Reductive Transamination of Pyridinium Salts to N-Aryl Piperidines.

Saturated N-heterocycles are found in numerous bioactive natural products and are prevalent in pharmaceuticals and agrochemicals. While there are many methods for their synthesis, each has its limitations, such as scope and functional group tolerance. Herein, we describe a rhodium-catalyzed transfer hydrogenation of pyridinium salts to access N-(hetero)aryl piperidines. The reaction proceeds via a reductive transamination process, involving the initial formation of a dihydropyridine intermediate via reduction of the pyridinium ion with HCOOH, which is intercepted by water and then hydrolyzed. Subsequent reductive amination with an exogenous (hetero)aryl amine affords an N-(hetero)aryl piperidine. This reductive transamination method thus allows for access of N-(hetero)aryl piperidines from readily available pyridine derivatives, expanding the toolbox of dearomatization and skeletal editing.

Regulation of adaptive growth decisions via phosphorylation of the TRAPPII complex in Arabidopsis.

Plants often adapt to adverse or stress conditions via differential growth. The trans-Golgi network (TGN) has been implicated in stress responses, but it is not clear in what capacity it mediates adaptive growth decisions. In this study, we assess the role of the TGN in stress responses by exploring the previously identified interactome of the Transport Protein Particle II (TRAPPII) complex required for TGN structure and function. We identified physical and genetic interactions between AtTRAPPII and shaggy-like kinases (GSK3/AtSKs) and provided in vitro and in vivo evidence that the TRAPPII phosphostatus mediates adaptive responses to abiotic cues. AtSKs are multifunctional kinases that integrate a broad range of signals. Similarly, the AtTRAPPII interactome is vast and considerably enriched in signaling components. An AtSK-TRAPPII interaction would integrate all levels of cellular organization and instruct the TGN, a central and highly discriminate cellular hub, as to how to mobilize and allocate resources to optimize growth and survival under limiting or adverse conditions.

Intervalence Charge Transfer in Nonbonding, Mixed-Valence, Homobimetallic Ytterbium Complexes.

There are several reports of compounds containing lanthanide ions in two different formal oxidation states; however, there are strikingly few examples of intervalence charge transfer (IVCT) transitions observed for these complexes, with those few occurrences limited to extended solids rather than molecular species. Herein, we report the synthesis, characterization, and computational analysis for a series of ytterbium complexes including a mixed-valence Yb25+ complex featuring a remarkably short Yb···Yb distance of 2.9507(8) Å. In contrast to recent reports of short Ln···Ln distances attributed to bonding through 5d orbitals, the formally Yb25+ complex presented here displays clear localization of Ln2+ and Ln3+ character and yet still displays an IVCT in the visible spectrum. These results demonstrate the ability to tune the electronic structure of formally mixed oxidation state lanthanide complexes: the high exchange stabilization of the Yb2+ 4f14 configuration disfavors the formation of a 5d1 bonding configuration, and the short metal-metal distance enforced by the ligand framework allows for the first observed lanthanide IVCT in a molecular system.

Structural distortion by alkali metal cations modulates the redox and electronic properties of Ce3+ imidophosphorane complexes.

A series of Ce3+ complexes with counter cations ranging from Li to Cs are presented. Cyclic voltammetry data indicate a significant dependence of the oxidation potential on the alkali metal identity. Analysis of the single-crystal X-ray diffraction data indicates that the degree of structural distortion of the secondary coordination sphere is linearly correlated with the measured oxidation potential. Solution electronic absorption spectroscopy confirms that the structural distortion is reflected in the solution structure. Computational studies further validate this analysis, deciphering the impact of alkali metal cations on the Ce atomic orbital contributions, differences in energies of Ce-dominant molecular orbitals, energy shift of the 4f-5d electronic transitions, and degree of structural distortions. In sum, the structural impact of the alkali metal cation is demonstrated to modulate the redox and electronic properties of the Ce3+ complexes, and provides insight into the rational tuning of the Ce3+ imidophosphorane complex oxidation potential through alkali metal identity.

Regulation of adaptive growth decisions via phosphorylation of the TRAPPII complex in Arabidopsis.

