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The High‐Intrinsic Diels−Alder Reactivity of (−)‐Galiellalactone; Generating Four Quaternary Carbon Centers under Mild Conditions
Author(s) -
von Nussbaum Franz,
Hanke Roman,
Fahrig Thomas,
BenetBuchholz Jordi
Publication year - 2004
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.200400137
Subject(s) - chemistry , stereoselectivity , natural product , reactivity (psychology) , enantioselective synthesis , quaternary carbon , stereochemistry , selectivity , derivatization , organic chemistry , high performance liquid chromatography , catalysis , medicine , alternative medicine , pathology
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 (4 S ,5a R ,7a R ,7b S ) configuration of natural (−)‐galiellalactone was confirmed by X‐ray crystallography with Cu‐ K α radiation. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)