Synthesis of Conformationally Liberated Yohimbine Analogues and Evaluation of Cytotoxic Activity.

A modular synthetic approach to strategically unique structural analogues of the alkaloid yohimbine is reported. The overall synthetic strategy couples the transition-metal-catalyzed decarboxylative allylation of 2,2-diphenylglycinate imino esters with a scandium triflate-mediated highly endo-selective intramolecular Diels-Alder (IMDA) cycloaddition to generate a small collection of de-rigidified yohimbine analogues lacking the ethylene linkage between the indole and decahydroisoquinoline units. One compound generated in this study contains an unprecedented pentacyclic urea core and appears to demonstrate increased cytotoxicity against the gastric cancer cell line SGC-7901 in comparison to a pancreatic cancer cell line (PATU-8988) and a normal human gastric mucosal cell line (GES-1).

Design and Synthesis of Fluorescent 1,3-Diaryl-ß-carbolines and 1,3-Diaryl-3,4-dihydro-ß-carbolines.

The 1,3-diaryl-ß-carboline derivatives, including 3,4-dihydro variants, were synthesized via a multiple-step approach. These compounds possess rigid and twisted configurations, which are expected to exhibit unique optical properties. The absorption and fluorescence properties of the newly synthesized compounds were investigated. These synthetic 1,3-diaryl-ß-carbolines displayed strong emission in the range of 387-409 nm and exhibited absolute photoluminescence quantum yields of up to 74%. Density functional theory calculations were performed to better elucidate the geometric, electronic, and optical properties of these novel 1,3-diaryl-ß-carbolines.

Visible-light photoredox-catalyzed umpolung carboxylation of carbonyl compounds with CO2.

Photoredox-mediated umpolung strategy provides an alternative pattern for functionalization of carbonyl compounds. However, general approaches towards carboxylation of carbonyl compounds with CO2 remain scarce. Herein, we report a strategy for visible-light photoredox-catalyzed umpolung carboxylation of diverse carbonyl compounds with CO2 by using Lewis acidic chlorosilanes as activating/protecting groups. This strategy is general and practical to generate valuable α-hydroxycarboxylic acids. It works well for challenging alkyl aryl ketones and aryl aldehydes, as well as for α-ketoamides and α-ketoesters, the latter two of which have never been successfully applied in umpolung carboxylations with CO2 (to the best of our knowledge). This reaction features high selectivity, broad substrate scope, good functional group tolerance, mild reaction conditions and facile derivations of products to bioactive compounds, including oxypheonium, mepenzolate bromide, benactyzine, and tiotropium. Moreover, the formation of carbon radicals and carbanions as well as the key role of chlorosilanes are supported by control experiments.

α-Amino Acids and Peptides as Bifunctional Reagents: Carbocarboxylation of Activated Alkenes via Recycling CO2.

Carboxylic acids, including amino acids (AAs), have been widely used as reagents for decarboxylative couplings. In contrast to previous decarboxylative couplings that release CO2 as a waste byproduct, herein we report a novel strategy with simultaneous utilization of both the alkyl and carboxyl components from carboxylic acids. Under this unique strategy, carboxylic acids act as bifunctional reagents in the redox-neutral carbocarboxylation of alkenes. Diverse, inexpensive, and readily available α-AAs take part in such difunctionalizations of activated alkenes via visible-light photoredox catalysis, affording a variety of valuable but otherwise difficult to access γ-aminobutyric acid derivatives (GABAs). Additionally, a series of dipeptides and tripeptides also participate in this photocatalytic carbocarboxylation. Although several challenges exist in this system due to the low concentration and quantitative amount of CO2, as well as unproductive side reactions such as hydrodecarboxylation of the carboxylic acids and hydroalkylation of the alkenes, excellent regioselectivity and moderate to high chemoselectivity are achieved. This process features low catalyst loading, mild reaction conditions, high step and atom economy, and good functional group tolerance, and it is readily scalable. The resulting products are subject to efficient derivations, and the overall process is amenable to applications in the late-stage modification of complex compounds. Mechanistic studies indicate that a carbanion is generated catalytically and it acts as the key intermediate to react with CO2, which is also generated catalytically in situ and thus remains in low concentration. The overall transformation represents an efficient and sustainable system for organic synthesis, pharmaceutics, and biochemistry.

