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Stereoselective Synthesis and Biological Evaluation of Ferrocene‐Containing 5‐Hydroxyeicosatetraenoic Acid Analogues
Author(s) -
KauschBusies Nina,
Neudörfl Jörg Martin,
Wefelmeier Pascal,
Prokop Aram,
Kühn Hartmut,
Schmalz HansGünther
Publication year - 2011
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.201100003
Subject(s) - chemistry , side chain , synthon , stereochemistry , stereoselectivity , wittig reaction , alkyne , ferrocene , aldehyde , organic chemistry , polymer , electrode , electrochemistry , catalysis
The stereoselective synthesis of a set of four stable 5‐hydroxyeicosatetraenoic acid (HETE) analogues with a ferrocene backbone is described. The common substructure of all HETEs, the (2 E ,4 Z )‐1‐hydroxyhexadiene moiety, was formally replaced by a ferrocenylmethanol fragment. Whereas the hydrophilic side chain remained the same as that of 5‐HETE (butyrate), the lipophilic side chain was simplified by replacing the “natural” ( Z , Z )‐1,4‐decadiene side chain with ( Z )‐1‐heptene, 1‐heptyne, 1‐octyne, or phenylacetylene. As a key building block, Kagan's chiral acetal (derived from ferrocenecarbaldehyde) was used for the stereoselective generation of the planar‐chiral substructure through diastereoselective ortho ‐lithiation and subsequent formylation, methoxycarbonylation or iodination, respectively. The lipophilic side chain was installed either by a “salt‐free” Wittig reaction or (better) by Pd‐catalyzed Sonogashira coupling. The ( Z )‐selective semi‐reduction of a (hindered) triple bond was achieved with NaBH 4 , PdI 2 and PEG200. The introduction of the hydrophilic side chain was found to proceed with complete diastereoselectivity through addition of a titanium–zinc organyl [prepared from ethyl 4‐iodobutyrate, activated Zn powder and Ti(O i Pr) 3 Cl] as a butyrate D 4 synthon to an aldehyde function using 2‐methyltetrahydrofuran (2‐Me‐THF) as a solvent. The expected ( R p ,5 S ) configuration of the products was confirmed by X‐ray crystallography of an intermediate and by chemical correlation and NMR spectroscopy of a Mosher‐type derivative. Preliminary biological experiments revealed that compound 4 [with a ( Z )‐heptenyl side chain] displayed significant apoptosis induction, whereas analogues with an alkynyl side chain were inactive. None of the HETE analogues prepared showed significant inhibition of lipoxygenase (15‐LOX) or cyclooxygenase (COX‐2).