Towards the total synthesis of chaetochalasin A

UoM administered thesis: Phd

  • Authors:
  • Mark Willis

Abstract

AbstractThis thesis describes tin and non-tin mediated approaches towards the total synthesis of chaetochalasin A 1 through an intramolecular domino Diels-Alder approach, and subsequent synthesis of the Diels-Alder analogues exo NH 13E-272, endo NH 13E-273, exo NH 13Z-287 and endo NH 13Z-288 through an intramolecular Diels-Alder approach.The initial tin mediated route involved the initial formation of alcohol 119, which exhibited a 2,4-syn methyl arrangement, put in place through the use of two chiral auxiliary mediated asymmetric alkylations. Subsequent functionalisation of alcohol 119 led to aldehyde 215, which incorporated a vinyl stannane functional group. The alpha,β-unsaturated aldehyde 215 was then reacted with β,γ-BT-sulphone 120 under trans selective Julia conditions to give predominantly the (1E,7E,9E,11E) isomer of vinyl stannane 117. However, subsequent Stille reactions to form the Z,E diene functional group, between vinyl stannane 117 and vinyl iodide 118 resulted in a product that exhibited extreme isomerisation of the triene functional group.A subsequent non-tin mediated route involved the synthesis of aldehyde 229 from alcohol 119, which then underwent a trans selective Julia olefination with BT-sulphone 120 to give predominantly the (2E,8E,10E,12E) isomer of ester 228. Ester 228 was then converted into aldehyde 227, which then underwent a Z-selective olefination to put in place the 2Z,4E diene of methyl ester 226. Further functionalisation of methyl ester 226 using past methodology within the Thomas group led to pyrrolinone 110. Subsequent small scale attempts to convert pyrrolinone 110 into chaetochalasin A 1 through a domino Diels-Alder reaction proved ineffective.Formation of the exo NH 13E-272, endo NH 13E-273, exo NH 13Z-287 and endo NH 13Z-288 Diels-Alder analogues involved the initial conversion of alcohol 119 into aldehyde 275, followed by trans selective Julia olefination with BT-sulphone 120 to give predominantly the (4E,10E,12E,14E) isomer of ester 274. Further functionalisation of ester 274 using past methodology within the Thomas group, led to pyrrolinone 243, which then underwent an intramolecular Diels-Alder reaction to give the 13E : 13Z isomers in a 1 : 1 ratio, with each isomer exhibiting an exo : endo geometry in a 5 : 4 ratio.

Details

Original languageEnglish
Awarding Institution
Supervisors/Advisors
  • Eric Thomas (Supervisor)
Award date31 Dec 2012