Lukas Kell

The copper-catalyzed oxidative C−H allylation reaction remains underdeveloped due to lacking a general concept and mechanistic understanding. The present study utilizes various spectroscopic techniques and DFT calculations to propose a reaction mechanism which resembles the Karash-Sosnovsky reaction. Notably, the results suggest no involvement of free organic radicals in this transformation.

Abstract

Allylic functionalization reactions are an important tool for constructing many organic compounds, as they allow for the insertion of the versatile allyl group. Numerous catalytic processes have been developed, primarily utilizing noble metals such as palladium and pre-functionalized substrates. Conversely, the copper-catalyzed oxidative C−H derivatization route, whether thermal or photocatalyzed, remains relatively underdeveloped. This is mostly due to the lack of a general concept and corresponding mechanistic understanding. Here we present a comprehensive analysis of the mechanism of this transformation. We utilized a range of spectroscopic techniques, including UV-Vis, NMR, and EPR, single crystal x-ray diffraction, as well as cyclovoltammetry, and DFT calculations. We propose that there are no free organic radicals involved in this cross-dehydrogenative coupling, and that the reaction pathway is analogous to the well-known Karash-Sosnovsky reaction.

Nature, Published online: 13 March 2024; doi:10.1038/d41586-024-00727-z

A hiring manager reveals the lessons he learnt when transitioning from a PhD programme to industry.

Science, Volume 383, Issue 6680, Page 285-289, January 2024.

Pig Liver Esterase and Novozym® 435 showed good selectivity for the enzymatic kinetic resolution of cyclic carbonates. Several glycerol-derived carbonates were converted reaching er values of up to 99 : 1. Scalability of the reaction and recyclability of Novozym® 435 were demonstrated. Bioactive products were synthesized in good yields (81–89 %) and selectivity (90 : 10–94 : 6 er) using chiral carbonates as building blocks.

Abstract

The biocatalytic kinetic resolution of cyclic carbonates derived from glycerol is reported. A selection of 26 esterases and lipases was tested for the asymmetric hydrolysis of the model substrate (epichlorohydrin carbonate) in aqueous medium. Among them, Pig Liver Esterase and Novozym® 435 showed the best selectivity with E=38 and 49, respectively. Both enzymes were employed for the conversion of 12 glycerol derivatives under optimized conditions. The resolution of halogenated carbonates afforded the unconverted enantiomer in up to >99 : 1 er. Furthermore, Novozym® 435 was successfully recycled 10 times without significant loss of activity. Upscaling and isolation of the chiral carbonate was also demonstrated. Subsequent conversion of this chiral building block allowed the direct one-pot synthesis of (S)-Guaifenesin, (S)-Mephenesin and (S)-Chlorphenesin in up to 89 % yield and 94 : 6 er.

The creation of enzymes containing non-biological functionalities with activation modes outside of Nature’s canon paves the way towards fully programmable biocatalysis. Here, we present a fully genetically encoded boronic acid containing designer enzyme with organocatalytic reactivity not achievable with natural or engineered biocatalysts. This boron enzyme catalyzes the kinetic resolution of hydroxyketones by oxime formation where crucial interactions with the protein scaffold assist in the catalysis. A directed evolution campaign lead to a variant with natural enzyme like enantioselectivities for a number of different substrates. The unique activation mode of the boron enzyme was studied via X-ray crystallography, high resolution mass spectrometry and 11B NMR spectroscopy and opens up the possibility for a new class of boron dependent biocatalysts.

The atroposelective formation of isoquinoline heterocycles by a P^III/P^V=O redox organocatalyzed Staudinger–aza-Wittig reaction is described. With N₂ release and aromatization as ideal driving forces, the method permits the synthesis of a broad range of atropisomeric isoquinolines under mild conditions with enantioselectivities of up to 98 : 2 e.r. and 93 % yield.

Abstract

Herein, we describe the feasibility of atroposelective P^III/P^V=O redox organocatalysis by the Staudinger–aza-Wittig reaction. The formation of isoquinoline heterocycles thereby enables the synthesis of a broad range of valuable atropisomers under mild conditions with enantioselectivities of up to 98 : 2 e.r. Readily prepared azido cinnamate substrates convert in high yield with stereocontrol by a chiral phosphine catalyst, which is regenerated using a silane reductant under Brønsted acid co-catalysis. The reaction provides access to diversified aryl isoquinolines, as well as benzoisoquinoline and naphthyridine atropisomers. The products are expeditiously transformed into N-oxides, naphthol and triaryl phosphine variants of prevalent catalysts and ligands. With dinitrogen release and aromatization as ideal driving forces, it is anticipated that atroposelective redox organocatalysis provides access to a multitude of aromatic heterocycles with precise control over their configuration.

