Synthesis and stereoselective catalytic transformations of 3-hydroxyisoindolinones
Nikola Topolovčan and Matija Gredičak*
Organic & Biomolecular Chemistry 2021, in print.
This review focuses on the synthesis of 3-hydroxyisoindolinones, and their application as substrates in stereoselective catalytic transformations reported from 2010 to date. These compounds have attracted much attention among synthetic chemists, as they are integral structural parts of a number of natural products and biologically active compounds. The first part of this review covers methods based on electrochemical, photochemical, and thermal reactions for the synthesis of 3-hydroxyisoindolinones. The second part focuses on their employment as substrates in transition metal-catalyzed and organocatalyzed stereoselective transformations for the preparation of chiral 3-substituted isoindolinone derivatives.
Comparison of nonheme manganese- and iron-containing flavone synthase mimics
Dóra Lakk-Bogáth, Natalija Pantalon Juraj, Bashdar I. Meena, Berislav Perić, Srećko I. Kirin and József Kaizer*
Molecules 2021, 26, 3220.
Heme and nonheme-type flavone synthase enzymes, FS I and FS II are responsible for the synthesis of flavones, which play an important role in various biological processes, and have a wide range of biomedicinal properties including antitumor, antimalarial, and antioxidant activities. To get more insight into the mechanism of this curious enzyme reaction, nonheme structural and functional models were carried out by the use of mononuclear iron, [FeII(CDA-BPA*)]2+ (6) [CDA-BPA = N,N,N’,N’-tetrakis-(2-pyridylmethyl)-cyclohexanediamine], [FeII(CDA-BQA*)]2+ (5) [CDA-BQA = N,N,N’,N’-tetrakis-(2-quinolilmethyl)-cyclohexanediamine], [FeII(Bn-TPEN)(CH3CN)]2+ (3) [Bn-TPEN = N-benzyl-N,N’,N’-tris(2-pyridylmethyl)-1,2-diaminoethane], [FeIV(O)(Bn-TPEN)]2+ (9), and manganese, [MnII(N4Py*)(CH3CN)]2+ (2) [N4Py* = N,N-bis(2-pyridylmethyl)-1,2-di(2-pyridyl)ethylamine)], [MnII(Bn-TPEN)(CH3CN)]2+ (4) complexes as catalysts, where the possible reactive intermediates, high-valent FeIV(O) and MnIV(O) are known and well characterised. The results of the catalytic and stoichiometric reactions showed that the ligand framework and the nature of the metal cofactor significantly influenced the reactivity of the catalyst and its intermediate. Comparing the reactions of [FeIV(O)(Bn-TPEN)]2+ (9) and [MnIV(O)(Bn-TPEN)]2+ (10) towards flavanone under the same conditions, a 3.5-fold difference in reaction rate was observed in favor of iron, and this value is three orders of magnitude higher than was observed for the previously published [FeIV(O)(N2Py2Q*)]2+ [N,N-bis(2-quinolylmethyl)-1,2-di(2-pyridyl)ethylamine] species.
Direct metal-free transformation of alkynes to nitriles: Computational evidence for the precise reaction mechanism
Lucija Hok and Robert Vianello*
International Journal of Molecular Sciences 2021, 22, 3193.
Density functional theory calculations elucidated the precise reaction mechanism for the conversion of diphenylacetylenes into benzonitriles involving the cleavage of the triple C≡C bond, with N-iodosuccinimide (NIS) as an oxidant and trimethylsilyl azide (TMSN3) as a nitrogen donor. The reaction requires six steps with the activation barrier ΔG‡ = 33.5 kcal mol−1 and a highly exergonic reaction free-energy ΔGR = −191.9 kcal mol−1 in MeCN. Reaction profiles agree with several experimental observations, offering evidence for the formation of molecular I2, interpreting the necessity to increase the temperature to finalize the reaction, and revealing thermodynamic aspects allowing higher yields for alkynes with para-electron-donating groups. In addition, the proposed mechanism indicates usefulness of this concept for both internal and terminal alkynes, eliminates the option to replace NIS by its Cl- or Br-analogues, and strongly promotes NaN3 as an alternative to TMSN3. Lastly, our results advise increasing the solvent polarity as another route to advance this metal-free strategy towards more efficient processes.
