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The synthesis of enantiomerically pure 4,5-disubstituted 2-furanones is accomplished in three steps from aldehydes. The steps involve a highly enantioselective Sharpless asymmetric dihydroxylation of α,β-unsaturated diazoketones, followed by a photochemical Wolff rearrangement. [ABSTRACT FROM AUTHOR]

Hydrogen-bond-donor catalysts enable a variety of formal insertion reactions of diazo compounds. The role of the catalyst in the reaction system may vary depending on several factors, including the nucleophilicity of the diazo compound and the acidity of the insertion partner. Ureas and phosphoric acid derivatives can offer complementary reactivity patterns when selected as catalysts for selected O-H and S-H insertion reactions of aryl- and diazo-substituted esters. [ABSTRACT FROM AUTHOR]

The conversion of biomass-derived levulinic acid (LA) into gamma-valerolactone (GVL) using formic acid (FA) and Fe3(CO)12 as the catalyst precursor was achieved in 92% yield. To mimic a biorefinery setting, crude liquor (containing 20% LA) from the acid hydrolysis of sugarcane biomass in a pilot plant facility was directly converted into GVL in good yield (50%), without the need for isolating LA. [ABSTRACT FROM AUTHOR]

A new method for the preparation of α,β-unsaturated diazoketones from aldehydes and a Horner-Wadsworth-Emmons reagent is reported. The method was applied to the short synthesis of two substituted pyrrolidines. [ABSTRACT FROM AUTHOR]

A novel study on the hypervalent iodine-mediated polyfluoroalkylation of sulfoxonium ylides was developed. Sulfoxonium ylides, known for their versatility and stability, are promising substrates for numerous transformations in synthetic chemistry. This report demonstrates the successful derivatization of sulfoxonium ylides with trifluoroethyl or tetrafluoropropyl groups, and provides valuable insights into the scope and limitations of this approach. Nineteen examples have been prepared (45-92% yields), with structural diversity modified at two key sites on the sulfoxonium ylide reactants. Finally, DFT calculations provided insights about the mechanism of this transformation, which strongly suggest that an S N 2 reaction is operative., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024, Echemendía et al.)

Organic molecules containing fluorine and sulfur atoms represent a large percentage of approved pharmaceuticals. Those with combination of both S and F atoms in their structure such as Xtandi, approved in 2012 for prostate cancer, indicates the importance of synthetic methods that accommodates both atoms in an organic moiety. In this study, a novel aspect of sulfoxonium ylide reactivity was explored, unveiling a streamlined and mild synthesis method for gem-difluorinated keto-sulfoxides. Our protocol offers a direct and practical approach to prepare these compounds in 14-80 % chemical yields, that were represented by 21 examples. NMR studies and Hammett correlations gave strong evidence about the mechanism of this transformation., (© 2024 Wiley‐VCH GmbH.)

Old Yellow Enzymes (OYEs) are flavin-dependent redox enzymes that promote the asymmetric reduction of activated alkenes. Due to the high importance of flavoenzymes in the metabolism of organisms, the interaction between OYEs from the parasites Trypanosoma cruzi and Leishmania braziliensis and three diterpene icetexanes (brussonol and two analogs), were evaluated in the present study, and differences in the binding mechanism and inhibition capacity of these molecules were examined. Although the aforementioned compounds showed poor and negligible activities against T. cruzi and L. braziliensis cells, respectively, the experiments with the purified enzymes indicated that the interaction occurs by divergent mechanisms. Overall, the ligands' inhibitory effect depends on their accessibility to the N5 position of the flavin's isoalloxazine ring. The results also indicated that the OYEs found in both parasites share structural similarities and showed affinities for the diterpene icetexanes in the same range. Nevertheless, the interaction between OYEs and ligands is directed by enthalpy and/or entropy in distinct ways. In conclusion, the binding site of both OYEs exhibits remarkable plasticity, and a large range of different molecules, including that can be substrates and inhibitors, can bind this site. This plasticity should be considered in drug design using OYE as a target., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The present study highlights a novel and advantageous protocol for accessing carbamates through the well-established three-component coupling reaction involving CO 2 , amines, and alkyl halides. By employing an immobilized organic base, operating under mild reaction conditions, an array of alkyl carbamates in yields of up to 95 % could be isolated. This approach offers a broad and versatile product scope, allowing for the facile modification of both the amine and alkyl halide reactants. Notably, the pioneering use of an immobilized organic base, specifically the polymer-supported 1,8-diazabicyclo[5.4.0]undec-7-ene (PS-DBU), in this three-component reaction eliminates the need for classical purification steps, streamlining the process. To ensure practicality and sustainability, extensive studies were conducted to verify the recovery and reusability of the polymer-supported DBU catalyst, which consistently maintained the high chemical yield of the carbamates across multiple cycles. Overall, this innovative protocol represents a significant advancement in carbamate synthesis, combining efficiency, generality, and the potential for DBU recycling., (© 2023 Wiley-VCH GmbH.)

