Steven V Ley

University of Cambridge | Cam · Department of Chemistry

The aminocarbonylation of 4-iodoanisole with morpholine using the palladium catalysts supported on biodegradable polyurea was investigated. Kinetic measurements carried out in mechanically stirred reactor allowed to estimate a reaction rate (TOF) 34.3 ± 4.2 mol Anis-I Pd.mol⁻¹ h⁻¹ at 130 °C and CO gas pressure of 8 bar. The calculated activation en...

This article defines the role that continuous flow chemistry can have in new reaction discovery, thereby creating molecular assembly opportunities beyond our current capabilities. Most notably the focus is based upon photochemical, electrochemical and temperature sensitive processes where continuous flow methods and machine assisted processing can...

A method to assemble (hetero)aryl sulfonamides via the reductive coupling of aryl sulfinates and nitroarenes is reported. Various reducing conditions with sodium bisulfite and with or without tin(II) chloride in DMSO were developed using an ultrasound bath to improve reaction homogeneity and mixing. A range of (hetero)aryl sulfonamides bearing a se...

Sulfonyl groups are widely observed in biologically relevant molecules and consequently, SO2 capture is an increasingly attractive method to prepare these sulfonyl‐containing compounds given the range of SO2‐surrogates now available as alternatives to using the neat gas. This, along with the advent of photoredox catalysis, has enabled mild radical...

This article seeks to provide an overview of the environmental factors within the pharmaceutical industry that have contributed to the emergence of flow chemistry over the past two decades. It highlights some of the challenges facing the industry and describes how they are being overcome by the exponential trajectory of scientific progress in the a...

Automated platforms allow for fast and efficient optimisation of single and multi-objective chemical systems. Herein, we report the application of automated optimisation platforms for the chemical screening of sulfide oxidations...

The rapid multistep synthesis of 2-pyrazolines from aldehydes via [3+2] cycloaddition of unstabilised diazo species and mono-substituted alkenes is reported. The development encompasses semi-continuous and fully continuous methods, including a...

N-heterospirocycles are interesting structural units found in both natural products and medicinal compounds but have relatively few reliable methods for their synthesis. Here, we enlist the photocatalytic generation of N-centered radicals to construct β-spirocyclic pyrrolidines from N-allylsulfonamides and alkenes. A variety of β-spirocyclic pyrrol...

Multi-objective optimisation algorithms (MOOAs) are, of increasing interest for the efficient optimisation of chemical processes. However, an algorithms performance can vary on a case-by-case basis, depending on the complexity of...

Executing photoredox reactions in flow offers solutions to frequently encountered issues regarding reproducibility, reaction time, and scale-up. Here, we report the transfer of a photoredox-catalyzed benzylic coupling of alkylarenes to aldehydes to a flow chemistry setting leading to improvements in terms of higher concentration, shorter residence...

In this study, we investigated enzymatic pre-treatment of grease trap waste (GTW) as an environmentally beneficial procedure for biodiesel production. Different enzymes, both commercial and newly designed industrial enzymes, were used to reduce the free fatty acids (FFA) level of GTW through an esterification reaction. The process conditions were o...

Continuous flow systems offer unique benefits in the generation and manipulation of sensitive reactive intermediates such as ketenes. To this end, the last decade has witnessed the development of continuous flow methods for the generation of ketenes by means of chemical, thermal, and photochemical activation modes. This perspective covers these adv...

Pregnenolone (P5) promotes prostate cancer cell growth, and de novo synthesis of intratumoural P5 is a potential cause of development of castration-resistance. Immune cells can also synthesize P5 de novo. Despite its biological importance, little is known about P5’s mode of actions, which appears to be context-dependent and pleiotropic. A comprehen...

An integrated batch and continuous flow process has been developed for the gram-scale synthesis of goniothalamin. The synthetic route hinges upon a telescoped continuous flow Grignard addition followed by an acylation reaction capable of delivering a racemic goniothalamin precursor (16) (20.9 g prepared over 3 h), with a productivity of 7 g·h–1. An...