Pig Liver Esterase and Novozym® 435 showed good selectivity for the enzymatic kinetic resolution of cyclic carbonates. Several glycerol-derived carbonates were converted reaching er values of up to 99 : 1. Scalability of the reaction and recyclability of Novozym® 435 were demonstrated. Bioactive products were synthesized in good yields (81–89 %) and selectivity (90 : 10–94 : 6 er) using chiral carbonates as building blocks.

Abstract

The biocatalytic kinetic resolution of cyclic carbonates derived from glycerol is reported. A selection of 26 esterases and lipases was tested for the asymmetric hydrolysis of the model substrate (epichlorohydrin carbonate) in aqueous medium. Among them, Pig Liver Esterase and Novozym® 435 showed the best selectivity with E=38 and 49, respectively. Both enzymes were employed for the conversion of 12 glycerol derivatives under optimized conditions. The resolution of halogenated carbonates afforded the unconverted enantiomer in up to >99 : 1 er. Furthermore, Novozym® 435 was successfully recycled 10 times without significant loss of activity. Upscaling and isolation of the chiral carbonate was also demonstrated. Subsequent conversion of this chiral building block allowed the direct one-pot synthesis of (S)-Guaifenesin, (S)-Mephenesin and (S)-Chlorphenesin in up to 89 % yield and 94 : 6 er.

This Concept summarizes recent advances in catalytic enantioselective CO₂ utilization reactions using chiral organocatalysts.

Abstract

The development of efficient CO₂ utilization reactions has gained a significant amount of attention in recent years. Although transformations of CO₂ to produce basic chemicals have been extensively investigated, the development of catalytic enantioselective CO₂ utilization reactions for the preparation of fine chemicals remains limited at this stage. Several excellent methods for catalytic enantioselective CO₂ utilization using chiral metal complex catalysts have been reported. Many researchers have also focused on developing organocatalyzed approaches to enantioselective CO₂ utilization, and several excellent examples have appeared in recent years. Herein, recent advances in catalytic enantioselective CO₂ utilization reactions using chiral organocatalysts are reviewed to provide a forecast for organocatalyzed enantioselective CO₂ utilization research.

“There is a great deal of ruin in a country” said Adam Smith about economics (and public order), and there’s a lot of ruin in scientific publishing as well. The traditional model for publishing research results has been taking torpedos for years now, but (contrary to earlier predictions) has not really sunk yet.  Perhaps the emphasis there should be on “yet”, because there’s another development just today. Before getting to that, let's look at where we were and how we got here.

Back In the Day, which I will define as Back When I Was in Grad School (the mid-1980s), publishing a paper worked the way that it had for many years. You wrote up a manuscript and sent the physical copy of it to the journal’s editorial office. E-mail was just barely a thing back then (I sent my first one in 1988, and it was a bit of a production), and I don’t think any major journal, at least not in chemistry, was experimenting with any kind of electronic submission. At most journals they then sent your paper out for peer review after a brief look over the submission. The higher-end ones would do more “desk rejections” at this point, though, in the “We’re not even sending this out for review; go somewhere else” vein. Your paper would work its way through reviewers (typically three of them) and the journal would get back to you based on the feedback, which could range from “Publish as is, every golden word of it” through “Definitely publish, but the authors really should address/mention X” and “Publish it only if the authors do a big revision to fix Y - otherwise reject” down to “Reject, reject, don’t publish this at all”. You could certainly go through more than one round of this sort of thing.

There were various levels of gamesmanship involved. You might be worried that a particular reviewer was likely to be given your manuscript and was likely to give you trouble, for example, and you could try to avoid that by sending your paper to a journal across the Atlantic (whatever direction that might be!) so as to hit a different suite of people when it was sent out for review. Perhaps you’d established a good relationship with the editorial staff of a particular journal and tended to get better or more expeditious treatment there. The advent of the “Communication-length-only” journals (Tetrahedron Letters being one of the first) gave you some more maneuvering room, since these didn’t require full experimental details and compound characterizations. You could sometimes get a paper through more easily by sending it to a slightly unexpected venue that was actively looking to publish more papers in your research area because they hadn’t been getting many.New journals were launched much less frequently back then, but they were also considered to be hungry for manuscripts when they did appear, so your paper might get accepted more readily there at the expense of appearing in a journal that perhaps fewer people had heard of and some libraries might not even have subscribed to yet - remember, we’re talking hard copies here, stacks of bound paper coming in the mail. No one knew what a PDF was in 1985, including the folks who would go on to invent the PDF. And (infamously) there was a backdoor route to publication in Proceedings of the National Academy of Sciences, where full members of the academy had several slots per year where they could recommend a manuscript from a third party while naming their own reviewer, or get it published in the journal with little or no review at all.