Malaria is a parasitic disease caused by protozoan parasites from the genus Plasmodium . Plasmodium falciparum is the most prevalent species worldwide and the causative agent of severe malaria. The spread of resistance to the currently available antimalarial therapy is a major concern. Therefore, it is imperative to discover and develop new antimalarial drugs, which not only treat the disease but also control the emerging resistance. Brussonol is an icetexane derivative and a member of a family of diterpenoids that have been isolated from several terrestrial plants. Here, the synthesis and antiplasmodial profiling of a series of brussonol derivatives are reported. The compounds showed inhibitory activities in the low micromolar range against a panel of sensitive and resistant P. falciparum strains (IC 50 s = 5-16 μM). Moreover, brussonol showed fast-acting in vitro inhibition and an additive inhibitory behavior when combined with the antimalarial artesunate (FIC index ~1). The mode of action investigation indicated that brussonol increased the cytosolic calcium levels within the parasite. Hence, the discovery of brussonol as a new scaffold endowed with antiplasmodial activity will enable us to design derivatives with improved properties to deliver new lead candidates for malaria.

Sulfoxonium ylides are important surrogates for diazo compounds, and their use in industry as safer alternatives has been evaluated during recent years. Beyond the known classical transformations, these ylides have also been used in a surprising plethora of novel and intrinsic chemical reactions, especially in recent years. Bench stability and handling are also an advantage of this class of organosulfur molecules. Despite this, efficient asymmetric transformations, specifically catalytic enantioselective versions, have only recently been reported, and there are specific reasons for this. This perspective article covers this topic from the first studies up to the latest advances, giving personal perspectives and showing the main challenges in this area in the coming years., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The structure-activity relationship for nitrile-based cruzain inhibitors incorporating a P2 amide replacement based on trifluoroethylamine was explored by deconstruction of a published series of inhibitors. It was demonstrated that the P3 biphenyl substituent present in the published inhibitor structures could be truncated to phenyl with only a small loss of affinity. The effects of inverting the configuration of the P2 amide replacement and linking a benzyl substituent at P1 were observed to be strongly nonadditive. We show that plotting affinity against molecular size provides a means to visualize both the molecular size efficiency of structural transformations and the nonadditivity in the structure-activity relationship. We also show how the relationship between affinity and lipophilicity, measured by high-performance liquid chromatography with an immobilized artificial membrane stationary phase, may be used to normalize affinity with respect to lipophilicity., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A Brønsted acid catalyzed intramolecular cyclization of N -Cbz-protected diazoketones, derived from α-amino acids, is described. The reaction proceeds under metal-free conditions and is promoted by ecofriendly silica-supported HClO 4 as the catalyst and methanol as the solvent. This transformation enables the short synthesis of various 1,3-oxazinane-2,5-diones under mild reaction conditions and in good yields (up to 90%). The set-up is very simple; by just mixing all reagents together with no work-up necessary before purification, this protocol takes a greener approach.

