Sebastian Beil

Better off alone: A nanoreactor approach was used to investigate the chemistry of2‐cyanobenzothiazole (CBT), an important bioorthogonal reagent, at the single‐molecule level. Reactions with thiols and aminothiols revealed mechanistic and kinetic information with important implications for several essential applications of CBT reagents.

Abstract

We report a single‐molecule mechanistic investigation into 2‐cyanobenzothiazole (CBT) chemistry within a protein nanoreactor. When simple thiols reacted reversibly with CBT, the thioimidate monoadduct was approximately 80‐fold longer‐lived than the tetrahedral bisadduct, with important implications for the design of molecular walkers. Irreversible condensation between CBT derivatives and N‐terminal cysteine residues has been established as a biocompatible reaction for site‐selective biomolecular labeling and imaging. During the reaction between CBT and aminothiols, we resolved two transient intermediates, the thioimidate and the cyclic precursor of the thiazoline product, and determined the rate constants associated with the stepwise condensation, thereby providing critical information for a variety of applications, including the covalent inhibition of protein targets and dynamic combinatorial chemistry.

Two in one: A photoinduced asymmetric radical decarboxylative alkynylation of bench‐stable racemic carboxylic acid derivatives with easily available terminal alkynes provides expedient access to diverse enantioenriched alkynes. The chiral copper catalyst serves as a dual photo‐ and cross‐coupling catalyst to achieve stereocontrol over the highly reactive prochiral alkyl radical intermediates.

Abstract

We describe a photoinduced copper‐catalyzed asymmetric radical decarboxylative alkynylation of bench‐stable N‐hydroxyphthalimide(NHP)‐type esters of racemic alkyl carboxylic acids with terminal alkynes, which provides a flexible platform for the construction of chiral C(sp³)−C(sp) bonds. Critical to the success of this process are not only the use of the copper catalyst as a dual photo‐ and cross‐coupling catalyst but also tuning of the NHP‐type esters to inhibit the facile homodimerization of the alkyl radical and terminal alkyne, respectively. Owing to the use of stable and easily available NHP‐type esters, the reaction features a broader substrate scope compared with reactions using the alkyl halide counterparts, covering (hetero)benzyl‐, allyl‐, and aminocarbonyl‐substituted carboxylic acid derivatives, and (hetero)aryl and alkyl as well as silyl alkynes, thus providing a vital complementary approach to the previously reported method.

Carboxylate, activate! Pd catalysis is generally assumed to be ineffective for cross‐coupling with most oxygen‐based electrophiles. It is demonstrated not only that alkenyl carboxylates are able to couple with boronic acids under extremely mild conditions, but that there are two distinct pathways for C−O activation. The result is an operationally simple arylation of many pharmaceutically relevant (hetero)cyclic cores with excellent functional‐group tolerance.

Abstract

Carboxylate esters have many desirable features as electrophiles for catalytic cross‐coupling: they are easy to access, robust during multistep synthesis, and mass‐efficient in coupling reactions. Alkenyl carboxylates, a class of readily prepared non‐aromatic electrophiles, remain difficult to functionalize through cross‐coupling. We demonstrate that Pd catalysis is effective for coupling electron‐deficient alkenyl carboxylates with arylboronic acids in the absence of base or oxidants. Furthermore, these reactions can proceed by two distinct mechanisms for C−O bond activation. A Pd^0/II catalytic cycle is viable when using a Pd⁰ precatalyst, with turnover‐limiting C−O oxidative addition; however, an alternative pathway that involves alkene carbopalladation and β‐carboxyl elimination is proposed for Pd^II precatalysts. This work provides a clear path toward engaging myriad oxygen‐based electrophiles in Pd‐catalyzed cross‐coupling.

Nature Communications, Published online: 26 June 2020; doi:10.1038/s41467-020-17057-z

DNA and proteins are chiral: Their three-dimensional structures cannot be superimposed with their mirror images. Circular dichroism spectroscopy is widely used to characterize chiral compounds, but data interpretation is difficult in the case of mixtures. We recorded the electronic circular dichroism spectra of DNA helices separated in a mass spectrometer. We studied guanine-rich strands having various secondary structures, electrosprayed them as negative ions, irradiated them with an ultraviolet nanosecond optical parametric oscillator laser, and measured the difference in electron photodetachment efficiency between left and right circularly polarized light. The reconstructed circular dichroism ion spectra resembled those of their solution-phase counterparts, thereby allowing us to assign the DNA helical topology. The ability to measure circular dichroism directly on biomolecular ions expands the capabilities of mass spectrometry for structural analysis.

Nature Chemistry, Published online: 22 June 2020; doi:10.1038/s41557-020-0482-8

Nature, Published online: 22 June 2020; doi:10.1038/s41586-020-2431-5

Make it shine: We report a photocatalyzed ring‐opening fluorination of cyclopropylamides and cyclobutylamides. Both cheap benzophenone with UVA light or organic and inorganic dyes with blue light could be used to promote this process. Various fluorinated amines were obtained through nucleophilic attack on the formed hemiaminals in one pot, giving access to a broad range of useful building blocks for medicinal chemistry.

Abstract

We report an oxidative ring‐opening strategy to transform cyclopropylamides and cyclobutylamides into fluorinated imines. The imines can be isolated in their more stable hemiaminal form, with the fluorine atom installed selectively at the γ or δ position. Both inexpensive benzophenone with UVA light or organic and inorganic dyes with blue light could be used as photoredox catalysts to promote this process. Various fluorinated amines were then obtained by nucleophilic attack on the hemiaminals in one pot, giving access to a broad range of useful building blocks for medicinal chemistry.

