Jason Williams

We’ve had several releases of remdesivir data, and this was not exactly one of those controlled-release formulations. No, this was more in the “chaotic mess” category, with news items coming from several sources with partial information. I decided not to blog on it until the loud banging noises stopped, and I’m glad I did, since I would have had to have revised (several times) whatever piece I managed to crank out.

Recall the previous state of affairs: we had a readout in 53 patients as reported by Gilead in the NEJM (of all places – future readers will be able to tell that they’ve hit the 2020 stratum in the literature when they run into a bunch of papers on clinical virology that all seem like they’re in the wrong journals). That one was interpreted as somewhat positive, although there was really no way of knowing. Then there was the news that a remdesivir trial had been suspended in China, which took everyone by surprise and did not breed confidence in anything: the drug’s prospects, the results themselves, the Chinese, you name it. A day or so later came word of leaked data from a trial in Chicago that sounded much more positive, and that threw some people’s opinions back the other way.

Now we have bits of data from an NIAID/NIH trial of the drug that began enrolling in Nebraska in late February (the first patient was one of the Diamond Princess cruise ship passengers, which seems long enough ago by now that it might as well be the Titanic). This one was double-blinded and placebo-controlled: patients in the treatment group received 200mg of the drug the first day and 100mg each day thereafter, for up to ten days. Participants needed to test positive for the virus and have evidence of lung involvement in the disease. The primary endpoint was improved time to recovery (discharge from the hospital or ability to return to normal activity), and it appears that remdesivir was statistically better than placebo: 11 days versus 15 days. The team also monitored overall survival in the >1000 patients, and there was a possible trend towards the drug, but it did not reach statistical significance (8% mortality in the treatment group, 11.6% in the placebo group).

That’s it. Those are the numbers we have. The rest will be in a “forthcoming report”, and we’re going to have to wait until it comes forth. This release was after an April 27 meeting of the data and safety monitoring board, and it’s worth noting that had there been “clear and substantial evidence of a treatment difference” during the trial that the DSMB was to have halted the study at that point. We can infer that nothing rose to that level, then: we have a difference, but not substantial enough to have ended the trial prematurely. And I have to note another issue: if you look at the Clinicaltrials.gov record for the trial, it appears that the outcomes measures for the trial were changed (as noted by Walid Gellad on Twitter). That primary endpoint of the trial mentioned above, time to recovery? It was originally an 8-point severity scale (death, on ventilator, hospitalized with oxygen, all the way down to discharged with no limits on activity). A similar ordinal scale measure is still in the secondary endpoints, as it was before, but we have no numbers for that yet, of course. But it’s clear that the primary endpoint was changed at some point in April.

The other piece of news is this paper in The Lancet describing a randomized, double-blind, placebo-controlled trial in China with 237 patients – in fact, the very one that was halted suddenly. This one enrolled patients that had 12 days or fewer of symptoms, confirmed viral infection, and involvement of the lungs as well (<94% oxygen saturation on room air and confirmed viral pneumonia on X-ray). The dosing of remdesivir was the same as in the NIH trial. But in this one, the use of the drug was not associated with a shorter time to clinical improvement. A subgroup analysis showed a trend (not statistically significant) towards shorter duration in the patients who overall showed symptoms for ten days or less, though. Mortality was identical between the two groups, although there was again a trend (not significant) towards less mortality on remdesivir in the shorter-duration patients, and thus a trend towards higher mortality in the others. The viral load was checked in both the upper and lower respiratory tracts of the patients, and remdesivir had no effect whatsoever on it compared to placebo, in any group.

So that paper’s results are not very impressive, frankly, and if you’d seen that one first then the NIAID results would have been even more surprising. I very much look forward to seeing the viral load numbers from that one, since that was one of the more striking misses in the Lancet paper. Remember, the mechanism of action of remdesivir, as a nucleoside mimic, is to interfere with viral replication. So if viral load isn’t be affected, you have to wonder what’s going on.

