Vitamin E succinate and its derivatives have demonstrated encouraging cytotoxic potential in preclinical models of gastric cancer, paving the way for a novel class of therapeutics. Building on a previously described synthetic methodology based on the alkoxy-aryloxycarbonylation of alkenes, this study reports the investigation of the antitumor effects in gastric cancer models of mixed aryl-alkyl succinates esters featuring various substituents on the backbone. Nine compounds were screened for cytotoxicity against AGS and KATO III gastric cancer cell lines. The most active compounds - 2d (R = (CH2)4CH3), 2a (R = Ph), and 2c (R = CH2CH2Ph) - were further evaluated for efficacy, with 2d emerging as the most potent agent (IC50 30.9 μM in AGS; IC50 19 μM in KATO III). Mechanistically, 2d enhanced the expression of activated/cleaved Caspase-3, augmented PARP cleavage, and promoted LC3B lipidation - indicative of programmed cell death. Consistently, ultrastructural analysis of 2d-treated cancer cells revealed morphological hallmarks of both early and late apoptosis, including cytoplasmic vacuolization and autophagic vacuoles. Conversely, treatment with compound 2d did not affect the expression of apoptosis markers in healthy GES-1 gastric epithelial cells, suggesting a favorable safety profile. Overall, our findings provide insights into how specific structural features of succinate derivatives contribute to their antitumor activity, laying the groundwork for the design of more potent succinate-based agents.

The catalytic carbonylation of alkynes is a powerful route to heteroaromatic scaffolds, yet achieving regioselectivity remains challenging. Herein, we report a divergent carbonylative cyclization of 2-alkynylphenol derivatives that affords either coumarins (6-endo-dig) or 2-coumaranones (5-exo-dig) by tuning the palladium-based catalytic system. Pd(OAc)2 in combination with TFA favored coumarins formation with high yield and selectivity (>15:1), whereas electron-deficient species such as Pd(MeCN)4(BF4)2 promoted 2-coumaranones with up to 84% yield and >25:1 selectivity. While many approaches exploit ligand design to steer selectivity, these results highlight counterion effects as a powerful tool to control regioselectivity in palladium-catalyzed carbonylative cyclization, expanding the utility of alkyne carbonylation for the synthesis of biologically relevant heterocycles.

Cinnamic Acid Sugar Ester Derivatives (CASEDs) are a class of natural compounds that exhibit several interesting biological activities. However, to date, no examples of their use in sunscreen formulations have been reported. Here, we describe the synthesis of a series of novel cinnamic acid esters of glucose (4a-g), ribose (4h) and lactose (4i) starting from the respective acetals 3. The latter were obtained through oxidative alkoxycarbonylation of olefins. For all compounds 3 and 4, UV-Vis spectra were recorded and lipophilicity (i.e., clogP) and cytotoxicity were evaluated. All but one of the synthesized compounds were found to be non-cytotoxic at the concentrations tested and, as expected, absorption spectra depended only on the substituents on the aromatic ring. Finally, the ad hoc synthesized compound 3k, featuring a 4-methoxy substituent on the phenyl ring and a 1,2-O-isopropylidene ribose moiety, provided the most promising results for a possible use as a sunscreen. Indeed, its Sun Protection Factor (SPF), calculated in vitro, was higher with respect to that of ethylhexyl methoxycinnamate (EHMC), which is already utilized in sun care products. Moreover, 3k showed greater antioxidant properties than EHMC, effectively protecting keratinocytes against H2O2-induced oxidative damage. At the same time, it showed no cytotoxic effects and preserved cellular metabolic activity and protein content. Based on these results, we believe that CASEDs could find valid applications in the skincare and cosmetics sectors.