Then came the internet. The first change was that (although the hard copies kept coming) you could start to access the journal archives online, a process whose speed and thoroughness varied widely across titles and publishers, and you could also start submitting your manuscripts electronically as well. This state of affairs went on for some years, as many readers will have experienced, with the journals themselves staying roughly in their former positions and doing roughly their traditional things. But cracks started to show. After a while, a person started to wonder what the purpose of having “issues” of a journal was, for one. The original idea behind “X issues per year” was that this established a sort of editorial cycle based on the workload that the staff could handle, and it also broke the journal’s output into “mailable chunks”. Admittedly some of those chunks were weightier than others - the Journal of Biological Chemistry was a famous shelf-filler back in the paper-issue days. But if papers were coming in continuously and being evaluated continuously, what was the point (outside of some special themed collection) of having separate issues? Or separate volumes that weren’t just tied to the year of publication? The Journal of Organometallic Chemistry was always weird about that multiple-volumes-per-year stuff; I see that they’re currently on Volume 982 and I am not making that up. Bibliographically, you could follow things perfectly well by renumbering year by year. And what was the point of page limits? Most journals had had these forever, with the most prestigious ones being particularly severe.  But even if you still liked those (as a way to force some discipline into the manuscript-writing process, for one thing), what was the point of limiting the size of the Supplementary Information files? These had actually been getting more useful in the electronic age, with piles of spectral data and details that could never have made it into print.

Bigger issues were looming as well. The advent of electronic publication of manuscripts led to the idea of preprint servers, which allow manuscripts to be read by anyone before the journal-submission stage and thus before any kind of review at all. That caught on in physics first, but has spread into biology, medicine, and chemistry as the usefulness of the idea has become apparent. Of course, some of the problems with it become apparent as well. You start to ask yourself what a publication is, really, and what it means to have an article peer-reviewed. That latter question is made even keener by the advent of online journals that don’t actually do peer review in the traditional sense - and no, I’m not talking about the pay-to-play dregs of the publishing world (there’s no bottom level, no matter how much you wish for one) but rather about legitimate outlets that have decided to say “We’re just going to do a brief sanity/accuracy check and then let things land where they may”. On the other end of the process, you have PubPeer, where papers are reviewed by their readers after publication (and not necessarily favorably, believe me) and whose importance and usefulness has been growing every year.

That all takes you to the big honkin’ question: what are scientific journals, anyway, and what are the advantages of them? One obvious answer is that they divide papers out by subject matter: the Journal of Organic Chemistry is what it says on the label. But there are now so many journals! For papers in just that field, you have in no particular order at all) the European Journal of Organic Chemistry, Tetrahedron, Heterocycles, Synthesis, Synthetic Communications, the Asian Journal of Organic Chemistry, Organic Chemistry Frontiers, Organic and Biomolecular Chemistry, Tetrahedron Letters, Organic Letters, SynLett, the Beilstein Journal of Organic Chemistry, the Journal of Heterocyclic Chemistry, Organic Preparations and Procedures International, and many more. If you move the focus just slightly in any direction, towards biochemistry, catalysis, physical organic chemistry, natural products, photochemistry, chemical biology, organometallic chemistry, medicinal chemistry, whatever, you find similar hosts of journals devoted to those topics. Similarly, if you believe that your paper is not “just” organic chemistry or of interest solely to organic chemists, you can aim for one of the more general chemistry journals like JACS, Angewandte Chemie, Chemistry: A European Journal  or Chemistry: An Asian Journal, ACS Central Science, Nature Chemistry, or many others. Higher still, you can try for one of the big journals that publishes what are supposed to be big papers from all fields of science in general, like Science or Nature.

This leads you to another thing that journals do: they also attempt to separate papers out by importance. You don’t see that stated explicitly in every case, or at least you didn’t before the journal “impact factor” rankings by citation counts starting being a thing, but it’s always been the case. Put bluntly, a paper in the Journal of Organic Chemistry is worth more on your publication list than one in Organic Preparations and Procedures International. A paper in JACS is worth more than one in JOC, and a paper in Science or Nature is worth more still. That sorting-by-importance works both at the journal end, where editorial staffs (as mentioned above) don’t even send a lot of stuff out for peer review at all and just reject it out of hand, and at the author end, where people consciously try to aim for the “best” journal that they can with their own manuscripts. There are people out there (and always have been) who would rather not publish at all than publish in a journal that they believe is too low-ranking to appear in, and at some level everyone is going to draw the line. There are plenty of horrible paper mills out there that will lower anyone’s reputation if you do business with them, and “business” is all that you’re doing, for sure. Those folks pay peer review the compliment of pretending to do it, but in fact just publish everything, anything, once the payment clears.

