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Synlett 2017; 28(20): 2697-2706
DOI: 10.1055/s-0036-1590975
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© Georg Thieme Verlag Stuttgart · New York

Asymmetric Synthesis of Pyrrolizidines, Indolizidines and Quinolizidines via a Double Reductive Cyclisation Protocol

Stephen G. Davies*
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK   eMail: steve.davies@chem.ox.ac.uk
,
Ai M. Fletcher
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK   eMail: steve.davies@chem.ox.ac.uk
,
Paul M. Roberts
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK   eMail: steve.davies@chem.ox.ac.uk
,
James E. Thomson
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK   eMail: steve.davies@chem.ox.ac.uk
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Publikationsverlauf

Received: 13. Juni 2017

Accepted: 03. Juli 2017

Publikationsdatum:
08. August 2017 (online)

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Dedicated to Professor Victor Snieckus on the occasion of his 80th birthday

Abstract

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 enolate functionalisation to introduce the second olefinic functionality. Alternatively, conjugate addition to the corresponding α-alkenyl α,β-unsaturated ester followed by α-protonation 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 azabicyclic core of each target molecule. This double reductive cyclisation strategy was successfully utilised in the syntheses of 13 azabicyclic alkaloids or closely related analogues.

1 Introduction

2 Asymmetric Syntheses of (–)-Isoretronecanol and (–)-Trachelanthamidine

3 Asymmetric Syntheses of (+)-Trachelanthamidine [(+)-Laburnine], (+)-Tashiromine and (+)-epi-Lupinine

4 Asymmetric Syntheses of (–)-Hastanecine, (–)-Turneforcidine and (–)-Platynecine

5 Asymmetric Syntheses of (–)-Macronecine, (–)-Petasinecine, (–)-1-epi-Macronecine, (+)-1-epi-Petasinecine and (+)-2-epi-Rosmarinecine

6 Conclusion

Key words

asymmetric synthesis - pyrrolizidines - indolizidines - quinolizidines - conjugate addition - lithium amide - reductive cyclisation