Rhodium-Catalyzed Allylic Addition as an Atom-Efficient Approach in Total Synthesis.

ConspectusFinding efficient synthetic methods for the asymmetric synthesis of complex molecules has always been of interest to organic chemists. Creating and controlling the stereochemistry of stereogenic centers bearing branched allylic moieties in organic molecules using a catalytic process is an attractive and successful method for the synthesis of several natural products and medicinally important compounds. Remarkable progress toward their synthesis has been achieved via transition-metal catalysis, especially in the case of allylic substitution and allylic C-H oxidation chemistry. However, for allylic substitution the preinstallation of a leaving group is essential, and for allylic C-H oxidation, stoichiometric amounts of oxidant are required. Besides that, the control of regioselectivity with these methods is often problematic because the linear product can be produced as a major isomer. Our research group has developed a regioselective, enantioselective, and atom economic route toward the more valuable branched product via a Rh-catalyzed coupling of easily accessible alkynes or the double-bond isomeric allenes with pronucleophiles. It was demonstrated that, using this new approach, it is possible to add different pronucleophiles to alkynes or allenes to form branched allylic moieties through C-C and C-heteroatom bond formation. Since new organic reactions offer new opportunities in chemical synthesis and the benchmark for new synthetic methods is their application in target-oriented synthesis, we have demonstrated several successful syntheses of natural products and medicinally relevant targets. For example, in the total syntheses of Quercuslactones, Helicascolides A-C, Epothilone D, Homolargazole, and Thailandepsin B, the Rh-catalyzed hydro-oxycarbonylation of allenes was used as key step via C-O bond formation. Remarkably, the Rh-catalyzed C2-symmetric dimerization strategy was used to synthesize the complex molecules Clavosolide A and Vermiculine, leading to an extreme increase in structural complexity within a single step. For the total syntheses of Centrolobine, Pitavastatin, and Rosuvastatin, C-O bond formation was achieved through the addition of a hydroxy function to the allene moiety. The potential of the addition of nitrogen pronucleophiles to allenes was demonstrated in the total syntheses of Cusparein, Angusterein, Cermicin C, Senepodin G, Homoproline, Pipecolinol, Coniceine, Coniine, Ruxolitinib, Sitagliptin, Abacavir, Glucokinase activators, and Chaetominine. All of these examples testify to the wide applicability of the Rh-catalyzed addition of pronucleophiles to allenes or alkynes in target-oriented synthesis, and in this Account we summarize our contribution.

A Tandem Hydroformylation-Organocatalyzed Friedel-Crafts Reaction for the Synthesis of Diindolylmethanes.

Herein, we present an efficient and atom-economic tandem hydroformylation organocatalyzed Friedel-Crafts reaction sequence for the synthesis of diindolylmethanes. Classic syntheses have relied on (Lewis) acid activation of aldehydes, which are often not commercially available and rather sensitive in handling. In contrast, the combination of rhodium-catalyzed hydroformylation and subsequent organocatalytic activation of the in-situ formed aldehydes allows the use of readily available and stable alkenes with various functional groups while avoiding acidic conditions to expand the range of available diindolylmethanes. A broad scope of diindolylmethanes was prepared in yields up to 85 % demonstrates the utility of the presented method.

Carbonylation as a Key Step in New Tandem Reactions - A Route to BODIPYs.

Herein, a highly efficient five-step reaction sequence to BODIPYs is presented. The key step is the combination of transition metal-catalyzed in-situ generation of aldehydes and their subsequent organocatalytic activation to yield dipyrromethanes, which are further converted to the corresponding BODIPY. Classic syntheses towards BODIPYs have relied on aldehydes or acid chlorides, which are often not commercially available and rather sensitive to handle. The presented approach starts from readily available and stable alkenes or aryl-bromides, which allows to extend the range of readily available BODIPYs that can be tailored for their specific use. The synthesis of 55 derivatives with overall yields of up to 78 % demonstrates the wide applicability and advantages of the presented method.

Acenaphthoimidazolylidene-Ligated Palladacycle Enabled Suzuki-Miyaura Cross-Coupling Employing Equimolar Organoboron for Tri-Ortho-Substituted Bi(hetero)aryls and Teraryls.

The Pd-catalyzed Suzuki-Miyaura cross-couplings (SMRs) are utilized as the most practical method to construct C-C bond, especial for biaryls. However, a major disadvantage of current protocols is the requirement of excess organoboron coupling partner (1.5-3.0 equiv.). Herein, a novel palladacyclic 1,3-bis(2,6-diisopropylphenyl)acenaphthoimidazol-2-ylidene (AnIPr) precatalyst possessing a chiral oxazoline was designed, which enabled a general protocol towards bulky tri-ortho-substituted biaryls, ternaphthalenes and diarylanthracenes via the Pd-catalyzed SMR employing equimolar organoborons and aryl bromides. A remarkable scope of substrates with various functional groups and heterocycles were well compatible with an adaptability to synthesize useful ligands.

