Towards the Total Synthesis of Diaporthichalasin

  • Hugh Hoather

Student thesis: Phd


Abstract(2E,4E,6E,8E)-2,4,6,8-Tetramethyldeca-2,4,6,8-tetraen-1-ol 267 was synthesised via three successive sequence of reactions comprising Horner-Wadsworth-Emmons olefination, followed by DIBAL-H reduction and then oxidation with activated manganese dioxide. When coupled with mono-methyl fumarate 273, the resulting tetraene methyl fumarate 272, comprising of a tri-substituted diene and doubly activated dienophile, cyclised in an intramolecular Diels Alder reaction to create adduct 274, with exclusive endo-stereochemistry. Four contiguous stereogenic centres were created in the reaction, one of which was a quaternary centre. This demonstrated the feasibility of the conjugated tetraene to successfully undergo Diels Alder reactions.A condensation reaction of (R)1-benzoyl-5-benzylpyrrolidin-2-one 303 with (5E,7E)-1-(1H-imidazol-1-yl)-5,7-dimethylnona-5,7-dien-1-one 324, followed by installation of the double bond of the dienophile, resulted (S)-1-benzoyl-5-benzyl-3-((5E,7E,)-5,7-dimethylocta-5,7-dienoyl)-1H-pyrrol-2(5H)-one 323. Adduct 323 cyclised in a Diels Alder reaction to give (3S,3aR,6aR,10aR)-2-benzoyl-3-benzyl-4,5,6a-trimethyl-2,3,3a,4,6a,7,8,9-octahydrobenzo(d)isoindole-1,10-dione 322. This intramolecular Diels Alder reaction generated four stereogenic centres, of which, two are quaternary centres. The structure exhibited exo-stereo chemistry with respect to the pyrrolinone. Acylation of (2E,4E,6E,8E)-2,4,6,8-Tetramethyldeca-2,4,6,8-tetraen-1-ol 267 gave (2E,4E,6E,8E)-2,4,6,8-Tetramethyldeca-2,4,6,8-tetraenyl-acetate 258, which was reacted with (E)-6-Bromo-1-tert-butyldimethylsilyl-2-hexene 280 to give (2E,8E,10E,12E)-8,10,12,14-Tetramethylhexadeca-2,8,12,14-pentaenal 23 after deprotection and oxidation. An Aldol reaction between (R)-tert-butyl 2-benzyl-5-oxopyrrolidine-1-carboxylate 292 and (2E,8E,10E,12E)-8,10,12,14-Tetramethylhexadeca-2,8,12,14-pentaenal 23 produced (5R)-tert-butyl-5-benzyl-3-((2E,8E,10E,12E,14E)-1-hydroxy-8,10,12,14-tetramethylhexadeca-2,8,10,12,14-pentaen-1-yl)-2-oxopyrrolidine-1-carboxylate 340. This brought the synthesis to within four steps of attempting the domino Diels Alder reactions to put in place the isoindolone core fused to the 13 membered tricyclic system of diaporthichalasin 1.
Date of Award1 Aug 2013
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorEric Thomas (Supervisor)

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