Towards the Synthesis of the Oxaspirobicyclic Unit of Tetronothiodin

Wang, Wei-Wei (2012) Towards the Synthesis of the Oxaspirobicyclic Unit of Tetronothiodin. Doctoral thesis, University of East Anglia.

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Abstract

The!work!described!in!this!thesis!is!focused!on!the!preparation!of!the!oxaspirobicyclic!tetronic!
acid!fragment!2!of!the!CCK%B!receptor!antagonist!tetronothiodin!1.!An!isomer!of!this!compound!
has! already! been! synthesized! within! the! Page! group,! however! this! was! found! to! have! the!
opposite!stereochemistry!at!the!spiro!centre!to!that!reported!for!the!natural!product.!!
!
!
Figure!1:!Structures!of!tetronothiodin!and!the!oxaspirobicyclic!unit.!
!
The! thesis! (chapter! I)! first!entails! the!biology!and! chemistry! related! to! tetronothiodin!and! its!
cholescystokinin!receptor.!Cholescystokinin!(CCK)!is!a!33%amino!acid!peptide,!which!functions!as!
a! digestive! peripheral! hormone! in! the! mammalian! gastrointestinal! tract! and! as! a!
neurotransmitter! in! the! central! nervous! system,! where! it! is! more! widely! distributed.!
Tetronothiodin!1!is!a!novel!brain%type!CCK!receptor!antagonist,!isolated!from!the!culture!broth!
of!Streptomyces!sp.!NR0489.!Various!strategies!of!oxaspirobicyclic!fragment!synthesis!using!the!
Diels%Alder! reaction! as! the! key! step! have! been! detailed,! especially! the! work! previously!
performed!within!the!Page!group.!
!
The! second! part! of! the! thesis! covers! research! work! towards! the! synthesis! of! the!
oxaspirobicyclic! unit.! The! synthetic! route! was! proposed! following! the! work! previously!
conducted!in!our!laboratories!and!a!solid!knowledge!acquired!about!the!target!molecule.!The!
different!investigations!carried!out!within!the!Page!group!have!led!to!a!new!approach,!based!on!
a! non%selective! α%hydroxylation! of! a! silyl! enol! ether!moiety,! resulting! in! the! formation! of! a!
mixture!of!two!diastereoisomers! in! a!5:3! ratio,! including! the!more!hindered! isomer!with! the!
desired! stereochemistry! at! the! pro%spiro! centre! as! the! minor! adduct.! However,! as! the!
HO
S
O
O
O
HO
O
HO2C
H O
O
O
HO
EtO
O
Tetronothiodin Oxaspirobicyclic tetronic acid unit
1
2
!
! iii!
separation! of! the!mixture!was! rather! challenging,!we! decided! to! attempt! different!methods!
such!as!the!inversion!of!configuration!of!the!pro%spiro!carbon!atom!bearing!the!hydroxyl!group.!
Obtainment! of! the! desired! hydroxyaldehyde! from! a! silyl! enol! ether! is! followed! by! a! Pinnick!
reaction!to!give!the!corresponding!carboxylic!acid.!
!
The!remaining!synthetic!steps!to!reach!the!oxaspirobicylic!unit!are!rapidly!described.!

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Chemistry
Depositing User: Mia Reeves
Date Deposited: 11 Mar 2014 11:32
Last Modified: 11 Mar 2014 11:34
URI: https://ueaeprints.uea.ac.uk/id/eprint/48045
DOI:

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