Sebastian Beil

Nature Communications, Published online: 03 January 2020; doi:10.1038/s41467-019-13784-0

Nature Communications, Published online: 09 January 2020; doi:10.1038/s41467-019-13994-6

Nature Nanotechnology, Published online: 10 January 2020; doi:10.1038/s41565-019-0613-9

The recognition of either homomeric or heteromeric pairs of pentoses in an aromatic oligoamide double helical foldamer capsule was evidenced by circular dichroism (CD), NMR and X‐ray crystallography. The cavity of the host was predicted to be large enough to accommodate simultaneously two xylose molecules and form a 1:2 complex (one container, two saccharides). Solution and solid state data revealed the selective recognition of the α‐4C1‐d‐xylopyranose tautomer, which is bound at two identical sites in the foldamer cavity. A step further was achieved by sequestering a heteromeric pair of pentoses, i.e. one molecule of α‐4C1‐D‐xylopyranose and one molecule of β‐1C4‐D‐arabinopyranose despite the symmetrical nature of the host and despite the similarity of the guests. Subtle induced‐fit and allosteric effects are responsible for the outstanding selectivities observed.

Diene to be chiral: The first general synthesis of 2,3‐diethynyl‐1,3‐butadienes (DEBDs) uses commodity precursors and involves, as a key step, an unprecedented twofold Sonogashira‐type cross‐coupling of a 2‐butyne‐1,4‐diol derivative. The value of DEBDs as building blocks for novel expanded dendralenes and expanded radialenes is also demonstrated. The latter exhibit an unprecedented form of atropisomerism.

Abstract

The first general preparative access to compounds of the 2,3‐diethynyl‐1,3‐butadiene (DEBD) class is reported. The synthesis involves a one‐pot, twofold Sonogashira‐type, Pd⁰‐catalyzed coupling of two terminal alkynes and a carbonate derivative of a 2‐butyne‐1,4‐diol. The synthesis is broad in scope and members of this structural family are kinetically stable enough to be handled using standard laboratory techniques at ambient temperature. They decompose primarily through heat‐promoted cyclodimerizations, which are impeded by alkyl substitution and accelerated by aryl or alkenyl substitution. An iterative sequence of these unprecedented Sonogashira‐type couplings generates a new type of expanded dendralene. A suitably substituted DEBD carrying two terminal alkyne groups undergoes Glaser–Eglinton cyclo‐oligomerization to produce a new class of expanded radialenes, which are chiral due to restricted rotation about their 1,3‐butadiene units. The structural features giving rise to atropisomerism in these compounds are distinct from those reported previously.

Fluorination for the nation: A method for the difluorination of unactivated alkenes with electron‐rich functionalities is described. Key to success is the electrochemical generation of a hypervalent iodine mediator using an “ex‐cell” approach, which avoids oxidative substrate decomposition.

Abstract

Fluorinated alkyl groups are important motifs in bioactive compounds, positively influencing pharmacokinetics, potency and conformation. The oxidative difluorination of alkenes represents an important strategy for their preparation, yet current methods are limited in their alkene‐types and tolerance of electron‐rich, readily oxidized functionalities, as well as in their safety and scalability. Herein, we report a method for the difluorination of a number of unactivated alkene‐types that is tolerant of electron‐rich functionality, giving products that are otherwise unattainable. Key to success is the electrochemical generation of a hypervalent iodine mediator using an “ex‐cell” approach, which avoids oxidative substrate decomposition. The more sustainable conditions give good to excellent yields in up to decagram scales.

A double‐double! Two new complementary classes of s‐aryl tetrazines are presented with two independently and selectively clickable functions. Constraints at the ortho‐positions generate unprecedented structural features such as [N]₈ London dispersion forces.

Abstract

Click chemistry at a tetrazine core is useful for bioorthogonal labeling and crosslinking. Introduced here are two new classes of doubly clickable s‐aryl tetrazines synthesized by Cu‐catalyzed cross‐coupling. Homocoupling of o‐brominated s‐aryl tetrazines leads to bis(tetrazine)s structurally characterized by tetrazine cores arranged face‐to‐face. [N]₈ π‐stacking interactions are essential to the conformation. Upon inverse electron demand Diels–Alder (iEDDA) cycloaddition, the bis(tetrazine)s produce a unique staple structure. The o‐azidation of s‐aryl tetrazines introduces a second proximal intermolecular clickable function that leads to double click chemistry opportunities. The stepwise introduction of fluorophores and then iEDDA cycloaddition, including bioconjugation to antibodies, was achieved on this class of tetrazines. This method extends to (thio)etherification, phosphination, trifluoromethylation and the introduction of various bioactive nitrogen‐based heterocycles.

