Helen F. Sneddon

Helen F. Sneddon
GlaxoSmithKline | GSK

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66
Publications
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3,399
Citations

Publications

Publications (66)
Article
A solvent-reagent selection guide for Steglich esterification has been developed. Safer, more sustainable solvent-reagent combinations were identified and optimized for this transformation effectively replacing the more harmful, toxic status quo .
Article
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.
Article
Full-text available
Herein we report our efforts to improve the sustainability of the Delépine reaction for the formation of primary amines from activated alkyl halides. A number of alternative greener, more sustainable solvents to the traditionally employed chloroform were identified and the use of dimethyl carbonate (DMC) as solvent was exemplified in the synthesis...
Article
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...
Article
Herein we report a green, chromatography-free Appel chlorination and bromination in both catalytic and stoichiometric form. Improved sustainability was achieved via the effective replacement of chlorinated solvents with dimethyl carbonate and the use of triphenylphosphine oxide (PPh3O) as a recyclable organocatalyst. The substrate scope of this hal...
Article
Full-text available
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 i...
Article
In an effort to improve sustainability and reduce the cost of goods for active pharmaceutical ingredients (APIs), pharma companies have partnered on varying portions of their supply chain with contract providers. This approach brings with it numerous cost benefits but also logistical challenges. However, it also offers opportunities to integrate su...
Article
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 desig...
Article
Full-text available
For the first time a solvent-reagent guide has been developed with a view to providing greener synthetic conditions for the preparation of thioesters. A number of solvents and reagents were...
Article
The synthesis of amides is of widespread importance, and there has been considerable recent interest in the development of catalytic methods to access these molecules. In this Perspective, we provide an overview of the current state of the art in amide synthesis, and assess new catalytic amide formation methods in the context of efficiency and sust...
Article
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. T...
Article
Palladium-catalyzed bond-forming reactions, such as the ­Suzuki–Miyaura and Mizoroki–Heck reactions, are some of the most broadly utilized reactions within the chemical industry. These reactions frequently employ hazardous solvents; however, to adhere to increasing sustainability pressures and restrictions regarding the use of such solvents, altern...
Chapter
As most reactions used in the pharmaceutical manufacturing industry are still conducted in "traditional" molecular solvents, this chapter discusses potentially greener alternatives and emerging new molecular solvents produced from renewable resources. A large number of solvent selection guides and tools exist and these have been extensively reviewe...
Article
The chemical industry is under pressure to increase the sustainability of its operations. Key focus areas include the use of more resource-efficient bond-forming methods and replacements for hazardous solvents. In this Synergy article, we discuss the potential benefits of using sustainable solvents in academic method development.
Article
Residual solvents often appear as nuisance signals in experimental NMR spectra, and many chemists turn to well-known literature sources to quickly identify such peaks. While these publications are very useful, they do not currently include many solvents exemplified in green chemistry-related literature. This work provides a single compiled referenc...
Article
GlaxoSmithKline (GSK) has previously reported on the development of a GSK solvent guide, the incorporation of lifecycle impact and the expansion of the guide including a customisable version intended for posting in different business areas. This guide has recently been enhanced by: (1) adding 44 additional solvents, many of which have literature cl...
Article
Editorial on the principle that substances and the forms of a substance used in a chemical process should be chosen so as to minimize the potential for chemical accidents, including releases, explosions, and fires.
Article
Full-text available
Correction for ‘CHEM21 selection guide of classical- and less classical-solvents’ by Denis Prat, et al., Green Chem., 2015, DOI: 10.1039/c5gc01008j.
Article
Full-text available
A selection guide of common solvents has been elaborated, based on a survey of publically available solvent selection guides. In order to rank less classical solvents, a set of Safety, Health and Environment criteria is proposed, aligned with the Global Harmonized System (GHS) and European regulations. A methodology based on a simple combination of...
Article
Ketenes are generated in situ by thermolysis of ethoxyalkynes under flow conditions and trapped with amines or alcohols to form amides and esters respectively.
Article
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....
Article
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....
Article
A facile protocol for the base-mediated SNAr coupling of 2-chloropyrimidine and 2-chloropyrazine with phenols and alcohols to produce heteroaryl ethers is presented.
Article
Full-text available
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 r...
Article
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...
Article
Under similar conditions, in situ generated cinnamyl alcohol is immediately oxidized into the corresponding alcohol (IV).
Article
Further to the introduction of solvent and reagent guides at GSK, the reagent guide methodology has been adapted to score common acids and bases, for use in situations where the chemistry is tolerant of a number of options. The pKa of each acid and base, and information as to whether they are generally recognised as safe are included to enhance the...
Article
Visible light has a dramatic effect on the oxidation of benzylic and allylic alcohols, including those deactivated by electron-withdrawing groups, and β-O-4 lignin models, using catalytic amounts of the organo-oxidant 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. Sodium nitrite or tert-butyl nitrite is used as cocatalyst, and oxygen is employed as the...
