Synthetic Building Research Articles

Highly Active Cooperative Lewis Acid-Ammonium Salt Catalyst for the Enantioselective Hydroboration of Ketones.

Enantiopure secondary alcohols are fundamental high‐value synthetic building blocks. One of the most attractive ways to get access to this compound class is the catalytic hydroboration. We describe a new concept for this reaction type that allowed for exceptional catalytic turnover numbers (up to 15 400), which were increased by around 1.5–3 orders of magnitude compared to the most active catalysts previously reported. In our concept an aprotic ammonium halide moiety cooperates with an oxophilic Lewis acid within the same catalyst molecule. Control experiments reveal that both catalytic centers are essential for the observed activity. Kinetic, spectroscopic and computational studies show that the hydride transfer is rate limiting and proceeds via a concerted mechanism, in which hydride at Boron is continuously displaced by iodide, reminiscent to an SN2 reaction. The catalyst, which is accessible in high yields in few steps, was found to be stable during catalysis, readily recyclable and could be reused 10 times still efficiently working.

Enantioselective extraction of unprotected amino acids coupled with racemization

Scalable and economical methods for the production of optically pure amino acids, both natural and unnatural, are essential for their use as synthetic building blocks. Currently, enzymatic dynamic kinetic resolution (DKR) underpins some of the most effective processes. Here we report the development of enantioselective extraction coupled with racemization (EECR) for the chirality conversion of underivatized amino acids. In this process, the catalytic racemization of amino acids in a basic aqueous solution is coupled with the selective extraction of one enantiomer into an organic layer. Back-extraction from the organic layer to an acidic aqueous solution then completes the deracemization of the amino acid. The automation of the EECR process in a recycling flow reactor is also demonstrated. Continuous EECR is made possible by the sterically hindered chiral ketone extractant 5, which prevents the coextraction of the copper racemization catalyst because of its nonplanar geometry. Furthermore, the extractant 5 unexpectedly forms imines with amino acids faster and with greater enantioselectivity than less bulky derivatives, even though 5 cannot participate in intramolecular resonance-assisted hydrogen bonding. These features may allow EECR to challenge the preponderance of enzymatic DKR in the production of enantiomerically enriched amino acids.

Hydrogenative Coupling of Nitriles with Diamines to Benzimidazoles Using Lignin-Derived Rh <sub>2</sub>p Catalyst

Nitrile is frequently high-available as commodity chemicals; however, nitrile (CΞN bond) activation for direct organic synthesis has been less explored so far due to a high redox potential of nitrile and its low dissociation energy of C-CN bond. Herein, we demonstrate a direct reductive coupling of nitriles and 1,2-phenylenediamines to yield various benzimidazoles in excellent yields (95%-99%) by using lignin-derived rhodium phosphide (Rh2P) catalyst with H2 (or hydrazine hydrate) as hydrogen sources. The high catalytic performance of Rh2P/LC is attributable to enhanced charge transfer on Rh site as well as strong interactions between P and Rh. Our isotope trace experiment confirms the presence of H/D exchange between H2 and the inert –CD3 group of CD3CN via an intramolecular D-shift. Reusability of Rh2P/LC is demonstrated by seven-time recycling without evident loss of activity. This research thus highlights a vast potential in organic transformation with nitrile as a synthetic building block.

The 1,3-dithiol-2-ide carbanion.

1,3-Dithiol-2-ide is a fully unsaturated five-membered heterocycle with a carbanion unit between two of the ring sulfur atoms. Derivatives thereof are important intermediates in synthetic protocols for preparing various 1,4-dithiafulvene (DTF) and tetrathiafulvalene (TTF) compounds by Wittig, Horner-Wadsworth-Emmons, or phosphite-mediated olefination reactions. When considering the electronic properties of DTF, one would usually consider this unit as an electron-donating group as it can form a 6π-aromatic 1,3-dithiolium ring by resonance. Yet, in this review, I will move forward a dual character of the DTF by which it can also act as an electron-withdrawing group, involving formation of the 1,3-dithiol-2-ide. In particular, this electronic effect can be used to explain its ability to promote the electrocyclic ring closure of a vinylheptafulvene into a dihydroazulene. This view on the properties of DTF is very much in line with the dual reactivity of ketene dithioacetals that react with both nucleophiles and electrophiles. Moreover, the 1,3-dithiol-2-ide unit was recently generated in the reduction of an extended and quinoid-like TTF where the core became an aromatic carbo-benzene moiety. This aspect is particularly interesting for future design of extended TTFs that can act as both electron donors and acceptors.

