Umpolung strategies for the functionalization of peptides and proteins

Umpolung strategies, defined as synthetic approaches which reverse commonly accepted reactivity patterns, are broadly recognized as enabling tools for small molecule synthesis and catalysis. However, methods which exploit this logic for peptide and protein functionalizations are comparatively rare, with the overwhelming majority of existing bioconjugation approaches relying on the well-established reactivity profiles of a handful of amino acids. This perspective serves to highlight a small but growing body of recent work that masterfully capitalizes on the concept of polarity reversal for the selective modification of proteinogenic functionalities. Current applications of umpolung chemistry in organic synthesis and chemical biology as well as the vast potential for further innovations in peptide and protein modification will be discussed.

This perspective highlights the growing body of literature that leverages polarity reversal (umpolung reactivity) for the selective modification of proteinogenic functionalities and identifies opportunities for further innovation.     

Distinctive features and challenges in catenane chemistry

From being an aesthetic molecular object to a building block for the construction of molecular machines, catenanes and related mechanically interlocked molecules (MIMs) continue to attract immense interest in many research areas. Catenane chemistry is closely tied to that of rotaxanes and knots, and involves concepts like mechanical bonds, chemical topology and co-conformation that are unique to these molecules. Yet, because of their different topological structures and mechanical bond properties, there are some fundamental differences between the chemistry of catenanes and that of rotaxanes and knots although the boundary is sometimes blurred. Clearly distinguishing these differences, in aspects of bonding, structure, synthesis and properties, between catenanes and other MIMs is therefore of fundamental importance to understand their chemistry and explore the new opportunities from mechanical bonds.

Catenane chemistry is closely associated with that of rotaxane and knot, and this perspective highlights their similarities and differences in various aspects including synthesis, structure and properties.     

Supramolecular chemistry in lipid bilayer membranes

Lipid bilayer membranes form compartments requisite for life. Interfacing supramolecular systems, including receptors, catalysts, signal transducers and ion transporters, enables the function of the membrane to be controlled in artificial and living cellular compartments. In this perspective, we take stock of the current state of the art of this rapidly expanding field, and discuss prospects for the future in both fundamental science and applications in biology and medicine.

This perspective provides an overview of the current state of the art in supramolecular chemistry in lipid bilayer membranes, including receptors, signal transducers, catalysts and transporters, and highlights prospects for the future.     

Sulfur stereogenic centers in transition-metal-catalyzed asymmetric C–H functionalization: generation and utilization

Transition-metal-catalyzed enantioselective C–H functionalization has emerged as a powerful tool for the synthesis of enantioenriched compounds in chemical and pharmaceutical industries. Sulfur-based functionalities are ubiquitous in many of the biologically active compounds, medicinal agents, functional materials, chiral auxiliaries and ligands. This perspective highlights recent advances in sulfur functional group enabled transition-metal-catalyzed enantioselective C–H functionalization for the construction of sulfur stereogenic centers, as well as the utilization of chiral sulfoxides to realize stereoselective C–H functionalization.

This perspective highlights sulfur functional groups enabled enantioselective C–H functionalization for the construction of sulfur stereogenic centers, and the utilization of chiral sulfoxide to realize stereoselective C–H functionalization.     

On-surface synthesis of organocopper metallacycles through activation of inner diacetylene moieties

The design of organometallic complexes is at the heart of modern organic chemistry and catalysis. Recently, on-surface synthesis has emerged as a disruptive paradigm to design previously precluded compounds and nanomaterials. Despite these advances, the field of organometallic chemistry on surfaces is still at its infancy. Here, we introduce a protocol to activate the inner diacetylene moieties of a molecular precursor by copper surface adatoms affording the formation of unprecedented organocopper metallacycles on Cu(111). The chemical structure of the resulting complexes is characterized by scanning probe microscopy and X-ray photoelectron spectroscopy, being complemented by density functional theory calculations and scanning probe microscopy simulations. Our results pave avenues to the engineering of organometallic compounds and steer the development of polyyne chemistry on surfaces.

The diacetylene skeletons of DNBD precursors are attacked on Cu(111) by copper adatoms resulting in the synthesis of organocopper metallacycles.     

Bottom-up supramolecular assembly in two dimensions

The self-assembly of molecules in two dimensions (2D) is gathering attention from all disciplines across the chemical sciences. Attracted by the interesting properties of two-dimensional inorganic analogues, monomers of different chemical natures are being explored for the assembly of dynamic 2D systems. Although many important discoveries have been already achieved, great challenges are still to be addressed in this field. Hierarchical multicomponent assembly, directional non-covalent growth and internal structural control are a just a few of the examples that will be discussed in this perspective about the exciting present and the bright future of two-dimensional supramolecular assemblies.