Guest-Binding-Induced Interhetero Hosts Charge Transfer Crystallization: Selective Coloration of Commonly Used Organic Solvents.

Unprecedented interheteromacrocyclic hosts charge transfer (CT) crystals were generated by cooling organic solutions containing p-dimethoxybenzene-constituted pillar[5]arene (P5A) and p-benzoquinone-constituted pillar[5]quinone (P5Q). Despite the weak CT interaction known between p-dimethoxybenzene and p-benzoquinone and the lack of formation of CT complexes between P5A and P5Q in the solution phase, CT cocrystals between P5A and P5Q were formed with solvent molecules included into the hosts' cavities. Such a cocrystallization arises from an elegant synergy between the CT interaction and solvent-binding-promoted crystallization. The interhetero hosts CT crystals were studied by optical and electron microscopic techniques, X-ray powder diffraction, solid-state NMR, UV-vis, IR spectroscopic studies, and X-ray single-crystal studies. The solvent complexation was critical for formation of the supramolecular CT microcrystals. The CT absorption bands faded upon removing the solvent molecules under vacuum, but they could be recovered by reuptake of the solvent molecules. Intriguingly, the CT absorption bands and uptake kinetics are distinguishably different for various organic solvents, thus providing a unique way to distinguish between different commonly used chemicals.

Enantioselective photoinduced cyclodimerization of a prochiral anthracene derivative adsorbed on helical metal nanostructures.

The generation of molecular chirality in the absence of any molecular chiral inductor is challenging and of fundamental interest for developing a better understanding of homochirality. Here, we show the manipulation of molecular chirality through control of the handedness of helical metal nanostructures (referred to as nanohelices) that are produced by glancing angle deposition onto a substrate that rotates in either a clockwise or counterclockwise direction. A prochiral molecule, 2-anthracenecarboxylic acid, is stereoselectively adsorbed on the metal nanohelices as enantiomorphous anti-head-to-head dimers. The dimers show either Si-Si or Re-Re facial stacking depending on the handedness of the nanohelices, which results in a specific enantiopreference during their photoinduced cyclodimerization: a left-handed nanohelix leads to the formation of (+)-cyclodimers, whereas a right-handed one gives (-)-cyclodimers. Density functional theory calculations, in good agreement with the experimental results, point to the enantioselectivity mainly arising from the selective spatial matching of either Si-Si or Re-Re facial stacking at the helical surface; it may also be influenced by chiroplasmonic effects.

A Quinoline-Appended Cyclodextrin Derivative as a Highly Selective Receptor and Colorimetric Probe for Nucleotides.

The design and development of specific recognition and sensing systems for biologically important anionic species has received growing attention in recent years, as they play significant roles in biology, pharmacy, and environmental sciences. Herein, a new supramolecular sensing probe L1 was developed for highly selective differentiation of nucleotides. L1 displayed extremely marked absorption and emission differentiation upon binding with nucleotide homologs of AMP, ADP, and ATP, due to the divergent spatial orientations of guests upon binding, which allowed for a naked-eye colorimetric differentiation for nucleotides. A differentiating mechanism was unambiguously rationalized by using various spectroscopic studies and theoretical calculations. Furthermore, we successfully demonstrated that L1 can be applied to the real-time monitoring of the enzyme-catalyzed phosphorylation/dephosphorylation processes and thus demonstrated an unprecedented visualizable strategy for selectively differentiating the structurally similar nucleotides and real-time monitoring of biological processes via fluorescent and colorimetric changes.

Redox-Triggered Chirality Switching and Guest-Capture/Release with a Pillar[6]arene-Based Molecular Universal Joint.