α-Aminoboronates: recent advances in their preparation and synthetic applications.

α-Aminoboronic acids and their derivatives are useful as bioactive agents. Thus far, three compounds containing an α-aminoboronate motif have been approved by the Food and Drug Administration (FDA) as protease inhibitors, and more are currently undergoing clinical trials. In addition, α-aminoboronic acids and their derivatives have found applications in organic synthesis, e.g. as α-aminomethylation reagents for the synthesis of chiral nitrogen-containing molecules, as nucleophiles for preparing valuable vicinal amino alcohols, and as bis-nucleophiles in the construction of valuable small molecule scaffolds. This review summarizes new methodology for the preparation of α-aminoboronates, including highlights of asymmetric synthetic methods and mechanistic explanations of reactivity. Applications of α-aminoboronates as versatile synthetic building blocks are also discussed.

An Organocatalytic Kinetic Resolution of Aziridines by Thiol Nucleophiles.

We report the first organocatalytic kinetic resolution of unactivated aziridines by sulfur nucleophiles with excellent enantioselectivity. A suitable chiral phosphoric acid was found to catalyze the intermolecular ring opening under mild conditions, furnishing a range of highly enantioenriched β-amino thioethers and aziridines, both of which are useful synthetic building blocks.

Electrochemical Aziridination of Internal Alkenes with Primary Amines

<h2>Summary</h2> Aziridines are useful synthetic building blocks, widely employed for the preparation of various nitrogen-containing derivatives. As the current methods require the use of prefunctionalized amines, the development of a synthetic strategy toward aziridines that can establish the union of alkenes and amines would be of great synthetic value. Herein, we report an electrochemical approach, which realizes this concept via an oxidative coupling between alkenes and primary alkylamines. The reaction is carried out in an electrochemical flow reactor leading to short reaction/residence times (5 min), high yields, and broad scope. At the cathode, hydrogen is generated, which can be used in a second reactor to reduce the aziridine, yielding the corresponding hydroaminated product. Mechanistic investigations and DFT calculations revealed that the alkene is first anodically oxidized and subsequently reacted with the amine coupling partner.

Silver‐Catalyzed Acyl Nitrene Transfer Reactions Involving Dioxazolones: Direct Assembly of N‐Acylureas

AbstractDioxazolones and isocyanides are useful synthetic building blocks, and have attracted significant attention from researchers. However, the silver‐catalyzed nitrene transfer reaction of dioxazolones has not been investigated to date. Herein, a silver‐catalyzed acyl nitrene transfer reaction involving dioxazolones, isocyanides, and water was realized in the presence of Ag2O to afford a series of N‐acylureas in moderate to good yields.

First-Principles Calculations on Ni,Fe-Containing Carbon Monoxide Dehydrogenases Reveal Key Stereoelectronic Features for Binding and Release of CO2 to/from the C-Cluster.