Plants often adapt to adverse or stress conditions via differential growth. The trans-Golgi Network (TGN) has been implicated in stress responses, but it is not clear in what capacity it mediates adaptive growth decisions. In this study, we assess the role of the TGN in stress responses by exploring the interactome of the Transport Protein Particle II (TRAPPII) complex, required for TGN structure and function. We identified physical and genetic interactions between TRAPPII and shaggy-like kinases (GSK3/AtSKs). Kinase assays and pharmacological inhibition provided in vitro and in vivo evidence that AtSKs target the TRAPPII-specific subunit AtTRS120/TRAPPC9. GSK3/AtSK phosphorylation sites in AtTRS120/TRAPPC9 were mutated, and the resulting AtTRS120 phosphovariants subjected to a variety of single and multiple stress conditions in planta . The non-phosphorylatable TRS120 mutant exhibited enhanced adaptation to multiple stress conditions and to osmotic stress whereas the phosphomimetic version was less resilient. Higher order inducible trappii atsk mutants had a synthetically enhanced defect in root gravitropism. Our results suggest that the TRAPPII phosphostatus mediates adaptive responses to abiotic cues. AtSKs are multifunctional kinases that integrate a broad range of signals. Similarly, the TRAPPII interactome is vast and considerably enriched in signaling components. An AtSK-TRAPPII interaction would integrate all levels of cellular organization and instruct the TGN, a central and highly discriminate cellular hub, as to how to mobilize and allocate resources to optimize growth and survival under limiting or adverse conditions.

Concise synthesis of (R)-reticuline and (+)-salutaridine by combining early-stage organic synthesis and late-stage biocatalysis.

Efficient access to the morphinan scaffold remains a major challenge in both synthetic chemistry and biotechnology. Here, a biomimetic chemo-enzymatic strategy to synthesize the natural promorphinan intermediate (+)-salutaridine is demonstrated. By combining early-stage organic synthesis with enzymatic asymmetric key step transformations, the prochiral natural intermediate 1,2-dehydroreticuline was prepared and subsequently stereoselectively reduced by the enzyme 1,2-dehydroreticuline reductase obtaining (R)-reticuline in high ee and yield (>99% ee, up to quant. conversion, 92% isol. yield). In the final step, membrane-bound salutaridine synthase was used to perform the selective ortho-para phenol coupling to give (+)-salutaridine. The synthetic route shows the potential of combining early-stage advanced organic chemistry to minimize protecting group techniques with late-stage multi-step biocatalysis to provide an unprecedented access to the medicinally important compound class of promorphinans.

Design and Piezoelectric Energy Harvesting Properties of a Ferroelectric Cyclophosphazene Salt.

Cyclophosphazenes offer a robust and easily modifiable platform for a diverse range of functional systems that have found applications in a wide variety of areas. Herein, for the first time, it reports an organophosphazene-based supramolecular ferroelectric [(PhCH2 NH)6 P3 N3 Me]I, [PMe]I. The compound crystallizes in the polar space group Pc and its thin-film sample exhibits remnant polarization of 5 µC cm-2 . Vector piezoresponse force microscopy (PFM) measurements indicated the presence of multiaxial polarization. Subsequently, flexible composites of [PMe]I are fabricated for piezoelectric energy harvesting applications using thermoplastic polyurethane (TPU) as the matrix. The highest open-circuit voltages of 13.7 V and the maximum power density of 34.60 µW cm-2 are recorded for the poled 20 wt.% [PMe]I/TPU device. To understand the molecular origins of the high performance of [PMe]I-based mechanical energy harvesting devices, piezoelectric charge tensor values are obtained from DFT calculations of the single crystal structure. These indicate that the mechanical stress-induced distortions in the [PMe]I crystals are facilitated by the high flexibility of the layered supramolecular assembly.

Characterization of a rhabdomyosarcoma reveals a critical role for SMG7 in cancer cell viability and tumor growth.

Soft-tissue sarcomas (STSs) are a rare and diverse group of mesenchymal cancers plagued with aggression, poor response to systemic therapy, and high rates of recurrence. Although STSs generally have low mutational burdens, the most commonly mutated genes are tumor suppressors, which frequently acquire mutations inducing nonsense-mediated mRNA decay (NMD). This suggests that STS cells may exploit NMD to suppress these anti-cancer genes. To examine the role that the NMD factor SMG7 plays in STS, we developed an inducible knockout mouse model in the Trp53-/- background. Here, we isolated a subcutaneous STS and identified it as a rhabdomyosarcoma (RMS). We report that knockout of SMG7 significantly inhibited NMD in our RMS cells, which led to the induction of NMD targets GADD45b and the tumor suppressor GAS5. The loss of NMD and upregulation of these anti-cancer genes were concomitant with the loss of RMS cell viability and inhibited tumor growth. Importantly, SMG7 was dispensable for homeostasis in our mouse embryonic fibroblasts and adult mice. Overall, our data show that the loss of SMG7 induces a strong anti-cancer effect both in vitro and in vivo. We present here the first evidence that disrupting SMG7 function may be tolerable and provide a therapeutic benefit for STS treatment.

