Search

Polymer modification is a fundamental scientific challenge, as a means of both upcycling plastics and extracting a stimulus response from them. To date, the overwhelming majority of polymer modifications has focused on the polymer periphery. Herein, we demonstrate nearly quantitative, scission-free modification of polymer backbones, namely, a metamorphosis of polyesters into vinyl polymers resembling commodity materials via the Ireland-Claisen sigmatropic rearrangement. The glass transition temperature (Tg) and thermal stability of the polyesters undergo dramatic changes post-transformation. Beyond polymer modification, our work advances the application of retrosynthetic analysis in polymer synthesis; the nontraditional production of vinyl polymers from lactones opens the door to a slew of previously inaccessible materials.

An overview of the current uptake of continuous flow techniques for various functional group interconversion reactions is presented. Besides highlighting a variety of prominent examples and their main features, this review provides insights into specific reaction classes, such as oxidations, reductions, rearrangements as well as different C-H functionalization processes. While this review can only include key examples from the last decade, the reader will find a solid foundation of important transformations along with further references to inform and appreciate the opportunities arising from modern synthesis technologies such as flow synthesis.

A series of distinctive gap-fill activities were designed to provide practice and test students’ knowledge in retrosynthetic analysis. Developed and tested during the COVID-19 pandemic, the activities allow students to work through authentic multistep syntheses of various organic target molecules. Students were asked to identify appropriate RSA terminology and suitable reagents and answer questions on reaction selectivity and mechanisms. Mark schemes were provided so students could quickly evaluate their answers. Feedback results showed students enjoyed these activities and found them beneficial to their learning.

β-Seleno-α-amino acids, known as selenocysteine (Sec) derivatives, have emerged as important targets because of their role in chemical biology, not only as part of selenoproteins with important redox properties, but also because of their activity as antivirals or metabolites effective in inhibiting carcinogenesis. In addition, there is demand for this type of compounds due to their use in native chemical ligation to construct large peptides. Therefore, this review summarizes the various synthetic methods that have been published to construct Sec derivatives. Most of them involve the generation of the C–Se bond by nucleophilic substitution reactions, but other reactions such as radical or multicomponent strategies are also reported. Of particular importance is the Se-Michael addition of Se-nucleophiles to chiral bicyclic dehydroalanines, in which the stereogenic center is generated under complete stereocontrol.1 Introduction2 Previously Reviewed Synthesis of Sec3 Retrosynthesis of Sec Derivatives4 Sec Derivatives by Nucleophilic Substitutions5 Sec Derivatives by Radical Processes6 Sec Derivatives by 1,4-Conjugate Additions7 Conclusion

As a fundamental problem in chemistry, retrosynthesis aims at designing reaction pathways and intermediates for a target compound. The goal of artificial intelligence (AI)-aided retrosynthesis is to automate this process by learning from the previous chemical reactions to make new predictions. Although several models have demonstrated their potentials for automated retrosynthesis, there is still a significant need to further enhance the prediction accuracy to a more practical level. Here we propose a local retrosynthesis framework called LocalRetro, motivated by the chemical intuition that the molecular changes occur mostly locally during the chemical reactions. This differs from nearly all existing retrosynthesis methods that suggest reactants based on the global structures of the molecules, often containing fine details not directly relevant to the reactions. This local concept yields local reaction templates involving the atom and bond edits. Because the remote functional groups can also affect the overall reaction path as a secondary aspect, the proposed locally encoded retrosynthesis model is then further refined to account for the nonlocal effects of chemical reaction through a global attention mechanism. Our model shows a promising 89.5 and 99.2% round-trip accuracy at top-1 and top-5 predictions for the USPTO-50K dataset containing 50 016 reactions. We further demonstrate the validity of LocalRetro on a large dataset containing 479 035 reactions (UTPTO-MIT) with comparable round-trip top-1 and top-5 accuracy of 87.0 and 97.4%, respectively. The practical application of the model is also demonstrated by correctly predicting the synthesis pathways of five drug candidate molecules from various literature.

