Scientific Update, established in 1989 by Dr. Trevor Laird, organises conferences and training courses for industrial chemists and chemical engineers in chemical development and scale-up and many other specialist topics in organic chemistry.
Dr John Studley, Scientific Director at Scientific Update recently spoke to Dr Boris Gorin, Eurofins Alphora, Toronto, Canada ahead of his presentation at the 2019 ‘Organic Process Research & Development’ Conference in Toronto, Canada. Boris will talk about “Eribulin Mesylate, a Journey from Synthetic Route Discovery to Scale-Up Manufacture”.
John Studley (JS): Can you tell us a bit about your background?
Boris Gorin (BG): I am a native of Ukraine and obtained a Master of Science, Magna Cum Laude in chemistry, followed by a Ph.D. in synthetic organic chemistry from Moscow State University for studies in the synthesis of heterocyclic compounds. I furthered my academic studies in Canada in the field of medicinal chemistry working with Dr. Greg Thatcher at Queens University, Kingston, Ontario. I have over 30 years of experience in synthetic organic chemistry and process development for the pharmaceutical industry. In 2004, I joined Alphora Research Inc. where I headed the process R&D team in progressive roles from R&D manager to Vice President, R&D. Currently, I hold a position of Senior Scientific Adviser at Eurofins Alphora and work on the introduction of new technologies such as High-Throughput-Screening, Continuous Flow Processes, Process Analytical Technology, and others to API process development and optimization. I am also the author of over 50 patents and scientific publications.
JS: What is the main focus of Eurofins Alphora?
BG: Eurofins Alphora provides integrated services for the pharmaceutical development of Active Pharmaceutical Ingredients (API). This includes development of technologies and analytical controls to manufacture APIs, discovery of new solid forms to enhance bioavailability of the API, and pre-formulation and formulation studies to enable drug product launch. Alphora’s range of services covers the developmental requirements from pre-clinical through phase III and to the successful drug product launch and commercial manufacture.
JS: Could you provide us with an overview of your upcoming presentation ‘Eribulin Mesylate, a Journey from Synthetic Route Discovery to Scale-Up Manufacture’
The Eribulin project started at Alphora about 7 years ago when we were asked by one of our clients to develop an innovative and economically viable synthetic route to one of the most complex pharmaceutical molecule, Eribulin Mesylate. Our talented team of scientists responded to the challenge and developed an elegant and innovative route in a less than two years (that was presented at the OPRD conference in Toronto in 2015). It occurred to us that the new synthetic route can be also used for the scale-up manufacture of this API, hence the journey started to convert a purely academic, laboratory scale synthesis into a commercially viable and scalable manufacturing process. In my presentation I will tell you about some challenges and achievements in process scale-up development towards pilot plant scale manufacture of this intricate API.
Eurofins Alphora are Platinum sponsors of the ‘Organic Process Research & Development’ Conference. Dr Claire Francis, Marketing Director said “We are delighted to be partnering with a local company at this our flagship meeting for process chemists in North America. Eurofins Alphora has been a prominent figure at our events both presenting and attending and it is great to be back in Toronto to learn about their developments. We are excited to be taking a group of people from the meeting to visit their Mississauga facility for a tour of their site and to hear more about their capabilities. We will also be welcoming many of their R&D scientists at the conference, who will hopefully be inspired to become our next generation of speakers”. They will also be hving a networking event after the tour for industry professionals to network with their scientists and other industry professionals. Drinks and refreshments will be provided. To join us at the conference in Toronto, meet Boris and visit Eurofins Alphora – Click HERE.
Chemical Industries Association (CIA) Awards Celebration
Thursday 13th June 2019
St George’s Hall, Liverpool
Scientific Update is proud to sponsor the ‘Young Ambassador’ Award at the Chemical Industries Association (CIA) Awards Celebration in Liverpool, 13th June. This award will be presented to an outstanding young person demonstrating communication skills and leadership associated with the chemical industry and contributing to its success.
The ceremony is an inspiring celebration of the best of the UK chemical and pharmaceutical industry. It provides an excellent opportunity to celebrate the outstanding achievements of colleagues or business partners. The ceremony regularly attracts some 500 diners including senior representatives of chemical companies, government, industry experts and the media.
Scientific Update is keen to support the UK Chemical Industry through provision of services for Continuous Professional Development (CPD) and is excited about the opportunities to work with the next generation of inspirational chemists. Watch this space…
Following a communication from a chemist at Merck / MSD I can now tell you about 2 more cocrystal APIs on the market – Lexapro (escitalopram oxalate) and Steglatro (ertugliflozin pyroglutamic acid cocrystal. Lexapro is actually a cocrystal of the salt escitalopram oxalate with oxalic acid, similar in some ways to the Praziquantel intermediate naproxen salt used for resolution.
The keynote speaker at our recent ‘Polymorphism and Crystallisation’ Conference in Boston was Dr Susan M. Reutzel-Edens from Eli Lilly, whose name will very familiar to anyone working in the solid form / crystallisation and she gave what one delegate described as “the best talk I have ever heard”. Now I can’t entirely agree with that delegate because I have seen Dr Reutzel-Edens talk several times before and every talk has been of a very high standard.