A chiral electrochemically responsive molecular universal joint (EMUJ) was synthesized by fusing a macrocyclic pillar[6]arene (P[6]) to a ferrocene-based side ring. A single crystal of an enantiopure EMUJ was successfully obtained, which allowed, for the first time, the definitive correlation between the absolute configuration and the circular dichroism spectrum of a P[6] derivative to be determined. The self-inclusion and self-exclusion conformational change of the EMUJ led to a chiroptical inversion of the P[6] moiety, which could be manipulated by both solvents and changes in temperature. The EMUJ also displayed a unique redox-triggered reversible in/out conformational switching, corresponding to an occupation/voidance switching of the P[6] cavity, respectively. This phenomenon is an unprecedented electrochemical manipulation of the capture and release of guest molecules by supramolecular hosts.

Supramolecular enantiomeric and structural differentiation of amino acid derivatives with achiral pillar[5]arene homologs.

Complexation of achiral pillar[5]arenes with chiral amines induced strong circular dichroism (CD) signals. The CD responses differed drastically depending on the nature of the amino acid guest, and they significantly varied and part of them even inverted, upon increasing the length of the alkyl chains of the pillar[5]arenes guests. Accordingly, this tactic allowed for the unprecedented simultaneous enantiomeric and structural differentiation of α-amino esters with homologous molecular hosts.

Efficient Triplet-Triplet Annihilation Upconversion with an Anti-Stokes Shift of 1.08 eV Achieved by Chemically Tuning Sensitizers.

A series of Pt(II)-Schiff base complexes were synthesized as triplet sensitizers for the purpose of tuning the singlet and triplet energy levels so as to minimize energy loss during triplet-triplet annihilation (TTA) upconversion (UC). A deep-red to blue TTA-UC was achieved with an unprecedentedly large anti-Stokes shift of 1.08 eV. UC quantum yields of up to 21% (with a theoretical maximum efficiency of 50%) were observed in solution. The complexes also showed efficient UC emission in air-saturated hydrogels with a UC quantum yield up to 14.8%, which is much higher than the highest previously reported value. The low threshold excitation intensity provided by the present system offers promising potential for application in terrestrial solar energy conversion.

Nickel-Catalyzed Decarboxylative Generation and Asymmetric Allylation of 2-Azaallyl Anions.

The first nickel-catalyzed asymmetric decarboxylative allylation (DcA) of allyl 2,2-diarylglycinate imines is reported. This transformation utilizes a chiral ferrocenyl bidentate ligand and a Ni(0) precatalyst to mediate the decarboxylative generation and asymmetric allylation of 2-azaallyl anions, affording α-aryl homoallylic imines in modest-to-high yields and moderate-to-high enantiomeric ratios. The resulting Ni-catalyzed transformation proved to be less general in comparison to our previously reported analogous Pd-mediated protocol, but it still exhibited certain advantages in regard to the regio- and enantioselectivity of the C-C bond formation.

Precise Manipulation of Temperature-Driven Chirality Switching of Molecular Universal Joints through Solvent Mixing.

Three chiral bicyclic pillar[5]arene derivatives termed as molecular universal joints (MUJs), were synthesized and separated enantiomerically. These MUJs showed temperature-driven chirality switching in certain solvents. Herein, it is demonstrated that temperature-driven chirality switching could also be realized by mixing two miscible organic solvents, in each of which chirality inversion is not accomplishable. Additionally, solvent mixing drastically varied the inversion temperature of the MUJs, for example, from far below zero to room temperature. Moreover, the temperature-driven Sp /Rp to Rp /Sp chirality switching direction could be reversed by the solvent mixing and it was critically controlled by the mixing ratios of the two solvents. These observations allowed precise manipulation of the chirality switching behavior of the MUJs. Such a chirality switching was ascribed to the influences of solvent and temperature on the in-out equilibrium of the side rings, which is delicately controlled by several processes, including the solvation/desolvation and the inclusion/exclusion of the side rings and solvent molecules. Crucially, the solvent mixing introduced new supramolecular processes, in particular the desolvation of solvent molecules from the mixed solvent system and the solvation of the side ring by the mixed solvent, which significantly disturbed the original in-out equilibrium of MUJs and drastically switched the entropy and enthalpy changes of conformational interconversion.

