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Total syntheses of (±)-vibralactone and 13c-labelled all-trans-retinals

Total syntheses of (±)-vibralactone and 13c-labelled all-trans-retinals
Total syntheses of (±)-vibralactone and 13c-labelled all-trans-retinals
Vibralactone is a potent inhibitor of pancreatic lipase and a potential candidate for a new anti-obesity therapeutic. Not only is vibralactone an interesting molecule due to its topical biological activity, but its unique fused bicyclic B-lactone structure also presents a challenging target for synthetic investigation. Herein two novel and highly diastereoselective total syntheses of (±)-vibralactone will be presented along with efforts towards an asymmetric synthesis of (-)-vibralactone.

Highly functionalised intermediates have been accessed by a unique titanium-induced acetal addition to malonate precursors, followed by a highly diastereoselective allylation to set the relative stereochemistry of the adjacent chiral centres of vibralactone. Two synthetic routes to vibralactone have been completed from these novel scaffolds in 17 and 11 steps with overall yields of 4.5% and 16% respectively. Both routes exploit aldol condensations to prepare the cyclopentene ring of vibralactone, and the second-generation synthesis employs a novel and very efficient deallylation/cyclisation reaction to form the B-lactone ring.

Two all-trans-retinals ([10-18-13C9] and [12,15-13C2]) containing multiple 13C labels have been synthesised to facilitate DNP enhanced solid-state MAS NMR investigations into the ring orientation and retinal interaction with transmembrane retinylidene proteins, proteorhodopsin, channelrhodopsin and KR2. Channelrhodopsin and KR2 have very important applications in optogenetics; a technique that can be used to probe how the brain functions and has the potential to relieve symptoms of neurological conditions.

The labelled retinal isotopomers have been accessed from simple and readily available 13C-enriched starting materials using a synthetic route that will ultimately permit access to other labelling patterns as required.
University of Southampton
Leeder, Alexander
eb778e32-652e-45d5-8f3d-259928c2d0cf
Leeder, Alexander
eb778e32-652e-45d5-8f3d-259928c2d0cf
Brown, Richard
21ce697a-7c3a-480e-919f-429a3d8550f5

Leeder, Alexander (2016) Total syntheses of (±)-vibralactone and 13c-labelled all-trans-retinals. University of Southampton, School of Chemistry, Doctoral Thesis, 219pp.

Record type: Thesis (Doctoral)

Abstract

Vibralactone is a potent inhibitor of pancreatic lipase and a potential candidate for a new anti-obesity therapeutic. Not only is vibralactone an interesting molecule due to its topical biological activity, but its unique fused bicyclic B-lactone structure also presents a challenging target for synthetic investigation. Herein two novel and highly diastereoselective total syntheses of (±)-vibralactone will be presented along with efforts towards an asymmetric synthesis of (-)-vibralactone.

Highly functionalised intermediates have been accessed by a unique titanium-induced acetal addition to malonate precursors, followed by a highly diastereoselective allylation to set the relative stereochemistry of the adjacent chiral centres of vibralactone. Two synthetic routes to vibralactone have been completed from these novel scaffolds in 17 and 11 steps with overall yields of 4.5% and 16% respectively. Both routes exploit aldol condensations to prepare the cyclopentene ring of vibralactone, and the second-generation synthesis employs a novel and very efficient deallylation/cyclisation reaction to form the B-lactone ring.

Two all-trans-retinals ([10-18-13C9] and [12,15-13C2]) containing multiple 13C labels have been synthesised to facilitate DNP enhanced solid-state MAS NMR investigations into the ring orientation and retinal interaction with transmembrane retinylidene proteins, proteorhodopsin, channelrhodopsin and KR2. Channelrhodopsin and KR2 have very important applications in optogenetics; a technique that can be used to probe how the brain functions and has the potential to relieve symptoms of neurological conditions.

The labelled retinal isotopomers have been accessed from simple and readily available 13C-enriched starting materials using a synthetic route that will ultimately permit access to other labelling patterns as required.

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More information

Published date: 10 September 2016
Organisations: University of Southampton, Chemistry

Identifiers

Local EPrints ID: 403844
URI: http://eprints.soton.ac.uk/id/eprint/403844
PURE UUID: 89c52515-8c1d-458a-890f-58ac7595bb5d
ORCID for Richard Brown: ORCID iD orcid.org/0000-0003-0156-7087

Catalogue record

Date deposited: 14 Dec 2016 15:22
Last modified: 14 Dec 2018 05:04

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