Towards the Synthesis of the Oxaspirobicyclic Unit of Tetronothiodin

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.!

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

University of East Anglia

Year dc:date.issued

2012

Author dc:creator

• Wang, Wei-Wei

Language dc:language

en