Replacement of Less-Preferred Dipolar Aprotic and Ethereal Solvents in Synthetic Organic Chemistry with More Sustainable Alternatives.

Dipolar aprotic and ethereal solvents comprise just over 40% of all organic solvents utilized in synthetic organic, medicinal, and process chemistry. Unfortunately, many of the common "go-to" solvents are considered to be "less-preferable" for a number of environmental, health, and safety (EHS) reasons such as toxicity, mutagenicity, carcinogenicity, or for practical handling reasons such as flammability and volatility. Recent legislative changes have initiated the implementation of restrictions on the use of many of the commonly employed dipolar aprotic solvents such as dimethylformamide (DMF) and N-methyl-2-pyrrolidinone (NMP), and for ethers such as 1,4-dioxane. Thus, with growing legislative, EHS, and societal pressures, the need to identify and implement the use of alternative solvents that are greener, safer, and more sustainable has never been greater. Within this review, the ubiquitous nature of dipolar aprotic and ethereal solvents is discussed with respect to the physicochemical properties that have made them so appealing to synthetic chemists. An overview of the current legislative restrictions being imposed on the use of dipolar aprotic and ethereal solvents is discussed. A variety of alternative, safer, and more sustainable solvents that have garnered attention over the past decade are then examined, and case studies and examples where less-preferable solvents have been successfully replaced with a safer and more sustainable alternative are highlighted. Finally, a general overview and guidance for solvent selection and replacement are included in the Supporting Information of this review.

Chlorinated Solvents: Their Advantages, Disadvantages, and Alternatives in Organic and Medicinal Chemistry.

Chlorinated solvents were once, and in many places are still, ubiquitous in chemistry laboratories. This review explores the properties that led to such widespread use, why there is now an increasing drive to minimize usage, and what alternatives are currently available.

The exploration of aza-quinolines as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors with low brain exposure.

GlaxoSmithKline and Astex Pharmaceuticals recently disclosed the discovery of the potent H-PGDS inhibitor GSK2894631A 1a (IC50 = 9.9 nM) as part of a fragment-based drug discovery collaboration with Astex Pharmaceuticals. This molecule exhibited good murine pharmacokinetics, allowing it to be utilized to explore H-PGDS pharmacology in vivo. Yet, with prolonged dosing at higher concentrations, 1a induced CNS toxicity. Looking to attenuate brain penetration in this series, aza-quinolines, were prepared with the intent of increasing polar surface area. Nitrogen substitutions at the 6- and 8-positions of the quinoline were discovered to be tolerated by the enzyme. Subsequent structure activity studies in these aza-quinoline scaffolds led to the identification of 1,8-naphthyridine 1y (IC50 = 9.4 nM) as a potent peripherally restricted H-PGDS inhibitor. Compound 1y is efficacious in four in vivo inflammatory models and exhibits no CNS toxicity.

The discovery of quinoline-3-carboxamides as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors.

With the goal of discovering more selective anti-inflammatory drugs, than COX inhibitors, to attenuate prostaglandin signaling, a fragment-based screen of hematopoietic prostaglandin D synthase was performed. The 76 crystallographic hits were sorted into similar groups, with the 3-cyano-quinoline 1a (FP IC50 = 220,000 nM, LE = 0.43) being a potent member of the 6,6-fused heterocyclic cluster. Employing SAR insights gained from structural comparisons of other H-PGDS fragment binding mode clusters, the initial hit 1a was converted into the 70-fold more potent quinoline 1d (IC50 = 3,100 nM, LE = 0.49). A systematic substitution of the amine moiety of 1d, utilizing structural information and array chemistry, with modifications to improve inhibitor stability, resulted in the identification of the 300-fold more active H-PGDS inhibitor tool compound 1bv (IC50 = 9.9 nM, LE = 0.42). This selective inhibitor exhibited good murine pharmacokinetics, dose-dependently attenuated PGD2 production in a mast cell degranulation assay and should be suitable to further explore H-PGDS biology.

Industry-Informed Workshops to Develop Graduate Skill Sets in the Circular Economy Using Systems Thinking.

Increasing demand for chemicals worldwide, depleting resources, consumer pressure, stricter legislation, and the rising cost of waste disposal are placing increasing pressure on chemical and related industries. For any organization to survive in the current arena of growing climate change laws and regulations, and increasing public influence, the issue of sustainability must be fundamental to the way it operates. A sustainable manufacturing approach will enable economic growth to be combined with environmental and social sustainability and will be realized via collaboration between a multidisciplinary community including chemists, biologists, engineers, environmental scientists, economists, experts in management, and policy makers. Hence, employees with new skills, knowledge, and experience are essential. To realize this approach, the design and development of a series of workshops encompassing systems thinking are presented here. After close consultation with industry, an annual program of interactive workshops has been designed for graduate students to go beyond examining the "greening" of chemical reactions, processes, and products, and instead embed a systems thinking approach to learning. The workshops provide a valuable insight into the issues surrounding sustainable manufacturing covering change management, commercialization, environmental impact, circular economy, legislation, and bioresources incorporating the conversion of waste into valuable products. The multidisciplinary course content incorporates industrial case studies, providing access to real business issues, and is delivered by experts from academic departments across campus and industry.

