Tamiflu, made by Roche and licensed by them from Gilead and stockpiled in many countries has proved to be a big money maker for Roche. It is one of two neuramidase inhibitors currently available for the treatment of influenza, the other being Zanamivir from Glaxo. Tamiflu is sold as its mono-phosphate salt. During the recent outbreak of avian flu due to the H5N1 virus Tamiflu was the drug treatment of choice for many physicians.
Now questions are being asked again about it’s effectiveness and it’s actual performance in clinical trials, the data of which has not been fully published by Roche in spite of promises to release this information. A new web site has been established to achieve the aim of providing doctors and patients’ access to this information. In a hard hitting editorial the editor of the British Medical Journal gives big Pharma a well deserved tongue (or in this case pencil) lashing, criticising the lack of information as to the clinical trial results of not just these two compounds but a number of others. Which she says must be made available to independent scrutiny.
It turns out that an review of the data on the available neuramidase inhibitors, commissioned by the British Government, discovered that around 60% of the data of the phase III trials collected by Roche has never been made available for examination.
Why does Big Pharma have a level of secrecy that would make the CIA look proud? Well I suppose in the first instance it’s about big money. One...
Synthesising small molecular machines has been somewhat limited to making molecules that can walk or spin round cogwheels. Mind you that is still pretty impressive. Now things are set to change with a recent publication in Science by Dr Leigh from the University of Manchester in the UK.
The Manchester group synthesised a rotaxane (a molecular ring) threaded through an axle that consists of peptides. The rotaxane has a thiolate moiety that removes the amino acids in sequence and transfers them to the site of the new growing peptide chain. There is a wonderful summary in C&E News, with an interesting video of how it all works.
The group used 1018 machines in parallel to generate milligram quantities of a single sequence peptide. This mimics the ribosome in its valuable function in the generation of peptides. The “arm” picks up the amino acid by a transacylation reaction and delivers them to a different place on the ring.
There are still some problems to be solved, for example the rather slow reaction rate as the ring needs about 12 hours to make the amide bonds. Compare this to the 15-20 bonds per second produced by the ribosome itself. There are a few other problems, and no doubt they are being addressed at this moment. However this paper and the technology are impressive and will probably have a great future.
Imagine what several moles of these could do once things become optimised, producing peptides of any sequence one desired, natural or unnatural. This is a fascinating...
Professor W. F. v. Gunsteren has written a very interesting essay for Angewandte entitled “The Seven Sins in Academic Behaviour in the Natural Sciences”. In this piece he defines the seven sins as follows (taken from the essay)
A poor or incomplete description of the work, for example, publishing pretty pictures instead of evidence of causality.
Failure to perform obvious, cheap tests that could confirm or repudiate a model, theory, or measurement, for example, to detect additional variables or to show under which conditions a model or theory breaks down.
Insufficient connection between data and hypothesis or message, leading to lack of support for the message or over-interpretation of data, for example, rendering the story more sensational or attractive.
The reporting of only favorable results, for example, reporting positive or desired (hoped for) results while omitting those that are negative.
Neglect of errors found after publication.
The direct fabrication or falsification of data.
Take the incomplete description of the work. Here the scientific journal(s) come in for some criticism; mainly for the restriction of journal space this in turn leading to more date being squeezed into the supplementary material. Interestingly this material is usually freely available while the actual article it corresponds to sits behind a paywall. So in my humble opinion this is a complete waste of time. Either one or the other but not...
In an essay to celebrate the 125th anniversary of Angewandte Chemie our friend and mentor Prof. K. C. Nicolaou had penned an essay for this august event. Which can be seen here.
Not to be outdone in this essay he examines the flow of chemical knowledge from its emergence in the 5th century B.C. to the present day, 2,500 years or so. Stopping along the way of this long journey, he highlights the leading scientific personalities of each age together with their theorems discoveries.
Emerging out of this primordial soup of chemical knowledge is the science of organic synthesis the “Flagship” of which is “the art of total synthesis”. This “Flagship” was launched in the 19th century and sat in the harbour for quite a few decades until the scientists of the day got their collective acts together and came up with atomic theory. I suppose somehow like hitchhikers in the galaxy. Indeed in 1845 two of these eminent thinkers and, more importantly experimentalists put their heads together and came up with the answer to the ultimate question, and it was not “24”.
Laurent and Gerhardt started to unfurl the sails of the flagship, which had been sitting there gathering dust, recognising that the molecules synthesised to that day could be classified into a “homologous” box and a “type” box, the latter assuming that all organic molecules belonged to three different types. This suggestion paved the way for the connection between inorganic and organic chemistry. Kekulé was...
The NHK reaction is nicely described in this Wiki article. Catalytic amounts of nickel were found to be beneficial in this system and Kishi used the reaction extensively during his synthesis of Halichondrin B, to great effect.
During a rather long synthesis we were trying to convert an aldehyde to a cis-diene using the NHK reaction as one of the steps. For various reasons we were locked into using the chromous chloride from one particular supplier and they kept us a larger quantity of that batch for our future use. As far as I remember the Ni content was not specified but here the quality of chromous chloride is obviously critical for the success of this reaction and it had not been adequately defined. Indeed this may be a reason for the extreme variability we observed during a scale-up campaign that was in direct contrast to the previous campaign, where all the batches went to completion, without problems, in 2 hours at room temperature.
