Promontorio, Rossella; (2019) Synthesis of polysubstituted oxygenated bicyclo compounds. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Saturated (or at least sp3-enriched) molecules have acquired an increasingly important role in medicinal and organic chemistry. The architectural complexity of three-dimensional, saturated molecules often confers greater biological activity and makes these compounds more likely to succeed as drugs. The challenge associated with their synthesis and the lower degree of toxicity compared to flat, aromatic molecules makes them very attractive synthetic targets. Polysubstituted bicyclo compounds are found in many biologically active natural products. In particular, the bicyclo[3.3.1]nonane system constitutes the core of the PPAP (polyprenylated acylphloroglucinol) family, whose members have shown multiple beneficial medicinal properties. A main approach to the construction the bicyclo[3.3.1]nonane core involves the biomimetic dearomatisation of prenylated phloroglucinols. The initial aim of the thesis work was to use chiral epoxides to achieve the dearomatisation of these derivatives and a consequent enantiodivergent synthesis of the PPAP scaffold. Inspired by the enantioselective total synthesis of hyperforin, achieved by Shair’s group through desymmetrisation of a cyclohexadiene ring, the thesis study initially focused on investigating an epoxide-mediated ring closure using more readily available 1,3-diketones. However, this approach met with little success, instead the products of O-cyclisation often being obtained. As an alternative, the construction of functionalised bicyclo[3.n.1]alkanes by a Michael-aldol type annulation was investigated. This method has previously furnished bicyclic compounds but was limited in scope and/or stereocontrol. We thus aimed to develop a general, reliable route for the synthesis of a variety of polysubstituted bicyclo[3.3.1]nonane derivatives using a Michael-aldol annulation. A novel and effective one-pot process was achieved by the reaction of substituted 1,3-cyclohexanediones with enals. The desired bicyclic ketols were generally obtained in good to excellent yields, and often with appreciable stereocontrol. The possibility to further functionalize the bicyclo system with other electrophiles was shown to be effective for fluorine, and afforded a selection of novel fluorinated bicyclic scaffolds of relevance to medicinal chemistry.

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