Abstract
The piperidine moiety is found in a vast number of bioactive natural products as well as numerous marketed drugs and is therefore an interesting target for synthetic modi cations. Synthetic piperidines currently in the clinic are predominantly limited to 1,4-disubstitution on the piperidine ring, hence it is important to develop strategies to access new drug candidates with diverse substitution con gurations on the ring. For this purpose, the aza-Michael reaction can be used as an atom-ecient method to access biologically important piperidines.An initial study into the utility of divinyl ketone as the substrate for a double aza- Michael addition has led to the development of a facile, manganese dioxide mediated, one-pot oxidation-cyclisation method for the preparation of a diverse range of N- substituted 4-piperidones in moderate to good yield over two steps. Substituted divinyl ketones were prepared from their corresponding alcohols and used in a subsequent aza- Michael cyclisation with benzylamine for the synthesis of racemic, aromatically and aliphatically 2-substituted N-benzylic 4-piperidones. Employing S- -phenylethylamine as the primary amine substrate in this protocol a orded separable, diastereomeric 4- piperidone products with resolved stereochemistry in position 2 on the piperidine ring.
The suitability of such 2-substituted 4-piperidones for the synthesis of biologically relevant compounds was demonstrated by employing these building blocks in the synthesis of analogues of the acetylcholinesterase inhibiting drug donepezil. Access to the important 4-formyl piperidines was accomplished through a concise and high yielding route via a Wittig reaction followed by acidic hydrolysis to the desired aldehydes. Further synthetic steps a orded the nal donepezil analogues as inseparable diastereomeric mixtures with resolved stereochemistry in position two on the piperidine ring. Evaluating the acetylcholinesterase inhibiting potency of these analogues compared to donepezil provided information about the sensitivity of donepezil's piperidine moiety towards stereoselective substitution in position two on the ring.
A detailed investigation of the manganese dioxide mediated side reaction, which is observed in the one-pot oxidation-cyclisation reaction, led to the nding that under the same reaction conditions the oxidation of primary benzylic amines proceeds smoothly to the corresponding amides. The interconversion of all intermediates in this process was demonstrated experimentally and the vital role of both manganese dioxide and the molecular sieves explored. A range of benzylic amides was prepared in good to excellent yield using the developed methodology.
| Date of Award | 2015 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | David Mountford (Supervisor) & Gerd Wagner (Supervisor) |