In view of the depletion of fossil fuel reserves and climatic effects of greenhouse gas emissions, Ni,Fe-containing carbon monoxide dehydrogenase (Ni-CODH) enzymes have attracted increasing interest in recent years for their capability to selectively catalyze the reversible reduction of CO2 to CO (CO2 + 2H+ + 2e– CO + H2O). The possibility of converting the greenhouse gas CO2 into useful materials that can be used as synthetic building blocks or, remarkably, as carbon fuels makes Ni-CODH a very promising target for reverse-engineering studies. In this context, in order to provide insights into the chemical principles underlying the biological catalysis of CO2 activation and reduction, quantum mechanics calculations have been carried out in the framework of density functional theory (DFT) on different-sized models of the Ni-CODH active site. With the aim of uncovering which stereoelectronic properties of the active site (known as the C-cluster) are crucial for the efficient binding and release of CO2, different coordination modes of CO2 to different forms and redox states of the C-cluster have been investigated. The results obtained from this study highlight the key role of the protein environment in tuning the reactivity and the geometry of the C-cluster. In particular, the protonation state of His93 is found to be crucial for promoting the binding or the dissociation of CO2. The oxidation state of the C-cluster is also shown to be critical. CO2 binds to Cred2 according to a dissociative mechanism (i.e., CO2 binds to the C-cluster after the release of possible ligands from Feu) when His93 is doubly protonated. CO2 can also bind noncatalytically to Cred1 according to an associative mechanism (i.e., CO2 binding is preceded by the binding of H2O to Feu). Conversely, CO2 dissociates when His93 is singly protonated and the C-cluster is oxidized at least to the Cint redox state.

Catalytic Enantioselective Reactions with (Benzo)Pyrylium Salts.

The use of (benzo)pyrylium salts as versatile synthetic building blocks has become an attractive platform for the preparation of valuable heterocyclic compounds. Besides other numerous direct applications of (benzo)pyryliums, the intrinsic electrophilic nature of these species or the dipole character of the related oxidopyrylium derivatives have been exploited towards the development of enantioselective transformations such as nucleophilic dearomatization and cycloaddition reactions. This review aims at providing an overview on the relevant catalytic enantioselective methodologies developed in the past years, which are presented considering the involved metal- and/or organic catalytic system, as well as the type of reaction.

A stimuli-responsive pillar[5]arene-based hybrid material with enhanced tunable multicolor luminescence and ion-sensing ability.

Tunable luminescent materials are becoming more and more important owing to their broad application potential in various fields. Here we construct a pillar[5]arene-based hybrid material with stimuli-responsive luminescent properties and ion-sensing abilities from a pyridine-modified conjugated pillar[5]arene and a planar chromophore oligo(phenylenevinylene) upon coordination of Cd (II) metal cores. This new material not only shows an optimized luminescence due to the minimized π–π stacking and efficient charge transfer properties benefitting from the existence of pillar[5]arene rings, but also exhibits tunable multicolor emission induced by different external stimuli including solvent, ions and acid, indicating great application potential as a fluorescent sensory material, especially for Fe3+. With this pillar[5]arene-based dual-ligand hybrid material, valid optimization and regulation on the fluorescence of the original chromophore have been achieved, which demonstrates a plausible strategy for the design of tunable solid-state luminescent materials and also a prototypical model for the effective regulation of fluorescent properties of planar π systems using synthetic macrocycle-based building blocks.

Nucleophilic Dearomatization of N-Heteroaromatics Enabled by Lewis Acids and Copper Catalysis.

Dearomative functionalization of heteroaromatics, a readily available chemical feedstock, is one of the most straightforward approaches for the synthesis of three-dimensional, chiral heterocyclic systems, important synthetic building blocks for both synthetic chemistry and drug discovery. Despite significant efforts, direct nucleophilic additions to heteroaromatics have remained challenging because of the low reactivity of aromatic substrates associated with the loss of aromaticity, as well the regio- and stereoselectivities of the reaction. Here we present a catalytic system that leads to unprecedented, high-yielding dearomative C-4 functionalization of quinolines with organometallics with nearly absolute regio- and stereoselectivities and with a catalyst turnover number (TON) as high as 1000. The synergistic action of the chiral copper catalyst, Lewis acid, and Grignard reagents allows us to overcome the energetic barrier of the dearomatization process and leads to chiral products with selectivities reaching 99% in most cases. Molecular modeling provides important insights into the speciation and the origin of the regio- and enantioselectivity of the catalytic process. The results reveal that the role of the Lewis acid is not only to activate the substrate toward a potential nucleophilic addition but also to subtly control the regiochemistry by preventing the C-2 addition from happening.