Catalyst Deactivation During Rhodium Complex-Catalyzed Propargylic C-H Activation.

Detailed mechanistic investigations on our previously reported synthesis of branched allylic esters by the rhodium complex-catalyzed propargylic C-H activation have been carried out. Based on initial mechanistic studies, we present herein more detailed investigations of the reaction mechanism. For this, various analytical (NMR, X-ray crystal structure analysis, Raman) and kinetic methods were used to characterize the formation of intermediates under the reaction conditions. The knowledge obtained by this was used to further optimize the previous conditions and generate a more active catalytic system.

Detection of Acute Tubular Necrosis Using Blood Oxygenation Level-Dependent (BOLD) MRI.

BACKGROUND/AIMS: To date, there is no imaging technique to assess tubular function in vivo. Blood oxygen level-dependent magnetic resonance imaging (BOLD MRI) measures tissue oxygenation based on the transverse relaxation rate (R2*). The present study investigates whether BOLD MRI can assess tubular function using a tubule-specific pharmacological maneuver. METHODS: Cross sectional study with 28 participants including 9 subjects with ATN-induced acute kidney injury (AKI), 9 healthy controls, and 10 subjects with nephron sparing tumor resection (NSS) with clamping of the renal artery serving as a model of ischemia/reperfusion (I/R)-induced subclinical ATN (median clamping time 15 min, no significant decrease of eGFR, p=0.14). BOLD MRI was performed before and 5, 7, and 10 min after intravenous administration of 40 mg furosemide. RESULTS: Urinary neutrophil gelatinase-associated lipocalin was significantly higher in ATN-induced AKI and NSS subjects than in healthy controls (p=0.03 and p=0.01, respectively). Before administration of furosemide, absolute medullary R2*, cortical R2*, and medullary/cortical R2* ratio did not significantly differ between ATN-induced AKI vs. healthy controls and between NSS-I/R vs. contralateral healthy kidneys (p>0.05 each). Furosemide led to a significant decrease in the medullary and cortical R2* of healthy subjects and NSS contralateral kidneys (p<0.05 each), whereas there was no significant change of R2* in ATN-induced AKI and the NSS-I/R kidneys (p>0.05 each). CONCLUSION: BOLD-MRI is able to detect even mild tubular injury but necessitates a tubule-specific pharmacological maneuver, e.g. blocking the Na+-K+-2Cl- transporter by furosemide.

Rhodium-Catalyzed Enantioselective Cyclization of 2-Allenylbenzoxazoles.

The enantioselective rhodium-catalyzed cyclization of 2-allenylbenzoxazoles to the corresponding vinyl-functionalized, fused heterocyclic structures is reported. The presented method offers several advantages, including the use of low catalyst loadings, commercially available catalyst precursors, and mild reaction conditions. Due to its broad scope, scalability, and valuable products, we consider this methodology to be a useful tool for the construction of benzoxazole-containing building blocks.

Metal- and solvent-free domino reaction of 2-isocyanophenol esters to benzoxazines: long-range 1,5-acyl migration on 1,4-diazabutatriene.

The first example of intramolecular nucleophilic addition of 1,4-diazabutatriene to ester is disclosed. This approach provides a facile and versatile synthesis for functionalized 2H-1,4-benzoxazines under metal-, reagent-, and solvent-free conditions. Experimental and computational studies revealed the pivotal role of 1,5-acyl migration as the self-catalytic step in the reaction selectivity.

Multi-year aboveground data of minirhizotron facilities in Selhausen.

Improved understanding of crops' response to soil water stress is important to advance soil-plant system models and to support crop breeding, crop and varietal selection, and management decisions to minimize negative impacts. Studies on eco-physiological crop characteristics from leaf to canopy for different soil water conditions and crops are often carried out at controlled conditions. In-field measurements under realistic field conditions and data of plant water potential, its links with CO2 and H2O gas fluxes, and crop growth processes are rare. Here, we presented a comprehensive data set collected from leaf to canopy using sophisticated and comprehensive sensing techniques (leaf chlorophyll, stomatal conductance and photosynthesis, canopy CO2 exchange, sap flow, and canopy temperature) including detailed crop growth characteristics based on destructive methods (crop height, leaf area index, aboveground biomass, and yield). Data were acquired under field conditions with contrasting soil types, water treatments, and different cultivars of wheat and maize. The data from 2016 up to now will be made available for studying soil/water-plant relations and improving soil-plant-atmospheric continuum models.

Inorganic Bottlebrush and Comb Polymers as a Platform for Supersoft, Solvent-Free Elastomers.