A ferrocene-based pseudopeptide chiroptical switch
Saša Opačak, Darko Babić, Berislav Perić, Željko Marinić, Vilko Smrečki, Barbara Pem, Ivana Vinković Vrček and Srećko I. Kirin*
Dalton Transactions 2021, 50, 4504-4511.
We present a double-stranded ferrocene pseudopeptide 2b which exhibits stimuli responsive chirality inversion triggered by solvent exchange or acid addition. Compound 2b exists as a mixture of self-assembled fast exchanging oligomers which macroscopically behave as a chiroptical switch with two stable states. The ferrocene group inversion results in a distinct CD signal in the visible part of the spectrum. The inversion is accomplished through a conformational change due to a rearrangement of hydrogen bonding forcing the rotation of ferrocene rings.
Halohydrin dehalogenases and their potential in industrial application – A viewpoint of enzyme reaction engineering
Zvjezdana Findrik Blažević,* Nevena Milčić, Martina Sudar and Maja Majerić Elenkov
Advanced Synthesis & Catalysis 2021, 363, 388-410.
At the moment, there are approx. 100 published papers investigating halohydrin dehalogenases from different aspects; enzymology, molecular biology and reactions they can catalyse. Unquestionably, these enzymes are of great importance and hold an immense potential due to the wide spectrum of different compounds that can be synthesized by their action. These compounds, such as chiral epoxides, β‐substituted alcohols, oxazolidinones etc., significantly enrich the chemist’s toolbox and, moreover, open the possibility for the synthesis of even more complex compounds. Still, there are many unknowns, and it is the purpose of this work to demonstrate the possibilities and bottlenecks, in scientific sense, that could further help in broadening the applicative potential of these fascinating enzymes.
Synthesis and biological evaluations of mono- and bis-ferrocene uracil derivatives
Senka Djaković, Ljubica Glavaš-Obrovac, Jasmina Lapić, Silvija Maračić, Juraj Kirchofer, Marija Knežević, Marijana Jukić
and Silvana Raić-Malić*
Applied Organometallic Chemistry 2021, 35, e6052.
Mono- (3a–3e and 4a–4e) and bis-ferrocene (5a–5e and 6a–6e) conjugated 5-substituted uracil derivatives that are bridged by 1,2,3-triazole linker were synthesized. The impact of ferrocene unit and spacer between ferrocene and triazole on radical scavenging potency was observed. Bis-ferrocenyl uracil derivatives exhibited better antiproliferative activities than their monoferrocenyl analogs. Bis-ferrocenyl methyl- (5b) and halogen-substituted (5e, 6c, and 6d) uracil derivatives showed pronounced and selective cytostatic activities on colon adenocarcinoma (CaCo-2) and Burkitt lymphoma (Raji) cells, with higher potency and selectivity than the reference drug 5-fluorouracil. Generation of reactive oxygen species (ROS) in CaCo-2 and Raji cells when treated with compounds 5b, 5e, and 6d was observed. Bisferrocenyl 5-chlorouracil 6c induced significant disruption in mitochondrial membrane potential that is accompanied by activation of apoptosis in CaCo-2, Raji, and acute lymphoblastic leukemia (CCRF-CEM) cells, while 6d caused mitochondrial dysfunction and apoptosis induction in CaCo-2 and Raji cells. Potent antiproliferative activity of 6c and 6d could be associated with mitochondrial membrane potential disruption accompanied by apoptosis induction. Our findings highlighted 6c and 6d with potent and selective antiproliferative activity on CaCo-2, Raji, and CCRF-CEM cells that may be associated with targeting cancer cell mitochondria, as a molecular target.