The self-assembly of molecules in two dimensions (2D) is gathering attention from all disciplines across the chemical sciences. This perspective discusses the main strategies to direct the supramolecular self-assembly of organic monomers in 2D.     

A direct-to-biology high-throughput chemistry approach to reactive fragment screening

Methods for rapid identification of chemical tools are essential for the validation of emerging targets and to provide medicinal chemistry starting points for the development of new medicines. Here, we report a screening platform that combines ‘direct-to-biology’ high-throughput chemistry (D2B-HTC) with photoreactive fragments. The platform enabled the rapid synthesis of >1000 PhotoAffinity Bits (HTC-PhABits) in 384-well plates in 24 h and their subsequent screening as crude reaction products with a protein target without purification. Screening the HTC-PhABit library with carbonic anhydrase I (CAI) afforded 7 hits (0.7% hit rate), which were found to covalently crosslink in the Zn²⁺ binding pocket. A powerful advantage of the D2B-HTC screening platform is the ability to rapidly perform iterative design–make–test cycles, accelerating the development and optimisation of chemical tools and medicinal chemistry starting points with little investment of resource.

A photoreactive fragment screening platform employing direct-to-biology high-throughput chemistry (D2B-HTC) for the rapid iterative synthesis and screening of libraries of photoaffinity bits.     

Vessel effects in organic chemical reactions; a century-old,overlooked phenomenon

One of the most intriguing aspects of synthetic chemistry is the interplay of numerous dependent and independent variables en route to achieve a successful, high-yielding chemical transformation. The experienced synthetic chemist will probe many of these variables during reaction development and optimization, which will routinely involve investigation of reaction temperature, solvent, stoichiometry, concentration, time, choice of catalyst, addition sequence or quenching conditions just to name some commonly addressed variables. Remarkably, little attention is typically given to the choice of reaction vessel material as the surface of common laboratory borosilicate glassware is, incorrectly, assumed to be chemically inert. When reviewing the scientific literature, careful consideration of the vessel material is typically only given during the use of well-known glass-etching reagents such as HF, which is typically only handled in HF-resistant, polyfluorinated polymer vessels. However, there are examples of chemical transformations that do not involve such reagents but are still clearly influenced by the choice of reaction vessel material. In the following review, we wish to condense the most significant examples of vessel effects during chemical transformations as well as observations of container-dependent stability of certain molecules. While the primary focus is on synthetic organic chemistry, relevant examples from inorganic chemistry, polymerization reactions, atmospheric chemistry and prebiotic chemistry are also covered.

One of the most intriguing aspects of synthetic chemistry is the interplay of numerous dependent and independent variables en route to achieve a successful, high-yielding chemical transformation.     

Generation of organo-alkaline earth metal complexes from non-polar unsaturated molecules and their synthetic applications

Organomagnesium compounds, represented by the Grignard reagents, are one of the most classical yet versatile carbanion species which have widely been utilized in synthetic chemistry. These reagents are typically prepared via oxidative addition of organic halides to magnesium metals, via halogen–magnesium exchange between halo(hetero)arenes and organomagnesium reagents or via deprotonative magnesiation of prefunctionalized (hetero)arenes. On the other hand, recent studies have demonstrated that the organo-alkaline earth metal complexes including those based on heavier alkaline earth metals such as calcium, strontium and barium could be generated from readily available non-polar unsaturated molecules such as alkenes, alkynes, 1,3-enynes and arenes through unique metallation processes. Nonetheless, the resulting organo-alkaline earth metal complexes could be further functionalized with a variety of electrophiles in various reaction modes. In particular, organocalcium, strontium and barium species have shown unprecedented reactivity in the downstream functionalization, which could not be observed in the reactivity of organomagnesium complexes. This perspective will focus on the newly emerging protocols for the generation of organo-alkaline earth metal complexes from non-polar unsaturated molecules and their applications in chemical synthesis and catalysis.

In this perspective, we highlight the recent development of metallation protocols of non-polar unsaturated molecules for the generation of organo-alkaline earth metal compounds and their applications in chemical synthesis and catalysis.     

Structure-mechanics statistical learning uncovers mechanical relay in proteins

A protein''s adaptive response to its substrates is one of the key questions driving molecular physics and physical chemistry. This work employs the recently developed structure-mechanics statistical learning method to establish a mechanical perspective. Specifically, by mapping all-atom molecular dynamics simulations onto the spring parameters of a backbone-side-chain elastic network model, the chemical moiety specific force constants (or mechanical rigidity) are used to assemble the rigidity graph, which is the matrix of inter-residue coupling strength. Using the S1A protease and the PDZ3 signaling domain as examples, chains of spatially contiguous residues are found to exhibit prominent changes in their mechanical rigidity upon substrate binding or dissociation. Such a mechanical-relay picture thus provides a mechanistic underpinning for conformational changes, long-range communication, and inter-domain allostery in both proteins, where the responsive mechanical hotspots are mostly residues having important biological functions or significant mutation sensitivity.

