Organometallic complexes: these two words jump to the mind of the chemist and are directly associated with their utility in catalysis or as a pharmaceutical. Nevertheless, to be able to use them, it ...is necessary to synthesize them, and it is not always a small matter. Typically, synthesis is via solution chemistry, using a round-bottom flask and a magnetic or mechanical stirrer. This review takes stock of alternative technologies currently available in laboratories that facilitate the synthesis of such complexes. We highlight five such technologies: mechanochemistry, also known as solvent-free chemistry, uses a mortar and pestle or a ball mill; microwave activation can drastically reduce reaction times; ultrasonic activation promotes chemical reactions because of cavitation phenomena; photochemistry, which uses light radiation to initiate reactions; and continuous flow chemistry, which is increasingly used to simplify scale-up. While facilitating the synthesis of organometallic compounds, these enabling technologies also allow access to compounds that cannot be obtained in any other way. This shows how the paradigm is changing and evolving toward new technologies, without necessarily abandoning the round-bottom flask. A bright future is ahead of the organometallic chemist, thanks to these novel technologies.
Acylation reactions are ubiquitous in the synthesis of natural products and biologically active compounds. Unfortunately, these reactions often require the use of large quantities of volatile and/or ...toxic solvents, either for the reaction, purification or isolation of the products. Herein we describe and discuss the possibility of completely eliminating the use of organic solvents for the synthesis, purification and isolation of products resulting from the acylation of amines and other nucleophiles. Thus, utilisation of N,N′‐carbonyldiimidazole (CDI) allows efficient coupling between carboxylic acids and various nucleophiles under solvent‐free mechanical agitation, and water‐assisted grinding enables both the purification and isolation of pure products. Critical parameters such as the physical state and water solubility of the products, milling material, type of agitation (vibratory or planetary) as well as contamination from wear are analysed and discussed. In addition, original organic‐solvent‐free conditions are proposed to overcome the limitations of this approach. The calculations of various green metrics are included, highlighting the particularly low environmental impact of this strategy.
Completely solvent free! N,N′‐Carbonyldiimidazole (CDI)‐mediated activation of carboxylic acids and subsequent reaction with N‐, O‐, S‐ and C‐nucleophiles under ball‐milling agitation enables the production, purification and recovery of the corresponding acylated products without using any organic solvent (see figure). The influence of multiple parameters on the performance of the reaction as well as on contamination from wear are analysed and discussed.
Peptides were produced in high yields and, if any, very low epimerization, by mechanochemical coupling of peptide fragments containing highly epimerization-prone and/or highly hindered amino acids at ...C-term. Ball milling was clearly identified as the key element enabling one to obtain such results.
Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) that is cytogenetically characterized by a balanced reciprocal translocation between chromosomes 15 and 17, ...which results in the fusion of the promyelocytic leukemia (
PML
) and retinoic acid receptor alpha (
RARα
) genes. Because patients with APL present a tendency for severe bleeding, often resulting in an early fatal course, APL was historically considered to be one of the most fatal forms of acute leukemia. However, therapeutic advances, including anthracycline- and cytarabine-based chemotherapy, have significantly improved the outcomes of APL patients. Due to the further introduction of all-
trans
retinoic acid (ATRA) and—more recently—the development of arsenic trioxide (ATO)-containing regimens, APL is currently the most curable form of AML in adults. Treatment with these new agents has introduced the concept of cure through targeted therapy. With the advent of revolutionary ATRA-ATO combination therapies, chemotherapy can now be safely omitted from the treatment of low-risk APL patients. In this article, we review the six-decade history of APL, from its initial characterization to the era of chemotherapy-free ATRA-ATO, a model of cancer-targeted therapy.
Recent advances have included insights into the clinical value of genomic abnormalities in acute myeloid leukemia (AML) and consequently the development of numerous targeted therapeutic agents that ...have improved clinical outcome. In this setting, various clinical trials have recently explored novel therapeutic agents either used alone or in combination with intensive chemotherapy or low-intensity treatments. Among them, menin inhibitors could represent a novel group of targeted therapies in AML driven by rearrangement of the lysine methyltransferase 2A (
KMT2A
) gene, previously known as mixed-lineage leukemia (
MLL
), or by mutation of the nucleophosmin 1 (
NPM1
) gene. Recent phase 1/2 clinical trials confirmed the efficacy of SNDX-5613 (revumenib) and KO-539 (ziftomenib) and their acceptable tolerability. Several small molecule menin inhibitors are currently being evaluated as a combination therapy with standard of care treatments. The current paper reviews the recent progress in exploring the inhibitors of menin–KMT2A interactions and their application prospects in the treatment of acute leukemias.
Synthesis of long peptides is generally considered as a challenge to peptide chemists, in addition to producing significant amounts of toxic waste, such as DMF. Here we show that using solvent‐less ...methods, such as ball milling, enabled the production of the hexapeptide Boc‐(Ala‐Phe‐Gly)2‐OBn at the gram scale with high overall yield (77 %, 5 linear steps). This is the longest peptide chain synthesized in a ball mill to date, in which the amino acid sequence is precisely controlled. This study complements the current fundamental knowledge required to synthesize longer and more difficult peptide chains (or small proteins) by using peptide fragment couplings in a ball mill.