The reactivity of 5-(2-aminophenyl)-4-yn-1-ols and 6-(2-aminophenyl)-5-yn-1-ols under PdI2/KI-catalyzed oxidative carbonylation conditions has been studied. It has been found that, with 5 mol% of PdI2 and 0.5 equiv. of KI, under 60 bar of a 4:1 mixture of CO-air, in MeOH as the solvent at 100 degrees C for 24 h, a mixture of isomeric indole-fused epsilon-lactone and pyranoquinolinone derivatives was formed from 5-(2-aminophenyl)-4-yn-1-ols, deriving from divergent 5-endo-dig N-cyclization - 7-O-cyclocarbonylation and 6-endo-dig O-cyclization - 6-Ncyclocarbonylation pathways, respectively. However, the process could be made selective toward the formation of the indole-fused epsilon-lactone (oxepinoindolone) product when performed in MeCN, thus establishing an unprecedented cyclization - seven-membered cyclocarbonylation process. Under the optimized conditions, a series of previously unknown 6-substituted 3,4,5,6-tetrahydro-1H-oxepino[4,3-b]indol-1-ones could be synthesized in moderate to satisfactory isolated yields (45-79 %) starting from differently substituted 5-(2-aminophenyl)-4-yn1-ols. Under the same conditions, 6-(2-aminophenyl)-5-yn-1-ols were converted into indole-fused zeta-lactones through an even more challenging cyclization - eight-membered cyclocarbonylation process. The structures of three representative products have been confirmed by XRD analysis.

Carbonylation reactions carried out at room temperature and at atmospheric pressure of carbon monoxide are highly attractive and extremely rare at the same time. Here, the oxidative alkoxycarbonylation of styrenes to industrially relevant cinnamates has been developed under such a mild conditions (rt, 1 atm of CO) in the presence of a palladium(II) complex bearing a bis(aryl)acenaphthenequinonediimine ligand, benzoquinone and p-toluenesulfonic acid. Remarkably, variously substituted styrene derivatives have been efficiently carbonylated using a nearly stoichiometric amount of alcohols, with a dramatic reduction of waste. Even reluctant internal alkenes have shown to be compatible under these carbonylative conditions. In consideration of experimental results and DFT calculations a mechanistic rationale has been proposed. Based on this study, the benzoquinone has been found to promote the final palladium reoxidation, and to boost the reaction under such unprecedent mild conditions. The present methodology has been successfully exploited for the synthesis of high value-added cinnamoyl glycerols and cinnamic acid sugar esters, including the 6-O-p-coumaroyl-D-glucose natural product.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

The direct alkoxy-aryloxycarbonylation reaction of olefins has been realized for the first time. Under pal-ladium(II) catalysis and with p-benzoquinone as oxidant, various olefins (aromatic, aliphatic and 1,2-disubstituted), alcohols (primary, secondary and tertiary) and phenols (with different para, meta and ortho substituents) have been converted in one-step into mixed alkyl aryl succinates in moderate to excellent yields (up to 90%). The reaction is completely regioselective, as the aryl ester moiety was con-sistently observed on the more substituted carbon of the starting alkene double bond. Based on experi-mental results and detailed DFT calculations, a plausible catalytic cycle has been proposed, accounting for the observed regioselectivity. Interestingly, from our computation studies, benzoquinone was found to be crucial not only to regenerate the catalytic active species, but also for promoting the final elimination step, leading to the desired succinate. Finally, some reactions were performed to prove the different chemical behavior of the two installed ester groups.(c) 2023 Elsevier Inc. All rights reserved.

The synthesis of dibenzyl-(1S*,2S*)-2,3-dihydro-1H-indene-1,2-dicarboxylate has been realized through a diastereospecific bis-alkoxycarbonylation reaction, which starts from the cheap and easily available 1H-indene, benzyl alcohol, and carbon monoxide. The catalyst is formed in situ by mixing Pd(TFA)2, the ligand N2,N3-bis(2,6-dimethylphenyl)butane-2,3-diimine, p-benzoquinone is used as an oxidant, and benzyl alcohol acts both as a nucleophile and as the main solvent.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