The catalytic Mitsunobu reaction: a critical analysis of the current state-of-the-art.

The Mitsunobu reaction is widely regarded as the pre-eminent method for performing nucleophilic substitutions of alcohols with inversion of configuration. However, its applicability to large-scale synthesis is undermined by the fact that alcohol activation occurs at the expense of two stoichiometric reagents - a phosphine and an azodicarboxylate. The ideal Mitsunobu reaction would be sub-stoichiometric in the phosphine and azodicarboxylate species and employ innocuous terminal oxidants and reductants to achieve recycling. This Review article provides a summary and analysis of recent advances towards the development of such catalytic Mitsunobu reactions.

Generation and Trapping of Ketenes in Flow.

Ketenes were generated by the thermolysis of alkoxyalkynes under flow conditions, and then trapped with amines and alcohols to cleanly give amides and esters. For a 10 min reaction time, temperatures of 180, 160, and 140 °C were required for >95 % conversion of EtO, iPrO, and tBuO alkoxyalkynes, respectively. Variation of the temperature and flow rate with inline monitoring of the output by IR spectroscopy allowed the kinetic parameters for the conversion of 1-ethoxy-1-octyne to be easily estimated (Ea = 105.4 kJ/mol). Trapping of the in-situ-generated ketenes by alcohols to give esters required the addition of a tertiary amine catalyst to prevent competitive [2+2] addition of the ketene to the alkoxyalkyne precursor.

Exploring diradical chemistry: a carbon-centered radical may act as either an anion or electrophile through an orbital isomer.

Diradical intermediates, formed by thermolysis of alkynylcyclobutenones, can display radical, anion, or electrophilic character because of the existence of an orbital isomer with zwitterionic and cyclohexatrienone character. Our realization that water, alcohols, and certain substituents can induce the switch provides new opportunities in synthesis. For example, it can be used to shut down radical pathways and to give access to aryl carbonates and tetrasubstituted quinones.

Experimental and computational insights into the mechanism of the copper(i)-catalysed sulfonylative Suzuki-Miyaura reaction.

A mechanistic study into the copper(i)-catalysed sulfonylative Suzuki-Miyaura reaction, incorporating sulfur dioxide, is described. Utilising spectroscopic and computational techniques, an exploration into the individual components of the competing catalytic cycles is delineated, including identification of the resting state catalyst, transmetalation of arylboronic acid onto copper(i), the sulfur dioxide insertion process, and the oxidative addition of aryl halide to CuI. Studies also investigated prominent side-reactions which were uncovered, including a competing copper(ii)-catalysed mechanism. This led to an additional proposed and connected CuI/CuII/CuIII catalytic cycle to account for by-product formation.

The NSAID glafenine rescues class 2 CFTR mutants via cyclooxygenase 2 inhibition of the arachidonic acid pathway.

Most cases of cystic fibrosis (CF) are caused by class 2 mutations in the cystic fibrosis transmembrane regulator (CFTR). These proteins preserve some channel function but are retained in the endoplasmic reticulum (ER). Partial rescue of the most common CFTR class 2 mutant, F508del-CFTR, has been achieved through the development of pharmacological chaperones (Tezacaftor and Elexacaftor) that bind CFTR directly. However, it is not clear whether these drugs will rescue all class 2 CFTR mutants to a medically relevant level. We have previously shown that the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen can correct F508del-CFTR trafficking. Here, we utilized RNAi and pharmacological inhibitors to determine the mechanism of action of the NSAID glafenine. Using cellular thermal stability assays (CETSAs), we show that it is a proteostasis modulator. Using medicinal chemistry, we identified a derivative with a fourfold increase in CFTR corrector potency. Furthermore, we show that these novel arachidonic acid pathway inhibitors can rescue difficult-to-correct class 2 mutants, such as G85E-CFTR > 13%, that of non-CF cells in well-differentiated HBE cells. Thus, the results suggest that targeting the arachidonic acid pathway may be a profitable way of developing correctors of certain previously hard-to-correct class 2 CFTR mutations.

New insights into cyclobutenone rearrangements: a total synthesis of the natural ROS-generating anti-cancer agent cribrostatin 6.

Aryl- and heteroarylcyclobutenone rearrangements proceed in excellent yield under continuous-flow conditions. The former shows a Hammett correlation with σ(I) providing strong evidence that electrocyclisation is the rate-determining step and has a late transition state. The reaction has been modelled by using DFT and CCSD(T) methods, with the latter giving excellent correlation with the experimental rate constant. A short and efficient total synthesis of cribrostatin 6, an anti-neoplastic and anti-microbial agent, provides a topical demonstration of the value of this method.

Mechanism of the cobalt oxazoline palladacycle (COP)-catalyzed asymmetric synthesis of allylic esters.