The description of substituents as electron donating or withdrawing leads to a perceived dominance of through‐bond influences. The situation is compounded by the challenge of separating through‐bond and through‐space contributions. Measurements of through‐space substituent effects question classic descriptions of substituent effects.

Abstract

The description of substituents as electron donating or withdrawing leads to a perceived dominance of through‐bond influences. The situation is compounded by the challenge of separating through‐bond and through‐space contributions. Here, we probe the experimental significance of through‐space substituent effects in molecular interactions and reaction kinetics. Conformational equilibrium constants were transposed onto the Hammett substituent constant scale revealing dominant through‐space substituent effects that cannot be described in classic terms. For example, NO₂ groups positioned over a biaryl bond exhibited similar influences as resonant electron donors. Meanwhile, the electro‐enhancing influence of OMe/OH groups could be switched off or inverted by conformational twisting. 267 conformational equilibrium constants measured across eleven solvents were found to be better predictors of reaction kinetics than calculated electrostatic potentials, suggesting utility in other contexts and for benchmarking theoretical solvation models.

A sea of expanding shapes: A combined experimental–computational approach enabled the synthesis of low‐symmetry imine cages from mixtures of tetraaldehyde building blocks. This “social self‐sorting” approach was applied to obtain a family of new cages containing heteroatoms, showing that pores of varying geometries and surface chemistries may be reliably accessed.

Abstract

Many interesting target guest molecules have low symmetry, yet most methods for synthesising hosts result in highly symmetrical capsules. Methods of generating lower symmetry pores are thus required to maximise the binding affinity in host–guest complexes. Herein, we use mixtures of tetraaldehyde building blocks with cyclohexanediamine to access low‐symmetry imine cages. Whether a low‐energy cage is isolated can be correctly predicted from the thermodynamic preference observed in computational models. The stability of the observed structures depends on the geometrical match of the aldehyde building blocks. One bent aldehyde stands out as unable to assemble into high‐symmetry cages‐and the same aldehyde generates low‐symmetry socially self‐sorted cages when combined with a linear aldehyde. We exploit this finding to synthesise a family of low‐symmetry cages containing heteroatoms, illustrating that pores of varying geometries and surface chemistries may be reliably accessed through computational prediction and self‐sorting.

Nature Chemistry, Published online: 15 June 2020; doi:10.1038/s41557-020-0481-9

Cool down: Depending on the cooling rate, a monomeric perylene bisimide equipped with four acyloxy bay substituents self‐assembles into two distinct polymorphs that exhibit distinctive optical properties and packing arrangements. The interchromophoric arrangement was elucidated in the liquid‐crystalline state, demonstrating the effect of homo‐ versus heterochiral self‐sorting, directing self‐assembly into one‐ or two‐dimensional structures, respectively.

Abstract

A new perylene bisimide (PBI), with a fluorescence quantum yield up to unity, self‐assembles into two polymorphic supramolecular polymers. This PBI bears four solubilizing acyloxy substituents at the bay positions and is unsubstituted at the imide position, thereby allowing hydrogen‐bond‐directed self‐assembly in nonpolar solvents. The formation of the polymorphs is controlled by the cooling rate of hot monomer solutions. They show distinctive absorption profiles and morphologies and can be isolated in different polymorphic liquid‐crystalline states. The interchromophoric arrangement causing the spectral features was elucidated, revealing the formation of columnar and lamellar phases, which are formed by either homo‐ or heterochiral self‐assembly, respectively, of the atropoenantiomeric PBIs. Kinetic studies reveal a narcissistic self‐sorting process upon fast cooling, and that the transformation into the heterochiral (racemic) sheetlike self‐assemblies proceeds by dissociation via the monomeric state.

Mechanically interlocked molecules are likely candidates for the design and synthesis of artificial molecular machines. Although polyrotaxanes have already found niche applications in exotic materials with specialized mechanical properties, efficient synthetic protocols to produce them with precise numbers of rings encircling their polymer dumbbells are still lacking. We report the assembly line–like emergence of poly[n]rotaxanes with increasingly higher energies by harnessing artificial molecular pumps to deliver rings in pairs by cyclical redox-driven processes. This programmable strategy leads to the precise incorporation of two, four, six, eight, and 10 rings carrying 8+, 16+, 24+, 32+, and 40+ charges, respectively, onto hexacationic polymer dumbbells. This strategy depends precisely on the number of redox cycles applied chemically or electrochemically, in both stepwise and one-pot manners.

Splashing down the ponds : The cascade photooxygenation of tetrahydrocarbazoles and cyclohepta[b ]indoles leads to chiral tricyclic perhydropyrido‐ and perhydroazepino[1,2‐a ]indoles, which are precursors to uncommon C ,N‐diacyliminium ions.

Abstract

Tetrahydrocarbazoles and perhydrocyclohepta[b]indoles undergo a catalytic cascade singlet oxygenation in alkaline medium, which leads to chiral tricyclic perhydropyrido‐ and perhydroazepino[1,2‐a]indoles in a single operation. These photooxygenation products are new synthetic equivalents of uncommon C,N‐diacyliminium ions and can be functionalized with the aid of phosphoric acid organocatalysis.