3-(2-(Methylthio)phenyl)prop-2-yn-1-ols have been successfully converted in one synthetic step into benzo[4,5] thieno[2,3-c]furan-1-ones by a PdI2/KI-catalyzed oxidative carbonylative double cyclization process, performed in MeCN under relative mild conditions (1-10 mol % PdI2, 7 equiv of KI, 80 degrees C, 60 atm of a 4:1 mixture CO-air). The process takes place through an ordered sequence of steps, involving 5-endo-dig S-cyclization, iodide-promoted demethylation of the ensuing sulfonium salt, CO insertion, a second cyclization (possibly, through the formation of a palladacycle intermediate followed by reductive elimination), and Pd(0) reoxidation by oxygen (from air) used as external benign oxidant. Under similar conditions, 4-(2-(methylthio)phenyl)but-3-yn-1-ols, bearing a butynol moiety ortho to the methylthio group, led to a mixture of double cyclization and dicarbonylation products, however, by slightly tuning the reaction conditions, dihydrobenzo[4,5]thieno[3,2-c]pyran-1-ones could be selectively obtained with no formation of the dicarbonylated byproduct. The structures of four representative products, including two tetracyclic derivatives, have been confirmed by XRD analysis.

A highly selective palladium-catalyzed carbonylation of 2-alkynylanilines bearing an amide moiety to condensed six-membered het-erocyclic structures has been developed under mild conditions(room temperature and atmospheric pressure of CO).The carbonyla-tive protocol is also compatible with CO surrogates,such as benzene-1,3,5-triyl triformate(TFBen)or the newly developed ca-lix[6]arenes functionalized with six formate groups(CLX[6]CO),which are both capable to release CO in situ.A series of tricyclic fused heterocycles containing the important oxazino-quinolinone scaffold have been selectively obtained(only the 6-endo-dig cyclization mode has been observed)in good to excellent yields(up to 99％).

The reactivity of 2-alkynylbenzoic acids under Pdl(2)/KI-catalyzed oxidative alkoxycarbonylation conditions, with oxygen (from air) as external oxidant and an alcohol as external nucleophile, has been studied. It was found that substrates with triple bond substituted with a bulky alkyl group, such as tert-butyl, selectively underwent a 6-endo-dig cyclization - alkoxycarbonylation pathway with ethanol or isopropanol as nucleophile, to give high value added isocoumarin-4-carboxylic esters in good to high yields (67-87%). When applied to alkynylthiophencarboxylic acids bearing an internal triple bond, the reaction turned out to be completely regioselective toward the formation of the corresponding alkyl thienopyranonecar-boxylates ensuing from 6-endo-dig cyclization-alkoxycarbonylation, regardless the nature of the substituent on the triple bond and the external alcohol (54-91% yields). To confirm the structure of the products deriving from different kinds of substrates, and therefore to corroborate the proposed mechanistic pathways, the crystalline structures of 11 new compounds have been resolved by XRD analysis. (C) 2021 Elsevier Inc. All rights reserved.

Succinic acid esters are important compounds that find many applications in various industrial fields. One of the most promising and easy ways of producing these molecules is represented by the bis-alkoxycarbonylation reaction of olefins. In particular, a recently developed catalytic system, consisting of an aryl α-diimine/palladium(II) catalyst and p-benzoquinone as an oxidant, has allowed succinates to be obtained in high yields. A similar methodology was applied here for the unprecedented synthesis of the bis(2-hydroxyethyl) 2-phenylsuccinate in 78% isolated yield, starting from the cheap and commercially available compounds styrene and ethylene glycol. To our knowledge, no other examples of bis-alkoxycarbonylations of olefins involving diols have been reported thus far. The obtained product was fully characterized by NMR and ESI-MS analyses.

The first example of palladium-catalysed oxidative carbonylation of unprotected α-amino amides to hydantoins is described here. The selective synthesis of the target compounds was achieved under mild conditions (1 atm of CO), without ligands and bases. The catalytic system overrode the common reaction pathway that usually leads instead to the formation of symmetrical ureas.

