One of the key challenges to overcome multidrug resistance (MDR) in cancer is the development of more effective and general strategies to discover bioactive scaffolds. Inspired by natural products, ...we describe a strategy to achieve this goal by modular biomimetic synthesis of scaffolds of (Z)-allylic-supported macrolides. Herein, an Rh(III)-catalyzed native carboxylic acid-directed and solvent-free C-H activation allylation with high stereoselectivity and chemoselectivity is achieved. The generated poly-substituted allylic alcohol as a multifunctional and biomimetic building block is crucial for the synthesis of (Z)-allylic-supported macrolides. Moreover, the unique allylic-supported macrolides significantly potentiate the sensitivity of tumor cells to cytotoxic agents such as vinorelbine and doxetaxel by reversing p170-glycoprotein-mediated MDR. Our findings will inspire the evolution of synthetic chemistry and open avenues for expedient and diversified synthesis of bioactive macrocyclic molecules.
A novel highly efficient regiodivergent Au-catalyzed cycloisomerization of allenyl and homopropargylic ketones into synthetically valuable 2- and 3-silylfurans has been designed with the aid of DFT ...calculations. This cascade transformation features 1,2-Si or 1,2-H migrations in a common Au-carbene intermediate. Both experimental and computational results clearly indicate that the 1,2-Si migration is kinetically favored over the 1,2-shifts of H, alkyl, and aryl groups in the beta-Si-substituted Au-carbenes. In addition, experimental results on the Au(I)-catalyzed cycloisomerization of homopropargylic ketones demonstrated that counterion and solvent effects could reverse the above migratory preference. The DFT calculations provided a rationale for this 1,2-migration regiodivergency. Thus, in the case of Ph(3)PAuSbF(6), DFT-simulated reaction proceeds through the initial propargyl-allenyl isomerization followed by the cyclization into the Au-carbene intermediate with the exclusive formation of 1,2-Si migration products and solvent effects cannot affect this regioselectivity. However, in the case of a TfO(-) counterion, reaction occurs via the initial 5-endo-dig cyclization to give a cyclic furyl-Au intermediate. In the case of nonpolar solvents, subsequent ipso-protiodeauration of the latter is kinetically more favorable than the generation of the common Au-carbene intermediate and leads to the formation of formal 1,2-H migration products. In contrast, when polar solvent is employed in this DFT-simulated reaction, beta-to-Au protonation of the furyl-Au species to give a Au-carbene intermediate competes with the ipso-protiodeauration. Subsequent dissociation of the triflate ligand in this carbene in polar media due to efficient solvation of charged intermediates facilitates formation of the 1,2-Si shift products. The above results of the DFT calculations were validated by the experimental data. The present study demonstrates that DFT calculations could efficiently support experimental results, providing guidance for rational design of new catalytic transformations.
With the aid of computations and experiments, the detailed mechanism of the phosphine‐catalyzed 3+2 cycloaddition reactions of allenoates and electron‐deficient alkenes has been investigated. It was ...found that this reaction includes four consecutive processes: 1) In situ generation of a 1,3‐dipole from allenoate and phosphine, 2) stepwise 3+2 cycloaddition, 3) a water‐catalyzed 1,2‐hydrogen shift, and 4) elimination of the phosphine catalyst. In situ generation of the 1,3‐dipole is key to all nucleophilic phosphine‐catalyzed reactions. Through a kinetic study we have shown that the generation of the 1,3‐dipole is the rate‐determining step of the phosphine‐catalyzed 3+2 cycloaddition reaction of allenoates and electron‐deficient alkenes. DFT calculations and FMO analysis revealed that an electron‐withdrawing group is required in the allene to ensure the generation of the 1,3‐dipole kinetically and thermodynamically. Atoms‐in‐molecules (AIM) theory was used to analyze the stability of the 1,3‐dipole. The regioselectivity of the 3+2 cycloaddition can be rationalized very well by FMO and AIM theories. Isotopic labeling experiments combined with DFT calculations showed that the commonly accepted intramolecular 1,2‐proton shift should be corrected to a water‐catalyzed 1,2‐proton shift. Additional isotopic labeling experiments of the hetero‐3+2 cycloaddition of allenoates and electron‐deficient imines further support this finding. This investigation has also been extended to the study of the phosphine‐catalyzed 3+2 cycloaddition reaction of alkynoates as the three‐carbon synthon, which showed that the generation of the 1,3‐dipole in this reaction also occurs by a water‐catalyzed process.
Think again: The results of an investigation into the detailed mechanism, regioselectivity, and kinetics of Lu's phosphine‐catalyzed 3+2 cycloaddition reaction of allenoates and electron‐deficient alkenes (see figure) give an insight into the chemistry of nucleophilic phosphine organocatalysis and will prompt chemists to rethink the role of water and other protic sources in organic reactions involving 1,n‐hydrogen shifts.