Industry 4.0 In-Line AI Quality Control of Plastic Injection Molded Parts.

Automatic in-line process quality control plays a crucial role to enhance production efficiency in the injection molding industry. Industry 4.0 is leading the productivity and efficiency of companies to minimize scrap rates and strive for zero-defect production, especially in the injection molding industry. In this study, a fully automated closed-loop injection molding (IM) setup with a communication platform via OPC UA was built in compliance with Industry 4.0. The setup included fully automated inline measurements, in-line data analysis, and an AI control system to set the new machine parameters via the OPC UA communication protocol. The surface quality of the injection molded parts was rated using the ResNet-18 convolutional neural network, which was trained on data gathered by a heuristic approach. Further, eight different machine learning models for predicting the part quality (weight, surface quality, and dimensional properties) and for predicting sensor data were trained using data from a variety of production information sources, including in-mold sensors, injection molding machine (IMM) sensors, ambient sensors, and inline product quality measurements. These models are the backbone of the AI control system, which is a heuristic model predictive control (MPC) method. This method was applied to find new sets of machine parameters during production to control the specified part quality feature. The control system and predictive models were successfully tested for two groups of quality features: Geometry control and surface quality control. Control parameters were limited to injection speed and holding pressure. Moreover, the geometry control was repeated with mold temperature as an additional control parameter.

Synthesis of Thiomorpholine via a Telescoped Photochemical Thiol-Ene/Cyclization Sequence in Continuous Flow.

A procedure for the continuous flow generation of thiomorpholine in a two-step telescoped format was developed. The key step was the photochemical thiol-ene reaction of cysteamine hydrochloride and vinyl chloride as low-cost starting materials. This reaction could be conducted under highly concentrated (4 M) conditions using a low amount (0.1-0.5 mol %) of 9-fluorenone as the photocatalyst, leading to the corresponding half-mustard intermediate in quantitative yield. Thiomorpholine was subsequently obtained by base-mediated cyclization. The robustness of the process was demonstrated by performing the reaction for 7 h (40 min overall residence time), isolating the desired thiomorpholine via distillation.

Chemoselective Oxyfunctionalization of Functionalized Benzylic Compounds with a Manganese Catalyst.

Whilst allowing for easy access to synthetically versatile motifs and for modification of bioactive molecules, the chemoselective benzylic oxidation reactions of functionalized alkyl arenes remain challenging. Reported in this study is a new non-heme Mn catalyst stabilized by a bipiperidine-based tetradentate ligand, which enables methylene oxidation of benzylic compounds by H2 O2 , showing high activity and excellent chemoselectivity under mild conditions. The protocol tolerates an unprecedentedly wide range of functional groups, including carboxylic acid and derivatives, ketone, cyano, azide, acetate, sulfonate, alkyne, amino acid, and amine units, thus providing a low-cost, more sustainable and robust pathway for the facile synthesis of ketones, increase of complexity of organic molecules, and late-stage modification of drugs.

Identification and characterization of a set of monocot BAHD monolignol transferases.

Plant BAHD acyltransferases perform a wide range of enzymatic tasks in primary and secondary metabolism. Acyl-CoA monolignol transferases, which couple a CoA substrate to a monolignol creating an ester linkage, represent a more recent class of such acyltransferases. The resulting conjugates may be used for plant defense but are also deployed as important "monomers" for lignification, in which they are incorporated into the growing lignin polymer chain. p-Coumaroyl-CoA monolignol transferases (PMTs) increase the production of monolignol p-coumarates, and feruloyl-CoA monolignol transferases (FMTs) catalyze the production of monolignol ferulate conjugates. We identified putative FMT and PMT enzymes in sorghum (Sorghum bicolor) and switchgrass (Panicum virgatum) and have compared their activities to those of known monolignol transferases. The putative FMT enzymes produced both monolignol ferulate and monolignol p-coumarate conjugates, whereas the putative PMT enzymes produced monolignol p-coumarate conjugates. Enzyme activity measurements revealed that the putative FMT enzymes are not as efficient as the rice (Oryza sativa) control OsFMT enzyme under the conditions tested, but the SbPMT enzyme is as active as the control OsPMT enzyme. These putative FMTs and PMTs were transformed into Arabidopsis (Arabidopsis thaliana) to test their activities and abilities to biosynthesize monolignol conjugates for lignification in planta. The presence of ferulates and p-coumarates on the lignin of these transformants indicated that the putative FMTs and PMTs act as functional feruloyl-CoA and p-coumaroyl-CoA monolignol transferases within plants.

