Asymmetric synthesis of pyrrolizidines, indolizidines and quinolizidines via a double reductive cyclisation protocol

Journal article

This account describes an overview of the asymmetric syntheses of pyrrolizidines, indolizidines and quinolizidines via a common double reductive cyclisation protocol. The highly diastereoselective conjugate addition of an enantiopure lithium amide to an α,β-unsaturated ester incorporating a terminal C=C bond installed the nitrogen bearing stereogenic centre and was followed by alkenylation of the corresponding enolate to introduce the second olefinic functionality. Alternatively, conjugate addition to the corresponding α-alkenyl α,β-unsaturated ester followed by α-pronation of the intermediate enolate may also be used to access the cyclisation precursor. After oxidation of the two terminal olefinic units to give the corresponding dialdehyde, tandem hydrogenolysis/hydrogenation was employed to efficiently construct the azabicylic core of each target molecule. This double reductive cyclisation strategy was successfully utilized in the syntheses of 13 azabicylic alkaloids or closely related analogues.

Authors: Davies, S; Fletcher, A; Roberts, P; Thomson, J

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Thieme Publishing
• Journal: Synlett
• Volume: 28
• Issue: 20
• Pages: 2697-2706
• Publication date: 2017-08-08
• Acceptance date: 2017-07-04
• DOI: 10.1055/s-0036-1590975
• EISSN: 1437-2096
• ISSN: 0936-5214
• Keywords: conjugate addition; indolizidine; lithium amide; reductive cyclisation; pyrrolizidine; quinolizidine; asymmetric synthesis