Cruzain is the major cysteine protease of Trypanosoma cruzi, the etiological agent of Chagas disease. Reversible covalent cruzain inhibitors can block the steps of cell differentiation in the parasite and kill the organism. To this end, the description of how inhibitors modified at the P2/P3 positions lead to analogs with greater cruzain affinity to the S2/S3 subsites is of fundamental importance. Albeit many efforts are being employed in the characterization of the interaction processes with S2 subsite, little is known about the cruzain S3 subsite. In this work, we show a brief but consistent study to identify favorable substitutions in P3 of dipeptidyl nitriles that increase cruzain affinity. Using molecular dynamics simulations, we have identified some dipeptidyl nitrile analogs with modifications at P3 position that had higher cruzain inhibition than the original unsubstituted compound. A matched molecular pair analysis shows the importance of including a chlorine atom in the P3-meta position. The modifications implemented in P3 are confirmed when profiling the thermodynamic parameters via isothermal titration calorimetry. The classical enthalpy-entropy compensation phenomenon, in which enthalpy changes are counterbalanced by entropy results in a small modification of ΔG. The inclusion of the chlorine atom in the P3-meta position results in the highest reduction of the detrimental entropic contribution observed in P3., (Copyright © 2018 Elsevier Inc. All rights reserved.)

For many years diazocarbonyl compounds have been studied due to their versatility and usability in many chemical transformations. In this review, we summarize the traditional methods to prepare these compounds as well as the new methods and recent improvements in experimental procedures. Moreover, emergence of continuous flow techniques has allowed safer and environmentally friendly procedures for the handling of diazomethane and diazo compounds and will also be a topic in this review.

The effects on potency of cruzain inhibition of replacing a nitrile group with alternative warheads were explored. The oxime was almost an order of magnitude more potent than the corresponding nitrile and has the potential to provide access to the prime side of the catalytic site. Dipeptide aldehydes and azadipeptide nitriles were found to be two orders of magnitude more potent cruzain inhibitors than the corresponding dipeptide nitriles although potency differences were modulated by substitution at P1 and P3. Replacement of the α methylene of a dipeptide aldehyde with cyclopropane led to a loss of potency of almost three orders of magnitude. The vinyl esters and amides that were characterized as reversible inhibitors were less potent than the corresponding nitrile by between one and two orders of magnitude., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Maleimides remain the reagents of choice for the preparation of therapeutic and imaging protein conjugates despite the known instability of the resulting products that undergo thiol-exchange reactions in vivo. Here we present the rational design of carbonylacrylic reagents for chemoselective cysteine bioconjugation. These reagents undergo rapid thiol Michael-addition under biocompatible conditions in stoichiometric amounts. When using carbonylacrylic reagents equipped with PEG or fluorophore moieties, this method enables access to protein and antibody conjugates precisely modified at pre-determined sites. Importantly, the conjugates formed are resistant to degradation in plasma and are biologically functional, as demonstrated by the selective imaging and detection of apoptotic and HER2+ cells, respectively. The straightforward preparation, stoichiometric use and exquisite cysteine selectivity of the carbonylacrylic reagents combined with the stability of the products and the availability of biologically relevant cysteine-tagged proteins make this method suitable for the routine preparation of chemically defined conjugates for in vivo applications.

Phenanthroindolizidine alkaloids are a well-known class of compounds due to their interesting biological activities, especially anticancer ones. Represented by more than 60 substances, they are mainly isolated from plants of the Moraceae and Asclepiadaceae families. In the last 30 years, a great effort has been made aiming the synthesis of these compounds and analogues to be applied in medicinal chemistry.

The coupling between cyclic and acyclic α-amino acid derivatives and methyl acrylate, mediated by samarium diiodide, is described. The method constitutes a powerful tool to construct indolizidine, quinolizidine, and piperidine systems in a straightforward two-step fashion. The formal synthesis of (-)-pumiliotoxin 251D and (±)-epiquinamide is achieved after two or three steps from these amino acid derivatives.

A four-step approach for the synthesis of dihydroxylated piperidine, quinolizidine and indolizidine systems is described employing α,β-unsaturated diazoketones as versatile building blocks. Unsaturated diazoketones were readily prepared from a Horner-Wadsworth-Emmons reaction between a diazophosphonate and amino-aldehydes. The strategy employs an asymmetric dihydroxylation reaction as the key step and is simple and straightforward enough to be extended to other nitrogen heterocycles.