Ferroelectric Behavior of an Octahedral Metal-Ligand Cage and Its 2D-Connected Cage Framework.

Supramolecular systems hold great potential as ferroelectric materials because they are easy to prepare and do not require toxic and environmentally damaging elements. However, directing the self-assembly process of a supramolecular array to yield polarizable solids is still challenging. Here, we describe induced ferroelectricity in a supramolecular framework of metal-organic cages that are supported by a flexible tripodal ligand (NHCH2 -(3-Py))3 PO (TPPA). Ferroelectric responses on the discrete cage [Cu6 (H2 O)12 (TPPA)8 ](NO3 )12 ⋅ 45H2 O (1) and its 2D-connected framework [{Cu6 Cl4 (H2 O)6 (TPPA)8 }(NO3 )8 ⋅ 60H2 O]n (2) yielded well-resolved rectangular hysteresis loops at room temperature with remnant polarization values of 27.27 and 29.09 µC/cm2 , respectively. Thermal hysteresis measurements (THM) and capacitance-voltage (C-V) plots further corroborate the ferroelectric behavior in these compounds. The polarization in them is due to the displacements of solvated molecules and nitrate ions in the pockets of these frameworks.

Reversible Solid-State Isomerism of Azobenzene-Loaded Large-Pore Isoreticular Mg-CUK-1.

A large-pore version of Mg-CUK-1, a water-stable metal-organic framework (MOF) with 1-D channels, was synthesized in basic water. Mg-CUK-1L has a BET surface area of 2896 m2 g-1 and shows stark selectivity for CO2 sorption over N2, O2, H2, and CH4. It displays reversible, multistep gated sorption of CO2 below 0.33 atm. The dehydrated single-crystal structure of Mg-CUK-1L confirms retention of the open-channel structure. The MOF can be loaded with organic molecules by immersion in hot melts, providing single crystals suitable for X-ray diffraction. trans-Azobenzene fills the channels in a 2 × 2 arrangement. Solid-state UV-vis spectroscopy reveals that azobenzene molecules undergo reversible trans-cis isomerization, despite being close-packed; this surprising result is confirmed by DFT-simulated UV-vis spectra.

Enhancing photosynthetic production of glycogen-rich biomass for use as a fermentation feedstock.

Current sources of fermentation feedstocks, i.e. corn, sugar cane, or plant biomass, fall short of demand for liquid transportation fuels and commodity chemicals in the United States. Aquatic phototrophs including cyanobacteria have the potential to supplement the supply of current fermentable feedstocks. In this strategy, cells are engineered to accumulate storage molecules including glycogen, cellulose, and/or lipid oils that can be extracted from harvested biomass and fed to heterotrophic organisms engineered to produce desired chemical products. In this manuscript, we examine the production of glycogen in the model cyanobacteria, Synechococcus sp. strain PCC 7002, and subsequent conversion of cyanobacterial biomass by an engineered Escherichia coli to octanoic acid as a model product. In effort to maximize glycogen production, we explored the deletion of catabolic enzymes and overexpression of GlgC, an enzyme that catalyzes the first committed step towards glycogen synthesis. We found that deletion of glgP increased final glycogen titers when cells were grown in diurnal light. Overexpression of GlgC led to a temporal increase in glycogen content but not in an overall increase in final titer or content. The best strains were grown, harvested, and used to formulate media for growth of E. coli. The cyanobacterial media was able to support the growth of an engineered E. coli and produce octanoic acid at the same titer as common laboratory media.

A High-Yielding Synthesis of EIDD-2801 from Uridine.

A simple reordering of the reaction sequence allowed the improved synthesis of EIDD-2801, an antiviral drug with promising activity against the SARS-CoV-2 virus, starting from uridine. Compared to the original route, the yield was enhanced from 17 % to 61 %, and fewer isolation/purification steps were needed. In addition, a continuous flow procedure for the final acetonide deprotection was developed, which proved to be favorable toward selectivity and reproducibility.

Interactions between Transport Protein Particle (TRAPP) complexes and Rab GTPases in Arabidopsis.