Synthesis of 4,4-Dimethyl-1,6-heptadiyne and Alcyopterosin O.

A four-step synthesis of 4,4-dimethyl-1,6-heptadiyne and an associated five-step synthesis of alcyopterosin O, an illudalane sesquiterpene natural product, are described starting from commercially available dimedone. The process features C-C bond-cleaving fragmentation and elimination methods for making alkynes, and it proceeds by way of nonsymmetrical diynes that are themselves valuable synthetic building blocks, as exemplified by the synthesis of alcyopterosin O.

β‐Trifluoromethyl α,β‐unsaturated Ketones: Efficient Building Blocks for Diverse Trifluoromethylated Molecules

AbstractThe trifluoromethyl (CF3) group is an advantageous structural motif in various biologically active molecules as well as materials, which is depicted by steadily increasing demand from the industries involved in drug discovery, agrochemicals and material development. β‐trifluoromethyl α,β‐unsaturated carbonyl compounds constitute a very efficient building blocks as starting material in the synthesis of fluorinated molecules. Their usage for the synthesis of various heterocycles and organic molecules bearing stereogenic carbon containing CF3 motif has received significant attention during the recent times. This review provides the existing methods for the synthesis of β‐substituted trifluoromethyl‐α,β‐unsaturated ketones and the efforts made by researchers for the synthetic development through various reactions by employing them as synthetic building blocks for trifluoromethylated organic scaffolds.magnified image

Amphiphilic Small-Molecule Assemblies to Enhance the Solubility and Stability of Hydrophobic Drugs.

Amphiphilic assemblies made from diverse synthetic building blocks are well known for their biomedical applications. Here, we report the synthesis of gemini-type amphiphilic molecules that form stable assemblies in water. The assembly property of molecule M2 in aqueous solutions was first inferred from peak broadening observed in the proton NMR spectrum. This was supported by dynamic light scattering and transmission electron microscopy analysis. The assembly formed from M2 (M2agg) was used to solubilize the hydrophobic drugs curcumin and doxorubicin at physiological pH. M2agg was able to effectively solubilize curcumin as well as protect it from degradation under UV irradiation. Upon solubilization in M2agg, curcumin showed excellent cell permeability and higher toxicity to cancer cells over normal cells, probably because of enhanced cellular uptake and increased stability. M2agg also showed pH-dependent release of doxorubicin, resulting in controlled toxicity on cancer cell lines, making it a promising candidate for the selective delivery of drugs to cancer cells.

Accounting for directivity-induced pulse-like ground motions in building portfolio loss assessment

Earthquake-induced pulse-like ground motions are often observed in near-source conditions due to forward-directivity. Recent worldwide earthquakes have emphasised the severe damage potential of such pulse-like ground motions. This paper introduces a framework to quantify the impact of directivity-induced pulse-like ground motions on the direct economic losses of building portfolios. To this aim, a simulation-based probabilistic risk modelling framework is implemented for various synthetic building portfolios located either in the fault-parallel or fault-normal orientations with respect to a case-study strike–slip fault. Three low-to-mid-rise building typologies representative of distinct vulnerability classes in the Mediterranean region are considered: non-ductile moment-resisting reinforced concrete (RC) frames with masonry infills, mainly designed to only sustain gravity loads (i.e. pre-code frames); moment-resisting RC infilled frames designed considering seismic provisions for high ductility capacity (i.e. special-code frames); special-code steel moment-resisting frames. Monte Carlo-based probabilistic seismic hazard analysis is first performed, considering the relevant modifications to account for the pulse-occurrence probability and the resulting spectral amplification. Hazard curves for sites/buildings located at different distances from the fault are obtained, discussing the spatial distribution of the hazard amplification. A set of pulse-like ground motions and a set of one-to-one spectrally-equivalent ordinary records are used to perform non-linear dynamic analysis and derive fragility relationships for each considered building typology. A vulnerability model is finally built by combining the derived fragility relationships with a (building-level) damage-to-loss model. The results are presented in terms of intensity-based and expected annual loss for synthetic portfolios of different sizes and distribution of building types. It is shown that, for particularly short-period structures (e.g. infilled RC frames), the influence of near-source directivity can be reasonably neglected in the fragility derivation while kept in place in the hazard component. Overall, near-source directivity effects are significant when estimating losses of individual buildings or small portfolios located very close to a fault. Nevertheless, the impact of pulse-like ground motions on losses for larger portfolios can be considered minimal and can be neglected in most of the practical large-scale seismic risk assessment applications.

