High-throughput discovery of organic cages and catenanes using computational screening fused with robotic synthesis
Department of Chemistry and Materials Innovation Factory, University of Liverpool
Department of Chemistry, Imperial College, London
Nature Communications Journal
Supramolecular synthesis is a powerful strategy for assembling complex molecules, but to do this by targeted design is challenging. This is because multicomponent assembly reactions have the potential to form a wide variety of products. High-throughput screening can explore a broad synthetic space, but this is inefﬁcient and inelegant when applied blindly. Here we fuse computation with robotic synthesis to create a hybrid discovery workﬂow for discovering new organic cage molecules, and by extension, other supramolecular systems. A total of 78 precursor combinations were investigated by computation and experiment, leading to 33 cages that were formed cleanly in one-pot syntheses. Comparison of calculations with experimental outcomes across this broad library shows that computation has the power to focus experiments, for example by identifying linkers that are less likely to be reliable for cage formation. Screening also led to the unplanned discovery of a new cage topology—doubly bridged, triply interlocked cage catenanes.
August 2018 – Dulles, USA
The Drug Enforcement Administration’s (DEA) Heroin Signature Program (HSP) and its Heroin Domestic Monitor Program (HDMP) aim to increase the DEA’s ability to identify the geographic origin of heroin in the U.S. wholesale and retail markets. These programs also gather data on heroin purity levels and trafficking trends into and across the United States. Both these programs require that many hundreds of heroin samples be analyzed at the DEA Special Testing and Research Laboratory (SFL1) every year. The DEA chose Chemspeed Technologies to provide an automated sample preparation platform to help handle this challenging workload by increasing throughput of sample analysis.
July 2018 – Nebraska, USA
Director of the Nebraska Food for Health Center states, “Our lab is screening 100’s of thousands of plant materials which requires repetitive, accurate dispensing of solids. Done manually, this work is tedious and prone to errors. After extensive research, we determined that Chemspeed’s FLEX POWDERDOSE was the only product available to provide accurate and reproducible “many to many” dispensing.”
Ghent University, Belgium
Advanced Functional Materials Journal
It is demonstrated how cellular uptake and protein corona of (co)polymer-coated gold nanoparticles can be altered by the hydrophilic-to-hydrophobic comonomer ratio. A novel, label-free ﬂow cytometry strategy is developed to investigate particle uptake. These ﬁndings offer insight in the design and analysis of hybrid nanomaterials for interfacing with biological systems.
Ghent University, Belgium
Polymer Chemistry Journal
In this paper the optimization of the Cu(0)-mediated polymerization of n-butyl acrylate and 2-methoxyethyl acrylate is reported using an automated parallel synthesizer. Using this robot, up to 16 kinetic reactions could be performed in parallel, resulting in a fast screening of diﬀerent reaction conditions. Several parameters were optimized to determine the optimal reaction conditions with regard to control over the polymerization and reaction rate. These optimal reaction conditions were then used for the one-pot two-step synthesis of diblock copolymers by sequential monomer addition.
”We are using our Chemspeed SWILE Catalyst Dispensing solution for the production of screening kits for cross coupling reaction such as Suzuki or Buchwald reactions. The system took over all our manual and tedious weighing tasks of small quantities between 1 and 3.5 mg. It produces reaction kits for screening reactions in 96-well format which can be used in our fully automated ISYNTH screening platform.”