This particular presentation – “Inconvenient Truths about Solid Form Landscapes” covered a variety of examples from her experience at Eli Lilly in many cases molecules which did not behave in line with conventional thinking about solid forms, such as a compound which formed a stoichiometric dihydrate and a non-stoichiometric hydrate. Conventional wisdom suggests the non-stoichiometric hydrate is probably a channel hydrate whilst the water in the dihydrate would be expected to be more tightly bound. So, the non-stoichiometric hydrate should be easier to dry but in fact quite the opposite was found to be the case. The non-stoichiometric hydrate appeared to have a somewhat flexible structure that would adapt to some loss of water meaning the remaining water became more tightly bound.
The other main area that was covered was crystal structure prediction and how sometimes the structures that are actually observed do appear to be the most stable forms when compared with the large number of predicted structures, but not always. As ever when studying crystal forms it is not just about thermodynamics, but also the kinetics of nucleation and crystal growth and also the relative stability of the required conformation in solution.
There are now 3 cocrystal API’s (Entresto, Suglat, and Depakote) on the market meaning that this area is no longer just an academic curiosity.
Entresto is a cocrystal formed from the sodium salts of sacubitril and valsartan, but I do not know whether that is affected by the current furore over N-nitrosoamine impurities found in Valsartan. Suglat is a cocrystal of proline and ipragliflozin. While Depakote is a cocrystal comprised of valproic acid and sodium valproate.
I have recently come across 3 examples of cocrystals, two related to resolution of API intermediates and the other from the material science area.
At the recent Scientific Update conference on Polymorphism and Crystallisation in Boston, MA David Maillard from Merck, Darmstadt described the resolution of an intermediate en route to R-Praziquantel1 (see Scheme 1 below).
Scheme 1: Resolution of a Praziquantel intermediate
Using 1 equivalent of R-naproxen as the resolving agent gave very good resolution but the isolated slat was found to be a cocrystal formed from the desired salt and another molecule of R-naproxen. This was great news from a cost perspective because all the naproxen ends up in the isolated intermediate making recovery and recycle much simpler than if half had remained in solution as part of the unwanted diastereomeric salt.
At the same conference Andréde Vries from Innosyn gave a presentation on Viedma ripening or attrition enhanced deracemization2. This is where grinding a racemate gives a single enantiomer which sounds good, but the compound must crystallise as a conglomerate and must be epimerizable. As it would happen I have just read a paper in Angewandte3 describing the work on the Viedma ripening approach to producing a single enantiomer of Mefloquine. Mefloquine it self is not a suitable substrate so they examined various derivatives and found one salt of a ketone derivative which was suitable (see Figure 1).
Figure 1: Mefloquine ketone
34 Salts were prepared and screened, but only the biphenylsulfonic acid salt possessed the right properties, i.e. formed a conglomerate. The salt turned out to be a rare example of a cocrystal slat hydrate that is also a conglomerate. In this case the solid contains 2 biphenylsulfonic acid molecules and two water molecules for each Mefloquine ketone.
And finally, another paper published in Angewandte describes the preparation of radical-radical cocrystals such as the one shown in Scheme 2, which are of interest as organic ferrimagnetic materials.
Scheme 2: Radical-radical cocrystal
D. Maillard, Scientific Update conference on Polymorphsim and Crystallisation, Boston, MA, April, 2019.
A. De Vries, Scientific Update conference on Polymorphsim and Crystallisation, Boston, MA, April, 2019.
John Studley (JS): What are the main challenges in metal catalysis? What will be the state of the art in 10 years? 100 years?
Dave Leahy (DL): I think site selectivity for C-H activation is really one of the next main challenges to overcome in metal catalysis. Jin-Quan Yu has begun to revolutionize the field but we are really just beginning to be able to think about how to make catalysts that do not rely on programmed, innate or directed reactivity for selectivity.
JS: What do you think are currently the most exciting research areas in metal catalysed chemical processes?
DL: I’m very interested in some of the great work by Paul Chirik, Neil Garg, Dan Weix and many others on non-precious metal catalysis. In addition to be able to have more sustainable versions of the transformations that we so heavily rely on, it is very exciting to see new orthogonal reactivities that these elements can provide.
JS: Do you believe that organocatalysis could ever completely replace transition metal processes?
DL: I think organocatalysis, biocatalysis, transition-metal catalysis and base-metal catalysis will all have their place. All will evolve and become more and more efficient, but it is hard to see any completely overshadowing the others.
JS: With the 2018 chemistry Nobel Prize being jointly awarded to Frances Arnold for biocatalytic engineering, how do you see this field developing over the next decade?
DL: There has been so much growth in this field, and certainly directed evolution approaches to enzyme evolution dramatically expands the potential toolbox for biocatalytic processes. During the next decade we should see new chemical reactions that are not part of nature’s toolbox being accomplished with engineered enzymes, inspired by Frances’s work in biocatalytic cyclopropanation, nitrene insertion and other non-natural transformations.
JS: A recent perspectives article by Manfred Reetz (Acc. Chem. Res. 2019, 52, 336-344) describes his efforts to tune transition metal catalysis with engineered metallo-enzymes. What are your views on this type of approach?
