Helliwell Madeleine, Karim Sufia, Parmee Emma R, Thomas Eric J
School of Chemistry, University of Manchester, Manchester, UKM13 9PL.
Org Biomol Chem. 2005 Oct 21;3(20):3636-53. doi: 10.1039/b508670a. Epub 2005 Sep 14.
Following studies using benzyloxymethyl isopropenyl ketone 5 and ethyl 3-(3-furyl)-3-oxopropanoate 6, Robinson reactions between aryloxymethyl isopropenyl ketones 19 and 5 and ethyl 3-(2-trimethylsilyl-3-furyl)-3-oxopropanoate 20 were found to be stereoselective giving cyclohexanones 21 and 41, in which the 3-(arylmethoxy) substituents were cis to the 2-hydroxyl groups, as the major products. After reduction and protection of ketone 21, selective PMB-deprotection, oxidation and stereoselective reduction inverted the configuration at C3 to give the diol 30. Protection of the secondary 3-hydroxyl group followed by modification of the protected 4-alcohol then gave the hydroxybutenolides 36 and 37 after oxidation of the silylated furan using singlet oxygen. The 3-benzyloxycyclohexanone 41 was also converted into the hydroxybutenolide 37 via the (2-trimethylsilylethoxy)methyl (SEM) ether 35. The Wittig reaction between the ylid generated from 2-methylpropyl(triphenyl)phosphonium salt and hydroxybutenolide 36 gave predominantly the (2Z,4Z)-dienyl acid 38 which was taken through to the butenolide 40. Similarly, the racemic hydroxybutenolide 37 was condensed with the racemic ylid derived from phosphonium salt 53 to give, after SEM-deprotection and 5-membered lactone formation, a mixture of the (9Z,2'Z)-dienyl lactones 58 and 59 containing ca. 10% of the corresponding (9Z,2'E)-isomers 60 and 61. (2'Z)/(2'E)-Isomerisation of the dienes 58 and 59 using iodine followed by deprotection gave a mixture of the seco-acids 62 and 63. Selective macrocyclisation of the seco-acid 62 in which the relative configuration of the C1-C7 and C17-C19 fragments (milbemycin numbering) corresponded to that present in the natural milbemycins, gave the beta-milbemycin analogue 65 after butenolide reduction. The hydroxybutenolide 37 was also condensed with the ylid derived from the phosphonium salt 1 and the product taken through to (6R)-6-hydroxy-3,4-dihydromilbemycin E 77. Preliminary attempts to convert the beta-milbemycin analogues 65 and 77 into tetrahydrofurans corresponding to analogues of alpha-milbemycins by treatment with toluene p-sulfonyl chloride under basic conditions gave the primary allylic chlorides 78 and 79.
在使用苄氧基甲基异丙烯基酮5和3-(3-呋喃基)-3-氧代丙酸乙酯6进行研究之后，发现芳氧基甲基异丙烯基酮19与5以及3-(2-三甲基甲硅烷基-3-呋喃基)-3-氧代丙酸乙酯20之间的罗宾逊反应具有立体选择性，生成环己酮21和41，其中3-(芳基甲氧基)取代基与2-羟基处于顺式，作为主要产物。在对酮21进行还原和保护、选择性的对甲氧基苄基（PMB）脱保护、氧化以及立体选择性还原后，C3位的构型发生翻转，得到二醇30。对仲3-羟基进行保护，然后对受保护的4-醇进行修饰，接着使用单线态氧氧化甲硅烷基化的呋喃后，得到羟基丁烯内酯36和37。3-苄氧基环己酮41也通过(2-三甲基甲硅烷基乙氧基)甲基（SEM）醚35转化为羟基丁烯内酯37。由2-甲基丙基(三苯基)鏻盐生成的叶立德与羟基丁烯内酯36之间的维蒂希反应主要生成(2Z,4Z)-二烯酸38，该二烯酸进一步转化为丁烯内酯40。类似地，外消旋羟基丁烯内酯37与由鏻盐53衍生的外消旋叶立德缩合，在SEM脱保护和形成五元内酯后，得到(9Z,2'Z)-二烯内酯58和59的混合物，其中含有约10%的相应(9Z,2'E)-异构体60和61。使用碘使二烯58和59进行(2'Z)/(2'E)-异构化，然后脱保护，得到裂酸62和63的混合物。对裂酸62进行选择性大环化，其中C1-C7和C17-C19片段（米尔倍霉素编号）的相对构型与天然米尔倍霉素中的构型相对应，在丁烯内酯还原后得到β-米尔倍霉素类似物65。羟基丁烯内酯37还与由鏻盐1衍生的叶立德缩合，产物进一步转化为(6R)-6-羟基-3,4-二氢米尔倍霉素E 77。初步尝试在碱性条件下用对甲苯磺酰氯处理β-米尔倍霉素类似物65和77，将其转化为与α-米尔倍霉素类似物相对应的四氢呋喃，得到伯烯丙基氯78和79。