Protein residues exhibit specific routes of mechanical relay as the adaptive responses to substrate binding or dissociation. On such physically contiguous connections, residues experience prominent changes in their coupling strengths.     

Proton to hydride umpolung at a phosphonium center via electron relay: a new strategy for main-group based water reduction

Generation of dihydrogen from water splitting, also known as water reduction, is a key process to access a sustainable hydrogen economy for energy production and usage. The key step is the selective reduction of a protic hydrogen to an accessible and reactive hydride, which has proven difficult at a p-block element. Although frustrated Lewis pair (FLP) chemistry is well known for water activation by heterolytic H–OH bond cleavage, to the best of our knowledge, there has been only one case showing water reduction by metal-free FLP systems to date, in which silylene (Si^II) was used as the Lewis base. This work reports the molecular design and synthesis of an ortho-phenylene linked bisborane-functionalized phosphine, which reacts with water stoichiometrically to generate H₂ and phosphine oxide quantitatively under ambient conditions. Computational investigations revealed an unprecedented multi-centered electron relay mechanism offered by the molecular framework, shuttling a pair of electrons from hydroxide (OH⁻) in water to the separated proton through a borane-phosphonium-borane path. This simple molecular design and its water reduction mechanism opens new avenues for this main-group chemistry in their growing roles in chemical transformations.

A (bisborane)triarylphosphine was developed to spontaneously generate H₂ from water under ambient conditions, revealing an unprecedented multi-centered electron relay mechanism for a metal-free umpolung of proton to hydride.     

Asymmetric transformations from sulfoxonium ylides

Sulfoxonium ylides are important surrogates for diazo compounds, and their use in industry as safer alternatives has been evaluated during recent years. Beyond the known classical transformations, these ylides have also been used in a surprising plethora of novel and intrinsic chemical reactions, especially in recent years. Bench stability and handling are also an advantage of this class of organosulfur molecules. Despite this, efficient asymmetric transformations, specifically catalytic enantioselective versions, have only recently been reported, and there are specific reasons for this. This perspective article covers this topic from the first studies up to the latest advances, giving personal perspectives and showing the main challenges in this area in the coming years.

Asymmetric transformations involving sulfoxonium ylides, culminating in catalytic enantioselective versions, are discussed in this perspective.     

Low-cost prediction of molecular and transition state partition functions via machine learning

We have generated an open-source dataset of over 30 000 organic chemistry gas phase partition functions. With this data, a machine learning deep neural network estimator was trained to predict partition functions of unknown organic chemistry gas phase transition states. This estimator only relies on reactant and product geometries and partition functions. A second machine learning deep neural network was trained to predict partition functions of chemical species from their geometry. Our models accurately predict the logarithm of test set partition functions with a maximum mean absolute error of 2.7%. Thus, this approach provides a means to reduce the cost of computing reaction rate constants ab initio. The models were also used to compute transition state theory reaction rate constant prefactors and the results were in quantitative agreement with the corresponding ab initio calculations with an accuracy of 98.3% on the log scale.

Deep neural networks accurately predict transition state partition functions at the low cost of reactant and product input features for organic chemistry gas phase reactions.     

f-Element silicon and heavy tetrel chemistry

The last three decades have seen a significant increase in the number of reports of f-element carbon chemistry, whilst the f-element chemistry of silicon, germanium, tin, and lead remain underdeveloped in comparison. Here, in this perspective we review complexes that contain chemical bonds between f-elements and silicon or the heavier tetrels since the birth of this field in 1985 to present day, with the intention of inspiring researchers to contribute to its development and explore the opportunities that it presents. For the purposes of this perspective, f-elements include lanthanides, actinides and group 3 metals. We focus on complexes that have been structurally authenticated by single-crystal X-ray diffraction, and horizon-scan for future opportunities and targets in the area.

In this perspective we review the molecular chemistry of f-element silicon and heavy tetrel complexes.     

An open source computational workflow for the discovery of autocatalytic networks in abiotic reactions

A central question in origins of life research is how non-entailed chemical processes, which simply dissipate chemical energy because they can do so due to immediate reaction kinetics and thermodynamics, enabled the origin of highly-entailed ones, in which concatenated kinetically and thermodynamically favorable processes enhanced some processes over others. Some degree of molecular complexity likely had to be supplied by environmental processes to produce entailed self-replicating processes. The origin of entailment, therefore, must connect to fundamental chemistry that builds molecular complexity. We present here an open-source chemoinformatic workflow to model abiological chemistry to discover such entailment. This pipeline automates generation of chemical reaction networks and their analysis to discover novel compounds and autocatalytic processes. We demonstrate this pipeline''s capabilities against a well-studied model system by vetting it against experimental data. This workflow can enable rapid identification of products of complex chemistries and their underlying synthetic relationships to help identify autocatalysis, and potentially self-organization, in such systems. The algorithms used in this study are open-source and reconfigurable by other user-developed workflows.