DL: It will be extremely interesting to see what happens to this area once machine learning approaches become more mainstream and accessible to chemists. This is already being applied to directed protein evolution.
JS: What do you think is the most efficient industrial catalytic process? If you had to re-design it what would you do differently?
DL: I love that the Haber-Bosch process, arguably one of the most important metal-catalysed processes known to man (at least if we want to eat), uses iron. That said, I’d think the entire process could be more sustainable if the needed hydrogen could come from electrolysis of water rather than steam reforming of methane. Perhaps one day in the not too distant future, ammonia will be prepared completely electrochemically.
JS: I enjoyed reading your article in Organometallics (2019, 38 (1), 36-46) and am looking forward to your presentation ‘A pharmaceutical perspective on sustainable metal catalysis’ -can you tell us a little more about what to expect?
DL: My presentation will further explore these themes but will include some even more current examples of sustainable metal-catalysis on scale practiced in the pharmaceutical industry.
JS: 2019 is the International year of the periodic table- What is your favourite metallic element and why?
DL: Rhodium – I guess I have expensive tastes. But I did my Ph.D. studying rhodium-catalyzed allylic substitutions, so I’ll always have a special affinity for this metal.
JS: Who inspired you to study chemistry?
DL: A lot of people have inspired me in chemistry over the years, but I’ll mention Paul Rider, who was the head of process chemistry at Merck for quite some time. I saw him give a lecture that really highlighted the importance of process chemistry and the innovation possible within that discipline. This lecture really shaped my interest in pursuing a career in process chemistry, as to that point I thought I wanted to do discovery chemistry.
David Leahy was talking to John Studley, Science Director at Scientific Update. For more information on Scientific Update or on the conference that David will be presenting his work, please contact John:
Dr John Studley Scientific Update
Dr John Studley, Scientific Director at Scientific Update recently spoke to Professor Ben List, Max Planck
Institute, Germany ahead of his Key Note lecture at the 2019 Catalysis in the Pharmaceutical and Fine Chemical Industry Conference, in Lucerne, Switzerland. Ben will talk about “how we have designed and developed a novel class of extremely reactive chiral Lewis acid catalysts that have a fundamentally different mode of activation. The potential of this catalyst class is nothing but spectacular as you will see in my talk!”
John Studley (JS): What are the main challenges in your organocatalysis research? What will be the state of the art in 10 years? 100 years?
Ben List (BL): I see three main challenges that I am particularly interested in:
The activation of previously unreactive substrates,
to solve real problems in chemical synthesis, and
the development of more technically useful high performance catalysts and reactions.
Some of these challenges will clearly be solved within the coming 10 years. Who knows what will happen in a 100 years…
JS: Do you believe that organocatalysis could ever completely replace transition metal processes?
BL: I think there are metal catalyzed processes that would be extremely challenging if not impossible for organocatalysis to replace. Consider for example olefin metathesis, certain very popular Pd-catalyzed cross couplings, hydroformylations and asymmetric hydrogenation reactions. However, I would argue that new and potentially simpler disconnections are now enabled with organocatalysis. In academic asymmetric synthesis, organocatalysis is now the number one. My expectation is that more and more, this will also translate into industrial processes. And yes, it is possible that some transition metal catalyzed processes will be replaced with organocatalysis, but not necessarily in a one to one exchange of catalysts but rather by enabling alternative routes.
JS: What are your views on the sustainability of transition metal catalyzed processes?
BL: As an organocatalysis scientist, I don’t think that my views are particularly relevant to this question. I have heard that Palladium is an “endangered element” but who knows if there are not as of yet unidentified resources. I still like the current move towards more abundantly available metals such as iron and nickel, even though toxicity and the requirement by drug agencies for the removal of metal traces can still be an issue.
JS: A common question relating to organocatalysis how can we increase potency and reduce catalyst loading? What are your thoughts on this?
BL: In contrast to the perhaps still pervading perception, I have to say that organic catalysts are not inherently less reactive than transition metal catalysts. In fact, just last year we have published a paper in which we report the lowest catalyst loadings ever used in any chemically catalyzed asymmetric carbon carbon bond forming reaction. We are approaching the parts per billion area now! On the other hand, with catalysts such as proline, which are non-toxic or even edible, I would argue that the catalyst loading is rather irrelevant. Still we should always aim at improving our catalysts – and this is currently one important line of research in my laboratory.
JS: Organic photocatalysis is an exciting new area that has seen rapid development in a relatively short timeframe, how do you see this field developing?
BL: I think this is a very exciting area of great potential. Perhaps some real and important problems could be solved by using light and catalysis.
JS: Photosynthesis is believed to exploit quantum effects to drive its exquisite efficiency. Do you think this is something that could one day be harnessed in fundamental catalyst design?
BL: I would say that catalysis fundamentally is a quantum mechanical phenomenon.
JS: The Nobel prize was jointly awarded last year to Frances Arnold for biocatalytic engineering – what do you think the next decade holds in this area? Have you ever met Prof. Arnold and if so do you have any stories or anecdotes you are able to share?
BL: Directed evolution of protein catalyst is a very exciting area. I expect the greatest things from this field in the coming years. Actually, I am somewhat frightened that biocatalysis will replace a lot of what we do right now. I know Frances Arnold well and admire her very much. I remember, when I met her the first time at the Bürgenstock, she responded to my question if she really was an engineer: “yes, I am a chemical engineer, but one that is as good as it gets!” She has been totally right.