When organic students are asked to design a total synthesis of a molecule, they are often overwhelmed by the multitude of possible transformations. A decision tree is a useful tool to break complex problems up into simpler steps and scaffold the thinking process that many seasoned chemists take for granted. While many comprehensive resources present the logic and reaction strategies of retrosynthetic analysis, students still require scaffolded training in analyzing the functional group patterns of a molecule to arrive at the most prudent reaction. This work presents a 1-page flowchart that is readily implemented by undergraduates, organizes content, and ultimately helps students gain an appreciation for the more systematic aspects of retrosynthesis and organic synthesis more broadly.

Since their industrial introduction in the 1980s, DPP pigments now constitute a highly important group of high-performance carbonyl pigments. The DPP system was first discovered by accident in 1974, and was subsequently re-investigated by Ciba Geigy who recognized its potential to provide commercial organic pigments. DPP pigments exhibit strong similarities compared with quinacridone pigments, in terms of their molecular and crystal structures and their properties, including low solubility and excellent fastness properties. X-ray crystal structural analysis has demonstrated that their technical performance is the result of intermolecular hydrogen bonding and π–π stacking interactions in the crystal lattice structure. Based on a simple retrosynthetic analysis, an efficient synthetic process was developed by Ciba Geigy for their large-scale manufacture. DPP pigments currently provide orange through to reddish violet shades and have become of special importance in providing brilliant saturated red shades with the outstanding durability required for applications such as automotive paints.

The practice of deploying and teaching retrosynthesis is on the cusp of considerable change, which in turn forces practitioners and educators to contemplate whether this impending change will advance or erode the efficiency and elegance of organic synthesis in the future. A short treatise is presented herein that covers the concept of retrosynthesis, along with exemplified methods and theories, and an attempt to comprehend the impact of artificial intelligence in an era when freely and commercially available retrosynthetic and forward synthesis planning programs are increasingly prevalent. Will the computer ever compete with human retrosynthetic design and the art of organic synthesis?

We report on the synthesis of polysarcosine-block-poly(S-alkylsulfonyl)-l-cysteine block copolymers, which combine three orthogonal addressable groups enabling site-specific conversion of all reactive entities in a single step. The polymers are readily obtained by ring-opening polymerization (ROP) of corresponding α-amino acid N-carboxyanhydrides (NCAs) combining azide and amine chain ends, with a thiol-reactive S-alkylsulfonyl cysteine. Functional group interconversion of chain ends using strain-promoted azide–alkyne cycloaddition (SPAAC) and activated ester chemistry with NHS- and DBCO-containing fluorescent dyes could be readily performed without affecting the cross-linking reaction between thiols and S-alkylsulfonyl protective groups. Eventually, all three functionalities can be combined in the formation of multifunctional disulfide core cross-linked nanoparticles bearing spatially separated functionalities. The simultaneous attachment of dyes in core and corona during the formation of core-cross-link...

In the area of human-made innovations to improve the quality of life, biocatalysis has already had a great impact and contributed enormously to a growing number of catalytic transformations aimed at the detection and analysis of compounds, the bioconversion of starting materials and the preparation of target compounds at any scale, from laboratory small scale to industrial large scale. The key enabling tools which have been developed in biocatalysis over the last decades also provide great opportunities for further development and numerous applications in various sectors of the global bioeconomy. Systems biocatalysis is a modular, bottom-up approach to designing the architecture of enzyme-catalyzed reaction steps in a synthetic route from starting materials to target molecules. The integration of biocatalysis and sustainable chemistry in vitro aims at ideal conversions with high molecular economy and their intensification. Retrosynthetic analysis in the chemical and biological domain has been a valuable tool for target-oriented synthesis while, on the other hand, diversity-oriented synthesis builds on forward-looking analysis. Bioinformatic tools for rapid identification of the required enzyme functions, efficient enzyme production systems, as well as generalized bioprocess design tools, are important for rapid prototyping of the biocatalytic reactions. The tools for enzyme engineering and the reaction engineering of each enzyme-catalyzed one-step reaction are also valuable for coupling reactions. The tools to overcome interaction issues with other components or enzymes are of great interest in designing multi-step reactions as well as in biocatalytic total synthesis.

