Abstract
Fused carbocycles are abundant in biologically pertinent molecules, notably steroids. Their pharmokinetic properties and wide range of physiological function has and continues to attract interest for the development of therapeutics. To discover their full potential, manipulation of the carbon skeleton is key in order to produce novel chemical analogues. Semisynthetic strategies often give rapid access to a library of compounds however further exploration of chemical space is then limited to deviation from the naturally occurring material. Furthermore if the supply of the natural product is scarce the approach may not be suitable. Enantioselective de novo strategies can give access to otherwise unattainable structures. Although often challenging due to the complexity of the scaffolds, multiple synthetic steps in which a framework is created gives a flexible approach allowing synthetic deviation at several stages. The work presented here employs organocatalysis for studies into the enantioselective synthesis of fused carbocyclic frameworks. Use of these as building blocks for the synthesis of steroidal structures is then investigated.Chapter 1 details methods of synthesizing optically active products leading to the formation and development of organocatalysis. The multiple modes of activating reactants for C-C bond formation are discussed as well the manner in which the stereochemical outcome is controlled. Finally a review of recent literature utilising enantioselective organocatalytic C-C bond formation for the synthesis of fused carbocyclic structures is presented, demonstrating the current interest in this approach.
Chapter 2 presents a highly enantioselective synthesis of a cis-decalin-cis-hydrindane tricyclic steroidal substructures, the first asymmetric synthesis of this system. An organocatalysed Michael addition, promoted by a primary amine cinchona alkaloid derivative, results in the formation a highly enantioenriched Michael adduct. The adduct is then transformed in high diastereoselectivity to the tricyclic structure via a Lewis acid mediated aldol cyclization. The product obtained exhibits five contiguous stereocentres, two of which are quaternary in nature, a reactive nitro group handle and ketone functionality. The highly functionalised structure required thorough optimisation and the many parameters screened are described. Lastly investigation into the scope of the Michael-aldol sequence gave access to a library of analogues in high selectivity with variation at the bridgehead position of the hydrindane.
Chapter 3 describes progress towards the synthesis of a cannogenol, a cardiotonic steroid, through application of the methodology established in chapter 2. Scale up of the Michael-aldol sequence as well as many key steps of the designed synthesis are established. Particularly of note is the demonstrated access to the naturally occurring a trans-decalin-cis-hydrindane BCD-ring system and regioselective carbonyl ketalisation. Optimisation of these and other transformations then culminates in the synthesis of a previously undescribed tetracyclic framework.
In chapter 4, studies into a more concise strategy to tetracyclic steroidal structures from a cis-decalin AB ring system are explored. Both an organocatalysed dienone desymmetrisation and a Diels-Alder, aldol condensation protocol for the synthesis of the key cis-decalin are investigated. Successful formation is achieved through a five step sequence developed from the Wieland-Miescher ketone and the fragment is then scrutinized for the synthesis of tetracyclic steroidal frameworks.
| Date of Award | 1 Sept 2020 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Andre Cobb (Supervisor) |