It’s possible that the drug’s efficacy, such as it is, is most apparent when the drug is given earlier in the disease course or to patients with are getting severe disease in general (those two categories probably have substantial overlap, and early in the infection you probably can’t tell the difference). Many people yesterday were saying that sure, the Chinese patients in the Lancet paper were in worse shape than the ones in the NIAID study, but looking at the inclusion criteria, I really don’t think that they were that different. The authors of this study note that their patient population was actually less ill than the ones reported in Gilead’s earlier NEJM paper, and that they had hoped, based on this, to have seen more of an effect than they did.

Taken together, the picture that’s emerging is that remdesivir may be of some help in less-severe cases. It is not a cure; a cure would have shown up in the trials we’ve run already, and cures are mighty thin on the ground for viral diseases. We can hope that the time-to-recovery is actually a useful measure and that the drug might get people out of hospitals a bit earlier, and hope a bit harder that there really is a mortality difference that will turn out to be real as we go into larger and larger numbers of patients. But working against that is the possibility that wider use of the drug will obscure the effect rather than make it more obvious.

To forestall some questions that I know will come up: what do I think about this versus hydroxychloroquine? Well, we have more controlled data to work with on remdesivir, for one thing, so whatever benefits there are, are more obvious. The balance of what controlled data we have on HCQ is negative, and here we’re at least more mixed. There is also (to the best of my knowledge) no particular safety signal for remdesivir, as opposed to HCQ (particularly the HCQ/azithromycin combination). So while I’m not bowled over, I’m more optimistic than I am about hydroxychloroquine.

That said, I continue to think that we do not yet have any treatment regimes that are making a big difference, unfortunately. I saw a tweet from Nate Silver, no fool, wondering about the possible effects of having some combination of drugs by this fall, things that could be widely administered so that anyone who needs them could get them, that reduces mortality by a significant amount (he mentioned 30%, 50%, or more). He started out by saying “Non-rhetorical question”, so taking that non-rhetorically, all I can say is that I don’t see it happening. Speculation about it seems a waste of mental effort. Remdesivir was honestly one of the better shots, and at best it might have decreased mortality from about 11% to about 8%. I don’t see any combination of repurposed drugs adding up to the numbers that Silver is wondering about. The only new (non-repurposed) therapy that could do it in that time frame is, I think, a monoclonal antibody. Having that widely available by the fall would really be pushing it, since it looks like the first patients will be dosed in June for the very fastest-running efforts. “Widely available” is the key phrase: I certainly think an effective mAb can be found, and the number of companies working on finding one makes it more likely than ever that we’ll get a good one. But proving that it’s good and (most importantly) getting it produced and distributed – well, “fall” to me starts in September, and that would be quite an accomplishment. Note that I have not even talked about cost. (This is a good point to mention that even remdesivir production is not a straightforward process, either).

Until we have such a mAb, and until the advent of a vaccine later on, I do not see any game-changers on the horizon. I will look forward to being wrong about how quickly these things will appear – that would be great – but I don’t think I’m wrong about those being the main things that will knock down the virus.

We report a C(sp³)‐C(sp³) cross‐coupling of alkyl bromides and alkyl chlorides with ethers by dual photoredox‐nickel catalysis. The catalytic system comprises of the organic photocatalyst 1,2,3,5‐tetrakis(carbazol‐9‐yl)‐4,6‐dicyanobenzene (4‐CzIPN) and bench stable nickel (II) acetylacetonate in the presence of visible‐light, providing the coupling products in up to 92% yield. Preliminary mechanistic studies suggest two catalytic cycles, as well as the photogeneration of bromine or chlorine radicals from halide atoms that are present in the structures of the coupling partners. The halide radical mediates the hydrogen atom transfer event, avoiding the need of an additional HAT catalyst.

Waste not, want not : Heterogeneous photocatalysts are a promising alternative to homogenous noble metal complexes and organic dyes that are not recyclable. This review summarized the application of inorganic and organic semiconductors, as well as well‐defined microporous materials as photocatalysts for light‐mediated organic synthesis.

