McGowan Graham, Thomas Eric J
The School of Chemistry, The University of Manchester, Manchester, M13 9PL, UK.
Org Biomol Chem. 2009 Jun 21;7(12):2576-90. doi: 10.1039/b903256h. Epub 2009 Apr 27.
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)methoxybicyclo[9.3.1]pentadec-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)methoxybicyclo[9.3.1]pentadec-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)methoxybicyclo[9.3.1]pentadeca-3,7-dien-2-ol 63 which has the full carbon skeleton of the phomactins.
将适当取代的环己烯基甲基炔丙基醚进行[2,3]-维蒂希重排，随后将炔烃转化为三取代烯烃，并通过分子内砜烷基化进行环化，这已被证明是一种有用的立体选择性方法，可用于合成用于预期的腐马菌素合成的高级大环中间体。因此，对(1RS,6SR)-2-(溴甲基)-1,6-二甲基-4-氧代环己-2-烯-1-羧酸甲酯24进行卢奇还原，得到(1RS,4RS,6SR)-2-溴甲基-4-羟基-1,6-二甲基环己-2-烯-1-羧酸甲酯26，其被保护为(2-三甲基硅基乙氧基)甲基醚27。使用该溴化物对(E)-8-叔丁基二苯基硅氧基-7-甲基辛-6-烯-2-炔-1-醇17进行O-烷基化，得到相应的醚28。将其还原，然后通过苯硫酚钠取代相应的甲磺酸酯，随后氧化，将所得的伯醇29转化为苯磺酰基。所得炔丙基醚31的[2,3]-维蒂希重排具有立体选择性，主要得到(2RS,3SR,5RS,6SR)-2-[(1RS,6E)-8-叔丁基二苯基硅氧基-1-羟基辛-6-烯-2-炔-1-基)]-5,6-二甲基-6-(苯磺酰基)甲基-3-(三甲基硅基乙氧基)甲氧基-1-亚甲基环己烷37及其在C(1')处的差向异构体38。在用O-脱硅基将其保护为4-甲氧基苄基醚39并将伯醇40转化为相应的溴化物41之后，通过砜的分子内烯丙基化进行环化，得到(1SR,2RS,11SR,12RS,14SR,7E)-10-苯磺酰基-8,11,12-三甲基-15-亚甲基-2-(4-甲氧基苄基)-14-(2-三甲基硅基乙氧基)甲氧基双环[9.3.1]十五-7-烯-3-炔42，然后进行还原脱磺酰化和O-脱保护，得到(1RS,2RS,11SR,12RS,14SR,7E)-8,11,12-三甲基-15-亚甲基-14-(2-三甲基硅基乙氧基)甲氧基双环[9.3.1]十五-7-烯-3-炔-2-醇44。在将维蒂希重排产物保护为其三异丙基硅醚45之后，进行了类似的化学操作。为了制备相应的(3E,7E)-3,7-二烯醇，将维蒂希重排产物37和38氧化为相应的酮54。苯硫酚进行共轭加成，然后使用二甲基铜锂取代主要的苯硫基加合物56，得到相应的(E)-共轭烯酮57，其用硼氢化钠还原，所得醇58转化为其苄氧基甲氧基醚59。将其进一步反应得到(1RS,2RS,11SR,12RS,14SR,3E,6E)-4,8,11,12-四甲基-15-亚甲基-14-(2-三甲基硅基乙氧基)甲氧基双环[9.3.1]十五-3,7-二烯-2-醇63，其具有腐马菌素的完整碳骨架。