A computational approach has been developed to automatically generate and analyse the structures of the intermediates of palladium-catalysed carbon–hydrogen (C–H) activation reactions as well as to predict the final products. Implemented as a high-performance computing cluster tool, it has been shown to correctly choose the mechanism and rationalis...

Various sulfone tetrazoles were activated via iridium photoredox catalysis in the presence of DMAP to give dialkyl sulfones. The presumed sulfone radical intermediates were trapped by a range of electron-deficient olefins in generally good to excellent yields.

With illustrative examples from our laboratories, we make the case for how our digital and machine-based world is impacting on the assembly of our functional molecules in a more sustainable fashion. Our equipment today is better able to deliver efficiencies through labour-saving methods, optimisation and scale-up, helping to minimise solvent usage,...

p>A computational approach has been developed to automatically generate and analyse the structures of the intermediates of palladium catalysed carbon-hydrogen (C-H) activation reactions as well as to predict the final products. Implemented as a high-performance computing cluster tool, it has been shown to correctly choose the mechanism and rational...

This Tutored Discourse constitutes a preliminary exposure on how synthesis chemists can engage positively with inexpensive, low-power microcontrollers to aid control, monitoring and optimisation of chemical reactions. The acquired skillset adds a new aspect to the toolbox of molecular construction, especially going forward in an ever-increasing dig...

A practically useful coupling reaction between aromatic halides and redox‐active esters was realized by nickel catalysis through the use of a packed zinc bed column in continuous flow. Multiple reuse of the column showed a negligible decrease in efficiency, affording high space/time yields. A wide range of substrates, including a number of heteroar...

This perspective seeks to provide an overarching vision of the current state of chemical synthesis methodology using machinery as enabling tools. It highlights current capabilities and limitations in this highly digitallyconnected world and suggests areas where new opportunities may arise in the future by going well beyond our present levels of inn...

This work discloses a continuous flow carbonylation reaction using iron pentacarbonyl as source of CO. The described transformation using this surrogate was designed for use in commonly accessible flow equipment. Optimized conditions were applied to a scalable synthesis of the natural compound isolated from perianal glandular pheromone secretion of...

Pregnenolone (P5) promotes prostate cancer cell growth, and de novo synthesis of intratumoural P5 is a potential cause of development of castration-resistance. Immune cells can also synthesize P5 de novo. Despite its biological importance, little is known about P5s mode of actions, which appears to be context-dependent and pleiotropic. A comprehens...

Mild cross-coupling reaction between benzylboronic esters with carbonyl compounds and some imines was achieved under visible-light-induced iridium-catalyzed photoredox conditions. Functional group tolerance was demonstrated by 51 examples, including 13 heterocyclic compounds. Gram-scale reaction was realized through the use of computer-controlled c...

In fragment-based drug discovery (FBDD), a weakly binding fragment hit is elaborated into a potent ligand by bespoke functionalization along specific directions (growth vectors) from the fragment core in order to complement the 3D structure of the target protein. This structure-based design approach can present significant synthetic challenges, as...

A fast, scalable, and safer Csp³−H oxidation of activated and un‐activated aliphatic chains can be enabled by methyl(trifluoromethyl)dioxirane (TFDO). The continuous flow platform allows the in situ generation of TFDO gas and its rapid reactivity toward tertiary and benzylic Csp³−H bonds. The process exhibits a broad scope and good functional group...

A continuous flow method for the direct conversion of alcohols to amines via a hydrogen borrowing approach is reported. The method utilises a low loading (0.5%) of a commercial catalyst system ([Ru(p-cymene)Cl2]2 and DPEphos), reagent grade solvent and is selective for primary alcohols. Successful methylation of amines using methanol and the direct...

Cheap and readily available aqueous formaldehyde was used as a formylating reagent in a homologation reaction with non-stabilized diazo compounds, enabled by the UV photolysis of bench-stable oxadiazolines in a flow photoreactor. Various aliphatic aldehydes were synthesized along with the corresponding derivatized alcohols and benzimidazoles. No tr...

