Synthesis of macrocyclic precursors of phomactins using 2,3-Wittig rearrangements

Graham McGowan, Eric J. Thomas

    Research output: Contribution to journalArticlepeer-review


    The combination of a 2,3-Wittig rearrangement of a suitably substituted cyclohexenylmethyl propargyl ether with a subsequent conversion of the alkyne to a trisubstituted alkene and cyclisation via intramolecular sulfone alkylation has proved to be a useful stereoselective approach to advanced macrocyclic intermediates for a projected synthesis of phomactins. Thus Luche reduction of methyl (1RS,6SR)-2-(bromomethyl)-1,6-dimethyl-4-oxocyclohex-2-ene-1-carboxylate 24 gave methyl (1RS,4RS,6SR)-2-bromomethyl-4-hydroxy-1,6-dimethylcyclohex-2-ene- 1-carboxylate 26 which was protected as its (2-trimethylsilylethoxy)methyl ether 27. O-Alkylation of (E)-8-tert-butyldiphenylsilyloxy-7-methyloct-6-en-2-yn-1-ol 17 using this bromide gave the corresponding ether 28. This was reduced and the resulting primary alcohol 29 converted into a phenylsulfonyl group by displacement of the corresponding mesylate by sodium thiophenoxide followed by oxidation. A 2,3-Wittig rearrangement of the resulting propargylic ether 31 was stereoselective and gave predominantly (2RS,3SR,5RS,6SR)-2-(1RS,6E)-8-tert- butyldiphenylsilyloxy-1-hydroxyoct-6-en-2-yn-1-yl)-5,6-dimethyl-6- (phenylsulfonyl)methyl-3-(trimethylsilylethoxy)methoxy-1-methylenecyclohexane 37 together with its epimer at C(1′)38. Following protection as its 4-methoxybenzyl ether 39 with O-desilylation and conversion of the primary alcohol 40 into the corresponding bromide 41, cyclisation by intramolecular allylation of the sulfone gave (1SR,2RS,11SR,12RS,14SR,7E)-10-phenylsulfonyl-8, 11,12-trimethyl-15-methylene-2-(4-methoxybenzyl)-14-(2-trimethylsilylethoxy) methoxybicyclo9.3.1pentadec-7-en-3-yne 42 and reductive desulfonylation and O-deprotection gave (1RS,2RS,11SR,12RS,14SR,7E)-8,11,12-trimethyl-15-methylene- 14-(2-trimethylsilylethoxy)methoxybicyclo9.3.1pentadec-7-en-3-yn-2-ol 44. Analogous chemistry was carried out following protection of the Wittig rearrangement product as its tri-isopropylsilylether 45. To prepare the corresponding (3E,7E)-3,7-dienol, the Wittig rearrangement products 37 and 38 were oxidised to the corresponding ketone 54. Conjugate addition of thiophenol followed by substitution of the major phenylthio adduct 56 using lithium dimethylcuprate gave the corresponding (E)-conjugated enone 57 which was reduced using sodium borohydride and the resulting alcohol 58 converted into its benzyloxymethoxy ether 59. This was taken through to give (1RS,2RS,11SR,12RS, 14SR,3E,6E)-4,8,11,12-tetramethyl-15-methylene-14-(2-trimethylsilylethoxy) methoxybicyclo9.3.1pentadeca-3,7-dien-2-ol 63 which has the full carbon skeleton of the phomactins. © The Royal Society of Chemistry 2009.
    Original languageEnglish
    Pages (from-to)2576-2590
    Number of pages14
    JournalOrganic and Biomolecular Chemistry
    Issue number12
    Publication statusPublished - 2009


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