Computational planning of the synthesis of complex natural products

Training algorithms to computationally plan multistep organic syntheses has been a challenge for more than 50 years(1-7). However, the field has progressed greatly since the development of early programs such as LHASA(1,7), for which reaction choices at each step were made by human operators. Multiple software platforms(6,8-14) are now capable of completely autonomous planning. But these programs 'think' only one step at a time and have so far been limited to relatively simple targets, the syntheses of which could arguably be designed by human chemists within minutes, without the help of a computer. Furthermore, no algorithm has yet been able to design plausible routes to complex natural products, for which much more far-sighted, multistep planning is necessary(15,16) and closely related literature precedents cannot be relied on. Here we demonstrate that such computational synthesis planning is possible, provided that the program's knowledge of organic chemistry and data-based artificial intelligence routines are augmented with causal relationships(17,18), allowing it to 'strategize' over multiple synthetic steps. Using a Turing-like test administered to synthesis experts, we show that the routes designed by such a program are largely indistinguishable from those designed by humans. We also successfully validated three computer-designed syntheses of natural products in the laboratory. Taken together, these results indicate that expert-level automated synthetic planning is feasible, pending continued improvements to the reaction knowledge base and further code optimization. A synthetic route-planning algorithm, augmented with causal relationships that allow it to strategize over multiple steps, can design complex natural-product syntheses that are indistinguishable from those designed by human experts

Expected Range of Cooperation Between Transmission System Operators and Distribution System Operators After Implementation of ENTSO-E Grid Codes

The authors present the prospects of cooperation between transmission system operators (TSO) and distribution system operators (DSO) after entry into force ENTSO-E (European Network of Transmission System Operators for Electricity) grid codes. New areas of DSO activities, associated with offering TSO aggregated services for national power system regulation based on the regulation resources connected to the distribution grid, and services on the distribution system level as part of the creation of local balancing areas (LBA) are presented. The paper also presents the possibilities of providing ancillary services by different types of distributed generation sources in the distribution network. The LBA concept, which involves integrated management of local regulation resources including generation, demand, and energy storage is described. The options of the renewable energy sources (RES) using for voltage and reactive power control in the distribution network with the use of wind farms (WF) connected to the distribution system are characterized

One-Pot, Three-Phase Recycling of Metals from Li-Ion Batteries in Rotating, Concentric-Liquid Reactors

Efficient recycling of spent lithium-ion batteries (LIBs) is essential for making their numerous applications sustainable. Hydrometallurgy-based separation methods are an indispensable part of the recycling process but remain limited by the extraction efficiency and selectivity, and typically require numerous binary liquid-liquid extraction steps in which the capacity of the extracting organic phase or partition coefficient of extracted metals become an overall bottleneck. Herein, rotating reactors are described, in which the aqueous feed, organic extractant, and aqueous acceptor phases are all present in the same rotating vessel and can be vigorously stirred and emulsified without the coalescence of aqueous layers. In this arrangement, the extractant molecules are not equilibrated with the feed and, instead, "shuttle" between the feed/extractant and the extractant/acceptor interfaces multiple times, with each such molecule ultimately transferring approximately ten metal ions. This shuttling allows for using extractant concentrations much lower than in previous designs even for extremely concentrated feeds and, simultaneously, ensures unprecedented speed and selectivity of the one-pot processes. These experimental results are accompanied by theoretical considerations of the selectivity versus speed trends as well as discussion of parameters essential for system upscaling.11Nsciescopu