The systematic exploration of synthetic pathways to afford a desired product through quantum chemical calculations remains a considerable challenge. In 2013, Maeda et al. introduced ‘quantum chemistry aided retrosynthetic analysis’ (QCaRA), which uses quantum chemical calculations to search systematically for the decomposition paths of a target product and proposes a synthesis method. However, until now, no new reactions suggested by QCaRA have been reported to lead to experimental discoveries. Using a difluoroglycine derivative as a target, this study investigated the ability of QCaRA to suggest various synthetic paths to the target without relying on previous data or the knowledge and experience of chemists. Furthermore, experimental verification of the most promising path chosen by an organic chemist among the predicted paths led to the discovery of a synthesis method for a difluoroglycine derivative. We emphasize that the purpose of this study is not to propose a fully automated workflow. Therefore, the extent of the hands-on expertise of chemists required during the verification process was also evaluated. These insights are expected to advance the applicability of QCaRA to the discovery of viable experimental synthetic routes., QCaRA successfully predicted a new synthetic path based on the reaction path network produced by quantum chemical calculation.

Exposure to diacetyl (DA) has been linked to the respiratory condition bronchiolitis obliterans. Previous research has demonstrated that DA and other α-dicarbonyl compounds can be detected in both the e-liquids and aerosols of e-vapor products (EVPs). While some EVP manufacturers may add these compounds as flavor ingredients, the primary objective of this work was to determine the potential for the formation of α-dicarbonyl compounds during the generation of aerosols from EVPs where no DA or other α-dicarbonyl compounds are added to the e-liquid. A novel ultraperformance liquid chromatography-mass spectrometry-based analytical method for the determination of DA, acetyl propionyl, glyoxal, and methylglyoxal was developed and validated. Next, eight commercially available cig-a-like-type EVPs were evaluated for α-dicarbonyl formation. Increased levels of α-dicarbonyls were observed in the aerosols of all evaluated EVPs compared to their respective e-liquids. Mechanistic studies were conducted using a model microwave reaction system to identify key reaction precursors for DA generated from propylene glycol (PG) and carbon-13-labeled glycerin (GLY). These studies, along with the corresponding retrosynthetic analysis, resulted in the proposed formation pathway where hydroxyacetone is generated from PG and/or GLY. Hydroxyacetone then participates in an aldol condensation with formaldehyde where formaldehyde can also be generated from PG and/or GLY; the resultant product then dehydrates to form DA. This proposed pathway was further investigated through in situ synthetic organic experiments within the model microwave reaction system. This work establishes that DA is formed in the aerosol generation process of the EVPs tested though at levels below toxicological concern.

We describe a methodology for the amidation of carboxylic acids by generating phosphonium salts in situ from N-chlorophthalimide and triphenylphosphine. Aliphatic, benzylic, and aromatic carboxylic acids can be transformed into their amide counter parts using primary and secondary amines. This functional group interconversion is achieved at room temperature in good to excellent yields. Mechanistic work shows the in situ formation of chloro- and imido-phosphonium salts that react as activating agents for carboxylic acids and generate an acyloxy-phosphonium species.

A short, enantioselective synthesis of (-)-maximiscin, a structurally intriguing metabolite of mixed biosynthetic origin, is reported. A retrosynthetic analysis predicated on maximizing ideality and efficiency led to several unusual disconnections and tactics. Formation of the central highly oxidized pyridone ring through a convergent coupling at the end of the synthesis simplified the route considerably. The requisite building blocks could be prepared from feedstock materials (derived from shikimate and mesitylene). Strategies rooted in hidden symmetry recognition, C-H functionalization, and radical retrosynthesis played key roles in developing this concise route.