Due to their unique rheological and mechanical properties, bottlebrush polymers are inimitable components of biological and synthetic systems such as cartilage and ultrasoft elastomers. However, while their rheological properties can be precisely controlled through their macromolecular structures, the current chemical spectrum available is limited to a handful of synthetic polymers with aliphatic carbon backbones. Herein we design and synthesize a series of inorganic bottlebrush polymers based on a unique combination of polydimethylsiloxane (PDMS) and polyphosphazene (PPz) chemistry. This non-carbon-based platform allows for simple variation of the significant architectural dimensions of bottlebrush-polymer-based elastomers. Grafting PDMS to PPz and vice versa also allows us to further exploit the unique properties of these polymers combined in a single material. These novel hybrid bottlebrush polymers were cured to give supersoft, solvent-free elastomers. We systematically studied the effect of architectural parameters and chemical functionality on their rheological properties. Besides forming supersoft elastomers, the energy dissipation characteristics of the elastomers were observed to be considerably higher than those for PDMS-based elastomers. Hence this work introduces a robust synthetic platform for solvent-free supersoft elastomers with potential applications as biomimetic damping materials.

Seedling root system adaptation to water availability during maize domestication and global expansion.

The maize root system has been reshaped by indirect selection during global adaptation to new agricultural environments. In this study, we characterized the root systems of more than 9,000 global maize accessions and its wild relatives, defining the geographical signature and genomic basis of variation in seminal root number. We demonstrate that seminal root number has increased during maize domestication followed by a decrease in response to limited water availability in locally adapted varieties. By combining environmental and phenotypic association analyses with linkage mapping, we identified genes linking environmental variation and seminal root number. Functional characterization of the transcription factor ZmHb77 and in silico root modeling provides evidence that reshaping root system architecture by reducing the number of seminal roots and promoting lateral root density is beneficial for the resilience of maize seedlings to drought.

EXODUS: Stable and efficient training of spiking neural networks.

Introduction: Spiking Neural Networks (SNNs) are gaining significant traction in machine learning tasks where energy-efficiency is of utmost importance. Training such networks using the state-of-the-art back-propagation through time (BPTT) is, however, very time-consuming. Previous work employs an efficient GPU-accelerated backpropagation algorithm called SLAYER, which speeds up training considerably. SLAYER, however, does not take into account the neuron reset mechanism while computing the gradients, which we argue to be the source of numerical instability. To counteract this, SLAYER introduces a gradient scale hyper parameter across layers, which needs manual tuning. Methods: In this paper, we modify SLAYER and design an algorithm called EXODUS, that accounts for the neuron reset mechanism and applies the Implicit Function Theorem (IFT) to calculate the correct gradients (equivalent to those computed by BPTT). We furthermore eliminate the need for ad-hoc scaling of gradients, thus, reducing the training complexity tremendously. Results: We demonstrate, via computer simulations, that EXODUS is numerically stable and achieves comparable or better performance than SLAYER especially in various tasks with SNNs that rely on temporal features.

A Diastereoselective Cascade Annulation Approach to Bridged Polycyclic Heterocycles Involving an Unexpected Rearrangement.

A diastereoselective cascade annulation between allenoates and in-situ generated isoquinoline N-oxides generating sp3-rich bridged polycyclic heterocycles is disclosed. The reaction proceeds through an unprecedented non-rearomatized rearrangement and allows access to a broad range of bridged heterocycles in 38-93% yields with excellent functional group tolerance and high diastereoselectivity. Density functional theory calculations provided key insights into the possible reaction pathway and the stereoselectivity of this procedure.

Multi-year belowground data of minirhizotron facilities in Selhausen.

The production of crops secure the human food supply, but climate change is bringing new challenges. Dynamic plant growth and corresponding environmental data are required to uncover phenotypic crop responses to the changing environment. There are many datasets on above-ground organs of crops, but roots and the surrounding soil are rarely the subject of longer term studies. Here, we present what we believe to be the first comprehensive collection of root and soil data, obtained at two minirhizotron facilities located close together that have the same local climate but differ in soil type. Both facilities have 7m-long horizontal tubes at several depths that were used for crosshole ground-penetrating radar and minirhizotron camera systems. Soil sensors provide observations at a high temporal and spatial resolution. The ongoing measurements cover five years of maize and wheat trials, including drought stress treatments and crop mixtures. We make the processed data available for use in investigating the processes within the soil-plant continuum and the root images to develop and compare image analysis methods.

Dependence of mechanical properties of lacewing egg stalks on relative humidity.