By using solvent‐less techniques such as ball milling, a hexapeptide was synthesized in gram scale without using any toxic solvents. To date, this hexapeptide is the largest precisely controlled amino acid sequence ever synthesized in a ball mill. This study paves the way to future developments for the synthesis of longer peptides (and proteins) by using ball milling.
The application of mechanical forces to enable a chemical reaction, also known as mechanochemistry, is actually experiencing an impressive renewal of interest among the chemists community. One major ...advantage of this approach in organic synthesis lies in the possibility to run essentially solvent-free reactions. In recent years, some research groups have combined these types of solvent-free processes with the use of an eco-friendly reagent: 1,1′-carbonyldiimidazole (CDI). Thus, a wide range of molecules, including carboxylic acids, amines, and alcohols, could react efficiently with CDI under ball-milling conditions. By providing a vast array of products (amides, carboxylic acids, esters, ureas, hydantoins, etc.) in an efficient, fast, user-friendly, and green manner, this approach presents all the prerequisites to soon become a first choice methodology for all organic chemists. The reasons for the past and future successes of this combination are summarized, analyzed, and discussed herein.
Allylation of phenols, a widely used reaction in multistep synthetic pathways, was herein investigated using mechanochemistry. This synthesis was first optimized on vanillin by varying key parameters ...including both chemical (
e.g.
, stoichiometry, reaction time) and mechanical (
e.g.
, rotational speed, material, size and number of beads, liquid additive) conditions, leading to the isolation of allylated vanillin at the gram scale in excellent yield (95%). The optimized procedure was also successfully implemented to another bio-based phenol of interest, ethyl ferulate (92% isolated yield). The environmental impact of these procedures was compared with more classical in-solution protocols by calculating
E
factors. When work-up solvents were not taken into account,
E
factor (sEF) clearly indicated the superiority of the ball-milling approach over the solution-based procedure, underscoring the capacity of ball-mills to drastically reduce the need for “reaction” solvents. On the other hand, when work-up solvents were taken into consideration,
E
factors (cEF) were in favor of the solvent-based approach, which could be explained by the solvent quantities required to recover the reaction mixture from the ball-mill reactor. Overall, these results highlight (i) the great potential of mechanochemistry to enable the development of both efficient and waste-less allylation of lignin-derived phenolic synthons, and (ii) the need to study higher-scale and continuous mechanochemical processes, such as by using extruders, to further improve efficiency and sustainability of such mechanochemical processes.
The use of ball-mills enabled the straightforward synthesis of a variety of silver(
i
) complexes featuring challenging NHC ligands. Sterically hindered including electron-poor or with very low ...solubility imidazolium salts were ground with silver(
i
) oxide to furnish heteroleptic or homoleptic complexes in high yields and short reaction times. The synthesis of heteroleptic bis-NHC silver(
i
) complexes was also performed for the first time in a ball mill. The efficiency and rapidity of the mechanochemical approach enabled the generation of a library of unprecedented NHC silver complexes, whose cytotoxicity on the HCT116 colorectal cancer cell line was evaluated providing a rare example of medicinal mechanochemistry. The cationic silver complexes were found to be more potent than the neutral analogues, with IC
50
values down to 21 nM and 256 times more potent than cisplatin.
Challenging silver(
i
) NHC complexes displaying cytotoxicity 256 times higher than cisplatin were synthesized by ball-milling.
The Zr‐based Metal Organic Framework (MOF) UiO‐66(Zr) is widely employed owing to its good thermal and chemical stabilities. Although the long‐range structure of this MOF is preserved in the presence ...of water during several days, little is known about the formation of defects, which cannot be detected using diffraction techniques. We apply here 17O solid‐state NMR spectroscopy at 18.8 T to investigate the reactivity of UiO‐66, through the exchange of oxygen atoms between the different sites of the MOF and water. For that purpose, we have selectively enriched in 17O isotope the carboxylate groups of UiO‐66(Zr) by using it with 17O‐labeled terephthalic acid prepared using mechanochemistry. In the presence of water at 50 °C and a following dehydration at 150 °C, we observe an overall exchange of O atoms between COO− and μ3‐O2− sites. Furthermore, we demonstrate that the three distinct oxygen sites, μ3‐OH, μ3‐O2− and COO−, of UiO‐66(Zr) MOF can be enriched in 17O isotope by post‐synthetic hydrothermal treatment in the presence of 17O‐enriched water. These results demonstrate the lability of Zr−O bonds and the reactivity of UiO‐66(Zr) with water.
The 17O labeled terephtalic acid ligand has been used for the synthesis of 17O enriched UiO‐66 compound. High‐field 17O solid‐state NMR experiments show an overall transfer of oxygen in the structure.
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