Total synthesis of Efomycine M
Total synthesis of Efomycine M
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DOI：
10.1002/anie.200701065
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Mulzer, Johann
中科院分区：
文献类型：
--
作者：
Barth, Roland;Mulzer, Johann
典型地，炎性皮肤病如牛皮癣和特应性皮炎伴随着内皮细胞表达E-和P-选择素。这些选择素通过与T细胞表达的唾液酸化Lewisx（sLex）表位相互作用介导T细胞滚动。[1]结构上模拟选择素配体结合位点的特异性小分子抑制剂可减少皮肤浸润性T细胞的数量。据报道，大双孢霉素M（1）通过干扰E-和P-选择素的结合，在两种不同的银屑病小鼠模型中表现出显著的抗炎活性。[2]这一结果被誉为治疗人类炎症性疾病的新治疗方法，[3]直到最近，von Bonin等人，虽然证实了1的抗炎特性，但强烈怀疑所报道的作用模式。[4]鉴于这一争议，详细的结构-活性关系（SAR）的研究似乎适合更深入地了解该化合物的生物学特性。[5]在先前的研究中，1已经通过L-脱氧岩藻糖部分的碱催化β消除从天然产物elaiophylin（阿扎霉素B，2）半合成获得（方案1）。[6-8]由于分子的不稳定性，从1的化学衍生化中获得合适的类似物的努力失败了。[5]因此，我们发起了一个全合成1，这应该是足够灵活的，以提供合适的衍生物，为以后的SAR实验。在结构上，1具有16元大二聚体核心，7个立体中心和不稳定的α，β-烯酮部分。由于C2对称性为1，我们设想了一种双向方法（方案2）。[9]C11-C12键是在后期阶段通过从乙烯基碘4到二醛3得到的有机金属物质的双重亲核攻击形成的。中心的立体五元C5-C11可以通过反羟醛反应，然后通过非对映选择性酮还原来合成。2 E，4 E-开环酸6的二聚化通过Yamaguchi大环内酯化实现。片段C12-C16可以由甲基
Characteristically, inflammatory skin diseases such as psoriasis and atopic dermatitis are accompanied by an expression of E-and P-selectins by endothelial cells. These selectins mediate T-cell rolling by their interaction with T-cellexpressed sialyl Lewisx (sLex) epitopes.[1] Specific smallmolecule inhibitors that structurally mimic the binding sites of selectin ligands reduce the number of skin-infiltrating T cells. The macrodiolide efomycineM (1) was reported to exhibit significant anti-inflammatory activity in two different mouse models of psoriasis by interfering with the binding of E-and P-selectins.[2] This result was hailed as a new therapeutic approach in the treatment of human inflammatory disorders,[3] until, quite recently, von Bonin et al., though confirming the anti-inflammatory profile of 1, strongly doubted the reported mode of action.[4] In light of this controversy, detailed studies on the structure–activity relationships (SAR) appear appropriate for more insight into the biological profile of the compound.[5] In previous studies, 1 had been obtained semisynthetically from the natural product elaiophylin (azalomycin B, 2) by base-catalyzed β elimination of the L-deoxyfucose moiety (Scheme 1).[6–8] Severe efforts to obtain suitable analogues from a chemical derivatization of 1 failed owing to the lability of the molecule.[5] Thus, we initiated a total synthesis of 1 which should be flexible enough to provide suitable derivatives for later SAR experiments. Structurally, 1 features a 16-membered macrodiolide core, seven stereogenic centers and a labile α, β-enone moiety. Prompted by the C2 symmetry of 1 we envisaged a twodirectional approach (Scheme 2).[9] The C11–C12 bond was to be formed at a late stage by a double nucleophilic attack of an organometallic species obtained from vinyliodide 4 to dialdehyde 3. The central stereopentad C5–C11 could be synthesized by an anti-aldol reaction followed by a diastereoselective ketone reduction. The dimerization of 2E, 4E-seco acid 6 was to be achieved by Yamaguchi macrolactonization. Fragment C12–C16 could be synthesized from methyl