Interleukin 6 (IL-6), a multifunctional cytokine, plays a central regulatory role in host defense mechanisms. 1 However, in tumor cells IL-6 stimulates cell proliferation in an autocrine/paracrine manner and is responsible for much of the metabolic change known as cancer cachexia. 2 Control of IL-6 activity thus holds great promise both for the suppression of IL-6-dependent tumor cell growth and for the relief of cancer cachexia. 3 In our program to discover new IL-6 modulators, we recently reported the isolation and planar structures of (+)-madindolines A and B (1 and 2), 4 novel antibiotics comprised of a 3a-hydroxyfuroindoline ring connected at nitrogen via a methylene bridge to a cyclopentene-1,3-dione ring. Structural assignments were based on extensive 1-and 2-D NMR studies, in conjunction with IR, UV, and MS data; the relative and absolute configurations, however, remained undefined. Bioassays revealed potent, selective inhibition of IL-6 activity in the IL-6-dependent cell line MH60; importantly the response was dose-dependent. 4 In addition, (+)-madindoline A (1), the more potent congener, inhibited the differentiation of osteoblast cells. 4 Preliminary studies suggest that 1 interacts with the IL-6 receptor. 5 Unfortunately, the original source, Streptomyces nitrosporeus K93-0711, no longer produces these antibiotics. 5Intrigued by the novel architecture, the significant IL-6 inhibitory activity, and the scarcity of these natural products, we recently undertook their total synthesis. Herein we report the first total synthesis and assignment of the relative and absolute configurations of (+)-madindoline A (1) and (-)-madindoline B (2), the latter the enantiomer of natural madindoline B (vide infra).As prelude to total synthesis, we devised an efficient, asymmetric synthesis of the 3a-hydroxyfuroindoline ring system. 6 On the basis of our observation that m-CPBA oxidation of tryptophol (3) furnished 3a-hydroxyfuroindoline (4) in 75% yield, we explored the Sharpless asymmetric epoxidation protocol. 7 Stoichiometric oxidation [2.5 equiv t-BuOOH, 1.2 equiv (+)-DIPT, 1.0 equiv Ti(Oi-Pr) 4 , CH 2 Cl 2 (0.01 M)] for 6 h at -20°C led to (-)-4 8 in 72% yield and 99% ee (Scheme 1); catalytic protocols proved less effective (e.g., 37% yield; 28% ee). The absolute configuration of (-)-4 (3aR,8aS), determined by single-crystal X-ray analysis of the N-methyl-O-MTPA ester, proved consistent with the Sharpless epoxidation mnemonic. 7Having secured a viable asymmetric protocol to access the 3a-hydroxyfuroindoline ring, we envisioned the total synthesis of 1 and 2 to entail reductive coupling of aldehyde 6 (Scheme 2) with tryptophol (3), followed by the stereocontrolled introduction of the 3a-hydroxyfuroindoline ring, exploiting the Sharpless protocol. Aldehyde 6 in turn would derive from 8, the product of a ringclosing metathesis reaction 9 on diene 7, followed by conjugate introduction of an n-butyl group and oxidation state adjustments. Diene 7 required for ring metathesis would be constructed beginning with an init...

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The stereoselective synthesis of tetracyclic intermediate, the indoline spiroaminal 3 for neoxaline (1) and oxaline (2), has been accomplished. The key step of the stereoselective synthesis of 3 was the Lewis acid mediated transcyclization of 4 to the diaminal 18, and the tungstate-catalyzed oxidation of 18 to obtain the nitrone 19, which easily cyclizes to the indoline spiroaminal framework 3. [structure: see text]