Efficient Enantioselectine Total Synthesis of Bioactiae natual Products

我们寻找新的IL-6活性抑制剂，最近从亚孢子链霉菌K93-0711中分离出madindolines A和B。这些化合物的结构最初通过广泛的光谱分析推断为3-羟基呋喃多啉环在氮上通过亚甲基桥连接到环戊烯- 1,3 -二酮环。Madindoline A是B在C-2'位置上的立体异构体。不幸的是，链霉菌的原始培养不再产生这些天然产物。第一次全合成吲哚啉A后，通过立体选择性醛醇反应(A)、闭合环复合反应(B)、还原n -烷基化反应(C)和吲哚(D)的不对称氧化闭合环来确定其绝对立体化学性质。此外，我们已经开发了更有效的全合成（第二代），通过立体选择性酰化酯3与3 -羟基呋喃吲哚胺部分作为手性配体(E)，以及烯丙基硅烷4的分子内酰化(F)（9步19%收率）（方案1）。我们发现[^3H]-madindoline A选择性地与gp-130结合。合成麦丁多林A在体外显著抑制破骨细胞生成和体内去卵巢小鼠骨吸收。

Our search for new inhibitors of IL-6 activity has recently led to the isolation of madindolines A and B from Streptomyces nitrosporeus K93-0711. The structures of these compounds were initially deduced by extensive spectroscopic analysis to be 3a-hydroxyfuroindoline ring connected at nitrogen via a methylene bridge to a cyclopentene-1, 3-dione ring. Madindoline A is a stereoisomer of B at the C-2' position. Unfortunately, the original culture of the Streptomyces no longer produces these natural products.The first total synthesis of madindoline A has been succeeded by the stereoselective aldol reaction (A), ring-closing metathesis (B), reductive N-alkylation (C), and asymmetric oxidative ring-closing of indole (D) to determine its absolute stereochemistry. Moreover, we have developed more efficient total synthesis (second generation) by stereoselective acylation of ester 3 in coordination with 3a-hydroxyfuroindoline moiety as the chiral ligand (E), and the intramolecular acylation of allylsilane 4 (F) (19% yield over 9 steps) (Scheme 1). We have found that [^3H]-madindoline A binds to gp-130, selectively. Synthetic madindoline A markedly inhibited osteoclastogenesis in vitro and bone resorption in ovariectomized mice in vivo.