Abstract

Visible light photocatalysis relies mainly on expensive noble metal complexes and organic dyes that are not recyclable. Heterogeneous semiconductors, which are mainly applied for artificial photosynthesis and wastewater treatment, are a promising sustainable alternative and gain increasing attention. Inorganic and organic semiconductors with suitable bandgaps are among the most widely studied heterogeneous photocatalysts due to their high stability and recyclability. More recently, microporous materials, such as conjugated organic polymers, covalent organic frameworks, and metal organic frameworks that can be tuned and designed on a molecular level showed promising results. This review provides an overview of the most common heterogeneous photocatalysts with a focus on their applicability in organic synthesis.

Three for three: A simple and efficient redox‐neutral three‐component synthesis of 1,2,3‐triazoles from α‐ketoacetals, N‐tosylhydrazide, and a primary amine is reported. This method provides access to all triazole substitution patterns, without the requirement for azides, alkynes, halides, transition metals, or oxidants.

Abstract

A scalable metal‐, azide‐, and halogen‐free method for the synthesis of substituted 1,2,3‐triazoles has been developed. The reaction proceeds through a 3‐component coupling of α‐ketoacetals, tosyl hydrazide, and a primary amine. The reaction shows outstanding functional‐group tolerance with respect to both the α‐ketoacetal and amine coupling partners, providing access to 4‐, 1,4‐, 1,5‐, and 1,4,5‐substituted triazoles in excellent yield. This robust method results in densely functionalised 1,2,3‐triazoles that remain challenging to prepare by azide–alkyne cycloaddition (AAC, CuAAC, RuAAC) methods and can be scaled in either batch or flow reactors. Methods for the chemoselective reaction of either aliphatic amines or anilines are also described, revealing some of the potential of this novel and highly versatile transformation.

A photo finish! The synergistic combination of organocatalysis and visible‐light photocatalysis offers a mild route to pyrazoles that proceeds under ambient conditions and with excellent levels of regiocontrol.

Abstract

Sydnone‐based cycloaddition reactions are a versatile platform for pyrazole synthesis, however they operate under harsh conditions (high temperature and long reaction times). Herein we report a strategy that addresses this limitation utilizing the synergistic combination of organocatalysis and visible‐light photocatalysis. This new approach proceeds under ambient conditions and with excellent levels of regiocontrol. Mechanistic studies suggest that photoactivation of sydnones, rather than enamines, is key to the successful implementation of this process.

An “ACE” in the hole: A range of angiotensin converting enzyme inhibitors were synthesized in continuous flow using a single synthetic approach in good overall yields (see scheme). Utilization of in situ IR analysis facilitated a rapid development process and provided kinetic insight to the key amide coupling step across the set of important active pharmaceutical ingredients.

Abstract

A strategy for the continuous flow synthesis of angiotensin converting enzyme (ACE) inhibitors is described. An optimization effort guided by in situ IR analysis resulted in a general amide coupling approach facilitated by N‐carboxyanhydride (NCA) activation that was further characterized by reaction kinetics analysis in batch. The three‐step continuous process was demonstrated by synthesizing 8 different ACE inhibitors in up to 88 % yield with throughputs in the range of ≈0.5 g h⁻¹, all while avoiding both isolation of reactive intermediates and process intensive reaction conditions. The process was further developed by preparing enalapril, a World Health Organization (WHO) essential medicine, in an industrially relevant flow platform that scaled throughput to ≈1 g h⁻¹.

Squaring up: A continuous‐flow approach has been developed to photoisomerize 1,2‐azaborines to cis‐1,2‐aminoborylated cyclobutanes and analogues bearing quaternary carbon centers. Further derivatizations at the borylated position led to a series of 2‐functionalized aminocyclobutanes. FG=functional group.