From concept to application: A review of use cases in urban building energy modeling

Urban building energy modeling (UBEM) is a bottom-up, physics-based approach to simulate the thermal performance of new or existing neighborhoods and cities. The field has flourished in recent years, creating increasingly robust urban data streams that lead from Geographical Information Systems, CityGML, Light Detection and Ranging, and tax assessor databases to synthetic hourly building energy demand profiles for current and potential future conditions. Depending on the availability of historic building energy use data, a variety of modeling, simulation, and calibration approaches as well as use cases have been proposed. This paper provides a consolidated UBEM workflow with data and process requirements, and organizes UBEM proposals into four main application categories: urban planning and new neighborhood design, stock-level carbon reduction strategies, individual building-level recommendations, and buildings-to-grid integration. For each application, the paper further introduces a minimum viable UBEM, a novel concept for UBEMs conceptualized in the spirit of a minimum viable product. Specific case studies and/or examples are listed for each application area where available.

Synthetic Approaches to Non-Tropane, Bridged, Azapolycyclic Ring Systems Containing Seven-Membered Carbocycles

AbstractThis Short Review highlights various synthetic approaches to bridged azabicyclic ring systems containing seven-membered carbocyclic rings. Such ring systems are common to a number of biologically active natural products. The seven-membered ring in such systems is generally formed in one of four ways: 1) cyclization of an acyclic precursor; 2) ring expansion or rearrangement of a different ring size; 3) cycloaddition; and 4) use of a synthetic building block with the seven-membered ring already present. Representative examples of each approach from both total synthesis and methodological studies are discussed, with an emphasis on work publishedin the last twenty years.1 Introduction2 Cyclization Reactions3 Ring Expansions and Rearrangements4 Cycloadditions5 Strategies Involving Seven-Membered Ring Building Blocks6 Conclusion

A Mild Method for the Generation and Interception of 1,2-Cycloheptadienes with 1,3-Dipoles.

1,2-Cycloheptadiene is a strained, transient species that has been underutilized as a synthetic building block. Seven-membered cyclic allenes are mostly known for their propensity to undergo rapid dimerization, and relatively little has been reported regarding their cycloaddition reactivity with 1,3-dienes or 1,3-dipoles. This work describes the trapping of 1-acetoxy-1,2-cycloheptadiene and its unsubstituted counterpart, generated via desilylative elimination, with a range of 1,3-dipolar trapping partners, affording complex polycyclic products with high regio- and diastereoselectivity.

Independent translation of ORFs in dicistronic operons, synthetic building blocks for polycistronic chloroplast gene expression.

We designed a dicistronic plastid marker system that relies on the plastid's ability to translate polycistronic mRNAs. The identification of transplastomic clones is based on selection for antibiotic resistance encoded in the first open reading frame (ORF) and accumulation of the reporter gene product in tobacco chloroplasts encoded in the second ORF. The antibiotic resistance gene may encode spectinomycin or kanamycin resistance based on the expression of aadA or neo genes, respectively. The reporter gene used in the study is the green fluorescent protein (GFP). The mRNA level depends on the 5'-untranslated region of the first ORF. The protein output depends on the strengths of the ribosome binding, and is proportional with the level of translatable mRNA. Because the dicistronic mRNA is not processed, we could show that protein output from the second ORF is independent from the first ORF. High-level GFP accumulation from the second ORF facilitates identification of transplastomic events under ultraviolet light. Expression of multiple proteins from an unprocessed mRNA is an experimental design that enables predictable protein output from polycistronic mRNAs, expanding the toolkit of plant synthetic biology.