JS: We are looking forward to presentation “a truly powerful, scalable and general approach to asymmetric Lewis acid catalysis” – can you tell us a little more about what to expect?
BL: Well, Lewis acids are nothing new but I would argue that they are the most general catalyst class there is! They are extremely powerful, utilized on a multi million ton scale, and it is not unlikely that the majority of all catalyzable transformations can be catalyzed by Lewis acids. However, enantioselective Lewis acid catalysis lags behind. We have now designed and developed a novel class of extremely reactive chiral Lewis acid catalysts that have a fundamentally different mode of activation. The potential of this catalyst class is nothing but spectacular as you will see in my talk!
JS: What do you think is the most efficient Industrial catalytic process? If you had to re-design it what would you do differently?
BL: I’m not sure what the most efficient industrial process is but I know which is the most important one: it is the Haber-Bosch ammonia synthesis. Life on earth for so many humans is only possible because of this reaction. I wish I could develop a truly efficient and mild version!
JS: What do you think are the greatest challenges in synthetic organic chemistry?
BL: How about making fuel from carbon dioxide and sunlight? Or the reaction mentioned above? Or to make biodegradable plastic?
JS: What / who inspired you to study chemistry?
Mostly gun powder. Possibly also hearing family stories about my great-great grandfather Jacob Volhard who was a chemist.
JS: What do you think of Brexit?
BL: My Trumpesc answer: Sad, very sad!
Ben List was talking to John Studley, Science Director at Scientific Update. For more information on Scientific Update or on the conference that Ben will be presenting his work, please contact John:
Dr John Studley Scientific Update
The use of fluorine and fluorine-containing functional groups in medicinal chemistry, agrochemicals and advanced materials has grown over the past fifty years.1 Not surprisingly this increase in utility tracks with notable developments and refinements in safe and accessible synthetic methodology, both on the discovery and development front and in subsequent manufacturing. A recent example that caught my eye is the aryl-pentafluorosulfanyl (ArSF5) group.2 Some reasons why it’s interesting a bit later- but to start let’s first focus on synthetic history.
First reported in the 1960’s by Sheppard working at DuPont,3 difficult and intractable synthetic methods and hazardous chemistry coupled with subsequently unfounded reports of hydrolytic instability condemned it to the chemical curiosity archives, where it remained for the next 40 years.4
A key breakthrough in advancing the state of the art came from the Umemoto group in 2008 with the development of a two-step route to Aryl-SF5derivatives involving initial formation of an Aryl-SF4Cl intermediate (aryl disulphide, Cl2, KF or CsF, CH3CN) and subsequent halogen (Cl/F) exchange using a Lewis acidic fluoride source such as ZnF2, AgF or HF. This patented process was published in 2012 and gives good yields for formation of the initial chlorinated intermediate and modest yields for introduction of the final fluorine atom.5 The mechanism of this process is shown below (Figure 1). The trans– sulfur stereochemistry predominates and is configurationally stable.6
Figure 1: Conversion of an aryl disulphide to intermediate ArSF4Cl
In a recent improvement of this process, circumventing the need for chlorine gas and the inherent mass transfer issues with scale-up of these type of processes, Tongi and Pitts have published a paper using TCCA (trichloroisocyanuric chloride) as a easy to handle solid chlorinating agent in combination with KF and catalytic acid to generate the key ArSF4Cl intermediates.7 The paper also describes conversion of the chlorinated compound to the Aryl SF5several different methods used historically by other groups.
So why the interest in this substituent? Often referred to as “super-trifluoromethyl” the SF5group is larger in volume (driving steric effects in chemistry and biochemical interactions) and more lipophilic than CF3. It is also a stronger electron withdrawing group both by resonance and induction and, despite those stability concerns I eluded to earlier, it is chemically (and thermally) inert, including during exposure to some extreme reaction conditions such as nitration, metallation and oxidative processes.8 Synthesis of some useful building blocks incorporating an aryl SF5substituent are listed in reference 8. Aryl SF5derivatives have a higher dipole moment than the corresponding trifluoromethyl compounds (2.60 D for benzotrifluoride v’s 3.44 D for the SF5derivative- for reference a nitro group falls in the range 3.5-4.0 D). These properties have been exploited in liquid crystal research and in fine-tuning the physical and electronic properties of molecules in drug and agrochemical development.9 Direct replacement of CF3with SF5 often improves the physical properties and in vitro activity of small molecules, especially where activity is correlated with lipophilicity.9
SF5analogues of the anti-malarial drug Mefloquine and the SSRI antidepressant Fluoxetine10 as well as agrochemical compounds such as Fipronil and Trifluralin11 are described in the literature (Figure 2). A recent publication by Cobb describes synthesis of SF5containing aromatic amino acids- a sure sign that peptide derivatives are not too far away (Figure 3).12 The SF5 group has been investigated as a direct replacement for tert-butyl, halogen and nitro functional groups.13
Figure 2: SF5analogues of pharmaceutical and agrochemical compounds
With improvements in synthetic tractability it’s likely we will see more compounds containing this functional group enter development.