Abstract

We provide a seminal example of the utility of the 1,2‐azaborine motif as a 4C+1N+1B synthon in organic synthesis. Specifically, conditions for the practically scalable photoisomerization of 1,2‐azaborine in a flow reactor are reported that furnish aminoborylated cyclobutane derivatives. The C−B bonds could also be functionalized to furnish a diverse set of highly substituted cyclobutanes.

The intermolecular carbonyl–olefin metathesis between aromatic ketones/aldehydes and vinyl ethers is accomplished with not only simple soluble but also solid acid catalysts to give trans alkenes in high yields, multi‐gram amounts, and in‐flow.

Abstract

The carbonyl–olefin metathesis reaction has experienced significant advances in the last seven years with new catalysts and reaction protocols. However, most of these procedures involve soluble catalysts for intramolecular reactions in batch. Herein, we show that recoverable, inexpensive, easy to handle, non‐toxic, and widely available simple solid acids, such as the aluminosilicate montmorillonite, can catalyze the intermolecular carbonyl–olefin metathesis of aromatic ketones and aldehydes with vinyl ethers in‐flow, to give alkenes with complete trans stereoselectivity on multi‐gram scale and high yields. Experimental and computational data support a mechanism based on a carbocation‐induced Grob fragmentation. These results open the way for the industrial implementation of carbonyl–olefin metathesis over solid catalysts in continuous mode, which is still the origin and main application of the parent alkene–alkene cross‐metathesis.

Selectivity snapshots with PALs: Photoaffinity probes were designed to target the cyclin‐dependent kinase family, and found to competitively enrich CDKs from cell lysates. Subsequently, a biochemical photoaffinity displacement assay was developed to measure compound potency.

Abstract

The CDK family plays a crucial role in the control of the cell cycle. Dysregulation and mutation of the CDKs has been implicated in cancer and the CDKs have been investigated extensively as potential therapeutic targets. Selective inhibition of specific isoforms of the CDKs is crucial to achieve therapeutic effect while minimising toxicity. We present a group of photoaffinity probes designed to bind to the family of CDKs. The site of crosslinking of the optimised probe, as well as its ability to enrich members of the CDK family from cell lysates, was investigated. In a proof of concept study, we subsequently developed a photoaffinity probe‐based competition assay to profile CDK inhibitors. We anticipate that this approach will be widely applicable to the study of small molecule binding to protein families of interest.

Go with the flow: A photochemical flow reactor was used to perform Norrish–Yang reactions to prepare a series of 3‐hydroxyazetidines gauging the structural influence of the starting material on reactivity. The flow process resulted in a dramatic reduction in reaction time and permitted ready scaling‐up of the reaction showing how flow chemistry is advantageous to the transformation allowing exploitation of its synthetic utility.

Abstract

A photo‐flow Norrish–Yang cyclisation has been devised that delivers 3‐hydroxyazetidines in good yields. The high reproducibility and short residence times of the flow process enables easy scaling of the transformation allowing access to these valuable chemical entities at synthetically useful multi‐gram scales. A systematic exploration of the constituent structural components was undertaken allowing an understanding of the reactivity and functional group tolerance of the transformation.

Here’s a ring system that you’ve never used before – the cyclopropyl system in purple at the end of the row in the diagram at right. It’s described in this paper from GSK-Stevenage as a new morpholine isostere. A 4-morpholino-pyrimidine hinge binder core is preferred in many PI3K and PIKK inhibitors, but the team was looking for a replacement to try to get better metabolic stability. As they describe it, brainstorming sessions led to someone drawing that ring system up on the board, so they took a closer look.

That’s a DFT energy plot calculated as you rotate the bond between the two rings, and you’ll see that the morpholine itself is strongly predicted to be coplanar to the pyrimidine (energy minima at 0 and 180). The tetrahydropyran (in orange) isn’t nearly so picky, apparently, and those analogs lose affinity because they don’t like being in the conformation that gives them a crucial hydrogen bond to the ring oxygen. Meanwhile, the dihydropyran (blue) has a profile a lot more like the morpholine, and indeed there are analogs known for these kinase inhibitors where it is a perfectly good substitute – until you start looking beyond the binding assay, that is. It’s not a particularly stable group, metabolically, so it’s not the answer to the question, either. You can put a methyl on the THP ring to kick it back into a better conformational space, but you’ve now introduced a chiral center and (as it turns out) have also not solved the metabolic stability problem.