ORR inspiring: Incorporating cobalt porphyrins into a porous supramolecular cage structure isolates molecular active sites for selective electrochemical oxygen reduction, leading to direct electrosynthesis of hydrogen peroxide in neutral pH water.

Abstract

We report a supramolecular strategy for promoting the selective reduction of O₂ for direct electrosynthesis of H₂O₂. We utilized cobalt tetraphenylporphyrin (Co‐TPP), an oxygen reduction reaction (ORR) catalyst with highly variable product selectivity, as a building block to assemble the permanently porous supramolecular cage Co‐PB‐1(6) bearing six Co‐TPP subunits connected through twenty‐four imine bonds. Reduction of these imine linkers to amines yields the more flexible cage Co‐rPB‐1(6). Both Co‐PB‐1(6) and Co‐rPB‐1(6) cages produce 90–100 % H₂O₂ from electrochemical ORR catalysis in neutral pH water, whereas the Co‐TPP monomer gives a 50 % mixture of H₂O₂ and H₂O. Bimolecular pathways have been implicated in facilitating H₂O formation, therefore, we attribute this high H₂O₂ selectivity to site isolation of the discrete molecular units in each supramolecule. The ability to control reaction selectivity in supramolecular structures beyond traditional host–guest interactions offers new opportunities for designing such architectures for a broader range of catalytic applications.

Building bridges: The reductive photocatalytic dearomatization of quinoline derivatives using N‐arylimines is described. The bridged 1,3‐diazepane architecture is constructed through the addition of an intermediary α‐amino radical to the C4‐position of a 4‐substituted quinoline and subsequent reductive cyclization.

Abstract

The construction of diverse sp³‐rich skeletal ring systems is of importance to drug discovery programmes and natural product synthesis. Herein, we report the photocatalytic construction of 2,7‐diazabicyclo[3.2.1]octanes (bridged 1,3‐diazepanes) via a reductive diversion of the Minisci reaction. The fused tricyclic product is proposed to form via radical addition to the C4 position of 4‐substituted quinoline substrates, with subsequent Hantzsch ester‐promoted reduction to a dihydropyridine intermediate which undergoes in situ two‐electron ring closure to form the bridged diazepane architecture. A wide scope of N‐arylimine and quinoline derivatives was demonstrated and good efficiency was observed in the construction of sterically congested all‐carbon quaternary centers. Computational and experimental mechanistic studies provided insights into the reaction mechanism and observed regioselectivity/diastereoselectivity.

Nature Catalysis, Published online: 23 December 2019; doi:10.1038/s41929-019-0398-0

Macrocycles, compounds containing a ring of 12 or more atoms, find use in human medicine, fragrances, and biological ion sensing. The efficient preparation of macrocycles is a fundamental challenge in synthetic organic chemistry because the high entropic cost of large-ring closure allows undesired intermolecular reactions to compete. Here, we present a bioinspired strategy for macrocycle formation through carbon–carbon bond formation. The process relies on a catalytic oligomer containing α- and β-amino acid residues to template the ring-closing process. The α/β-peptide foldamer adopts a helical conformation that displays a catalytic primary amine–secondary amine diad in a specific three-dimensional arrangement. This catalyst promotes aldol reactions that form rings containing 14 to 22 atoms. Utility is demonstrated in the synthesis of the natural product robustol.

Over the past decade, photoredox catalysis has harnessed light energy to accelerate bond-forming reactions. We postulated that a complementary method for the redox-activation of small organic molecules in response to applied mechanical energy could be developed through the piezoelectric effect. Here, we report that agitation of piezoelectric materials via ball milling reduces aryl diazonium salts. This mechanoredox system can be applied to arylation and borylation reactions under mechanochemical conditions.

Dye hard: Translating from a “beat and heat” method, a continuous, scalable, and solvent‐free method for the synthesis of various naphthalic imides (3 examples) and perylene diimides (PDIs, 21 examples) using twin‐screw extrusion (TSE) is reported. The TSE method provides substantial reductions in waste and improved efficiency compared to conventional solvent‐based methods.

Abstract

A continuous, scalable, and solvent‐free method for the synthesis of various naphthalic imides and perylene diimides (PDIs) using twin‐screw extrusion (TSE) is reported. Using TSE, naphthalic imides were obtained quantitatively without the need for excess amine reactant or product purification. With good functional‐group tolerance, alkyl and benzyl amine derived PDIs (incl. commercial dyes) were obtained in 50–99 % yield. Use of K₂CO₃, enabled synthesis of more difficult aniline‐derived PDIs. Furthermore, an automated continuous TSE process for Pigments Black 31 and 32 is demonstrated, with a throughput rate of about 1500 g day⁻¹, corresponding to a space time yield of about 30×10³ kg m⁻³ day⁻¹, which is 1–2 orders of magnitude greater than for solvent‐based batch methods. These methods provide substantial waste reductions and improved efficiency compared to conventional solvent‐based methods.