Figure 3: SF5derivative of tyrosine (see ref 12)
Scientific Update offer a training course in which we highlight the reasons fluorine is ubiquitous in the pharmaceutical and fine chemical industries, summarize the traditional methods for preparing organofluorine compounds and highlight new developments in the field. For more information contact me at email@example.com.
Njardarson et al Med. Chem. 2014, 57, 2832-2842.
Review article: Preparation and utility of organic pentafluorosulfanyl-containing compounds, J. T. Welch et al Rev. 2015, 115, 1130-1190.
Umemoto US20080234520A; Umemoto et al Beilstein J. Org. Chem. 2012, 8, 461-471.
Highly fluorinated derivatives give some cis– products. Ortho-substitution tends to shut the reaction down.
Pitts et al, Angew. Chem. Int Ed. 2019, 58, 1950-1954.
http://www.colorado-hiking.net/ArSF5.html; C-H borylation and Suzuki coupling in the presence of SF5: Carreira et al Org. Lett. 2013, 15, 5147-5149; Bier et al, Beilstein J. Org. Chem. 2013, 9, 411-416; synthesis of SF5substituted phenylboronic acid building blocks: P Beier et al Beilstein J. Org. Chem. 2015, 11, 1494-1502, see also T. Braun et al Chem. Comm. 2016, 52, 3931-3934.
Hypervalent sulfur fluorides and the design of liquid crystals: P. Kirsch et alChimia 2014, 68, 363-370; Fluorinated Compounds in Medicinal Chemistry: Recent Applications, Synthetic Advances and Matched-Pair Analyses: Topics in Med. Chem. 2014, 14, 855-864; Allostericagonists of the calcium receptor (CaR): fluorine and SF5 analogues of cinacalcet Org. Biomol. Chem. 2012, 10, 7922-7927.
Synthesis and biological evaluation of the first pentafluorosulfanyl analogs of mefloquine: Wipf et al, Biomol. Chem.2009, 7, 4163-4165; WO 2010/144434; The synthesis and biological activity of pentafluorosulfanyl analogs of fluoxetine, fenfluramine, and norfenfluramine J.Welch et al Bioorg. Med. Chem. Lett. 2007, 15, 6659-6666.
Crowley et al, Chimica 2004, 58, 138-142; J. Welch et al J. Pestic. Sci. 2007, 32, 255-259.
Cobb et al J. Fluorine Chem.2018, 212, 166-170.
See F. Diederich et al ChemBioChem 2009, 10, 79-83; J. Welch et al, J. Med. Chem. 2012, 55, 2311-2323; ibid 2011, 54, 5540-5561.
Osmium, a group 8 d-block transition metal discovered in 1803 by the English chemist Smithson Tennant, is the rarest of the stable elements. Concentrations in the Earth’s crust are around 50 parts per trillion. The metal is found in nature uncombinrd or alloyed with its neighbour, iridium, in the alloys iridosmine or osmiridium. Around 500Kg of osmium are produced industrially per year as a by-product of refining nickel and other more abundant platinum group metals. Canada is a main country of origin.1a
The name ‘osmium’ comes from the Greek word ‘osme’meaning smell. The metal itself is odourless- the pungent smell derives from it’s oxide, OsO4. The oxide has proved useful industrially, however it has significant toxicity. More about this later. The metal itself has limited direct industrial application. That said it forms alloys with other platinum group metals giving very hard wearing and chemically inert materials that are extremely resistant to compression.
The geologists have found a practical application: rhenium-osmium dating. This is a radiometric dating procedure based on the beta-decay of 187Re to 187Os and can be used to study mantle crust evolution and the age of ore deposits. The extremely long half-life (>40 billion years) can also be used to study the solidification of materials during Earth’s early history.1b
Historically osmium and its next-door neighbour iridium have been fighting over the title of densest element on Earth. The currently accepted values put osmium ahead by a hair’s breadth (22.587 g/cm3 at 20°C for Os v’s 22.562 g/cm3 for Ir). Having said that, osmium is the densest metal at all temperatures and ambient pressure(although there is an ambiguity below 150 K). However, at room temperature iridium becomes the densest metal above a pressure of 2.98 GPa, at which point the density is 22.750 g/cm3.2
Osmium has a very wide range of oxidation states- 11 in total ranging from -2 to +8. Although +8 is very high (OsO4 being an example), the high oxidation state trophy goes to its sparring partner iridium with an impressive +9.3
Osmium has no biological role but is present at a very low back-ground levels in the body. Medically, however, complexes of osmium have been found to inhibit the growth and proliferation of human cancer cells. Although this area is largely dominated by ruthenium several osmium complexes are comparable to the standard of care in this field, cisplatin, – at least in vitro.4 Many of these complexes are isostructural with the corresponding ruthenium derivatives. Mechanistically, depending on the metal ligand environment, a diverse range of modalities are possible including redox activation, DNA targeting or inhibition of protein kinases (Figure 2).5 An interesting paper just published by Fus et aldescribes replacement of the b- aromatic ring in 4-hydroxytamoxifen by metallocene’s (Fe, Ru and Os) to drive both hormone-dependant and independent antiproliferative activity in cancer cells.6a There is growing evidence that these so called metallocifens are prodrugs and are rapidly converted in vivo into electrophilic quinone-methides that react with thiol functionality viaa 1,8-Michael addition reaction.6b The team from Grenoble used the osmium complex to image and quantify intracellular distribution in triple negative breast cancer cells and used this data to propose a comprehensive mode of action for this promising new class of metallodrugs.6c
Figure 2: Osmium staurosporin-complex binding in the ATP binding pocket of Pim-1 kinase
More resent applications of the metal in medicine include photodynamic therapy (PDT), a less invasive strategy that leverages the photophysical and photostability properties of these osmium complexes and cell imaging using organelle-targeting luminescent probes.7 One major advantage of osmium over ruthenium is the relative stability of the coordination sphere with respect to ligand exchange or hydrolysis and subsequent inactivation of the complex. An important factor for any perceived in vivoapplications.
