Rearrangement Pathways Research Articles

Ambimodal Pericyclic Rearrangements of Dialkenyl-Bullvalenes Give Tetrahydro-1,8-ethenoheptalenes.

The fluxional structure of bullvalene is expanded by the discovery of a [5,5]-sigmatropic rearrangement of dialkenyl substituted derivatives. This gives rise to tetrahydro-1,8-ethenoheptalenes (THEH), representing the first examples of this tricyclic scaffold. Variation of the substitution pattern alters the product distribution, including one thermodynamically balanced between THEH and bullvalene isomers. DFT calculations are used to explore the thermodynamic landscape and reaction mechanism revealing a pretransition state bifurcation leading to a concerted ambimodal rearrangement pathway.

Quantitative Tyrosine Phosphoproteome Profiling of AXL Receptor Tyrosine Kinase Signaling Network.

Simple SummaryAXL is a receptor tyrosine kinase belonging to the TAM (Tyro3, Axl and Mer) family. The AXL protein plays an important role in promoting cancer development, such as proliferation, migration, invasion and survival of cancer cells. In this study, we used mass spectrometry-based proteomics to quantify the cancer signaling regulated by AXL activation. Our study identified more than 1000 phosphotyrosine sites and discovered that activation of AXL can upregulate multiple cancer-promoting and cell migration/invasion-related signaling pathways. We also observed significant crosstalk as evidenced by rapid phosphorylation of multiple receptor tyrosine kinases and protein tyrosine phosphatases, including PTPN11 and PTPRA, upon GAS6 stimulation. These discoveries should serve as a potentially useful resource for studying AXL functions as well as for the development of effective therapeutic options to target AXL.Overexpression and amplification of AXL receptor tyrosine kinase (RTK) has been found in several hematologic and solid malignancies. Activation of AXL can enhance tumor-promoting processes such as cancer cell proliferation, migration, invasion and survival. Despite the important role of AXL in cancer development, a deep and quantitative mapping of its temporal dynamic signaling transduction has not yet been reported. Here, we used a TMT labeling-based quantitative proteomics approach to characterize the temporal dynamics of the phosphotyrosine proteome induced by AXL activation. We identified >1100 phosphotyrosine sites and observed a widespread upregulation of tyrosine phosphorylation induced by GAS6 stimulation. We also detected several tyrosine sites whose phosphorylation levels were reduced upon AXL activation. Gene set enrichment-based pathway analysis indicated the activation of several cancer-promoting and cell migration/invasion-related signaling pathways, including RAS, EGFR, focal adhesion, VEGFR and cytoskeletal rearrangement pathways. We also observed a rapid induction of phosphorylation of protein tyrosine phosphatases, including PTPN11 and PTPRA, upon GAS6 stimulation. The novel molecules downstream of AXL identified in this study along with the detailed global quantitative map elucidating the temporal dynamics of AXL activation should not only help understand the oncogenic role of AXL, but also aid in developing therapeutic options to effectively target AXL.

When a “Dimroth Rearrangement” Is Not a Dimroth Rearrangement

In the Dimroth rearrangement of heterocycles, often pyrimidines, an exocyclic and a ring substituent are interchanged. However, the term Dimroth rearrangement is frequently used even when there is no knowledge of the reaction mechanism and alternatives are likely. Here, we have employed density functional theory (DFT) calculations at the M06-2X/6-311+G(d,p) level to determine the most plausible rearrangement pathways of 3-aminothiocarbonylquinazoline 5, tetrahydrofuranylpyrimidine 21, and 5-allyltriazocine 30. For the rearrangement of quinazoline 5 to 9, the [1,3]-sigmatropic shift of the thioamido group with an activation barrier of 26.7 kcal/mol is much preferred over the Dimroth rearrangement (∼46 kcal/mol). An even lower barrier of 21.6 kcal/mol applies to a stepwise [1,3]-shift. The migration of the tetrahydrofuranyl unit in pyrimidines like 21 → 23 can take place by means of a [1,3]-sigmatropic shift with a low barrier (≤17.5 kcal/mol) rather than a Dimroth rearrangement under acidic conditions and most likely also under neutral conditions (∼30 kcal/mol). In the rearrangement of 5-allyl-6-iminotriazocine 30 to 32, the [3,3]-sigmatropic shift (aza-Cope rearrangement) is preferred over the Dimroth mechanism under neutral conditions, but in the presence of acid, the azonia-Cope rearrangement of an allyl group and the true Dimroth rearrangement have comparable activation energies.