Silk fibers are well known for their mechanical properties such as strength and toughness and are lightweight, making them an interesting material for a variety of applications. Silk mechanics mainly rely on the secondary structure of the underlying proteins. Lacewing egg stalk silk proteins obtain a cross-ß structure with individual ß strands aligned perpendicular to the fiber axis. This structure is in contrast with that of silks of spiders or silkworms with ß strands parallel to the fiber axis and to that of silks of honeybees with α helices arranged in coiled coils. On the basis of the cross-ß structure the mechanical properties of egg stalks are different from those of other silks concerning extensibility, toughness, and bending stiffness. Here we show the influence of relative humidity on the mechanical behavior of lacewing egg stalks and propose a model based on secondary structure changes to explain the differences on a molecular level. At low relative humidity, the stalks rupture at an extension of 3%, whereas at high relative humidity the stalks rupture at 434%. This dramatic increase corresponds to breakage of hydrogen bonds between the ß strands and a rearrangement thereof in a parallel-ß structure.

Artificial egg stalks made of a recombinantly produced lacewing silk protein.

Rigid threads: Lacewings protect their eggs from predators by laying them on small stalks (see picture). The stalks have good mechanical properties and, unlike most other silks, a cross ß structure. An artificial egg stalk was produced using a designed recombinant variant of a sequenced lacewing egg stalk protein, and it attained 90 % of the tensile strength of a natural egg stalk.

A General C-N Cross-Coupling to Synthesize Heteroaryl Amines Using a Palladacyclic N-Heterocyclic Carbene Precatalyst.

A new palladacyclic N-heterocyclic carbene precatalyst was designed by the combination of 1,3-bis(2,6-diisopropylphenyl)acenaphthoimidazol-2-ylidene (AnIPr) with an achiral 2-naphthyl-4,4-dimethyloxazoline palladacyclic fragment. Applying this precatalyst enabled a general protocol for Pd-catalyzed C-N cross-coupling reactions of challenging five- or six-membered ring heteroaryl chlorides and various heterocyclic amines. The desired aminated products, including commercial pharmaceuticals or key intermediates such as piribedil, cyprodinil, V600EBRAF inhibitor, tripelennamine, 517-ß-hydroxysteroid dehydrogenase inhibitor, brexpiprazole, and sonidegib, were achieved in good to excellent yields (>61 examples, ≤99% yields).

Development and Validation of a Deep Learning Based Automated Minirhizotron Image Analysis Pipeline.

Root systems of crops play a significant role in agroecosystems. The root system is essential for water and nutrient uptake, plant stability, symbiosis with microbes, and a good soil structure. Minirhizotrons have shown to be effective to noninvasively investigate the root system. Root traits, like root length, can therefore be obtained throughout the crop growing season. Analyzing datasets from minirhizotrons using common manual annotation methods, with conventional software tools, is time-consuming and labor-intensive. Therefore, an objective method for high-throughput image analysis that provides data for field root phenotyping is necessary. In this study, we developed a pipeline combining state-of-the-art software tools, using deep neural networks and automated feature extraction. This pipeline consists of two major components and was applied to large root image datasets from minirhizotrons. First, a segmentation by a neural network model, trained with a small image sample, is performed. Training and segmentation are done using "RootPainter." Then, an automated feature extraction from the segments is carried out by "RhizoVision Explorer." To validate the results of our automated analysis pipeline, a comparison of root length between manually annotated and automatically processed data was realized with more than 36,500 images. Mainly the results show a high correlation (r = 0.9) between manually and automatically determined root lengths. With respect to the processing time, our new pipeline outperforms manual annotation by 98.1-99.6%. Our pipeline, combining state-of-the-art software tools, significantly reduces the processing time for minirhizotron images. Thus, image analysis is no longer the bottle-neck in high-throughput phenotyping approaches.

Asymmetric hydroalkylation of alkynes and allenes with imidazolidinone derivatives: α-alkenylation of α-amino acids.

This work reports a new method for the synthesis of quaternary α-alkenyl substituted amino acids by the enantio- and diastereoselective addition of imidazolidinone derivatives to alkynes and allenes. Further hydrolysis of the imidazolidinone products under acidic conditions afforded biologically relevant amino acid derivatives. This method is geometry-selective (E-isomer), enantio- and diastereoselective, and products were obtained in good to excellent yields. The utility of this new methodology is proved by its operational simplicity and the successful accomplishment of gram-scale reactions. Experimental and computational studies suggest the key role of Li in terms of selectivity and support the proposed reaction mechanism.

Cobalt-Catalyzed Hydroboration of Terminal and Internal Alkynes.

A novel methodology to access synthetically versatile vinylboronic esters through a ligand-controlled cobalt-catalyzed hydroboration of terminal and internal alkynes is reported. The approach relies on the in situ reduction of Co(II) by H-BPin in the presence of bisphosphine ligands generating catalytically active Co(I) hydride complexes. This procedure avoids the use of stoichiometric amounts of base, and no boron-containing byproducts are generated which is translated into high functional group tolerance and atom economy.