A total synthesis of milbemycin G: approaches to the C(1)-C(10)-fragment and completion of the synthesis
A total synthesis of milbemycin G: approaches to the C(1)-C(10)-fragment and completion of the synthesis
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DOI：
10.1039/b508675b
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发表时间：
2005-10-21
影响因子：
3.2
通讯作者：
Thomas, EJ
中科院分区：
文献类型：
--
作者：
Bailey, S;Helliwell, M;Thomas, EJ
报道了α-米尔贝霉素合成所需的羟基丁烯酰亚胺（-）-6的合成，并完成了米尔贝霉素G7的全合成。在初步研究之后，开发了从羟基酮38合成羟基丁烯二酸（-）-6的优化合成，其涉及通过分离3-（O-氯乙酰基）-（S）-扁桃酸酯80和83来拆分38。对应于羟基酮38的所需对映异构体的酯80从非对映异构体酯80和83的混合物中结晶，在乙醇分解后以47%的总产率（基于外消旋体38）得到（-）-羟基酮（-）-38。羟基酮（-）-38氧化成烯醇二酮（-）-39，苯基硒化和立体选择性还原得到三羟基环己基硒醚（-）-43。然后，通过使用三氯乙酸酯化4-羟基，将非共轭双键区域选择性地引入六元环中，得到三氯乙酸酯（-）-69。用叔丁基过氧化氢从三氯乙酸酯中进行氧化消除具有高度的区域选择性，三氯乙酸酯经乙醇解后得到比例为95：5的内环和外环烯烃（-）-44和（-）-46。通过环状亚甲锡烷基55选择性O-甲基化4-羟基，并将3-羟基保护为其2-三甲基甲硅烷基乙氧基甲基（SEM）醚，得到酯（-）-57。在乙酯皂化后，使用2-三甲基甲硅烷基乙醇再酯化，并使用单线态氧氧化2-三甲基甲硅烷基呋喃基片段，得到所需的羟基丁烯二酸（-）-6。季鏻盐2与羟基丁烯二酰亚胺（-）-6之间的Wittig反应得到约100.第二章：1酯84的（4 Z）-和（4 E）-异构体的混合物，其在用催化量的碘处理时转化为（4 E）-异构体（4 E）-84。脱保护得到开环酸85，但将其大环化的尝试不成功，消除产物86是分离的唯一产物。Wittig产物84通过除去SEM基团、环化形成丁烯二醇环和二烯异构化而被引入丁烯二醇（2 ′ E）-91，但这不能转化为相应的开环酸92。然而，从开环酸85中除去SEM基团得到三羟基酸93，将其在改进的Yamaguchi条件下环化，得到大环内酯94和少量大环丁烯二酸95。用氢化二异丁基铝还原该混合物，得到（6 R）-6-羟基米尔贝霉素E 96，通过伯氯化物97的环化将其转化为米尔贝霉素G 7。合成的米尔贝霉素G 7与通过米尔贝霉素D 98的商业样品的甲基化制备的样品相同，7-O-甲基米尔贝霉素G 99是该甲基化的副产物。
A synthesis of the hydroxybutenolide (-)-6 required for synthesis of a-milbemycins and the completion of a total synthesis of milbemycin G 7 is reported. Following preliminary studies, an optimised synthesis of the hydroxybutenolide (-)-6 from the hydroxyketone 38 was developed which involved the resolution of 38 by separation of the 3-(O-chloroacetyl)-(S)-mandelates 80 and 83. Ester 80, which corresponded to the required enantiomer of the hydroxyketone 38, crystallized from the mixture of the diastereoisomeric esters 80 and 83 giving the (-)-hydroxyketone (-)-38 in an overall yield of 47% (based on racemic 38) after ethanolysis. Hydroxyketone (-)-38 was oxidised to the enolic diketone (-)-39 and phenylselenation and stereoselective reduction gave the trihydroxycyclohexyl selenide (-)-43. The regioselective introduction of the non-conjugated double-bond into the six-membered ring was then achieved by esterification of the 4-hydroxyl group using trichloroacetic acid to give the trichloroacetate (-)-69. Oxidative elimination from the trichloroacetate using tert-butyl hydroperoxide was highly regioselective and gave the endo- and exocyclic alkenes (-)-44 and (-)-46 in a ratio of 95 : 5 after ethanolysis of the trichloroacetates. Selective O-methylation of the 4-hydroxyl group via the cyclic stannylene 55 and protection of the 3-hydroxyl group as its 2-trimethylsilylethoxymethyl (SEM) ether gave the ester (-)-57. Following saponification of the ethyl ester, re-esterification using 2-trimethylsilylethanol and oxidation of the 2-trimethylsilyifuryl fragment using singlet oxygen gave the required hydroxybutenolide (-)-6. The Wittig reaction between the phosphonium salt 2 and the hydroxybutenolide (-)-6 gave a ca. 2 : 1 mixture of the (4Z)- and (4E)-isomers of the ester 84 which on treatment with a catalytic amount of iodine was converted into the (4E)-isomer (4E)-84. Deprotection gave the seco-acid 85 but attempts to macrocyclise this were unsuccessful, the elimination product 86 being the only product isolated. The Wittig product 84 was taken through to the butenolide (2'E)-91 by removal of the SEM group, cyclisation to form the butenolide ring and diene isomerization, but this could not be converted into the corresponding seco-acid 92. However, removal of the SEM group from the seco-acid 85 gave the trihydroxy-acid 93 which was cyclized under modified Yamaguchi conditions to give the macrolide 94 together with a small amount of the macrocyclic butenolide 95. Reduction of this mixture using diisobutylaluminium hydride gave (6R)-6-hydroxymilbemycin E 96 which was converted to rnilbemycin G 7 by cyclisation of the primary chloride 97. The synthetic milbemycin G 7 was identical to a sample prepared by methylation of a commercial sample of milbemycin D 98, 7-O-methylmilbemycin G 99 being a side-product of this methylation.