Several ruthenium-based molecules have been investigated clinically including IT-139 from Interzyne, currently in phase ½ for pancreatic and gastric cancers (Figure 3).8 However to date the are no osmium complexes in clinical trials.
Figure 3: IT-139 (Interzyne), A ruthenium based anti-cancer complex currently in the clinic
Not surprisingly the medicinal application of osmium beyond the oncology field has had little traction. That said, if you look back far enough someone, somewhere will have probably given it a try. In 1980 the journal Rheumatologypublished results of a five-year study on the intra-articular application of osmic acid (synonym for osmium tetroxide) in rheumatoid arthritis patients.9 With few available disease-modifying treatments back in the 1970’s and the historical precedent of gold as an inflammatory cytokine modulator (since the 1900’s) it was probably not a bad thing to look at- under very close medical supervision of course.10 The results were somewhat disappointing, with good scores reported after 1 year declining significantly over the 5 year period. With the high degree of toxicity associated with osmium tetroxide the risks very much outweighed the benefits.
Osmium tetroxide is perhaps the compound most people associate with osmium. It’s a solid and surprisingly, given the density of osmium, is volatile. Exquisitely toxic, chronic exposure to low levels (below olfactory detection) can cause fatal pulmonary edema. The volatile oxide can also stain human corneas resulting in permanent blindness.11 A somewhat horrifying account of do-it-yourself toxicology can be found in paper published by McLaughlin et al in the British journal of industrial medicine.12 The paper describes experiments by F.R. Brunot in 1933, in which he deliberately exposes himself to OsO4vapour and documents the ill effects. Most notable were a “metallic taste in the mouth’ at the 10-minute timepoint and ‘smoking was unpleasant’. After 30 minutes he reports “a smarting sensation in my eyes” and at 3 hours a “a definite constriction in the chest and breathing was difficult”. He continued “Upon going out into the street the lamps appeared to be surrounded by large haloes as if there were a dense fog”. I’m sure the grim reaper was sharpening his scythe at his point. I don’t know what happened to Brunot- surely a candidate for a Darwin award….
If nothing else his fingertips should have become darker- osmium tetroxide is used as a lipid staining agent in microscopy and has been used historically to detect fingerprints. Presumably the osmium seeks out the unsaturation in the lipids and residual oils and does its thing.
Continuing in this insidious vein, in April 2004 British intelligence services foiled a plot to detonate an explosive device containing osmium tetroxide- a so called “dirty bomb”.13 This is bizarre on many levels, not least because the material would probably disintegrate during the blast and the osmium disperse so widely as to cause no acute risk to health. In addition, the high cost of the material (current price of osmium is $400/troy ounce- roughly 30g) and the rarity of the element would leave a trail back to the hapless perpetrator.
Osmium tetroxide is not all bad by any means. In organic synthesis it has a rich history and is utilized in arguably one of the most important catalytic asymmetric processes ever discovered- the asymmetric dihydroxylation reaction. In 1908 it was reported by Makowka that olefins could be cis-dihydroxylated using stochiometric quantities of OsO4. In 1912 Hoffmann described a major advance in this methodology- the use of metal chlorates as co-oxidants- enabling a reduction in the amount of toxic, rare and expensive osmium needed for the reaction. In 1936 Rudolf Criegee observed that addition of amines to the reaction mixture accelerated the rate and proposed a mechanism. In 1976 chemists at Upjohn Pharmaceuticals reported a procedure using catalytic osmium tetroxide and N-methylmorpholine-N-oxide as co-oxidant to generate racemic diols.14 Around the same time K. Barry Sharpless described the use of tert-butyl hydroperoxide as a co-oxidant, however in light of the Upjohn procedure this was never widely adopted. In 1980 Sharpless, building on the work of Criegee, reported the first asymmetric dihydroxylation using catalytic osmium and stochiometric chiral tertiary amines derived from the chinchona alkaloids.15 The final piece of the puzzle- the use of sub-stochiometric amounts of amine- was achieved with the introduction of pseudo-enantiomeric (DHQ)2PHAL and (DHQD)2PHAL diamine ligands (Figure 4). The diamine ligands significantly accelerated the rate of the process enabling use of catalytic quantities- so called ligand accelerated catalysis.
