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Synthesis of (+)-β-isosparteine and (+)-sparteine from syn and anti β- amino esters

Synthesis of (+)-β-isosparteine and (+)-sparteine from syn and anti β- amino esters
Synthesis of (+)-β-isosparteine and (+)-sparteine from syn and anti β- amino esters
The sparteine series of alkaloids are a subset of the lupin alkaloids, a diverse family
of over 200 natural products all containing a quinolizidine core. The sparteine series itself is comprised of three stereoisomers: sparteine, α-isosparteine and β-isosparteine. Whilst these alkaloids have found use medicinally in the past, contemporary use has focused on their applications within organic synthesis as asymmetric ligands. This is best exemplified in the use of (–)-sparteine as the ligand of choice for a range of enantioselective transformations.

This thesis describes the total synthesis of (+)-β-isosparteine and the formal synthesis
of (+)-sparteine. The synthetic strategy employed for these syntheses is based upon highly diastereoselective imino-aldol reactions of functionalised ester and N-sulfinylimine fragments. (+)-β-isosparteine was accessed by a syn-selective imino aldol, whereas (+)-sparteine was delivered via a formal anti-imino aldol strategy. Both syntheses would also make use of a key N-acyl iminium cyclisation, in order to furnish the quinolizidine core.

In order to put these syntheses into context with almost 170 years of work on the
sparteine series, a comprehensive review on the synthesis of the sparteine alkaloids is
included. The privilege of modern synthetic knowledge and analytical techniques are
applied to the early literature, and a scholarly eye is applied to much of the early structural elucidations and syntheses.

Efforts to explore the formal anti-imino aldol reaction are also disclosed. Significant
progress has been made on improving the substrate scope for the anti-alkylation step itself. These insights would lead to the successful synthesis of an anti-substituted piperidine, affording novel access into a privileged medicinal chemistry motif. Finally, initial progress in the intramolecular cyclisation of tethered imides to styrenes using synthetic organic electrochemistry is also disclosed.
University of Southampton
Wheatley, David
259931a5-d5a7-4400-80c9-2a7e8d161a74
Wheatley, David
259931a5-d5a7-4400-80c9-2a7e8d161a74
Brown, Richard
21ce697a-7c3a-480e-919f-429a3d8550f5

Wheatley, David (2019) Synthesis of (+)-β-isosparteine and (+)-sparteine from syn and anti β- amino esters. University of Southampton, Doctoral Thesis, 349pp.

Record type: Thesis (Doctoral)

Abstract

The sparteine series of alkaloids are a subset of the lupin alkaloids, a diverse family
of over 200 natural products all containing a quinolizidine core. The sparteine series itself is comprised of three stereoisomers: sparteine, α-isosparteine and β-isosparteine. Whilst these alkaloids have found use medicinally in the past, contemporary use has focused on their applications within organic synthesis as asymmetric ligands. This is best exemplified in the use of (–)-sparteine as the ligand of choice for a range of enantioselective transformations.

This thesis describes the total synthesis of (+)-β-isosparteine and the formal synthesis
of (+)-sparteine. The synthetic strategy employed for these syntheses is based upon highly diastereoselective imino-aldol reactions of functionalised ester and N-sulfinylimine fragments. (+)-β-isosparteine was accessed by a syn-selective imino aldol, whereas (+)-sparteine was delivered via a formal anti-imino aldol strategy. Both syntheses would also make use of a key N-acyl iminium cyclisation, in order to furnish the quinolizidine core.

In order to put these syntheses into context with almost 170 years of work on the
sparteine series, a comprehensive review on the synthesis of the sparteine alkaloids is
included. The privilege of modern synthetic knowledge and analytical techniques are
applied to the early literature, and a scholarly eye is applied to much of the early structural elucidations and syntheses.

Efforts to explore the formal anti-imino aldol reaction are also disclosed. Significant
progress has been made on improving the substrate scope for the anti-alkylation step itself. These insights would lead to the successful synthesis of an anti-substituted piperidine, affording novel access into a privileged medicinal chemistry motif. Finally, initial progress in the intramolecular cyclisation of tethered imides to styrenes using synthetic organic electrochemistry is also disclosed.

Text
Wheatley Final Thesis for Award - Version of Record
Restricted to Repository staff only until 30 June 2021.
Available under License University of Southampton Thesis Licence.

More information

Published date: June 2019

Identifiers

Local EPrints ID: 433266
URI: http://eprints.soton.ac.uk/id/eprint/433266
PURE UUID: 5580c35c-c1d8-4be1-bc89-4c044341d8e4
ORCID for Richard Brown: ORCID iD orcid.org/0000-0003-0156-7087

Catalogue record

Date deposited: 12 Aug 2019 16:30
Last modified: 13 Aug 2019 00:37

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Contributors

Author: David Wheatley
Thesis advisor: Richard Brown ORCID iD

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