For today, I'm not even getting into the "open access" debates. Suffice it to say that the traditional model has been that you pay to subscribe to a journal, and that only subscribers get the current papers in it. An open-access journal, on the other hand, is what it says: anyone can read anything that's in it. How you pay for that is another matter, because if you're doing editorial review and all its associated functions (see above!) then that has to be paid for somehow. As it stands now, that's generally done by charging the authors, but that led very quickly to the development of the swamp just mentioned in the last paragraph. People realized that there was money to be made by "publishing" these "scientific papers" in some sort of "journal" and just short-cutted right to the money-changing-hands part.

How does this all work in the modern world, then? A world with preprint servers? A world with eleventy thousand journals for every subject you can think of, or a world where some journals bypass traditional peer review as a matter of policy (and where others on the low end bypass it as a business practice)? The example of the open-access journal eLife is instructive. Its first editor famously criticized Nature, Science, and Cell as “luxury journals” that made a (lucrative) living off of scarcity, and the journal and its funders have been very critical of the impact-factor culture. That said, it's a very selective journal itself, and has an acceptance rate only slightly more generous than the titles just mentioned. In late 2020 they announced that they were going to deal with the rise of preprint servers by only accepting papers that had appeared on one - in their own words, moving to a "publish, then review" model. I found that interesting, but a bit mis-stated, because they would still be refereeing and reviewing preprints to give them a seal of approval, and some (many) people would consider that step to represent "actual" publication. The editors of course realized this, and also said that ". . .while our long-term goal is to move science away from the use of journal titles as the primary measure of the quality of research, until an alternative takes hold, we will still be selecting papers to be "published" in eLife"

Another key statement in that announcement was on the idea of public-facing reviews, which concluded "There is no reason for papers to be reviewed only once, or by only one entity. The review process should involve multiple voices and go on for as long as the work is relevant." That's a good response to a world with PubPeer (and other ways to comment on papers) in it. And today the journal took another step: they're now going to publish every paper that they review, along with the reviews from their staff and an assessment of the paper as a "reviewed preprint". This is said to get rid of the "accept/reject" decision, but just as with last year's announcement, I find that harder to get away from than that makes it seem. eLife is going to pick only a certain number of papers to be reviewed, and doesn't that turn into an "accept" by the journal's editorial staff?

At the same time, I do think that they're going in the right direction here. The editors note that peer review should be valuable, and it should be a lot more valuable than it is. But it became linked to the decision to publish, rather than standing by itself as an assessment of a paper, and the reviews themselves were never seen by anyone except the authors, the editors, and the reviewers themselves. As the journal says:

Having been written for authors and editors, the peer reviews themselves are rarely seen, their contents reduced to an accept/reject decision – a relic of pre-Internet times, when journals had to identify papers that warranted the expense of printing and mailing to subscribers. The aspects of the review that would be of most value to the community – the strengths and weaknesses of the work the reviewers identify, aspects of the findings and methods that excite them, questions that remain, how it fits in with other work and into the broader field – are all discarded once a decision is made.

Most significantly, the emphasis placed on directing papers into journals has turned journal names into the de facto currency of academic research careers, and institutionalized the practice of judging scientists based on where, rather than what, they publish. This has, in turn, transformed journals from a means of communicating science into gatekeepers whose judgments – ones that are heavily influenced by bias, faddishness and chance – can determine which science gets seen, and which scientists succeed.

They see the changes in scientific publishing as linked to the (now antiquated) problems of the printing press and the postal service, which have led to a system that we don't have to hang on to any more. But "We should have rebuilt this system from the ground up to take advantage of our liberation from the constraints of print. Instead, we built online submission and review systems, and replaced printed articles with pdfs, but nothing fundamental has changed." They are also completely correct when they say that nobody who actually deals with the current system is happy with it or thinks that it's working well.