As shown, the bicyclo ring compound is predicted to be coplanar in the DFT calculations, but interestingly, a force-field minimization (MMFF94X) predicted strongly that it would be (uselessly) 90 degrees out of plane (just like the plain tetrahydropyran in those calculations comes out, too). Sometimes there’s no alternative to actually running the experiment, you know, so the group took the dihydropyran-pinacolboronate intermediate that they had on hand and cyclopropanated it using chloroiodomethane and diethylzinc. I mean, you never want to miss a chance to use diethylzince, am I right? Especially if you’re into sudden flames, although they did use just the 1M solution in hexane, which is (fortunately) a far less fraught experience than the neat liquid. It took some hammering (multiple additions of both reagents over an extended period), but they pulled about a 40% yield out eventually and used the corresponding trifluoroborate in the subsequent coupling reaction.

Well, the DFT is right in this case and the molecular-mechanics calculations are wrong, which is the sort of thing that’s worth remembering. The bicyclo analog is indeed a perfectly good replacement for the morpholine and the 3-methyl THP, and what’s more, it shows greatly improved metabolic stability and clearance. An X-ray crystal structure confirmed the coplanar geometry. So congratulations to whoever it was on the list of authors who put that one up on the whiteboard. The sharp-eyed will have noticed, though, that this compound (like the methyl-THP) is now chiral, and the GSK team admits that so far they haven’t been able to come up with a chiral synthesis of the intermediate (everything’s been brute-forced by chiral chromatography at the end). That’s of course doable while you’re optimizing a compound series, but no one wants to go that way on scale – for one thing, you’re throwing away half your time, money, and effort, and for another, scaling up those chiral separations adds a whole new set of problems. So that’s still an unsolved problem. (Update: for more on this issue, see Henry Rzepa here.)

And while we’re talking small saturated heterocycles, this paper is worth a look, too. It’s an extension of some work that I blogged about last year, about how adding a bridging group in rings like morpholine, piperazine, or piperidine doesn’t always have the effects that you’d predict. And now comes work that the small spiro replacements for those have their oddities, too. For one thing, their measured logD values show that they’re almost all significantly more polar, even though you’ve added another carbon to form the bicyclo system. That seems to be down to increased basicity, and I’m not sure that everyone appreciates either of those effects. And something that I’m sure that people haven’t realized is the later claim in the paper that the diaza [3.3] systems isn’t a good isostere for piperazine in the first place. You have that basicity change, but also the distance between the two nitrogens is increased, and they’re now forced ninety degrees around from each other compared to the starting heterocycle. As mentioned in the discussion of the previous paper above, this is surely going to mess up any well-formed hydrogen bond that the original compound had.

So these compounds may have their own virtues – that polarity and that geometry might be just what your binding site has been pining for – but you should make them for chemical diversity, not because you’re trying to mimic something else. . .

Divide et impera: A general strategy to access both aryl and alkyl radicals by photosensitized decarboxylation of the corresponding carboxylic esters is based on an energy‐transfer‐mediated homolysis of unsymmetric σ‐bonds. The independent aryl/alkyl radical generation step enables a series of key C−X and C−C bond‐forming reactions by simply changing the radical trapping agent.

Abstract

Despite significant progress in aliphatic decarboxylation, an efficient and general protocol for radical aromatic decarboxylation has lagged far behind. Herein, we describe a general strategy for rapid access to both aryl and alkyl radicals by photosensitized decarboxylation of the corresponding carboxylic acids esters followed by their successive use in divergent carbon–heteroatom and carbon–carbon bond‐forming reactions. Identification of a suitable activator for carboxylic acids is the key to bypass a competing single‐electron‐transfer mechanism and “switch on” an energy‐transfer‐mediated homolysis of unsymmetrical σ‐bonds for a concerted fragmentation/decarboxylation process.

