The High-Intrinsic Diels−Alder Reactivity of (−)-Galiellalactone; Generating Four Quaternary Carbon Centers under Mild Conditions

• Published in: European journal of organic chemistry 2004-07, Vol.2004 (13), p.2783-2790
• Main Authors: von Nussbaum, Franz, Hanke, Roman, Fahrig, Thomas, Benet-Buchholz, Jordi
• Format: Article
• Language: English
• Subjects: Biological activity; Biosynthesis; Medicinal chemistry; Natural products; Polyketides; Signal transduction
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.200400137

The Interleukin‐6 (IL‐6) responsive JAK/STAT pathway seems to be correlated with major diseases such as chronic inflammation, arteriosclerosis, liver fibrosis, Parkinson and Alzheimer disease. In order to take a look at (−)‐galiellalactone as a potential low‐molecular‐weight lead structure for non‐proteinogenic IL‐6 antagonists we carried out a microderivatization program that was aiming at bioactive congeners of the natural product and a preliminary structure‐activity relationship. During this effort, galiellalactone showed reactivity generally governed by convex‐concave face selectivity. O‐Acyl derivatives of galiellalactone turned out to be precursors of bis(dehydratogaliellalactone), a novel oligocyclic Diels−Alder product of complicated architecture. During this extraordinary Diels−Alder‐type conversion four quaternary carbon centers were generated at room temperature under mild conditions in a regio‐ and stereoselective fashion. The novel Diels−Alder transformation was used for a stereoselective hetero‐derivatization of the natural product leading to an aza congener of altered IL‐6 antagonistic activity in HepG2 hepatoma cells. The absolute (4S,5aR,7aR,7bS) configuration of natural (−)‐galiellalactone was confirmed by X‐ray crystallography with Cu‐Kα radiation. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)