Concentric liquid reactors for chemical synthesis and separation

Recent years have witnessed increased interest in systems that are capable of supporting multistep chemical processes without the need for manual handling of intermediates. These systems have been based either on collections of batch reactors1 or on flow-chemistry designs2,3,4, both of which require considerable engineering effort to set up and control. Here we develop an out-of-equilibrium system in which different reaction zones self-organize into a geometry that can dictate the progress of an entire process sequence. Multiple (routinely around 10, and in some cases more than 20) immiscible or pairwise-immiscible liquids of different densities are placed into a rotating container, in which they experience a centrifugal force that dominates over surface tension. As a result, the liquids organize into concentric layers, with thicknesses as low as 150 micrometres and theoretically reaching tens of micrometres. The layers are robust, yet can be internally mixed by accelerating or decelerating the rotation, and each layer can be individually addressed, enabling the addition, sampling or even withdrawal of entire layers during rotation. These features are combined in proof-of-concept experiments that demonstrate, for example, multistep syntheses of small molecules of medicinal interest, simultaneous acid???base extractions, and selective separations from complex mixtures mediated by chemical shuttles. We propose that ???wall-less??? concentric liquid reactors could become a useful addition to the toolbox of process chemistry at small to medium scales and, in a broader context, illustrate the advantages of transplanting material and/or chemical systems from traditional, static settings into a rotating frame of reference

Computational prediction of complex cationic rearrangement outcomes

ISSN:0028-0836ISSN:1476-468

Chematica: A Story of Computer Code That Started to Think like a Chemist

In this Backstory, Bartosz Grzybowski and co-workers narrate their long, long route to a computer program that, as described in more technical terms in their research article in this issue of Chem, is finally capable of autonomous planning of synthetic routes that are subsequently proven to work in the laboratory

On-Nanoparticle Gating Units Render an Ordinary Catalyst Substrate- and Site-Selective

When an organometallic catalyst is tethered onto a nanoparticle and is embedded in a monolayer of longer ligands terminated in "gating" end-groups, these groups can control the access and orientation of the incoming substrates. In this way, a nonspecific catalyst can become enzyme-like: it can select only certain substrates from substrate mixtures and, quite remarkably, can also preorganize these substrates such that only some of their otherwise equivalent sites react. For a simple, copper-based click reaction catalyst and for gating ligands terminated in charged groups, both substrate- and site-selectivities are on the order of 100, which is all the more notable given the relative simplicity of the on-particle monolayers compared to the intricacy of enzymes' active sites. The strategy of self-assembling macromolecular, on-nanoparticle environments to enhance selectivities of "ordinary" catalysts presented here is extendable to other types of catalysts and gating based on electrostatics, hydrophobicity, and chirality, or the combinations of these effects. Rational design of such systems should be guided by theoretical models we also describe

Computer-Assisted Synthetic Planning: The End of the Beginning

Exactly half a century has passed since the launch of the first documented research project (1965 Dendral) on computer-assisted organic synthesis. Many more programs were created in the 1970s and 1980s but the enthusiasm of these pioneering days had largely dissipated by the 2000s, and the challenge of teaching the computer how to plan organic syntheses earned itself the reputation of a "mission impossible". This is quite curious given that, in the meantime, computers have "learned" many other skills that had been considered exclusive domains of human intellect and creativity-for example, machines can nowadays play chess better than human world champions and they can compose classical music pleasant to the human ear. Although there have been no similar feats in organic synthesis, this Review argues that to concede defeat would be premature. Indeed, bringing together the combination of modern computational power and algorithms from graph/network theory, chemical rules (with full stereo- and regiochemistry) coded in appropriate formats, and the elements of quantum mechanics, the machine can finally be taught how to plan syntheses of non-trivial organic molecules in a matter of seconds to minutes. The Review begins with an overview of some basic theoretical concepts essential for the big-data analysis of chemical syntheses. It progresses to the problem of optimizing pathways involving known reactions. It culminates with discussion of algorithms that allow for a completely de novo and fully automated design of syntheses leading to relatively complex targets, including those that have not been made before. Of course, there are still things to be improved, but computers are finally becoming relevant and helpful to the practice of organic-synthetic planning. Paraphrasing Churchill's famous words after the Allies' first major victory over the Axis forces in Africa, it is not the end, it is not even the beginning of the end, but it is the end of the beginning for the computer-assisted synthesis planning. The machine is here to stayclos