But there are a lot of questions that are going to have to be worked through. What if people put their preprints up, and then just use an eLife "selected for review" decision as leverage to go publish the work in a "big name" journal? What will those journals think of that? Will it seem strange to them to review a paper all over again, will they see it as adding more comments to an evolving process of publication review, as eLife sees it (but while not publishing their own reviewer statements?) Or will they just roll along hoping that their traditional gatekeeper functions, and the business model built on them, will somehow survive this challenge as well? On the other hand, will there be more big, significant papers that end up never being sent to the big-name journals at all, gradually draining them of their reason to continue as they are? I have no idea how all this will play out, but this is surely (in hindsight) going to be seen as some kind of turning point. How long do we have to wait to see what scientific publishing turns into?

Science, Volume 377, Issue 6612, Page 1251-1251, September 2022.

This Viewpoint Article provides tips on how to increase the chances of securing a European Research Council (ERC) Starting Grant.

Abstract

European Research Council (ERC) Starting Grants are arguably the most competitive grants in Europe and their prestige is fully justified considering that they (i) allow focus on a high risk/high gain project through generous funding of 1.5–2 million Euros, (ii) they can enable the foundation of a new academic group and earn the submitting principal investigator a professorship, and (iii) they serve as a highly reputable award that can either facilitate tenure/promotion or assist in securing a subsequent academic position. However, the journey to getting one is far from easy. In this Viewpoint Article, I will discuss my first two unsuccessful attempts to secure an ERC Starting Grant and how the lessons learned during the process led me to ultimately secure a grant upon my third attempt.

Synlett
DOI: 10.1055/s-0042-1751363

Spirocyclic diindenothiophenes were prepared by cyclization of tosylhydrazones, readily available from ketones, with 3,4-dibromo-2,5-bis(2-bromphenyl)thiophene. For bicyclic ketones, the bis-spirocycles were formed with very good diastereoselectivity.
[...]

Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

By the action of a strong Lewis acid, isomerization of the tricyanomethane to the ketenimine, HN=C=C(CN)₂, is triggered, which in turn directly attacks an aromatic species in an electrophilic aromatic substitution.

Abstract

Electrophilic aromatic substitution (EAS) can provide a straightforward approach to the efficient synthesis of functionalized complex aromatic molecules. In general, Lewis acids serve as a beneficial stimulus for the formation of a Wheland complex, the intermediate in the classical S_EAr mechanism of EAS, which is responsible for H/E (E=electrophile) substitution under formal H⁺ elimination. Herein, we report an unusual variant of EAS, in which a complex molecule such as the tricyanomethane, HC(CN)₃, is activated with a strong Lewis acid (B(C₆F₅)₃) to the point where it can finally be used in an EAS. However, the Lewis acid here causes the isomerization of the tricyanomethane to the ketenimine, HN=C=C(CN)₂, which in turn directly attacks the aromatic species in the EAS, with simultaneous proton migration of the aromatic proton to the imino group, so that no elimination occurs that is otherwise observed in the S_EAr mechanism. By this method, it is possible to build up amino-malononitrile-substituted aromatic compounds in one step.

Nature Chemistry, Published online: 26 August 2022; doi:10.1038/s41557-022-01028-6

The application of machine learning to big data, to make quantitative predictions about reaction outcomes, has been fraught with failure. This is because so many chemical-reaction data are not fit for purpose, but predictions would be less error-prone if synthetic chemists changed their reaction design and reporting practices.

Science, <a href="https://www.science.org/toc/science/376/6592">Volume 376, Issue 6592</a>, Page 532-539, April 2022.

Synlett
DOI: 10.1055/s-0040-1719906

Palladium-catalyzed cross-coupling reactions of polyhalogenated heterocycles provide a convenient access to multifold arylated and alkynylated ring systems with a broad spectrum of physical and medicinal properties. Products include thiophenes, selenophenes, pyrroles, indoles, furans, benzofurans, pyrazoles, pyridines, quinolines, pyrimidines, pyrazines, naphthyridines, quinoxalines, and others. The regioselectivity of the coupling reactions is controlled by a combination of electronic and steric parameters. While a number of couplings can be carried out essentially under standard conditions, others require the use of more sophisticated ligands and a thorough optimization of the conditions, such as solvent, temperature, or reaction time. The present Account provides a personalized overview of coupling reactions of polyhalogenated heterocycles.1 Introduction2 Thiophenes3 Selenophenes4 Pyrroles and Indoles5 Furans and Benzofurans6 Pyrazoles7 Pyridines8 Quinolines9 Pyrimidines and Pyrazines10 Naphthyridines and Quinoxalines11 Miscellaneous12 Conclusions
[...]

Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

Nature Machine Intelligence, Published online: 07 March 2022; doi:10.1038/s42256-022-00465-9

An international security conference explored how artificial intelligence (AI) technologies for drug discovery could be misused for de novo design of biochemical weapons. A thought experiment evolved into a computational proof.