Cathepsin K: A Novel Diagnostic and Predictive Biomarker for Renal Tumors.

Simple SummaryOur understanding of renal tumors has increased in the last years with the description of several novel entities. The expanding morphological spectrum complicates the pathologist’s diagnosis, often requiring immunohistochemical analysis. The role of cathepsin K immunoexpression is widened as a diagnostic tool in several renal tumors. This review describes the usefulness of cathepsin K in the differential diagnosis of renal neoplasms, highlighting the biological knowledge underpinning its expression. Moreover, cathepsin K seems to be a downstream marker of different genetic alterations, with a possible role as a predictive marker that may prospectively guide the development of therapeutic approaches as a molecular target.Cathepsin K is a papain-like cysteine protease with high matrix-degrading activity. Among several cathepsins, cathepsin K is the most potent mammalian collagenase, mainly expressed by osteoclasts. This review summarizes most of the recent findings of cathepsin K expression, highlighting its role in renal tumors for diagnostic purposes and as a potential molecular target. Indeed, cathepsin K is a recognized diagnostic tool for the identification of TFE3/TFEB-rearranged renal cell carcinoma, TFEB-amplified renal cell carcinoma, and pure epithelioid PEComa/epithelioid angiomyolipoma. More recently, its expression has been observed in a subgroup of eosinophilic renal neoplasms molecularly characterized by TSC/mTOR gene mutations. Interestingly, both TSC mutations or TFE3 rearrangement have been reported in pure epithelioid PEComa/epithelioid angiomyolipoma. Therefore, cathepsin K seems to be a downstream marker of TFE3/TFEB rearrangement, TFEB amplification, and mTOR pathway activation. Given the established role of mTOR inhibitors as a pharmacological option in renal cancers, cathepsin K could be of use as a predictive marker of therapy response and as a potential target. In the future, uropathologists may implement the use of cathepsin K to establish a diagnosis among renal tumors with clear cells, papillary architecture, and oncocytic features.

Reaction of 3-Cl/OMe-Substituted 5-Nitrobenzisothiazoles with Hydrazine: Structural and Computational Evidence for Rearrangement Pathways Implicating Intramolecular Formation of Pivotal Meisenheimer Complexes.

In projected structure-activity relationship studies of the novel diheteroarylamide-based anti-HIV agent 2 (1C8), one objective was to evaluate the influence of incorporating the central amide motif in 2 into a five-membered pyrazolone ring, as found in 3. It was envisaged that compound 3 could be prepared through reaction of 3-hydrazino-5-nitrobenzisothiazole 5 with the methyl ester of 4-chloropyridine-3-carboxylic acid, followed by N-methylation of the pyridine nitrogen. However, the reaction of 3-methoxyl-5-nitrobenzisothiazole with hydrazine resulted in formation of ring-opened hydrazonate product 18. In the corresponding reaction with 3-chloro-5-nitrobenzisothiazole, a different rearrangement product 19 was formed, in which two 2,1-benzisothiazole units are joined by a sulfur bridge. Meisenheimer complex formation, favored by the presence of the 5-nitro substituent on the benzisothiazole ring, was postulated to be a key feature in the formation of these deep-seated rearrangement products. Support for the proposed formation of the pivotal Meisenheimer complexes and their subsequent evolution to the observed products in which the benzisothiazole sulfur atom is either expelled or maintained in the isomeric 2,1-benzisothiazole system was obtained by density function theory calculations.

