chemistry
Funders: Engineering and Physical Sciences Research Council
Subjects: Q Science > QD Chemistry


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