A catalytic asymmetric method is described for the synthesis of enantioenriched cyclohexanes from racemic 1,5‐diols by hydrogen borrowing catalysis. This reaction is mediated by a chiral iridium(I) complex which is able to impart high levels of enantioselectivity to the process.

Abstract

Hydrogen borrowing catalysis serves as a powerful alternative to enolate alkylation, enabling the direct coupling of ketones with unactivated alcohols. However, to date, methods that enable control over the absolute stereochemical outcome of such a process have remained elusive. Here we report a catalytic asymmetric method for the synthesis of enantioenriched cyclohexanes from 1,5‐diols via hydrogen borrowing catalysis. This reaction is mediated by the addition of a chiral iridium(I) complex, which is able to impart high levels of enantioselectivity upon the process. A series of enantioenriched cyclohexanes have been prepared and the mode of enantioinduction has been probed by a combination of experimental and DFT studies.

Iron shines in the spotlight: An accelerated, visible‐light‐promoted iron‐catalyzed Kumada cross‐coupling reaction enabled the high‐yielding coupling of electron‐rich aryl chlorides with aliphatic Grignard reagents, which is normally very challenging in the absence of light. The use of flow conditions enabled full conversion in a matter of minutes and scalability to multigram amounts of substrates and products.

Abstract

A continuous‐flow, visible‐light‐promoted method has been developed to overcome the limitations of iron‐catalyzed Kumada–Corriu cross‐coupling reactions. A variety of strongly electron rich aryl chlorides, previously hardly reactive, could be efficiently coupled with aliphatic Grignard reagents at room temperature in high yields and within a few minutes’ residence time, considerably enhancing the applicability of this iron‐catalyzed reaction. The robustness of this protocol was demonstrated on a multigram scale, thus providing the potential for future pharmaceutical application.

No solution necessary: A graphitic carbon nitride in combination with nickel catalysis can induce selective C−O cross‐coupling. The organic semiconductor exhibits a broad substrate scope, is able to harvest green light, and can be recycled multiple times. It thus provides a sustainable alternative to the non‐recyclable noble‐metal complexes typically used as photocatalysts.

Abstract

Cross‐coupling reactions mediated by dual nickel/photocatalysis are synthetically attractive but rely mainly on expensive, non‐recyclable noble‐metal complexes as photocatalysts. Heterogeneous semiconductors, which are commonly used for artificial photosynthesis and wastewater treatment, are a sustainable alternative. Graphitic carbon nitrides, a class of metal‐free polymers that can be easily prepared from bulk chemicals, are heterogeneous semiconductors with high potential for photocatalytic organic transformations. Here, we demonstrate that graphitic carbon nitrides in combination with nickel catalysis can induce selective C−O cross‐couplings of carboxylic acids with aryl halides, yielding the respective aryl esters in excellent yield and selectivity. The heterogeneous organic photocatalyst exhibits a broad substrate scope, is able to harvest green light, and can be recycled multiple times. In situ FTIR was used to track the reaction progress to study this transformation at different irradiation wavelengths and reaction scales.

I did a post a few years ago that was a sort of informal salary survey for biopharma folks (I asked initially about the Boston/Cambridge area, but responses came in from many other places as well). I’ve had a recent request for an update, and I think it would make an interesting comparison..

So break out the comment-section pseudonyms! Let’s hear what the rough salary ranges are these days. Relevant information would be your level of experience, the broad scientific area/job function that you’re working in, and your geographical region, as well as your general pay level. If you’re just starting out, it would be worth knowing if you’re coming out of a post-doc and how long that took as well. At the other end, if you’ve moved into the world of consulting, I think people would like to know how that’s going, too.

This will be far from a controlled scientific survey, but I think that last time around it proved to be of some value, and we can also see if things come out any differently than they did in 2014. . .