Why is an experimental regioselectivity of Fischer indole syntheses observed: A mechanistic model DFT study

The Fischer indole synthesis of the ketone 1 with phenylhydrazine is studied using DFT methods. A detailed reaction mechanism is proposed and evaluated, including different plausible diaza-Cope rearrangement pathways. Cis -/ trans -stereochemistry of the substrate 1 leads to different pathways and products. In addition, the influence of hydrazine protonation on the mechanism is investigated. Only implicit solvation at the PCM-M06–2X/6–311++G(d,p) level of theory predicts correctly the product stability. Furthermore, the importance of nitrogen protonation resulting in lower (and feasible) activation energies for the key step is shown. In agreement with experimental data, the pathways leading to observed products possess the lowest activation barriers. With the proposed mechanism, the correct thermodynamic and kinetic control for this rather complicated reaction is calculated, and the procedure should be able further predict regioselectivity of related systems. • The complete mechanism of a Fischer Indol Cyclization is investigated. • Regioselectivity can be explained with DFT calculations. • Proton catalysis and implicit solvation mandatory for correct results.

Describing Polytopal Rearrangement Processes of Octacoordinate Structures. I. Renewed Insights into Fluxionality of the Rhenium Polyhydride Complex ReH5(PPh3)2(Pyridine)

Hydride ligands of transition metal polyhydride complexes with a high coordination number are prone to fluxionality leading to interesting structural dynamics. However, the underlying polytopal rearrangement pathways have been rarely studied. Based on quantum chemical calculations carried out in this work with density functional theory and coupled-cluster theory, two new fluxional mechanisms have been identified for the rhenium polyhydride complex ReH5(PPh3)2(pyridine) to jointly account for two consecutive coalescence events in the variable-temperature NMR spectra upon heating: lateral and basal three-arm turnstile rotation. The frequently cited pseudorotation in ReH5(PPh3)2(pyridine) (Lee et al. Inorg. Chem. 1996, 35, 695) turns out to be a three-step process including two lateral three-arm turnstile steps and one basal turnstile step in between. The new fluxional mechanisms discovered in this work may also exist in other transition metal polyhydrides.

Pd-Catalyzed Rearrangement of N-Alloc-N-allyl Ynamides via Auto-Tandem Catalysis: Evidence for Reversible C-N Activation and Pd(0)-Accelerated Ketenimine Aza-Claisen Rearrangement.

An auto-tandem catalytic double allylic rearrangement of N-alloc-N-allyl ynamides was developed. This reaction proceeds through two separate and distinct catalytic cycles with both decarboxylative Pd-π-allyl and Pd(0)-promoted aza-Claisen rearrangements occurring. A detailed mechanistic study supported by computations highlights these two separate mechanisms. Previously unreported reversible C-N ionization and a Pd(0)-catalyzed [3,3]-sigmatropic rearrangement were discovered. This study provides new reaction pathways for both π-allyl and sigmatropic rearrangements.

Exploring reaction pathways for the structural rearrangements of the Mn cluster induced by water binding in the S3 state of the oxygen evolving complex of photosystem II

Photosynthetic oxidation of water to dioxygen is catalyzed by the Mn4CaO5 cluster in the protein-cofactor complex photosystem II. The light-driven catalytic cycle consists of four observable intermediates (S0, S1, S2, and S3) and one transient S4 state. Recently, using X-ray free-electron laser crystallography, two experimental groups independently observed incorporation of one additional oxygen into the cluster during the S2 to S3 transition, which is likely to represent a substrate. The present study implicates two competing reaction routes encountered during the structural rearrangement of the catalyst induced by the water binding and immediately preceding the formation of final stable forms in the S3 state. This mutually exclusive competition involves concerted versus stepwise conformational changes between two isomers, called open and closed cubane structures, which have different consequences on the immediate product in the S3 state. The concerted pathway involves a one-step conversion between two isomeric hydroxo forms without changes to the metal oxidation and total spin (Stotal = 3) states. Alternatively, in the stepwise process, the bound waters are oxidized and transformed into an oxyl–oxo form in a higher spin (Stotal = 6) state. Here, density functional calculations are used to characterize all relevant intermediates and transition structures and demonstrate that the stepwise pathway to the substrate activation is substantially favored over the concerted one, as evidenced by comparison of the activation barriers (11.1 and 20.9 kcal mol−1, respectively). Only after formation of the oxyl–oxo precursor can the hydroxo species be generated; this occurs with a slow kinetics and an activation barrier of 17.8 kcal mol−1. The overall thermodynamic driving force is likely to be controlled by the movements of two glutamate ligands, D1-Glu189 and CP43-Glu354, in the active site and ranges from very weak (+0.4 kcal mol−1) to very strong (–23.5 kcal mol−1).

