Novel Catalytic Asymmetric Methodologies: Biocatalysed Synthesis of N-Heterocyclic Systems and Enantioselective Addition of Organozirconium Reagents to Aliphatic Aldehydes

Vaccari, Jade (2021) Novel Catalytic Asymmetric Methodologies: Biocatalysed Synthesis of N-Heterocyclic Systems and Enantioselective Addition of Organozirconium Reagents to Aliphatic Aldehydes. Doctoral thesis (PhD), Manchester Metropolitan University.

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Abstract

This thesis focuses on the development of new methodologies for asymmetric synthesis. Here, we will investigate two independent methodologies: i) biocatalysed synthesis of N-heterocyclic systems and ii) enantioselective C-C bond formation with organometallic reagents. The first chapter of the thesis summarises the state of the art in the synthesis of N-heterocyclic systems from chiral amines. The background on asymmetric synthesis of amines via classical and biocatalytic methodologies, is also described here. The second chapter of the thesis discusses our optimisation results on the biocatalysed transaminase triggered intramolecular aza-Michael reaction (IMAMR) of a keto-cyclohexanone substrate in the presence of different organocatalysts, with the aim to improve the diastereomeric ratio and the overall efficiency of the synthesis of histrionicotoxin (HTX) derivatives. We found that the use of (S)-diphenyl prolinol improved the diastereoselectivity of the spontaneous IMAMR, providing the corresponding spirocyclic HTX derivative with a modest 3:2 d.r. (versus the 1:1 d.r. obtained in the absence of organocatalyst). The biocatalysed IMAMR of various alkyl substituted keto-cyclohexanones in the presence of (S)-diphenylprolinol as organocatalysts was also attempted. The third chapter of this thesis investigates the expansion of biocatalysed IMAMR to the vinylogous aza-Michael reaction. The attempted biocatalysed transamination reaction of two different ketodienones substrates resulted in complete decomposition under the reaction conditions. However, the biocatalysed triggered vinylogous aza-Michael reaction of two different ketodieno esters proved successful, providing the corresponding 2,6-disubstituted piperidine and 2,5-disubstituted pyrrolidine as a mixture of inseparable diastereoisomers, respectively. Subsequent epimerisation and isomerisation of the double bond, provided the cis-2,6-disubstituted piperidine, bearing a conjugated ester as the only diastereomer. However, in the case of the 2,5-disubstituted pyrrolidine, the tandem epimerisation-isomerisation proved unsuccessful. The hydrogenation of the double bond in the lateral ester chain, allowed for the synthesis of ethyl 4-((2S,6S)-6-methylpiperidin-2-yl)butanoate and provided a mixture of the cis- and trans- 5-methylpyrrolidin-2-yl butanoates. Subsequent cyclisation to the corresponding quinolizinone and indolizidine was attempted. In this chapter, we also describe the first attempts in the use of thioesters and nitriles as Michael acceptors for biocatalysed IMAMR. The fourth chapter of this thesis focuses on the catalytic enantioselective addition of organozirconium reagents to aliphatic aldehydes using versatile Ar-BINMOLs as ligands. The optimal catalytic procedure for the addition of 1-hexene to cyclohexanecarboxaldehyde using (Ra,S)-Ph-BINMOL in the presence of Ti(OiPr)4 and ZnBr2 was found and the scope of the reaction was expanded to a variety of aliphatic aldehydes and functionalised nucleophiles. The reaction proceeds under mild conditions and provides moderate yields and excellent enantioselectivities, making it an efficient procedure for the synthesis of valuable chiral aliphatic secondary alcohols.