The power of the Cloud has been harnessed for pharmaceutical compound production with remote servers based in Tokyo, Japan being left to autonomously find optimal synthesis conditions for three active pharmaceutical ingredients (APIs) in laboratories in Cambridge, UK. A researcher located in Los Angeles, USA controlled the entire process via an int...

The power of the Cloud has been harnessed for pharmaceutical compound production with remote servers based in Tokyo, Japan being left to autonomously find optimal synthesis conditions for three active pharmaceutical ingredients (APIs) in laboratories in Cambridge, UK. A researcher located in Los Angeles, USA controlled the entire process via an int...

Oxadiazolines are bench-stable diazo precursors, which are activated under UV radiation in the presence of vinylboronic acids and aldehydes to enable a one-step three-component assembly of densely functionalized homoallylic alcohols. Substitution on all positions of the homoallylic alcohol product were achieved with high functional group tolerance....

A new bespoke semi-continuous parallel column supercritical fluid chromatography unit has been developed that solves the problem of effective separation of continuous, multicomponent reaction mixtures. It enables the rapid in-line separation of crude mixtures produced during batch and continuous flow reactions. It overcomes limitations inherent to...

The difficulty in accessing and safely utilising non-stabilised diazo species has in the past limited the application of this class of compounds. Here we explore further the use of oxadiazolines, non-stabilised diazo precursors which are bench stable, in direct, non-catalytic, aldehyde C–H functionalisation reactions under UV photolysis in flow and...

A three-component synthesis of homoallylic amines is described. The allylboronic species were generated in situ by homologation of vinyl boroxines with trimethylsilyldiazomethane, then followed by trapping of the allylboron intermediate with imines. Twenty-seven compounds were successfully prepared in moderate to high yields. Imines bearing various...

We report the integration of flow chemistry with plug flow crystallisation. Catalytic flow hydration of pyrazinecarbonitrile to pyrazinamide was performed in a packed bed column of MnO 2 . The effluent of...

We report a strategy designed for the rapid and convergent assembly of C4-oxime substituted thiazoles. Our approach relied on 3-bromo-2-oxopropanal O-methyl oxime 7 as a key building block. A three-step sequence to 7 was designed, which for safety concerns, could only be operated in batch mode on limited scales (<< 100g). We describe herein how we...

Societal and commercial pressures are impacting more than ever on the methods and techniques by which we assemble today's functional molecules. A holistic appreciation of this complex eco-system necessitates the invention of new tools and stimulates innovative thinking. In particular, the labour intensive and unsustainable practices of the past are...

Professor Steven Ley is currently Professor of Chemistry and Director of Research at at the University of Cambridge. He is also a Fellow of Trinity College and was BP 1702 Professor of Chemistry for 21 years. Steve obtained his PhD from Loughborough University with Professor Harry Heaney and afterwards carried out postdoctoral research with Profess...

A procedure that yields pyrazinamide as a fine white powder is presented. A glass column reactor is used containing Celite and manganese dioxide and is mounted vertically in a heating jacket. Following the procedure are notes on the instruments and chemicals used and required. The chapter concludes with a discussion on the general concepts regardin...

A mannitol derived 2,3-butanediacetal ethyl ketone displays high levels of diastereoselectivity in boron and titanium mediated aldol reactions with a range of aliphatic and aromatic aldehydes to afford syn aldol products in high yield. The stereochemical outcome of the reaction was determined using J-value analysis, NMR analysis of O-acetylmandelat...

We report an acridium-based organic photocatalyst as an efficient replacement for iridium-based photocatalysts to oxidise boronic acid derivatives by a single electron process. Furthermore, we applied the developed catalytic system to the synthesis of four active pharmaceutical ingredients (APIs). A straightforward scale up approach using continuou...

--- Supporting Information ---- We report an acridium-based organic photocatalyst as an efficient replacement for iridium-based photocatalysts to oxidise boronic acid derivatives by a single electron process. Furthermore, we applied the developed catalytic system to the synthesis of four active pharmaceutical ingredients (APIs). A straightforward s...

When considering life's aetiology, the first questions that must be addressed are "how?" and "where?" were ostensibly complex molecules, considered necessary for life's beginning, constructed from simpler, more abundant feedstock molecules on primitive Earth. Previously, we have used multiple clues from the prebiotic synthetic requirements of (prot...