Acid-Mediated Autocatalysis in Vinylogous Urethane Vitrimers.

Vitrimers are a class of polymeric materials with outstanding properties. Intramolecular substitution reactions lead to a dynamic exchange within the polymer network which enables thermoreversible stress relaxation in yet permanently crosslinked materials. In this paper, the acid-mediated autocatalysis is explored as a rearrangement pathway for vinylogous urethane vitrimers. The autocatalysis enables transimination reactions, resulting in a dynamic exchange among the enamine-one species, without an excess of free amines. Therefore, the enamine-ones are protonated by a Brønsted acid and turn into electrophilic iminium-ones, thus enabling fast backward and substitution reactions with water and free amines. This work provides an in-depth investigation of the mechanism by kinetic studies of selected compounds. In addition, novel elastomeric and thermosetting poly(vinylogous urethane) networks with and without free amine groups and additional para-toluene sulfonic acid as a Brønsted catalyst are prepared by bulk polymerization of hexane-1,6-diylbis(3-oxobutanoate) and tris(2-aminoethyl)amine. The underlying exchange mechanisms are determined by stress-relaxation experiments with stress relaxation times of 0.3-54000s at 110°C.

Molecular rearrangement of aniline in femtosecond radiation

In this work we investigate the interaction of aniline in the gas phase with 50 fs pulses of radiation at a wavelength of 800 nm. Ion yields were measured using a reflectron time-of-flight mass spectrometer that avoids spatial averaging by collecting ion from a micrometer-sized volume within the focal region. This measuring technique allows for accurate measurements and quantification of relative ion yields at a well-defined intensity. Our results show the production of benzene C6H6 ions from the interaction of aniline C6H7N with femtosecond radiation. Quantum chemical calculation reveal an unusual reaction pathway for this molecular rearrangement. Lastly metastable ions are observed in the spectrum and their precursors are investigated.

Formation of phytosterol photooxidation products: A chemical reaction mechanism for light-induced oxidation

Phytosterols (PS) are a group of sterols distributed in foods and plants, where it is prone to oxidation. In this work, we studied the reaction mechanism of phytosterols, using density functional theory (DFT) calculation and experimental methods to study the photooxidation of phytosterols. Under LED light illumination, experimental photooxidation of these phytosterols gives rise to the prior three kind oxides of phytosterol: 6α-OH, 7α-OH, and 7β-OH. The mechanistic investigations by DFT suggest that singlet oxygen (1O2)-mediated photooxidation (Type II mechanism) generated radical adds to the C5 and C6 on the B Ring of steroid nucleus and reaction in C7 initiated from C5 products through rearrangement pathway. Furthermore, the stereoselectivity at C5, C6 and C7 provides a mechanistic guide for phytosterols photooxidation. These efforts are expected to serve as an essential exploratory study for the oxidation mechanism of phytosterols in the complex food matrix and antioxidation technology for phytosterols.

Stereospecific Asymmetric Synthesis of Tertiary Allylic Alcohol Derivatives by Catalytic [2,3]-Meisenheimer Rearrangements.

Chiral acyclic tertiary allylic alcohols are very important synthetic building blocks, but their enantioselective synthesis is often challenging. A major limitation in catalytic asymmetric 1,2‐addition approaches to ketones is the enantioface differentiation by steric distinction of both ketone residues. Herein we report the development of a catalytic asymmetric Meisenheimer rearrangement to overcome this problem, as it proceeds in a stereospecific manner. This allows for high enantioselectivity also for the formation of products in which the residues at the generated tetrasubstituted stereocenter display a similar steric demand. Low catalyst loadings were found to be sufficient and the reaction conditions were mild enough to tolerate even highly reactive functional groups, such as an enolizable aldehyde, a primary tosylate, or an epoxide. Our investigations suggest an intramolecular rearrangement pathway.