A chemoselective method for the carbonylation of allylic substrates CH2=CHCH2X (X= OAc, OC(O)CH2CN, OPh, OEt, OC(O)OPh, OC(O)OiBu, N(H)C(O)Ph, N(Ph)C(O)Ph, N(H)Boc, N(Ph)Boc, Ph, CO2Bn, CN), leading to alkyl succinates with preservation of the X group, under Pd(II)-catalyzed oxidative carbonylation conditions, has been developed. Our method shows a completely different inverse chemoselectivity with respect to the "classical" substitutive carbonylation of the allyl compounds, which is known to provide beta,gamma-unsaturated carbonyl derivatives through the formation of a p-allylpalladium intermediate. An accurate study, carried out using allyl acetate as model substrate, allowed to maximize the selectivity in the envisioned 2-CH2X substituted succinates. The best catalyst is generated in situ by mixing Pd(TFA) 2 (TFA= trifluoroacetate) and the N,N'-di(anthracen-9-yl)butane-2,3-diimine ligand. pBenzoquinone was used as oxidant in presence of benzyl alcohol, which acts as a nucleophile and as a solvent, under 4 bar of CO at 20 degrees C. A combined effect of the ligand and the nucleophile, rationalized through DFT calculations, has been observed both in promoting the bis-alkoxycarbonylation process and in preventing p-allylpalladium-mediated side reactions, allowing the attainment of succinate derivatives with moderate to good yields.

The abundant and inexpensive carbon monoxide (CO) is widely exploited as a C1 source for the synthesis of both fine and bulk chemicals. In this context, photochemical carbonylation reactions have emerged as a powerful tool for the sustainable synthesis of carbonyl-containing compounds (esters, amides, ketones, etc.). This review aims at giving a general overview on visible light-promoted carbonylation reactions in the presence of metal (Palladium, Iridium, Cobalt, Ruthenium, Copper) and organocatalysts as well, highlighting the main features of the presented protocols and providing useful insights on the reaction mechanisms.

A comprehensive density functional theory analysis is reported for the one-pot bis-alkoxycarbonylation reaction of olefins to form succinic acid esters by action of the catalyst (N-N)Pd(TFA)(2) (N-N = bis(2,6-dimethylphenyl)-2,3-dimethyl-1,4-diazabutadiene, TFA(-) = CF3CO2-). The selective and efficient process involves alkene (H2C=CHR), CO, methanol, and p-benzoquinone (BQ) molecules as reactants. The catalytic mechanism, previously proposed on the basis of available experimental and literature data, is critically revised here. A plethora of optimized intermediates and transition states and their correlating energy profiles allow a step by step reconstruction of the entire cycle, highlighting key mechanistic aspects, such as the role of the R substituent in the olefin. One of its effects is determined by the presence of a 2e(-) donor group, which, depending on its power, may affect the catalysis up to its total inhibition. As another aspect, the key diester product forms through a reductive elimination step (Pd(II) -> Pd(0) transformation) that excludes the previously proposed attainment of a Pd(II)-hydride complex Finally, the paper illustrates the action of the sacrificial BQ oxidant in the restoration of the original Pd(II) catalyst, as found for other strictly related cases. The energy profile indicates that the rate-determining step occurs in the initial part of the reaction, given a +29.6 kcal mol(-1) energy barrier, associated with a methoxo migration into an adjacent CO ligand. The result foreshadows a rather slow activation of the catalyst and a long duration of the cycle.

The first example of the bis-alkoxycarbonylation of acrylic esters and acrylic amides, leading to differently substituted 1,1,2-ethanetricarboxylate compounds and 2-carbamoylsuccinates respectively, is reported. The catalyst is formed in situ by mixing Pd(TFA)(2) (TFA=trifluoroacetate) and the ligand bis(2,6-dimethylphenyl)butane-2,3-diimine. The reaction, that proceeds using p-benzoquinone as oxidant and p-toluenesulfonic acid as additive, has been applied to variously substituted electron-poor alkenes, employing different alcohols as nucleophiles, under very mild reaction conditions (4 bar of carbon monoxide at 20 degrees C). Remarkably, this catalytic system is able to promote the carbonylation of both the beta- and the generally unreactive alpha-positions of acrylic esters and amides, allowing the formation of bis-alkoxycarbonylated products in good to excellent yields (up to 98%). The trend of reactivity, observed with the different electron-deficient olefins, has been rationalized on the basis of the proposed catalytic cycle and DFT calculations.