Figure 4: (DHQ)2PHAL ligand and its complex with Osmium
Refinements to the process continued over the next decade, with the introduction of potassium ferricyanide as co-oxidant and the use of the non-volatile potassium osmate salt (K2OsO4(H2O)2in place of OsO4. Addition of methanesulfonamide was also found to accelerate rate-limiting hydrolysis of the intermediate osmate (VI) ester when using the ferricyanide co-oxidant. A commercially available mixture of pre-mixed solids containing whichever ligand is predicted to give your required stereochemistry- the so-called AD-mix- was the final icing on the cake. I used AD-mix during my PhD for dihydroxylation of a protected allylic amine and it worked very nicely- thank you very much.
Major (heated) disagreements over the mechanism of the reaction raged for many years and makes interesting reading.15 In 2001 Sharpless shared the chemistry Nobel prize with Knowles and Noyori for his work on osmium catalysed reactions and ligand accelerated catalysis.16 Sharpless went on to develop the amino-hydroxylation reaction, first disclosed in 1996, with osmium again taking centre stage in the catalytic cycle.17
Further innovations to attenuate the possible toxicity exacerbated by volatility of the oxide include a polymer supported reagent prepared by Herrmann et al based on cross-linked poly(4-vinylpyridine)18a and immobilization of the oxide in a microreactor using poly(4-vinylpyridine) nanobrushes.18b Both appear to have come and gone without making a significant impact in the field. A quick check on the Sigma website revealed the former, once offered in their catalogue, has now been discontinued.
Our final delve into the chemistry of Osmium involves its use as a catalyst for asymmetric transfer hydrogenation. Sound a little boring? Perhaps. But what if I told you the reaction takes place in a cancer cell and could provide a new strategy for fighting the disease?
As one might expect the direct osmium analogue of the well-established and highly efficient Noyori ruthenium catalyst [Ru(p-cymene)(TsDPEN)Cl], (H)TsDPEN=N-p-tosyl-1,2-diphenylethylenediamine, gives very similar yields and ee’s in the asymmetric hydrogenation of aryl ketones.19 X-ray structures of the 16-electron Os (II) catalyst are almost identical to the Ru (II) species. The advantage of osmium systems are the apparent ease of synthesis and the additional hydrolytic stability of the complexes, particularly in cellular environments- a factor I mentioned earlier in the article (Figure 5).
Figure 5: Noyori’s [Ru(p-cymene) (TsDPEN) Cl] catalyst, the Osmium analogue and the proposed transition state for the asymmetric hydrogenation of pyruvic acid to lactate
Will’s and Sadler at Warwick University have extended the application of transfer hydrogenation of prochiral ketones to reduction of intracellular substrates- namely the conversion of pyruvate to D-lactate- in both model aqueous systems and cancer cells.20 This utilizes the increased robustness of the osmium complex and uses sodium formate as a hydride source (Figure 5). The idea of targeting cancer cells is not the production of D- or L– lactate per se (these are non-cytotoxic natural products), but to perturb local concentrations of lactate in the cancer cell, or reduce levels of pyruvate, and in doing so inhibit or activate a key downstream signalling pathway that might prove fatal to the cancer cell. The team have shown that asymmetric reduction is possible (generating either enantiomer of lactate depending on the catalyst configuration) and to some extent demonstrated the biocompatibility of the catalyst. A significant hurdle, in common with many approaches of this type, is delivery of the catalyst (or pre-catalyst) and reductant to the cancer cell in vivo. The paper concludes with a few thoughts on this- nanoparticle encapsulation or polymeric micelles are suggested. Both are desperately difficult to achieve. This is an interesting idea and an innovative use of a metal that most people will never come across. Hiding in plain sight- it’s there on the table if you look hard enough.
Hope you enjoyed the article- See you next time.
a) John Emsley Nature’s Building Blocks: An A-Z Guide to the Elements, OUP Oxford, 2011 (p603-608); b) https://www.britannica.com/science/rhenium-osmium-dating.
Is osmium always the densest metal? A comparison of the densities of osmium and iridium: Johnson Matthey Technol. Rev. 2014, 58(3), 137-141.
Identification of an iridium-containing compound with a formal oxidation state of IX: Nature 2014, 514, 475-477.
Structure-activity relationships between ruthenium and osmium anticancer agents- towards clinical development: Chem. Soc. Rev. 2018, 47, 909-928; Development of anticancer agents: wizardry with osmium Drug Disc. Today 2014, 19(10), 1640-1648; J. Coord. Chem. 2018, 71(2), 342-354; Mini Rev. med. Chem. 2016, 16(17), 1359-1373; The contrasting chemical reactivity of potent isoelectronic iminopyridine and azopyridine osmium (II) arene anticancer complexes: Chem. Sci. 2012, 3, 2485-2494; Osmium (IV) complexes as a new class of potential anti-cancer agents: Chem. Comm. 2011, 47, 2140-2142; Metallomics 2014, 6, 1014-1022.
Future potential of osmium complexes as anticancer drug candidates, photosensitizers and organelle-targeted probes: Dalton Trans. 2018, 47, 14841-14854; ibid 2018, 47, 9934-9974.
a) Intracellular localization of an osmocenyl-tamoxifen derivative in breast cancer cells revealed by synchrotron radiation X-ray fluorescence nanoimaging: Angew. Chem. Int. Ed. 2019, 58, 3461-3465; b) Organometallic antitumor compounds: ferrocifens as precursors to quinone methides: Angew. Chem. Int. Ed. 2015, 54, 10230-10233; c) For synthesis of the complex see Eur. J. Inorg. Chem. 2015, 25, 4217-4226.