Transport Protein Particle II (TRAPPII) is essential for exocytosis, endocytosis, protein sorting and cytokinesis. In spite of a considerable understanding of its biological role, little information is known about Arabidopsis TRAPPII complex topology and molecular function. In this study, independent proteomic approaches initiated with TRAPP components or Rab-A GTPase variants converge on the TRAPPII complex. We show that the Arabidopsis genome encodes the full complement of 13 TRAPPC subunits, including four previously unidentified components. A dimerization model is proposed to account for binary interactions between TRAPPII subunits. Preferential binding to dominant negative (GDP-bound) versus wild-type or constitutively active (GTP-bound) RAB-A2a variants discriminates between TRAPPII and TRAPPIII subunits and shows that Arabidopsis complexes differ from yeast but resemble metazoan TRAPP complexes. Analyzes of Rab-A mutant variants in trappii backgrounds provide genetic evidence that TRAPPII functions upstream of RAB-A2a, allowing us to propose that TRAPPII is likely to behave as a guanine nucleotide exchange factor (GEF) for the RAB-A2a GTPase. GEFs catalyze exchange of GDP for GTP; the GTP-bound, activated, Rab then recruits a diverse local network of Rab effectors to specify membrane identity in subsequent vesicle fusion events. Understanding GEF-Rab interactions will be crucial to unravel the co-ordination of plant membrane traffic.

Polyanionic Ligand Platforms for Methyl- and Dimethylaluminum Arrays.

Trimethylaluminum finds widespread applications in chemical and materials synthesis, most prominently in its partially hydrolyzed form of methylalumoxane (MAO), which is used as a cocatalyst in the polymerization of olefins. This work investigates the sequential reactions of trimethylaluminum with hexaprotic phosphazenes (RNH)6P3N3 (=XH6) equipped with substituents R of varied steric bulk including tert-butyl (1H6), cyclohexyl (2H6), isopropyl (3H6), isobutyl (4H6), ethyl (5H6), propyl (6H6), methyl (7H6), and benzyl (8H6). Similar to MAO, the resulting complexes of polyanionic phosphazenates [XH n] n-6 accommodate multinuclear arrays of [AlMe2]+ and [AlMe]2+. Reactions were monitored by 31P NMR spectroscopy, and structures were determined by single-crystal X-ray diffraction. They included 1H4(AlMe2)2, 1H3(AlMe2)3, 2H3(AlMe2)3, 3(AlMe2)4AlMe, 4H(AlMe2)5, 4(AlMe2)6, {5H(AlMe2)4}2AlMe, 5(AlMe2)6, 6(AlMe2)6, {7(AlMe2)4AlMe}2, and 8(AlMe2)6. The study shows that subtle variations of the steric properties of the R groups influence the reaction pathways, levels of aggregation, and fluxional behavior. While [AlMe2]+ is the primary product of the metalation, [AlMe]2+ is utilized to alleviate overcrowding or to aid aggregation. At the later stages of metalation, [AlMe2]+ groups start to scramble around congested sites. The ligands proved to be very robust and extremely flexible, offering a unique platform to study complex multinuclear metal arrangements.

Independent yet overlapping pathways ensure the robustness and responsiveness of trans-Golgi network functions in Arabidopsis.

The trans-Golgi-network (TGN) has essential housekeeping functions in secretion, endocytosis and protein sorting, but also more specialized functions in plant development. How the robustness of basal TGN function is ensured while specialized functions are differentially regulated is poorly understood. Here, we investigate two key regulators of TGN structure and function, ECHIDNA and the Transport Protein Particle II (TRAPPII) tethering complex. An analysis of physical, network and genetic interactions suggests that two network communities are implicated in TGN function and that ECHIDNA and TRAPPII belong to distinct yet overlapping pathways. Whereas ECHIDNA and TRAPPII colocalized at the TGN in interphase cells, their localization diverged in dividing cells. Moreover, ECHIDNA and TRAPPII localization patterns were mutually independent. TGN structure, endocytosis and sorting decisions were differentially impacted in echidna and trappii mutants. Our analyses point to a partitioning of specialized TGN functions, with ECHIDNA being required for cell elongation and TRAPPII for cytokinesis. Two independent pathways able to compensate for each other might contribute to the robustness of TGN housekeeping functions and to the responsiveness and fine tuning of its specialized functions.

Hierarchical Frameworks of Metal-Organic Cages with Axial Ferroelectric Anisotropy.

Designing molecular crystals with switchable dipoles for ferroelectric applications is challenging and often serendipitous. Herein, we show a systematic approach toward hierarchical 1D, 2D and 3D frameworks that are assembled through successive linkage of metal-organic cages [Cu6 (H2 O)12 (TPTA)8 ]12+ with chloride ions. Their ferroelectric properties are due to the displacement of channel-bound nitrate counterions and solvated water molecules relative to the framework of cages. Ferroelectric measurements of crystals of discrete and 1D-framework assemblies showed axial ferroelectric anisotropy with high remnant polarisation. Both, the reversible formation of cage-connected networks and the observation of ferroelectric anisotropic behaviour are rare among metal-ligand cage assemblies.