Synthesis of (-)-octalactin a by a strategic vanadium-catalyzed oxidative kinetic resolution.
Synthesis of (-)-octalactin a by a strategic vanadium-catalyzed oxidative kinetic resolution.
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通过战略性钒催化氧化动力学拆分合成 (-)-八乳素 a。
DOI：
10.1002/anie.200800554
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Toste,FDean
中科院分区：
文献类型：
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作者：
Radosevich,AlexanderT;Chan,VincentS;Shih,Hui-Wen;Toste,FDean
外消旋物质的动力学拆分是一种成熟的方法，用于制备多种对映体富集型化合物。[1]然而，标准动力学拆分的总体效率被限制在最大理论产率为50%的富集型手性化合物，其余的不需要的物质在大多数应用中被丢弃。[2]由于这种固有的整体效率，除了最简单和最便宜的底物外，[3]动力学拆分在制备规模上通常是不可接受的。因此，动力学拆分方法，特别是在复杂分子合成的背景下，在很大程度上被归类为在合成的早期阶段制备小的手性构建块。在最近开发了一种钒催化的不对称有氧氧化羟基羰基化合物[4]之后，我们开始对探索这种动力学拆分方法的潜力感兴趣，从制备简单的构建块转向更有意义的、战略性的合成功能。观察到含有多个立体中心的底物被催化量的[VO(OIPR)3]和(S)-2-(3，5-di-tert-butylsalicylideneamino)-tert-butyl-1-ethanol(1))不对称氧化导致对映体富集醇和酮产品的分离，促使我们考虑一种合成策略(图1)，其中拆分的两个组分可以被杠杆用于单个合成目标。这样，动力学拆分成为合成序列中关键的结构和立体化学分支点，拆分的整体效率提高了50%以上。在此，我们报道了这种拆分/重组合成策略[5]成功地应用于海洋生物活性代谢物Octalactin A的全合成[6]Octalactin A(2)是从海洋微生物中分离出来的一小类中环内酯。体外生物测定表明，octalactin A对B-16-F10小鼠黑色素瘤和HCT-116人结肠肿瘤细胞株具有显著的细胞毒性。[6，7]因此，大量的合成研究，包括几个全合成，[8]一直指向它的制备。[9]我们对octalactin A的方法以相反的意义开始，断开C10-C15侧链和八元核心的逆内酯化，从而导致简化的片段3和4(方案1)。从这里，我们的策略的基础来自于第二酸组分3中的假对称元素的鉴定。具体地说，我们设想重复的抗1，2-Vic-羟甲基立体二酸可以从外消旋的抗1，2-Vic-羟甲基立体构筑(？)-5的对映体中衍生出来。因此，(？)-5的氧化拆分和随后的精制片段的头尾重组将允许快速获得3。C10-C15侧链4可以通过将异丙基不对称地加成到适当官能化的醛上来获得，其中三取代的烯烃构型可以通过立体定向铜酸盐诱导的2，3-二氢呋喃的变力重排来获得。
The kinetic resolution of racemic material is a well-established approach used to prepare a wide range of enantiomerically enriched compounds.[1] However, the overall efficiency of a standard kinetic resolution is limited to a maximum theoretical yield of 50% of the enriched chiron, with the balance of undesired material being discarded in most applications.[2] As a result of this inherent overall efficiency,[3] kinetic resolution is often deemed unacceptable on a preparative scale except for the most simple and inexpensive of substrates. Consequently, kinetic resolution methods, especially in the context of complex molecule synthesis, have largely been relegated to the preparation of small chiral building blocks at an early stage of the synthesis. Having recently developed a vanadium-catalyzed asymmetric aerobic oxidation of a hydroxycarbonyl compounds,[4] we became interested in exploring the potential of this kinetic resolution methodology, to move beyond the preparation of simple building blocks toward a more meaningful, strategic synthetic function. The observation that asymmetric oxidation of substrates bearing multiple stereocenters by catalytic amounts of [VO (OiPr) 3] and (S)-2-(3, 5-di-tert-butylsalicylideneamino)-tert-butyl-1-ethanol (1) resulted in the isolation of both enantioenriched alcohol and ketone products motivated us to consider a synthetic strategy (Figure 1) wherein both components of the resolution might be leveraged toward a single synthetic target. By doing so, the kinetic resolution serves as the key structural and stereochemical branching point in the synthetic sequence and the overall efficiency of the resolution is improved beyond 50%. Herein, we report the successful implementation of this type of resolution/recombination synthetic strategy [5] to the total synthesis of the bioactive marine metabolite octalactin A.[6] Octalactin A (2) belongs to a small class of medium-ring lactones isolated from marine microorganisms. In vitro bioassays have shown octalactin A to possess significant cytotoxicity toward B-16-F10 murine melanoma and HCT-116 human colon tumor cell lines.[6, 7] As a result, numerous synthetic investigations, including several total syntheses,[8] have been directed towards its preparation.[9] Our approach to octalactin A begins in an antithetic sense with disconnection of the C10–C15 side chain and retrolactonization of the eight-membered core, thus leading to the simplified fragments 3 and 4 (Scheme 1). From here, the basis of our strategy stems from the identification of an element of pseudosymmetry in the seco-acid component 3. Specifically, we envisioned that the repeating anti-1, 2-vic-hydroxymethyl stereodiad could be derived from the enantiomers of racemic anti-1, 2-vic-hydroxymethyl stereoconstruct (Æ)-5. As such, oxidative resolution of (Æ)-5 and subsequent head-to-tail recombination of elaborated fragments would allow rapid access to 3. The C10–C15 side chain 4 could be obtained by asymmetric addition of an isopropyl group to a suitably functionalized aldehyde, wherein the trisubstituted olefin geometry might be secured by stereospecific cuprate-induced dyotropic rearrangement of 2, 3-dihydrofuran.