Photolabile ruthenium (II)–purine complexes: phototoxicity, DNA binding, and light‐triggered drug release: Eur. J. Inorg. Chem. 2017, 12, 1745-1752.
Safety and activity of IT-139, a ruthenium-based compound, in patients with advanced solid tumours: a first-in-human, open-label, dose-escalation phase I study with expansion cohort: EMSOopen 2016, doi:1136/esmoopen-2016-000154.
Rheumatology 1980, 19(1), 25-29.
Gold was also used historically to treat TB, J. Public. Health 1925, 15(7), 631.
When approaching the synthesis of an aryl- or heteroaryl- amine most people would turn to a suitable transition metal (Pd, Cu or Ni) catalysed C-N cross-coupling reaction- most likely a Buchwald-Hartwig reaction, or, if this has limited success, Ullmann or Chan-Evans-Lam couplings.1 Photoredox approaches using aryloxy amides as a source of amidyl radicals began a trend in moving away from transition metals and more recently catalytic redox cycling of main group elements offers a complementary approach to these important pharmaceutical and agrochemical intermediates.2 In a recent blog post I described a paper by McNally on the synthesis of heterobiaryl compounds using a phosphorus(V) contractive C-C coupling reaction- an alternative to the Suzuki-Mayara coupling.3 Another group led by Alex Radosevich at MIT have targeted aryl C-N cross-coupling chemistry and recently described an organophosphorus catalysed C-SP2-H intramolecular amination of ortho-nitrobiaryls (Cadogan cyclization).4 The Radosevich group have now extended the scope of this work to include intermolecular coupling of nitroarenes with boronic acids using the same redox-recycling (PIII/PV=O) phosphorus catalyst (J. Am. Chem. Soc. 2018, 140(45), 15200)- Figure 1.
Figure 1: P-mediated reductive C-N cross coupling of nitroarenes and boronic acids
Conversion of PIII to PV=O is a strong driving force for many synthetic transformations.5 A limitation of these methods is poor atom economy and the generation of stochiometric quantities of phosphine oxide waste. Recently several groups have addressed this challenge and published catalytic methods in which cycling of the phosphine oxide intermediates through redox-neutral or redox-driven modes is achieved.6 The Radosevich group have focused heavily on development of biphilic catalysts which unify the nucleophilic donor and electrophilic acceptor reactivity of the phosphorus atom (Figure 2).4 They have demonstrated that a small-ring phosphacycle (typically a core 4-membered ring system) in combination with a phenylsilane terminal reductant promotes reductive O-transfer from a substrate nitroarene by cycling in the PIII / PV=O couple.
Figure 2: biphilic organophosphorus compounds utilize the s5-P phosphoranes for catalysis
The Radosevich group used the reaction of nitrobenzene with phenylboronic acid as suitable baseline process for optimisation and started with the same conditions reported for the intramolecular Cadogan cyclisation (59% yield, 1 eqv nitrobenzene, 1.5 eqv phenylboronic acid, 20 mol% phosphine oxide, 2 eqv PhSiH3, toluene, 100°C, 16hrs, Figure 3) .4
Figure 3: initial coupling conditions
A DoE approach, evaluating temperature, concentration and reagent stoichiometry in m-xylene solvent increased the isolated yield to over 80% (1 eqv nitrobenzene, 1.1 eqv phenylboronic acid, 15 mol% phosphine oxide, 2 eqv PhSiH3, 0.5M m-xylene, 120°C, 4 hrs). A comparable yield was obtained using the PIII phosphetane confirming that cycling to PV=O was occurring. Use of stochiometric phosphetane (3 eqv) again gave comparable results. Control experiments omitting silane reductant and phosphorus catalyst gave no conversion. The nature of the boron source was important- boronic esters gave low yields of coupled product compared to boronic acid or cyclic boroxine trimers.
Electronic demands for both coupling partners revealed election-withdrawing p-substitution on the nitroarene promoted a faster rate of reaction and higher yields of cross coupling products, with a complimentary inverse empirical demand for donating substituents in the boronic acid intermediate. This is a key differentiating observation over palladium catalysed C-N cross couplings where arylation of electron deficient aryl amines are challenging. PIII/PV=O coupling may provide a future path forward for construction of deactivated C-N bonds.
The paper describes examples of various substituted aryl- and heteroaryl- nitro compounds and boronic acids, including a few alkyl-boronic acids. The latter tend to give lower yields, as one might expect. As is the modern trend with methodology papers a couple of drugs were prepared to demonstrate utility. Mefenamic acid and tolfenamic acid (NSAIDs marked as Ponstel and Clotam respectively) were prepared in one pot (two step) processes in good yield on a 1 mmol scale.
The reaction was demonstrated to be stereospecifc with respect to the boronic acid component enabling future application in asymmetric synthesis.
This is an interesting area and is sure to be of interest to the organocatalysis community. I look forward to reading more from the Radosevich group.