Efficient Enantioselectine Total Synthesis of Bioactiae natual Products

最近，我们寻找新的IL-6活性抑制剂，从亚硝化链霉菌K93-0711中分离出了马吲哚A和B。通过广泛的光谱分析，初步推断这些化合物的结构为3a-羟基呋喃吲哚环通过亚甲基桥连接到环戊烯-1，3-二酮环上。马吲哚A是B在C-2‘位的立体异构体。首次通过立体选择性的羟醛缩合反应(A)、闭环歧化反应(B)、还原N-烷基化反应(C)和吲哚的不对称氧化闭环反应(D)确定了其绝对立体化学。此外，我们还开发了更有效的全合成(第二代)，通过以3a-羟基呋喃吲哚为手性配体(E)配位的3酯的立体选择性酰化反应，以及烯丙基硅烷4(F)的分子内酰化反应(9步得率19%)(方案1)。我们发现[~3H]-Madindoline A选择性地与GP-130结合。人工合成的马朵林A在体外能明显抑制破骨细胞的形成，在体内能明显抑制去卵巢小鼠的骨吸收。

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.