Archibald Sarah C, Barden David J, Bazin Jérôme F Y, Fleming Ian, Foster Colin F, Mandal Ajay K, Mandal Amit K, Parker David, Takaki Ken, Ware Anne C, Williams Anne R B, Zwicky Anna B
Department of Chemistry, Lensfield Road, Cambridge, UK CB2 1EW.
Org Biomol Chem. 2004 Apr 7;2(7):1051-64. doi: 10.1039/b316899a. Epub 2004 Mar 5.
Several approaches to the synthesis of ebelactone A 2 are described, culminating in the synthesis of the benzenesulfonate of 2-epi-ebelactone A 161. All the approaches were based on three fragments A, B and C, originally defined in general terms in, but eventually used as the aldehyde 72, the allenylsilane 3 and the aldehyde 139, respectively. They were joined, first B with C, and then B+C with A. In the main routes to fragments A and C, the relative stereochemistry was controlled by highly stereoselective enolate methylations 67-->67, 68-->69, and 135-->136, in each case anti to an adjacent silyl group, and by a highly stereoselective hydroboration of an allylsilane 137-->138, also anti to the silyl group. The hydroxyl groups destined to be on C-3 and C-11 were unmasked by silyl-to-hydroxy conversions 69-->70 and 138-->139 with retention of configuration. The stereochemistry created in the coupling of fragment B to C was controlled by the stereospecifically anti S(E)2' reaction between the enantiomerically enriched allenylsilane 3 and the aldehyde 139. The double bond geometry was controlled by syn stereospecific silylcupration 148-->151, and preserved by iododesilylation 151-->152 of the vinylsilane with retention of configuration, and Nozaki-Hiyama-Kishi coupling with the aldehyde 72 gave the whole carbon skeleton 153 of ebelactone A with the correct relative configuration, all of which had been controlled by organosilicon chemistry. In the steps to remove the superfluous allylic hydroxyl, an intermediate allyllithium species 156 abstracted the proton on C-2, and its reprotonation inverted the configuration at that atom. Other routes to the fragments A and C were also explored, both successful and unsuccessful, both silicon-based and conventional, and a number of unexpected side reactions were investigated.
本文描述了几种合成埃博内酯A 2的方法，最终合成了2-表埃博内酯A的苯磺酸盐161。所有方法均基于三个片段A、B和C，最初在文献中以一般术语定义，但最终分别用作醛72、烯丙基硅烷3和醛139。它们首先通过B与C连接，然后B + C与A连接。在片段A和C的主要合成路线中，相对立体化学通过高度立体选择性的烯醇盐甲基化反应67→67、68→69和135→136来控制，在每种情况下均与相邻的硅烷基呈反式，并且通过烯丙基硅烷137→138的高度立体选择性硼氢化反应来控制，同样与硅烷基呈反式。通过硅烷基到羟基的转化反应69→70和138→139，构型得以保留，从而使注定位于C-3和C-11上的羟基得以脱保护。片段B与C偶联时产生的立体化学由对映体富集的烯丙基硅烷3与醛139之间的立体专一性反式S(E)2'反应控制。双键几何结构通过顺式立体专一性硅氢化铜化反应148→151控制，并通过乙烯基硅烷的碘代脱硅反应151→152构型得以保留而得以保持，与醛72的野依-日山-岸偶联反应给出了具有正确相对构型的埃博内酯A的整个碳骨架153，所有这些均由有机硅化学控制。在去除多余烯丙基羟基的步骤中，中间体烯丙基锂物种156夺取了C-2上的质子，其再质子化使该原子处的构型翻转。还探索了其他合成片段A和C的路线，既有成功的也有失败的，既有基于硅的也有传统的，并且研究了一些意外的副反应。
