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Transaminase triggered aza-Michael approach for the enantioselective synthesis of chiral alkaloids

Ryan, James (2018) Transaminase triggered aza-Michael approach for the enantioselective synthesis of chiral alkaloids. Doctoral thesis (PhD), Manchester Metropolitan University.


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This thesis focuses on the development of new biocatalytic strategies as a contemporary solution to synthetic design. Here we have put to use the unique regio-, stereo- and/or chemoselectivity offered by biocatalysts to develop synthetically attractive routes to enantiopure materials. The first chapter discusses the development of a transaminase triggered aza-Michael cascade towards the synthesis of enantioenriched 2,6-disubstituted piperidines in good yield with >99% e.e. and >99% d.e. This methodology utilises a favourable spontaneous intramolecular aza-Michael reaction (IMAMR) to drive the reversible enzymatic transformation towards the formation of cyclic products, thus removing the need for additional approaches to displace the reaction equilibrium towards product formation. The alkaloid, (-)-pinidinone, was synthesised in three steps on a 0.5 g scale and a range of analogues was also successfully prepared to demonstrate the scope of the reaction. The reversible transamination reaction in combination with the thermodynamically favourable IMAMR, forming a stable cyclic product, results in a regioselective transamination of (3E)-dec-3-ene-2,8-dione. This inspired us to develop an amino donor and acceptor substrate that was successfully transaminated to form pinidinone with no external source of amine. The second chapter discusses the synthesis of novel bis-conjugated enones and their subsequent transamination to provide bicyclic alkaloids via double aza-Michael additions. However, under the tested reaction conditions, the TA reaction resulted in complete decomposition of all but two of the tested substrates. 1-Methyldecahydropyrrolo[1,2-a]quinolin-5(1H)-one was produced as three isomers whose relative stereochemistry was assigned by NMR. Interestingly, transamination of (2E)-1-(cyclohex-1-en-1-yl)oct-2-ene-1,7-dione provided 1-(cyclohex-1-en-1-yl)-2-[(2S,6S)-6-methylpiperidin-2-yl]ethanone as the major product and an inseparable mixture of 1-methyldodecahydro-6H-pyrido[1,2-a]quinolin-6-one isomers as the minor product. Initiating the second IMAMR of 1-(cyclohex-1-en-1-yl)-2-[(2S,6S)-6-methylpiperidin-2-yl]ethanone was attempted. The epimerisation of 1-methyldecahydropyrrolo[1,2-a]quinolin-5(1H)-one and 1-methyldodecahydro-6H-pyrido[1,2-a]quinolin-6-one proved unproductive. The third chapter investigates the synthesis of 2-alkyl-3-(4-oxopentyl)cyclohex-2-en-1-one and their subsequent use in a TA-IMAMR cascade towards the pragmatic synthesis of the natural product histrionicotoxin (HTX) and its derivatives. A Baylis-Hillman reaction was optimised for the insertion of the α-alkyl substituent into the cyclohexanone scaffolds. TA conditions were found to convert the unsubstituted scaffold to provide (2S)-2-methyl-1-azaspiro[5.5]undecan-8-one as a 1:1 mixture of diastereoisomers. The optimal epimerisation conditions found provided a 3:1 mixture of diastereoisomers, however, isolation of the compounds proved unsuccessful. Reduction of the carbonyl to provide the core HTX structure was tested. This provided an inseparable mixture of products. Under the biocatalytic reaction conditions, the IMAMR of 2-ethyl-3-(4-oxopentyl)cyclohex-2-en-1-one provided 3-[(4S)-4-aminopentyl]-2-ethylcyclohex-2-en-1-one as the major product. This is due to the (2S)-7-ethyl-2-methyl-1-azaspiro[5.5]undecan-8-one being an unfavourable product, which is in agreement with current literature.

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