Total synthesis of a cuticular hydrocarbon utilizing bismuth(III) coupling chemistry and towards the total synthesis of vioprolide D

  • Leo Liu

Student thesis: Phd


Section One: Total synthesis of a cuticular hydrocarbon from the cane beetle Antitrogus parvulus utilizing bismuth mediated reactionsThis section describes investigations of 1,5-stereocontrol bismuth(III) mediated coupling reactions between allylbromide and aldehydes and successful application of this coupling chemistry in the total synthesis of a cuticular hydrocarbon. The bismuth(III) mediated coupling reaction was investigated using chiral bromide [(E,2R)-5-bromo-2,4-dimethyl-pent-3-enoxy]methylbenzene 1.79 with benzaldehyde and butyraldehyde; 12:1 diastereoselectivity in favour of forming the 1,5-anti product was observed in both model studies. This bismuth(III) coupling chemistry has been successfully applied in the construction of (4S,6R,8R,10S,16S)-4,6,8,10,16-pentamethyldocosane 1.21 and (4S,6R,8R,10S,16R)-4,6,8,10,16-pentamethyldocosane 1.22. 13C NMR spectroscopic comparison of the synthetic diastereomers with the natural product 1.17 revealed that (4S,6R,8R,10S,16S)-4,6,8,10,16-pentamethyldocosane 1.21 was consistent with the natural product. Therefore, it was concluded that the natural product 1.17 possesses the same relative stereoconfiguration as (4S,6R,8R,10S,16S)-4,6,8,10,16-pentamethyldocosane 1.21. Section Two: Towards the total synthesis of vioprolide DThis section describes attempts towards the total synthesis of vioprolide D. Initial disconnection revealed three tripeptide fragments. Fragment one benzyl (2R)-2-[[(2S)-2-[[(2S)-3-[tert-butyl(dimethyl)silyl]oxy-2-triisopropylsilyloxy-propanoyl]amino]propanoyl]amino]-4-methyl-pentanoate 2.26 was synthesized from commercial amino acid building blocks. Attempts to synthesize fragment two (S)-(9H-fluoren-9-yl)methyl 2-(((2S,3R)-1-(((S)-1-(allyloxy)-3-methyl-1-oxobutan-2-yl)(methyl)amino)-3-hydroxy-1-oxobutan-2-yl)carbamoyl)pyrrolidine-1-carboxylate 2.40 were unsuccessful because of a intramolecular cyclization reaction which led to the formation of piperazinedione 2.50, and this process stopped peptide elongation. Literature search showed that this side reaction could be prevented by changing the allyl ester group in dipeptide (S)-allyl 2-((2S,3R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)-N-methylbutanamido)-3-methylbutanoate 2.42 to a tert-butyl ester group. Synthesis of thiazoline containing fragment three (E)-allyl 2-((R)-2-((S)-1-((2-nitrophenyl)sulfonyl)pyrrolidin-2-yl)-4,5-dihydrothiazole-4-carboxamido)but-2-enoate 2.57 was initially attempted via a cysteine cyclization reaction with an adjacent amide bond, this approach was unsuccessful due to extensive epimerization observed. In the modified synthetic strategy, thiazoline containing (E)-allyl 2-((R)-2-((S)-1-((R)-2-((tert-butoxycarbonyl)amino)-4-methylpentanoyl)pyrrolidin-2-yl)-4,5-dihydrothiazole-4-carboxamido)but-2-enoate 2.73 was successfully constructed as a single diastereomer via dehydration reaction of thioamide with adjacent serine residue using diethylaminosulfur trifluoride. The successful synthesis of tetrapeptide 2.73 would not only lead to the total synthesis of vioprolide D, but also potential access to other vioprolide analogues.
Date of Award1 Aug 2013
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorEric Thomas (Supervisor)

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