Merck Sharp & Dohme Corporation, Rahway/Kenilworth, NJ, USA
Accounts of Chemical Research, ACS Publications
Conspectus: The structural complexity of pharmaceuticals presents a signiﬁcant challenge to modern catalysis. Many published methods that work well on simple substrates often fail when attempts are made to apply them to complex drug intermediates. The use of high-throughput experimentation (HTE) techniques oﬀersameanstoovercomethis fundamental challenge by facilitating the rational exploration of large arrays of catalysts and reaction conditions in a time-and material-eﬃcient manner. Initial forays into the use of HTE in our laboratories for solving chemistry problems centered around screening of chiral precious-metal catalysts for homogeneous asymmetric hydrogenation. The success of these early eﬀorts in developing eﬃcient catalytic steps for late-stage development programs motivated the desire to increase the scope of this approach to encompass other high-value catalytic chemistries. Doing so, however, required signiﬁcant advances in reactor and workﬂow design and automation to enable the eﬀective assembly and agitation of arrays of heterogeneous reaction mixtures and retention of volatile solvents under a wide range of temperatures. Associated innovations in high-throughput analytical chemistry techniques greatly increased the eﬃciency and reliability of these methods. These evolved HTE techniques have been utilized extensively to develop highly innovative catalysis solutions to the most challenging problems in large-scale pharmaceutical synthesis. Starting with Pd- and Cu-catalyzed cross-coupling chemistry, subsequent eﬀorts expanded to other valuable modern synthetic transformations such as chiral phase-transfer catalysis, photoredox catalysis, and C−H functionalization. As our experience and conﬁdence in HTE techniques matured, we envisioned their application beyond problems in process chemistry to address the needs of medicinal chemists. Here the problem of reaction generality is felt most acutely, and HTE approaches should prove broadly enabling. However, the quantities of both time and starting materials available for chemistry troubleshooting in this space generally are severely limited. Adapting to these needs led us to invest in smaller predeﬁned arrays of transformation-speciﬁc screening “kits” and push the boundaries of miniaturization in chemistry screening, culminating in the development of “nanoscale” reaction screening carried out in 1536-well plates. Grappling with the problem of generality also inspired the exploration of cheminformatics-driven HTE approaches such as the Chemistry Informer Libraries. These next-generation HTE methods promise to empower chemists to run orders of magnitude more experiments and enable “big data” informatics approaches to reaction design and troubleshooting. With these advances, HTE is poised to revolutionize how chemists across both industry and academia discover new synthetic methods, develop them into tools of broad utility, and apply them to problems of practical signiﬁcance.
‘’Automation of our foundation formulations has provided a significant gain of time once the initial color definition has been established and iterations and fine tuning are needed. An estimated increase of productivity by a factor of three was fulfilled thus considerably reducing the Time to Market. Notable and important point is the excellent reproducibility of the Chemspeed Technologies automated foundation formulation solution leading to exploitable scalable formulations for our development and pilot activities.’’
January 2018 – The Laboratory of Molecular Simulation (LSMO) at EPFL Valais Wallis
“The Laboratory of Molecular Simulation (LSMO) at EPFL has selected Chemspeed Technologies in order to accelerate their research work in discovering novel nanoporous materials. The overarching goal of this project is to identify a ‘wonder’ material that can outperform existing materials reported and available in the market for energy, environmental and sensing applications!
High-throughput methods represent a very promising approach for accelerating the discovery of metal-organic frameworks (MOFs) as a large number of automated and integrated reactions can be prepared in one batch by screening a wide variety of parameters: metal source and solvent mixtures, concentrations, ratio between the metal and ligand, pH of the reaction, heating temperature, time and others. The utilization of RoSy (Robotic Synthesiser ISYNTH SWAVE) at EPFL Valais Wallis is an ideal tool for the discovery of new materials as it allows the LSMO researchers to run a series of 50 (or more) simultaneous experiments for the synthesis of MOFs (automated dispensing of solids – ligands, metal salts and liquids with high quality; automated capping and crimping of the reaction vials without manual interference; microwave heating; confirmation of the product formation with the integrated camera). The experimental results (successful and failed) are then utilized to rank each synthetic reaction with the Genetic Algorithms (GAs) – an approach that the computational scientists in LSMO have developed. After this ranking, a set of new synthetic conditions is generated and run experimentally using RoSy. This can lead in multiple generations of MOFs (set of 50 reactions) and it continues until the best conditions are identified. Recent advances from this research activity include the discovery of new MOFs and the optimisation of the synthetic conditions for the synthesis of stable, originally reported as unstable MOFs. Additionally by establishing this robust iterative method, the design and synthesis of specific MOF for the capture / storage of strategically critical gases (CH4, CO2, H2) can be achieved!”
December 2017 – French National Institute for Agricultural Research, BIBS Platform
The French National Institute for Agricultural Research (INRA) is celebrating its 5th successful year of automating demanding sample preparation/derivatization with Chemspeed technology!
INRA is Europe’s top agricultural research institute and the world’s number two centre for the agricultural sciences. Its scientists are working towards solutions for society’s major challenges. The Biopolymères, Biologie Structurale (BIBS platform) – of INRA, Nantes, France is part of Biopolymers Interactions Assemblies (BIA) of the characterization and development of agricultural products (CEPIA).
BIBS has been certified ISO 9001 and is recognized as a strategic platform of INRA. The Chemspeed’s SWING system is at the heart of the BIBS platform and is being used for the automation of demanding sample preparation/derivatization workflow campaigns for screening structural properties of agricultural derived biopolymers.
Research Engineer of INRA states, “The Chemspeed system allows us to perform more sample preparation screening campaigns while freeing up our staff from very constraining and repetitive manipulations that require the use of highly toxic chemicals. In addition, the system eliminates analyst to analyst variation and performs highly complex chemical synthesis-like sample preparations that only highly trained staff can manage.”