Words and phrases such as Artificial Intelligence, Machine Learning, Neural Networks, Robotics, the Cloud, Big Data and the Internet of Things are typically associated with many modern technological and scientific developments. Until recently, however, they have not been applied systematically to the chemical assembly of society’s functional molecu...

“Chemical synthesis has previously tended to rely heavily on robust labour‐intensive processes. We have been advocating a machine‐assisted approach to synthesis for many years. To replace a bench chemist with a machine is not only unrealistic but impossible. What is realistic is to use this rapidly developing array of equipment and novel concepts t...

„Die chemische Synthese ist zum heutigen Stand noch auf arbeitsintensive Prozesse angewiesen. Wir postulieren nun schon seit einigen Jahren eine maschinell unterstützte Synthese. Es ist zwar unrealistisch, einen Laborchemiker durch eine Maschine ersetzen zu wollen, realistisch ist es dagegen, die zahlreichen neuartigen Geräte und Konzepte zu nutzen...

A strategy for biocatalyst immobilization in flow directly from the crude cell extract is described. The efficiency and the stability of the immobilized enzyme were demonstrated during the asymmetric reduction of a range of ketones. The cascade two-step chemo-enzymatic preparation of chiral epoxides was possible through the initial ketone bioreduct...

A new three-component coupling protocol for preparation of functionalized indolines, with a high degree of diastereoselectivity, has been developed. The protocol is based on the in situ homologation of vinyl boronic acids to allylboronic acids, using TMSCHN2 as carbon source, and subsequent coupling reaction with indoles to give 2-substituted indol...

A strategy for biocatalyst immobilization in flow directly from the crude cell extract is described.

Multistep continuous-flow processing enables the direct preparation of complex chemical materials from simple input streams through a series of complexity-adding reaction steps. The use of polymer-supported reagents can greatly facilitate this process through the inline hosting of reagents or catalysts, the scavenging of spent materials or impuriti...

A new three-component coupling protocol for preparation of functionalized indolines, with a high degree of diastereoselectivity, has been developed. The protocol is based on the in situ homologation of vinyl boronic acids to allylboronic acids, using TMSCHN2 as carbon source, and subsequent coupling reaction with indoles to give 2-substituted indol...

Coupling of readily available boronic acids and diazo compounds has emerged recently as a powerful metal-free carbon-carbon bond forming method. However, the difficulty in forming the unstable diazo compound partner in a mild fashion has hitherto limited their general use and scope of the transformation. Here, we report the application of oxadiazol...

We are grateful to Novartis Pharma AG (F.L.), the Erasmus Scholarship Scheme (L.G. and S.J.), and the EPSRC (S.V.L., Grants EP/K009494/1, EP/K039520/1, and EP/M004120/1) for financial support. U.K.S. and D.S. are thankful to the University of Leuven for postdoctoral funding and the FWO for a visiting postdoctoral scholarship (U.K.S.) at the Univers...

A visible-light mediated annulation of N-sulfonylallylamines and olefins is reported. Rapid access to highly functionalized chloromethylated pyrrolidines can be achieved using mild conditions for the generation of nitrogen-centered radicals. Both a transition metal based catalyst and an organic dye can be used as photosensitizers, with 0.5 mol% loa...

The continious production of benzyl amides by anodic oxidation in flow was developed. The stability and productivity of the equipment was examined over time and monitored by means of in-line...

Synthesis is changing in response to our modern resource conscious world. The principles of green chemistry are evolving as the interfaces and boundaries in science are less obvious and providing a new stimuli for future discovery. The invention and application of new chemical reactivity continues to be a primary driver since this opens up so many...

Coupling of readily available boronic acids and diazo compounds has emerged recently as a powerful metal-free carbon-carbon bond forming method. However, the difficulty in forming the unstable diazo compound partner in a mild fashion has hitherto limited their general use and scope of the transformation. Here, we report the application of oxadiazol...