The Vagabond Fluorine Atom: Dissociative Photoionization of trans-1,3,3,3-Tetrafluoropropene.

The dissociative photoionization of trans-1,3,3,3-tetrafluoropropene (HFO-1234ze) was investigated by imaging photoelectron photoion coincidence (PEPICO) spectroscopy. From the threshold photoelectron spectrum (TPES), an adiabatic ionization energy of 10.91 ± 0.05 eV is determined and reported for the first time. Over a 4 eV wide range, internal-energy selected trans-1,3,3,3-tetrafluoropropene cations decay by three parallel dissociative photoionization channels, which were modeled using statistical theory. The 0 K appearance energies of CF2CHCF2 (H-loss, m/z 113), CFHCHCF2 (F-loss, m/z 95), and CH2═CF2 (CF2-loss, m/z 64) fragment ions were determined to be 12.247 ± 0.030, 12.66 ± 0.10, and 12.80 ± 0.05 eV, respectively. From the last, the heat of formation of neutral trans-1,3,3,3-tetrafluoropropene was determined to be -779.9 ± 9.7 kJ/mol. While the lowest-energy fluorine loss occurs directly, the first H-loss and CF2-loss channels involve both a fluorine- and a hydrogen-migration prior to dissociation. At higher internal energies, several other rearrangement pathways open up, which involve fluorine and hydrogen transfer and, through fluorine loss, lead to the formation of several additional isomeric allylic fragment ions.

Describing Polytopal Rearrangements of Fluxional Molecules with Curvilinear Coordinates Derived from Normal Vibrational Modes: A Conceptual Extension of Cremer-Pople Puckering Coordinates.

In this work a new curvilinear coordinate system is presented for the comprehensive description of polytopal rearrangements of N-coordinate compounds (N = 4-7) and systems containing an N-coordinate subunit. It is based on normal vibrational modes and a natural extension of the Cremer-Pople puckering coordinates ( J. Am. Chem. Soc. 1975, 97, 1354) together with the Zou-Izotov-Cremer deformation coordinates ( J. Phys. Chem. A 2011, 115, 8731) for ring structures to N-coordinate systems. We demonstrate that the new curvilinear coordinates are ideal reaction coordinates describing fluxional rearrangement pathways by revisiting the Berry pseudorotation and the lever mechanism in sulfur tetrafluoride, the Berry pseudorotation and two Muetterties' mechanisms in pentavalent compounds, the chimeric pseudorotation in iodine pentafluoride, Bailar and Ray-Dutt twists in hexacoordinate tris-chelates as well as the Bartell mechanism in iodine heptafluoride. The results of our study reveal that this dedicated curvilinear coordinate system can be applied to most coordination compounds opening new ways for the systematic modeling of fluxional processes.

Re-Engineering of Yohimbine's Biological Activity through Ring Distortion: Identification and Structure-Activity Relationships of a New Class of Antiplasmodial Agents.

Select natural products are ideal starting points for ring distortion, or the dramatic altering of inherently complex molecules through short synthetic pathways, to generate an array of novel compounds with diverse skeletal architectures. A major goal of our ring distortion approach is to re-engineer the biological activity of indole alkaloids to identify new compounds with diverse biological activities in areas of significance to human health and medicine. In this study, we re-engineered the biological activity of the indole alkaloid yohimbine through ring rearrangement and ring cleavage synthesis pathways to discover new series of antiplasmodial agents. One new compound, Y7j, was found to demonstrate good potency against chloroquine-resistant Plasmodium falciparum Dd2 cells (EC50 = 0.33 μM) without eliciting cytotoxicity against HepG2 cells (EC50 > 40 μM). Y7j demonstrated stage-specific action against parasites at the late ring/trophozoite stage. A series of analogues was synthesized to gain structure-activity relationship insights, and we learned that both benzyl groups of Y7j are required for activity and fine-tuning of antiplasmodial activities could be accomplished by changing substitution patterns on the benzyl moieties. This study demonstrates the potential for ring distortion to drive new discoveries and change paradigms in chemical biology and drug discovery.