Correction: Room-temperature phosphorescent γ-cyclodextrin-cucurbit[6]uril-cowheeled [4]rotaxanes for specific sensing of tryptophan.

Correction for 'Room-temperature phosphorescent γ-cyclodextrin-cucurbit[6]uril-cowheeled [4]rotaxanes for specific sensing of tryptophan' by Xingke Yu et al., Chem. Commun., 2019, 55, 3156-3159.

Room-temperature phosphorescent γ-cyclodextrin-cucurbit[6]uril-cowheeled [4]rotaxanes for specific sensing of tryptophan.

Room temperature phosphorescent (RTP) γ-CD-CB[6]-cowheeled [4]rotaxanes were synthesized by implanting a naphthalene axle into the cavity of iodine-substituted γ-CDs. The strong green RTP was quenched exclusively by Trp while no RTP quenching was observed with other major physiological amino acids or with the Trp-containing protein HSA, demonstrating a highly specific sensing of free Trp.

2-Azaallyl Anions, 2-Azaallyl Cations, 2-Azaallyl Radicals, and Azomethine Ylides.

This review covers the use of 2-azaallyl anions, 2-azaallyl cations, and 2-azaallyl radicals in organic synthesis up through June 2018. Particular attention is paid to both foundational studies and recent advances over the past decade involving semistabilized and nonstabilized 2-azaallyl anions as key intermediates in various carbon-carbon and carbon-heteroatom bond-forming processes. Both transition-metal-catalyzed and transition-metal-free transformations are covered. Azomethine ylides, which have received significant attention elsewhere, are discussed briefly with the primary focus on critical comparisons with 2-azaallyl anions in regard to generation and use.

Exploring the Steric and Electronic Factors Governing the Regio- and Enantioselectivity of the Pd-Catalyzed Decarboxylative Generation and Allylation of 2-Azaallyl Anions.

The impact of the steric and electronic factors in both the para-substituted benzaldimine and 2,2-diarylglycine components on the regioselectivity and enantioselectivity of the palladium-catalyzed decarboxylative allylation of allyl 2,2-diarylglycinate aryl imines was explored. These studies revealed that using 2,2-di(2-methoxyphenyl)glycine as the amino acid linchpin allowed for the exclusive synthesis of the desired homoallylic benzophenone imine regioisomers, independent of the nature of the imine moiety, in typically high yields. The resulting enantiomeric ratios, however, are slightly decreased in comparison to the transformations involving the corresponding allyl 2,2-diphenylglycinate imines, but this is more than balanced out by the increases in yield and regioselectivity. Overall, these studies suggest a general strategy for the highly regioselective functionalization of 2-azaallyl anions.

Supramolecular Photochirogenesis Driven by Higher-Order Complexation: Enantiodifferentiating Photocyclodimerization of 2-Anthracenecarboxylate to Slipped Cyclodimers via a 2:2 Complex with ß-Cyclodextrin.

Chiral slipped 5,8:9',10'-cyclodimers were preferentially produced over classical 9,10:9',10'-cyclodimers upon supramolecular photocyclodimerization of 2-anthracenecarboxylate (AC) mediated by ß-cyclodextrin (ß-CD). This photochirogenic route to the slipped cyclodimers, exclusively head-to-tail (HT) and highly enantioselective, has long been overlooked in foregoing studies but is dominant in reality and is absolutely supramolecularly activated by 2:2 complexation of AC with ß-CD. The intricate structural and photophysical aspects of this higher-order complexation-triggered process have been comprehensively elucidated, while the absolute configurations of the slipped cyclodimers have been unambiguously assigned by comparing the experimental and theoretical circular dichroism spectra. In the 2:2 complex, two ACs packed in a dual ß-CD capsule are not fully overlapped with each other but are only partially stacked in a slipped anti- or syn-HT manner. Hence, they do not spontaneously cyclodimerize upon photoexcitation but instead emit long-lived excimer fluorescence at wavelengths slightly longer than the monomer fluorescence, indicating that the slipped excimer is neither extremely reactive nor completely relaxed in conformation and energy. Because of the slipped conformation of the AC pair in the soft capsule, the subsequent photocyclodimerization becomes manipulable by various internal or external factors, such as temperature, pressure, added salt, and host modification, enabling us to exclusively obtain the slipped cyclodimers with high regio- and enantioselectivities. In this supramolecularly driven photochirogenesis, the dual ß-CD capsule functions as a chiral organophotocatalyst to trigger and accelerate the nonclassical photochirogenic route to slipped cyclodimers by preorganizing the conformation of the encapsulated AC pair, formally mimicking a catalytic antibody.