Retrosynthetic analysis is a canonical technique for planning the synthesis route of organic molecules in drug discovery and development. In this technique, the screening of synthetic tree branches requires accurate forward reaction prediction, but existing software is far from completing this step independently. Previous studies attempted to apply a neural network to forward reaction prediction, but the accuracy was not satisfying. Through using the Edit Vector-based description and extended-connectivity fingerprints to transform the reaction into a vector, this study focuses on the update of the neural network to improve the template-based forward reaction prediction. Hard-threshold activation and the target propagation algorithm are implemented by introducing mixed convex-combinatorial optimization. Comparative tests were conducted to explore the optimal hyperparameter set. Using 15,000 experimental reaction data extracted from granted United States patents, the proposed hard-threshold neural network was systematically trained and tested. The results demonstrated that a higher prediction accuracy was obtained than that for the traditional neural network with backpropagation algorithm. Some successfully predicted reaction examples are also briefly illustrated.

Visible-light-mediated chemical reactions have become very popular within the last 15 years. Many excellent reviews have summarized reaction principles and recent results in photochemistry and photocatalysis. However, despite their popularity photochemistry and photoredox catalysis are not regular parts of the bachelor and master curriculum of chemistry education. As a consequence, most chemists will use in synthesis planning classic retrosynthetic disconnections and only rarely consider photocatalytic steps. The aim of this article is to be a useful tool for synthetic chemists, that are interested in the synthetic aspects of photocatalysis and looking for a specific retrosynthetic disconnection. Not only are informative schemes provided but also are the availability of the catalysts and reagents as well as the functional group tolerance of the respective method briefly discussed.

We report here the efficient synthesis of 6,6′-diamido-2,2′-dipicolylamines (DA-DPAs) which could be applied to phosphate anion sensing via pre-formed metal complexes. The design was based on the retrosynthetic analysis. This strategy enabled us to achieve the functionalized DA-DPAs in satisfactory yields with high purity using the Boekelheide rearrangement. Meanwhile, all the intermediates could be easily purified by silica gel column chromatography.

The challenge of pharmacological effect prediction and its relation to analog design consists of the decision of which molecule to make next on the basis of the available data, medicinal chemistry knowledge, experience, and intuition. In the second half of the 1900s century, attempts were made to relate narcotics pharmacology to their physicochemical properties by specifically using distribution and partition coefficients. This was shortly followed by Paul Ehrlich's observation to attribute the pharmacological effect of a compound to a specific functional group. However, it was only in 1971 that this observation was called pharmacophore. About 30 years after Ehrlich, Hammett related the effect of changes in structure on reaction mechanisms, specifically based on resonance interaction of an aromatic ring. This model was later extended by Taft by separating the inductive effects from the steric properties of substituents. This concept was formalized with the work of Hansch, Free, and Wilson which reasoned that the biological activity for a set of analogs could be described by the contributions that substituents or structural elements make to the activity of a parent structure. This led to the analytical description of general quantitative-structure–activity relationship studies (QSAR). If the question “What to synthesize next?” is answered then “How to synthesize it?” follows up. The prediction of chemical reactions starting from educts or the product and educing input reactants and reaction conditions is a fundamental scientific problem. As QSAR computer-aided synthesis planning (CASP) has a long history starting in the 1960s with LHASA a rule-based approach to retrosynthesis planning.

Biocatalysis has traditionally been viewed as a field that primarily enables access to chiral centers. This includes the synthesis of chiral alcohols, amines and carbonyl compounds, often through functional group interconversion via hydrolytic or oxidation-reduction reactions. This limitation is partly being overcome by the design and evolution of new enzymes. Here, we provide an overview of a recently thriving research field that we summarize as biocatalytic alkylation chemistry. In the past 3-4 years, numerous new enzymes have been developed that catalyze sp3 C-C/N/O/S bond formations. These enzymes utilize different mechanisms to generate molecular complexity by coupling simple fragments with high activity and selectivity. In many cases, the engineered enzymes perform reactions that are difficult or impossible to achieve with current small-molecule catalysts such as organocatalysts and transition-metal complexes. This review further highlights that the design of new enzyme function is particularly successful when off-the-shelf synthetic reagents are utilized to access non-natural reactive intermediates. This underscores how biocatalysis is gradually moving to a field that build molecules through selective bond forming reactions. © 2021 The Authors. ChemPlusChem published by Wiley-VCH GmbH.