Article
Chromatography is routinely used in drug discovery as a means to isolate intermediates and final compounds. From a sustainability perspective, it is one of the largest contributors of solvent waste in the drug discovery process. The medicinal chemistry subgroup within the American Chemical Society's Green Chemistry Institute Pharmaceutical Roundtab...
Article
The concept of molar efficiency is introduced as a new metric to enable assessment of reaction efficiency in discovery medicinal chemistry. Calculations from molar units enable cross-comparison of the broad range of transformations employed in discovery-phase medicinal chemistry research and is proposed to facilitate identification of more sustaina...
Article
Full-text available
The reaction of heteroaryl chlorides in the pyrimidine, pyrazine and quinazoline series with amines in water in the presence of KF results in a facile SN Ar reaction and N-arylation. The reaction is less satisfactory with pyridines unless an additional electron-withdrawing group is present. The results showed that the transition-metal-free SN Ar re...
Article
Reagent guides ranking commonly used reagents for 15 transformations have been developed to reduce the environmental impact of drug discovery and development. Reagents have been scored by a combination of health, safety and environmental risk phrases, life cycle analysis (where possible) and an assessment of the chemistry including considerations o...
Article
A range of alternative, more environmentally conservative solvents have been evaluated for use within the direct reductive amination reactions of aldehydes using borane-based reductants. The data generated has been used to develop a guide to facilitate replacement of less desirable chlorinated solvents, such as DCE, from these widely used synthetic...
Article
The Medicinal Chemistry sub-group of the American Chemical Society's (ACS) Green Chemistry Institute (GCI) Pharmaceutical Roundtable (PR) offers a perspective on the current state of environmentally sustainable practices in Medicinal Chemistry with the aim of sharing best practices more widely, and highlighting some potential future directions.
Article
A range of alternative solvents have been evaluated within amidation reactions employing common coupling reagents with a view to identifying suitable replacements for dichloromethane and N,N-dimethylformamide.
Article
Full-text available
Replacement of dichloromethane as the bulk medium within chromatographic purification has been evaluated with a broad range of molecules containing functionality common within Medicinal Chemistry programmes. Analysis of the data set has generated a set of general guidelines to assist in the selection of alternative solvents for CH2Cl2 as the bulk m...
Article
Go with the flow: 4-Hydroxycyclobutenones were efficiently transformed into 5H-furanones using an inexpensive flow-photochemical setup. The results challenge the notion that this and the related thermochemical rearrangement display torquoselectivity in their electrocyclic opening to a vinylketene intermediate. Selectivity in the photochemical rearr...
Article
Selektivität welcher Art? 4‐Hydroxycyclobutenone wurden in einem photochemischen Strömungsreaktor in 5H‐Furanone umgewandelt. Die Ergebnisse stellen die Vorstellung in Frage, dass diese und die verwandte thermochemische Umlagerung in der elektrocyclischen Ringöffnung zu einem Vinylketenzwischenprodukt torquoselektiv sind. Die Selektivität der photo...
Article
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 latte...
Article
A connective Pummerer-type cyclisation involving a cysteine derivative and an N-benzyl glyoxamide 3 has been applied in an asymmetric synthesis of the protected ABH rings 2 of the antitumour and antimicrobial natural product ecteinascidin 597.
Article
An acid-catalysed conversion of N-arylcarboxy-4-quinazolinones into 2-(2-aminoaryl)-4(1H)-quinazolinones has been observed. This reaction allows for a nucleophilic aromatic substitution reaction between aminobenzoic acids and 4-chloroquinazolines to form N-arylcarboxy-4-quinazolinones to be followed in situ by a conversion into 2-(2-aminoaryl)-4(1H...
Article
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 enantiodeterminin...
Article
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.
Article
Seit den frühen 1960er Jahren hat sich die Pummerer-Reaktion zu einem unentbehrlichen Syntheseverfahren in der organischen Chemie entwickelt. Viele interessante Fortschritte in den vergangenen Jahren unterstreichen die breite Anwendbarkeit und den Nutzen dieser Methode sowie die Vielseitigkeit von Thioniumionen als Intermediate.
Article
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 readil...
Article
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.
Article
The work describes the efficient double conjugate addition of ethane and propane dithiols in the presence of sodium methoxide to a wide variety of propargylic carbonyl containing compounds. The products of these reactions are differentiated, 1,3-dicarbonyl systems useful for various synthesis programs. By judicious use of hydroxylated substrates ta...
Article
β-Keto 1,3-dithianes can be generated by the double conjugate addition of dithiols to propargylic ketones, esters and aldehydes in excellent yields. As masked 1,3-dicarbonyl systems these substrates can be converted to a range of functionalised oxygen-containing heterocycles that can be used in natural product synthesis.
Article
[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 C...
Article
Full-text available
beta-Keto 1,3-dithianes can be generated by the double conjugate addition of dithiols to propargylic ketones, esters and aldehydes in excellent yields. As masked 1,3-dicarbonyl systems these substrates can be converted to a range of functionalised oxygen-containing heterocycles that can be used in natural product synthesis.
Article
beta-Keto 1,3-dithianes can be generated by the double conjugate addition of dithiols to propargylic ketones, esters and aldehydes in excellent yields. As masked 1,3-dicarbonyl systems these substrates can be converted to a range of functionalised oxygen-containing heterocycles that can be used in natural product synthesis.
Article
A polymer-supported hydrazine reagent has been applied to the conversion of a range of aldehydes to nitriles, providing a clean and efficient route to more diverse building blocks for combinatorial chemistry programmes.

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