Polyunsaturated fatty acid amides from the Zanthoxylum genus - from culinary curiosities to probes for chemical biology.

Covering up to February 2017The pericarps of several species from the Zanthoxylum genus, a.k.a. the "prickly ash", have long been used for culinary purposes throughout Asia, most notably in the Sichuan (previously Szechuan) cuisine of Southwestern China, due to the unique tingling and numbing orosensations arising from a collection of polyunsaturated fatty acid amide (alkamide) constituents. The past decade has experienced dramatically increased academic and industrial interest in these pungent Zanthoxylum-derived alkamides, with a concomitant explosion in studies aimed at elucidating the specific biochemical mechanisms behind several medically-relevant biological activities exhibited by the natural products. This rapid increase in interest is partially fueled by advances in organic synthesis reported within the past few years that finally have allowed for the production of diastereomerically-pure Zanthoxylum alkamides and related analogs in multigram quantities. Herein is a comprehensive review of the discovery, total synthesis, and biological evaluation of Zanthoxylum-derived polyunsaturated fatty acid amides and synthetic analogues. Critical insights into how chemical synthesis can further benefit future chemical biology efforts in the field are also provided.

Transition-Metal-Free Radical C(sp3)-C(sp2) and C(sp3)-C(sp3) Coupling Enabled by 2-Azaallyls as Super-Electron-Donors and Coupling-Partners.

The past decade has witnessed the rapid development of radical generation strategies and their applications in C-C bond-forming reactions. Most of these processes require initiators, transition metal catalysts, or organometallic reagents. Herein, we report the discovery of a simple organic system (2-azaallyl anions) that enables radical coupling reactions under transition-metal-free conditions. Deprotonation of N-benzyl ketimines generates semistabilized 2-azaallyl anions that behave as "super-electron-donors" (SEDs) and reduce aryl iodides and alkyl halides to aryl and alkyl radicals. The SET process converts the 2-azaallyl anions into persistent 2-azaallyl radicals, which capture the aryl and alkyl radicals to form C-C bonds. The radical coupling of aryl and alkyl radicals with 2-azaallyl radicals makes possible the synthesis of functionalized amine derivatives without the use of exogenous radical initiators or transition metal catalysts. Radical clock studies and 2-azaallyl anion coupling studies provide mechanistic insight for this unique reactivity.

Temperature-Driven Planar Chirality Switching of a Pillar[5]arene-Based Molecular Universal Joint.

The study of an enantiopure bicyclic pillar[5]arene-based molecular universal joint (MUJ) by single-crystal X-ray diffraction allowed for the first time the unequivocal assignment of the absolute configuration of a planar chiral pillar[5]arene by circular dichroism spectroscopy. Crucially, the absolute configuration of the MUJ was switched reversibly by temperature, with an accompanying sign inversion of the anisotropy factor that varied by as much as 0.03, which is the largest value ever reported. Mechanistically, the reversible chirality switching of the MUJ is driven by the threading/dethreading motion of the fused ring and hence is dependent on both the size and nature of the ring and the solvent employed, reflecting the critical balance between the self-complexation of the ring by pillar[5]arene, the solvation to the excluded ring, and the inclusion of solvent molecules in the cavity.