We present an open-source chemoinformatic workflow to generate and analyze complex abiological chemical networks to discover novel compounds and autocatalytic processes. We demonstrate this pipeline''s capabilities against a well-studied model system.     

A general strategy for the synthesis of α-trifluoromethyl- and α-perfluoroalkyl-β-lactams via palladium-catalyzed carbonylation

β-Lactam compounds play a key role in medicinal chemistry, specifically as the most important class of antibiotics. Here, we report a novel one-step approach for the synthesis of α-(trifluoromethyl)-β-lactams and related products from fluorinated olefins, anilines and CO. Utilization of an advanced palladium catalyst system with the Ruphos ligand allows for selective cycloaminocarbonylations to give diverse fluorinated β-lactams in high yields.

β-Lactam compounds play a key role in medicinal chemistry, specifically as the most important class of antibiotics.     

Automation isn't automatic

Automation has become an increasingly popular tool for synthetic chemists over the past decade. Recent advances in robotics and computer science have led to the emergence of automated systems that execute common laboratory procedures including parallel synthesis, reaction discovery, reaction optimization, time course studies, and crystallization development. While such systems offer many potential benefits, their implementation is rarely automatic due to the highly specialized nature of synthetic procedures. Each reaction category requires careful execution of a particular sequence of steps, the specifics of which change with different conditions and chemical systems. Careful assessment of these critical procedural requirements and identification of the tools suitable for effective experimental execution are key to developing effective automation workflows. Even then, it is often difficult to get all the components of an automated system integrated and operational. Data flows and specialized equipment present yet another level of challenge. Unfortunately, the pain points and process of implementing automated systems are often not shared or remain buried deep in the SI. This perspective provides an overview of the current state of automation of synthetic chemistry at the benchtop scale with a particular emphasis on core considerations and the ensuing challenges of deploying a system. Importantly, we aim to reframe automation as decidedly not automatic but rather an iterative process that involves a series of careful decisions (both human and computational) and constant adjustment.

The process of automating chemistry involves a wide variety of considerations that are often overlooked.     

Catalytic defluorinative ketyl–olefin coupling by halogen-atom transfer

Ketyl–olefin coupling reactions stand as one of the fundamental chemical transformations in synthetic chemistry and have been widely employed in the generation of complex molecular architectures and natural product synthesis. However, catalytic ketyl–olefin coupling, until the recent development of photoredox chemistry and electrosynthesis through single-electron transfer mechanisms, has remained largely undeveloped. Herein, we describe a new approach to achieve catalytic ketyl–olefin coupling reactions by a halogen-atom transfer mechanism, which provides innovative and efficient access to various gem-difluorohomoallylic alcohols under mild conditions with broad substrate scope. Preliminary mechanistic experimental and computational studies demonstrate that this radical-to-polar crossover transformation could be achieved by sequentially orchestrated Lewis acid activation, halogen-atom transfer, radical addition, single-electron reduction and β-fluoro elimination.

A catalytic ketyl–olefin coupling reaction including sequentially orchestrated Lewis acid activation, halogen-atom transfer, radical addition, single-electron reduction and β-fluoro elimination has been developed.     

Chiral assembly of organic luminogens with aggregation-induced emission

Chirality is important to chemistry, biology and optoelectronic materials. The study on chirality has lasted for more than 170 years since its discovery. Recently, chiral materials with aggregation-induced emission (AIE) have attracted increasing interest because of their fascinating photophysical properties. In this review, we discussed the recent development of chiral materials with AIE properties, including their molecular structures, self-assembly and functions. Generally, the most effective strategy to design a chiral AIE luminogen (AIEgen) is to attach a chiral scaffold to an AIE-active fluorophore through covalent bonds. Moreover, some propeller-like or shell-like AIEgens without chiral units exhibit latent chirality upon mirror image symmetry breaking. The chirality of achiral AIEgens can also be induced by some optically active molecules through non-covalent interactions. The introduction of an AIE unit into chiral materials can enhance the efficiency of their circularly polarized luminescence (CPL) in the solid state and the dissymmetric factors of their helical architectures formed through self-assembly. Thus, highly efficient circularly polarized organic light-emitting diodes (CPOLEDs) with AIE characteristics are developed and show great potential in 3D displays. Chiral AIEgens are also widely utilized as “turn on” sensors for rapid enantioselective determination of chiral reagents. It is anticipated that the present review can entice readers to realize the importance of chirality and attract much more chemists to contribute their efforts to chirality and AIE study.

This review highlights the recent development of chiral materials with aggregation-induced emission properties, including their molecular structures, self-assembly and functions.