Coupling of readily available boronic acids and diazo compounds has emerged recently as a powerful metal-free carbon-carbon bond forming method. However, the difficulty in forming the unstable diazo compound partner in a mild fashion has hitherto limited their general use and scope of the transformation. Here, we report the application of oxadiazol...

We report the multistep continuous process for the preparation of dibromoformaldoxime (DBFO) as a precursor to generate 3-bromoisoxazolines. We also report process improvements that afford a productivity of over 620 mmol h−1 of DBFO.

We report herein the use of a dual catalytic system comprising of a Lewis base catalyst such as quinuclidin-3-ol or 4-dimethylaminopyridine combined with a photoredox catalyst to generate carbon radicals from either boronic acids or esters. This system enabled a wide range of alkyl boronic esters and aryl or alkyl boronic acids to react via radical...

We report herein the use of a dual catalytic system comprising of a Lewis base catalyst such as quinuclidin-3-ol or 4-dimethylaminopyridine combined with a photoredox catalyst to generate carbon radicals from either boronic acids or esters. This system enabled a wide range of alkyl boronic esters and aryl or alkyl boronic acids to react via radical...

Synthesis is changing in response to our modern resource conscious world. The principles of green chemistry are evolving as the interfaces and boundaries in science are less obvious and providing a new stimuli for future discovery. The invention and application of new chemical reactivity continues to be a primary driver since this opens up so many...

A continuous flow method for the selective reduction of aromatic nitriles to the corresponding amine is reported. The method is based on a ruthenium-catalysed transfer-hydrogenation process, requires no additives, and uses isopropanol as both solvent and reducing agent. The process utilizes 1 mol% of the commercially available [Ru(p-cymene)Cl2]2, w...

A continuous flow method for the selective reduction of aromatic nitriles to the corresponding amine is reported. The method is based on a ruthenium-catalysed transfer-hydrogenation process, requires no additives, and uses isopropanol as both solvent and reducing agent. The process utilizes 1 mol% of the commercially available [Ru(p-cymene)Cl2]2, w...

A continuous flow method for the selective oxidation of secondary alcohols is reported. The method is based on an Oppenauer-type Ruthenium-catalyzed hydrogen-transfer process that uses acetone as both solvent and oxidant. The process utilizes a low loading (1 mol%) of the commercially available ruthenium catalyst [Ru(p-cymene)Cl2]2 and triethylamin...

A continuous flow method for the selective oxidation of secondary alcohols is reported. The method is based on an Oppenauer-type ruthenium-catalyzed hydrogen-transfer process that uses acetone as both solvent and oxidant. The process utilizes a low loading (1 mol%) of the commercially available ruthenium catalyst [Ru(p-cymene)Cl₂]₂and triethylamine...

We report the multistep continuous process for the preparation of dibromoformaldoxime (DBFO) as a precursor to generate bromoisoxazolines. We also report process improvements that afford a productivity of over 620 mmol h-1 of DBFO.

Supplementary

By means of computational and experimental mechanistic studies the fundamental role of boroxines in the reaction between diazo compounds and boronic acids was elucidated. Consequently, a selective metal-free carbon-carbon homologation of aryl and vinyl boroxines using TMSCHN2, giving access to TMS-pinacol boronic ester products, was developed.

By means of computational and experimental mechanistic studies the fundamental role of boroxines in the reaction between diazo compounds and boronic acids was elucidated. Consequently, a selective metal-free carbon–carbon homologation of aryl and vinyl boroxines using TMSCHN₂, giving access to TMS-pinacol boronic ester products, was developed.

A flow chemistry process for the synthesis of 2-substituted cyclobutanones, via [2 + 2] cycloaddition of keteneiminium salts and ethylene gas, is reported. Our approach uses rapid and mild reaction conditions to access a diverse array of products with good to excellent yield, alongside a good level of functional group compatibility.

Stapled peptides have arisen as a new class of chemical probe and potential therapeutic agents to modulate protein-protein interactions. Here, we report the first two-component i,i+7 stapling methodology using two orthogonal, on-resin stapling reactions to incorporate linkers bearing a chiral center on a p53-derived stapled peptide. Post-stapling m...