The catalytic enantioselective S(N)2' displacement of (Z)-allylic trichloroacetimidates catalyzed by the palladium(II) complex [COP-OAc](2) is a broadly useful method for the asymmetric synthesis of chiral branched allylic esters. A variety of experiments aimed at elucidating the nature of the catalytic mechanism and its rate- and enantiodetermining steps are reported. Key findings include the following: (a) the demonstration that a variety of bridged-dipalladium complexes are present and constitute resting states of the COP catalyst (however, monomeric palladium(II) complexes are likely involved in the catalytic cycle); (b) labeling experiments establishing that the reaction proceeds in an overall antarafacial fashion; (c) secondary deuterium kinetic isotope effects that suggest substantial rehybridization at both C1 and C3 in the rate-limiting step; and (d) DFT computational studies (B3-LYP/def2-TZVP) that provide evidence for bidentate substrate-bound intermediates and an anti-oxypalladation/syn-deoxypalladation pathway. These results are consistent with a novel mechanism in which chelation of the imidate nitrogen to form a cationic palladium(II) intermediate activates the alkene for attack by external carboxylate in the enantiodetermining step. Computational modeling of the transition-state structure for the acyloxy palladation step provides a model for enantioinduction.

Beyond the Pummerer reaction: recent developments in thionium ion chemistry.

Since the early 1960s the Pummerer reaction has evolved to become an indispensable tool for synthesis, and continues to serve as a source of inspiration for organic chemists. In recent years, many exciting advances have demonstrated the broad scope and synthetic utility of Pummerer methodology and the versatility of thionium ion intermediates.

Synthesis of 18O-labelled alcohols from unlabelled alcohols.

The synthesis of primary, secondary and tertiary 18O-enriched alcohols from readily available 16O-alcohols via a Mitsunobu esterification and hydrolysis is described. The method is further exemplified in the labelling of the active pharmaceutical ingredient, dropropizine and is shown to be tolerant of modern, separation friendly Mitsunobu reagents.

Catalytic Asymmetric Synthesis of Branched Chiral Allylic Phenyl Ethers from (E)-Allylic Alcohols.

The first di-µ-amidate dipalladium complexes and a new di-µ-carboxylate dipalladium complex of the COP (cobalt oxazoline palladacycle) palladium(II) catalyst family are reported and characterized crystallographically. The di-µ-amidate complex 3 or its enantiomer (ent-3) are the first asymmetric catalysts that allow commercially available, or readily accessible, (E)-2-alkene-1-ols to be transformed to enantioenriched branched allylic aryl ethers upon reaction of their trichloroacetimidate derivatives with phenols. The 3-aryloxy-1-alkene products are formed in high enantiomeric purity (typically 90-98% ee) and useful yields (61-88%).

Redox-neutral organocatalytic Mitsunobu reactions.

Nucleophilic substitution reactions of alcohols are among the most fundamental and strategically important transformations in organic chemistry. For over half a century, these reactions have been achieved by using stoichiometric, and often hazardous, reagents to activate the otherwise unreactive alcohols. Here, we demonstrate that a specially designed phosphine oxide promotes nucleophilic substitution reactions of primary and secondary alcohols in a redox-neutral catalysis manifold that produces water as the sole by-product. The scope of the catalytic coupling process encompasses a range of acidic pronucleophiles that allow stereospecific construction of carbon-oxygen and carbon-nitrogen bonds.

Catalytic asymmetric synthesis of allylic thiol derivatives.

The palladium(II) complex [(Rp,S)-COP-Cl]2 and its enantiomer catalyze the rearrangement of linear prochiral O-allyl carbamothioates under mild conditions to provide branched S-allyl carbamothioates in high yield and high enantiomeric purity.

Validation and optimization of novel high-throughput assays for human epithelial sodium channels.

The epithelial sodium channel (ENaC) plays a crucial role in salt and water homeostasis and is primarily involved in sodium reabsorption in the kidney and lung. Modulators of ENaC function, particularly within lung epithelia, could offer potential treatments for a number of diseases. As a constitutively active sodium channel, ENaC expression at the cell membrane is highly regulated through rapid turnover. This short half-life of the channel at the membrane and cytotoxicity from overexpression pose a problem for reagent generation and assay development in drug discovery. We have generated an HEK293 stable cell line expressing ENaC ß and γ subunits containing the PY motif trafficking mutations found in Liddle's syndrome to overcome rapid channel turnover at the membrane. A BacMam virus was used to transiently express the ENaC α subunit to reconstitute channel function to reduce the toxicity associated with long-term overexpression. We have configured a 384-well FLIPR membrane potential antagonist assay for high-throughput screening and an IonWorks Quattro electrophysiology antagonist assay that is predictive of potency values derived from primary lung epithelial cell short-circuit measurements. The triage strategy for compound screening and profiling against this target using these assays has resulted in the discovery of novel chemotypes.

Addition of dithiols to bis-ynones: development of a versatile platform for the synthesis of polyketide natural products.

[reaction: see text] The conjugate addition of dithiols to bis-ynones generates a versatile masked 1,3,5-triketone platform. These functional units are useful intermediates for the synthesis of oxygen-containing heterocycles commonly found in polyketide natural products. The tetrahydropyranyl fragments of the marine macrolides Lyngbouilloside and Callipeltoside A have been synthesized with use of this methodology.