Diastereoselective synthesis and conformational analysis of 4,5-difluoropipecolic acids.

Stereoselectively-fluorinated analogs of pipecolic acid have been investigated through a combined theoretical and experimental approach. Three of the four possible diastereoisomers of 4,5-difluoropipecolic acid were successfully synthesized via deoxyfluorination chemistry, navigating a complex reaction network that included neighboring group participation, rearrangement, and elimination pathways. A DFT-based conformational study, supported by NMR J-based analysis, revealed that the different diastereoisomers of 4,5-difluoropipecolic acid preferentially adopt different puckers of the six-membered ring. These findings could have future relevance for the conformational control of biologically active peptides.

Quantum tunnelling pathways of the water pentamer.

We apply the semiclassical instanton method to calculate all feasible tunnelling pathways in the water pentamer. Similarly to the water trimer, there are labile flip dynamics as well as a number of different bifurcation pathways coupled to flips. In contrast to the trimer, the puckering motion of the oxygen ring makes the ring-polymer instanton approach difficult to converge, a problem which is resolved by using a recently developed time-independent formalism of the method. We use the results to predict the complete ground-state tunnelling splitting pattern of 320 states, which should help in the continuing effort to assign the experimental spectrum. A comparison between the rearrangement pathways in the water trimer and pentamer sheds light on the many-body cooperative effects of hydrogen bonding which are important for a full understanding of the liquid state.

Flip rearrangement in the water pentamer: Analysis of electronic structure

AbstractTunneling pathways of the flip rearrangement between permutation‐inversion isomers corresponding to the energetically degenerate global energy minima of (H2O)5 are analyzed in terms of the electronic structure. We demonstrate that charge density‐based scalar measures quantify the responses of the bonding to the flip rearrangement and we discovered a high degree of continuity of the values that depend on the presence of the sliding motion of the bond critical point relative to the oxygen atom. The scalar measures can distinguish the pairs of permutation‐inversion isomers everywhere except at the transition state due to the asymmetrical energy barrier; however, they cannot determine the most and least facile directions of the flip rearrangement. The vector or directional character of the two sides of the pathway is captured by the stress tensor trajectories constructed in a non‐Cartesian space, defined by the variation of the position of the bond critical point. The stress tensor trajectories are presented in terms that enable bond‐flexing, bond‐twist, and bond‐anharmonicity of the flip rearrangement between permutation‐inversion isomers to be quantified. The stress tensor trajectories can distinguish the isomers at the transition state and demonstrate that the clockwise and counter‐clockwise directions of the flip rearrangement are the most and least facile respectively.

New insight into the substituents affecting the peroxydisulfate nonradical oxidation of sulfonamides in water

The large consumption and discharge of sulfonamides (SAs) have potentially induced antibiotic resistance genes, posing inestimable threats to humans and ecosystems. In the present study, five SAs with different substituents were regarded as target compounds to be degraded using the nonradical dominated peroxydisulfate (PDS) activation process by the combination of 1O2 oxidation and direct electron transfer. The degradation rates, toxicities and pathways of SAs largely varied with their substituents. For instance, sulfathiazole with five-membered substituent had the highest degradation rate of 0.19 min−1, which was 3.8 times as the rate of sulfanilamide (0.05 min−1) without substituent. Then the theoretical calculation was adopted to further confirm that different substituents on the SAs could influence the molecular orbital distribution and their stability, thus resulting in the different removal rate of SAs. Finally, the products of different SAs were concisely deduced to take insight into the effects of different substituents on SAs degradation pathways. It was demonstrated that the geometrical differences among various SAs caused by the different substituents contributed to the different degradation pathways of SAs. Representatively, the special Smiles-type rearrangement pathway was occurred in the six-membered SAs instead of in the five-membered SAs, which inversely resulted in the slower degradation rate of six-membered SAs than the five-membered SAs. Thus, the present study provides a valuable insight into the effects of substituents on the degradation rate and transformation pathways of SAs in the nonradical PDS activation process.