Synthesis and First Biological Evaluation of an Iron‐Containing HETE Analogue

Abstract

As previous studies in the field of bioorganometallic chemistry have unveiled, metal‐containing analogues of natural products frequently exhibit surprising biological activities. In this context, a synthetic approach to analogues of the eicosanoids 5‐HETE and 8‐HETE possessing a 1,3‐butadiene–Fe(CO)3 substructure was elaborated. The chosen structures are characterized by a central (2E,4Z)‐hexa‐2,4‐dien‐1‐ol–Fe(CO)3 moiety (as the potential “metal pharmacophore”) and carry a lipophilic ω‐6‐substituent as well as a hydrophilic α‐side chain (carboxylic acid). Using the cationic complex tricarbonyl[η5‐1‐(methoxycarbonyl)pentadienyl]iron hexafluorophosphate (rac‐4) as a starting material, the synthesis of a simplified Fe(CO)3‐complexed HETE analogue (rac‐3) was achieved by exploiting the addition of an alkynyl Cu species to rac‐4. The carbon skeleton was completed through diastereo(Ψ‐exo)selective addition of a titanium–zinc organyl [prepared from ethyl 4‐iodobutyrate, activated Zn powder, and Ti(OiPr)3Cl] as a butyrate D4 synthon to an aldehyde function by using 2‐Me‐THF as the solvent of choice. The (sensitive) target compound rac‐3 was shown to induce apoptosis at moderate concentrations in cancer cells (BJAB and Nalm‐6).

Reactivity of (1-methoxycarbonylpentadienyl)iron(1+) cations with hydride, methyl, and nitrogen nucleophiles

“…δ 6.0 and 5.3 ppm in their 1 H NMR spectra are characteristic of C3 and C4 and their attached hydrogens respectively. 3a,b For the corresponding ( E,Z -diene)Fe(CO) 1 PPh 3 complex 12a , the signals for H3 and H4 appear at δ 5.87 and 4.28 ppm; shifted upfield (compared to 10a-b ) due to the anisotropic effect of the triphenylphosphine ligand. 3d,5b Finally, for ( E,E -diene)Fe(CO) 3 complexes 14d-e signals at ca.…”

“…3a,5b Cationic complex (±) -8 was isolated as an amorphous solid. Recrystallization from acetone/diethyl ether gave yellow block crystals that were characterized by X-ray diffraction analysis (Figure 1).…”

“…5b As anticipated, the Fe–CO bond distances (Table 1) are shorter (1.784-1.812 Å) and the carbonyl C–O distances (1.133-1.142Å) for 8 compared to those observed in the crystal structure of 7 (Fe–CO = 1.835-1.837Å; FeC–O = 1.121-1.137Å). 3c In contrast , the C4-C5, C5-C6 and C6-C7 distances within the pentadienyl ligand and the iron-to-pentadienyl distances Fe-C4, Fe-C5 and Fe-C6 for 7 and 8 are relatively similar, while the C-7-C8, Fe-C7 and Fe-C8 distances (1.395Å, 2.102Å and 2.165Å) are slightly shorter for 8 , compared to those for 7 (1.419Å, 2.141Å and 2.207Å).…”

“…3,4,5 This reactivity has been utilized in the synthesis of methyl 5-hydroxyeicosatetraenoate (5-HETE), 3a iron containing HETE analogs, 3c and the C7-C24 segments of macrolactin A, 3b (path A), and 2-(2’-carboxycyclopropyl)-glycines, 5c bicyclopropanes, 5h and dysibetaine CPa 5i (path C). There are fewer examples of the reaction of (dienyl)iron cations 7 and 8 with non-carbon nucleophiles.…”

Robust eco-friendly protocol for the preparation of γ-hydroxy-α,β-acetylenic esters by sequential one-pot elimination–addition of 2-bromoacrylates to aldehydes promoted by LTMP in 2-MeTHF

“…For this reason, we decided to carry out the reaction in the biomass-derived solvent 2-MeTHF, and therefore obeying the 7th Principle of Green Chemistry. 1 This solvent is being increasingly used both in organic chemistry [34][35][36][37][38][39][40][41][42] and biocatalysis [43][44][45] and, although it is an ether-type solvent, it resembles toluene in terms of physical properties. 46 Effectively, we could observe both a huge improvement of the yield of 2a, with a concomitant and significant decrease of the side-product 3d (16%, entry 9).…”