The reaction mechanisms of the PtCl4- and Au(I)-catalyzed intramolecular acetylenic Schmidt reactions were analyzed by means of hybrid density functional calculations at the B3LYP/6-31G*(LANL2DZ) ...level of theory for better understanding of the acceleration effect of ethanol solvent in PtCl4-catalyzed reaction and the different catalytic activities of Au and Pt catalysts. Calculations indicate the rate of the PtCl4-catalyzed reaction in noncoordinative solvent of 1,2-dichloroethane is limited by isomerization of the relatively stable chelate complex to the reactive π-complex of PtCl4 with the acetylenic moiety of homopropargyl azide substrate, which requires an activation energy of 29.6 kcal/mol. All nucleophilic cyclization, dinitrogen elimination, and 1,2-H shift of metal-carbene steps are quite facile. The generation of 2H-pyrrole intermediate in PtCl4-catalyzed reaction is completed by a ligand substitution reaction, and the final 2H-pyrrole to 1H-pyrrole isomerization is an intermolecular process with another 2H-pyrrole as a proton shuttle. When in ethanol solution, the favorable coordination of solvent molecules with PtCl4 could inhibit the chelation of PtCl4 with the homopropargyl azide. Besides, the alcohol coordination also facilitates the generation of 2H-pyrrole intermediate and the intermolecular isomerization of 2H-pyrrole to 1H-pyrrole. Consequently, the overall activation barrier of PtCl4-catalyzed reaction in ethanol solution is lowered to 21.5 kcal/mol, determined by the H-abstraction step of the intermolecular 2H-pyrrole to 1H-pyrrole isomerization. The basic steps in the Au(I)-catalyzed reaction are similar to those in the PtCl4-catalyzed one. However, no chelate complex could be formed from PR3AuSbF6 and homopropargyl azide, and the 2H-pyrrole generation step is much more favorable, indicating weaker interactions of Au(I) catalyst with the homopropargyl azide and the C-C double bond of 2H-pyrrole.
The efficient and stereoselective synthesis of polysubstituted butadienes, especially the multifunctional butadienes, represents a great challenge in organic synthesis. Herein, we wish to report a ...distinctive Pd(0) carbene-initiated decarboxylative olefination approach that enables the direct coupling of diazo esters with vinylethylene carbonates (VECs), vinyl oxazolidinones, or vinyl benzoxazinones to afford alcohol-, amine-, or aniline-containing 1,3-dienes in moderate to high yields and with excellent stereoselectivity. This protocol features operational simplicity, mild reaction conditions, a broad substrate scope, and gram-scalability. Notably, a structurally unique allylic Pd(II) intermediate was isolated and characterized. DFT calculation and control experiments demonstrated that a rare Pd(0) carbene intermediate could be involved in this reaction. Moreover, the polysubstituted butadienes as novel building blocks were unprecedentedly assembled into macrocycles, which efficiently inhibited the P-glycoprotein and dramatically reversed multidrug resistance in cancer cells by 190-fold.
Trapping of arynes with various nucleophiles provides a range of heteroatom-functionalized arene derivatives, but the corresponding reaction with water does not provide phenol derivatives. Silver ...trifluroacetate (AgO₂CCF₃) can nicely solve this problem. It was found that in typical organic solvent, AgO₂CCF₃ readily reacts with arynes to generate trifluoroacetoxy organosilver arene intermediate, which, upon treating with silica gel, provides phenolic products. This protocol can be extended to the synthesis of α-halofunctionalized phenol derivatives by simply adding NBS (N-bromosuccinimides) or NIS (N-iodosuccinimides) to the reaction along with silver trifluroacetate, which provided α-bromo or α-iodophenol derivatives in good yield. However, the similar reactions with NCS (N-chlorosuccinimides) afforded only the protonated product instead of the expected α-chlorophenols derivatives. Interestingly, substrates containing silyl substituents on 1,3-diynes resulted in α-halotrifluoroacetates rather than their hydrolyzed product. Additionally, trapping the same arynes with other oxygen-based nucleophiles containing silver counter cation, along with NXS (N-halosuccinimides), generated α-halooxyfunctionalized products.
The processing of tea leaves plays a crucial role in the formation of the taste of the resulting tea. In order to study the compositions of and changes in taste-related substances during the ...processing of Rizhao green tea, non-targeted metabolomics was used, based on UHPLC-Q Exactive MS. Totals of 529, 349, and 206 non-volatile metabolites were identified using three different detection modes, of which 112 secondary metabolites were significantly changed. Significant variations in secondary metabolites were observed during processing, especially during the drying stage, and the conversion intensity levels of non-volatile metabolites were consistent with the law of “Drying > Fixation > Rolling”. The DOT method was used to screen tea-quality-related compounds that contributed significantly to the taste of Rizhao green tea, including (−)-epicatechin gallate, (−)-epicatechin gallate, gallic acid, L-theanine, and L-leucine, which make important contributions to taste profiles, such as umami and bitterness. Metabolic pathway analysis revealed that purine metabolism, caffeine metabolism, and tyrosine metabolism perform key roles in the processing of Rizhao green tea in different processing stages. The results of this study provide a theoretical basis for tea processing and practical advice for the food industry.
An efficient palladium‐catalyzed tandem addition/cyclization of 2′‐formyl‐1,1′‐biaryl‐2‐carbonitriles with arylboronic acids is reported. This reaction affords dibenzoc,eazepin‐5‐ols and ...benzocpyrido2,3‐eazepin‐5‐ols with excellent selectivity and wide functional group compatibility. The dibenzoc,eazepin‐5‐ols show good cell growth inhibitory activity against a triple‐negative breast cancer cell line. Moreover, the proposed mechanistic rationale for this tandem process is supported by theoretical calculations.
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