Ch‐ch‐change S: A nickel‐catalyzed aryl thioether metathesis with high functional‐group tolerance was developed, with bis(dicyclohexylphosphino)ethane (dcype) being essential to promote the reaction. Synthetically challenging macrocycles were obtained in good yield in an unusual example of ring‐closing metathesis that does not involve alkene bonds. In‐depth organometallic studies support a reversible Ni⁰/Ni^II pathway to product formation.

Abstract

A nickel‐catalyzed aryl thioether metathesis has been developed to access high‐value thioethers. 1,2‐Bis(dicyclohexylphosphino)ethane (dcype) is essential to promote this highly functional‐group‐tolerant reaction. Furthermore, synthetically challenging macrocycles could be obtained in good yield in an unusual example of ring‐closing metathesis that does not involve alkene bonds. In‐depth organometallic studies support a reversible Ni⁰/Ni^II pathway to product formation. Overall, this work not only provides a more sustainable alternative to previous catalytic systems based on Pd, but also presents new applications and mechanistic information that are highly relevant to the further development and application of unusual single‐bond metathesis reactions.

Heterogeneous ligand: A highly efficient heterogeneous palladium‐catalyzed oxidative cyclization of enallenols is developed here for the construction of highly substituted furan and oxaborole derivatives. The support (AmP‐MCF) of the heterogeneous catalyst (Pd‐AmP‐MCF) protect Pd species from aggregating to Pd black during the catalytic cycle, which leads to the high Pd efficiency of Pd‐AmP‐MCF.

Abstract

A heterogeneous palladium‐catalyzed oxidative cyclization of enallenols has been developed for the construction of highly substituted furan and oxaborole derivatives. The heterogeneous catalyst (Pd‐AmP‐MCF) exhibits high activity, high site‐ and stereoselectivity, and efficient palladium recyclability in the transformations.

Boron nucleophile: The 9H‐9‐borafluorene dianion behaves as a boron‐centered nucleophile with minimal steric shielding. The boron‐bonded hydrogen atom can subsequently be abstracted from the primary products, thereby rendering the title compound a masked diarylboryl anion.

Abstract

Double reduction of the THF adduct of 9H‐9‐borafluorene (1⋅THF) with excess alkali metal affords the dianion salts M₂[1] in essentially quantitative yields (M=Li–K). Even though the added charge is stabilized through π delocalization, [1]²⁻ acts as a formal boron nucleophile toward organoboron (1⋅THF) and tetrel halide electrophiles (MeCl, Et₃SiCl, Me₃SnCl) to form B−B/C/Si/Sn bonds. The substrate dependence of open‐shell versus closed‐shell pathways has been investigated.

1D nonplanar graphene nanoribbon, namely dodecatwistarene imide featuring twelve linearly fused benzene rings, was obtained by Pd‐catalyzed Stille coupling and C−H activation. It has a zigzag‐twisted conformation with the pendulum angle of 53°, and is very stable even when heated up to 250 °C. An organic field‐effect transistor based on it exhibits electron mobility up to 1.5 cm² V⁻¹ s⁻¹.

Abstract

1D nonplanar graphene nanoribbons generally have three possible conformers: helical, zigzag, and mixed conformations. Now, a kind of 1D nonplanar graphene nanoribbon, namely dodecatwistarene imides featuring twelve linearly fused benzene rings, was obtained by bottom‐up synthesis of palladium‐catalyzed Stille coupling and C−H activation. Single‐crystal X‐ray diffraction analyses revealed that it displays a zigzag‐twisted conformation caused by steric hindrance between imide groups and neighboring annulated benzene rings with the pendulum angle of 53°. This conformation is very stable and could not convert into other conformations even when heated up to 250 °C for 6 h. Despite of the highly twisted topology, organic field‐effect transistor based on it exhibits electron mobility up to 1.5 cm² V⁻¹ s⁻¹ after annealing.

Imine synthesis has enjoyed a long history as the dynamic covalent reaction of choice for the construction of purely covalent molecular architectures. In organic solvents, the formation of imine bonds is reversible but leads to thermodynamically stable products. In the presence of water, however, imine bonds are labile, a fact which limits their utility as mediators of self‐assembly in aqueous and biological media. In this review, we discuss water‐compatible dynamic covalent bonds based on N‐substituted imine derivatives, namely hydrazones and oximes, for self‐assembly of metal‐free organic architectures with well‐defined structures. The reasons why hydrazones and oximes are more robust in water in comparison to their parent imines are explained. Recent progress on the self‐assembly, characterization and design principles of a variety of complex molecules including macrocycles, cages, catenanes and knots in aqueous‐media is highlighted. Emerging applications for these molecules, including guest recognition and separations, are also discussed.