Now each of the three batch reactions behaved differently, the first was not complete after 2 hours and required more (20%) CrCl2 to be added with stirring for 18 hours at RT before it was complete.
Because of this hiccup, prior to the second batch we made sure that the reaction started by taking a small sample and running it in the lab. It behaved as we expected it worked. However, the second batch reaction did not budge one inch. Having a keen eye for detail I observed that the samples taken from the reactor for reaction monitoring had all...
Macrolactonization: Now here is a word to strike fear into the heart of any synthetic organic chemist. It’s usually the last step, or one of the last steps in a long complicated natural product synthesis. Not much material left to experiment with so each crumb of unreacted starting material, usually the seco-acid has to be recovered. So which method do you choose? Off to the library may no longer be required, as recently Campagne etal have kindly updated their comprehensive review on the subject1 containing 860 references and covering the literature in the review up to 2011.
Upon reading this I was astounded with the number of methods, obviously I was acquainted with some of them, even done a few in the lab, but the scope here is tremendous. There are some 26 or so methods discussed in this review. Which begs the question: Which one do you choose? Stick with the older well-documented ones or go for a newer method? Well it obviously depends upon your molecule and its functionality. I will just pick out some of the reactions discussed, mainly those I am not so well acquainted with and hope that you will find something useful for your own synthesis.
Let’s begin by looking at macrolactonizations by the Boeckman method. This is based on the known formation of ketenes by thermolysis of dioxolenones2. The conditions are mild and hydroxy or amino groups can trap the ketene. Here is the general idea:
Boeckman3 applied it in the following step note the high dilution.
A testimony to...
The last part of the trilogy: In the last two I wrote about my first impressions as a chemist in chemical development blessed with a late stage project involving some azide chemistry. This project continued when I received a message that it was actually going into production. In the meantime all the use tests1 I had carried out bore fruit and we were able to define three suppliers for the benzyl alcohol and registered it as the starting material for the drug substance manufacture. So now I only had the synthesis of the benzyl chloride and its conversion to the azide to worry about.
Due to lack of capacity in chemical production it was decided to outsource these two steps to an external manufacturer and after a series of meetings with this particular company we went to their facilities to work with them in carrying out a pilot scale series so that they could get to grips with the chemistry. So off we trundled (the production chemist and I) to spend ten days or so to familiarise them with the chemistry.
We spent the first morning just finding the place, the taxi driver got lost! Ending up back at the hotel I decided to rent a car and eventually found the site. After discussing the chemistry in depth they decided to run the first 1 kMol reaction. Off they went and we disappeared back to the hotel to get some decent food and wait for a phone call. Five hours reaction time came and went, no call, so off we went back to the plant. The place looked suspiciously quiet, I thought “Oh...
In the first part of this little series I recounted my experience with two steps of a four-step sequence, now I would like to move on to the last two steps: The preparation of a benzyl chloride and it’s conversion to a benzyl azide.
If you remember I had to convert 7098 kg of the benzyl alcohol ultimately to the azide. According to the plan:
Now benzyl halides are well known for their lachrymatory properties and this one made me cry just thinking about it. All that was required was to walk past the building, where it was being produced, to burst into tears and I had to run 46 batches (1.02 kMol) to make this stuff plus 9 for use tests. In fact we made the chloride then almost immediately concerted it to the azide.
As part of the safety checks in the pre-reaction control of the equipment the conductance of the enamelled stainless steel reactor was checked to make sure there were no cracks in the enamelling, it was deemed to be ok so we carried on. The alcohol was placed in a 630 L reactor and 312.8 kg of 37% hydrochloric acid was pumped in. The solution was heated slowly to an internal temperature of 90-93°C ( to avoid loosing too much HCl) and held there for 5 hours. During the reaction a two-phase system formed and we all cried. The product was on the bottom and it was separated from the acid after cooling to 40°- 45°C because the compound solidified at 37°C. It was then filtered and the pH adjusted to 9-12 with 30% NaOH solution and stored at 40°C as a two-phase system...
In a recent discussion (Nicolau), about the suggested move of Prof. NicoIau from Scripps, the issue of the practicality of natural product total synthesis was raised. Here is a wonderful example of just that very usefulness, a wonderful piece of science extending over many years. It concerns the journey from Halichondrin B to Eribulin (E7389) a novel anti-cancer drug. The two compounds have the following structures:
I think you can see the relationship and as a development chemist I am glad they managed to simplify things (a bit).
Both compounds have an enormous number of possible isomers: Halichondrin B, with 32 stereocenters has 232 possible isomers; Eribulin has 19 with 219 isomers (if I have counted correctly, it does not really matter, there are lots of isomers). Remarkable is the fact that only one of these isomers is active in the given area of anti-cancer agents.
An excellent review of the biology and chemistry of these compounds has been published by Phillips etal1. This review is an excellent read and is to be commended. Another one written by Kishi2, is also full of information about the discovery of E7389 and I hope you will all get a chance to read this chapter.
The history of Halichondrin B goes back to 1987 when Blunt2-5 isolated it with other similar compounds from extraction of 200Kg of a sponge. Independently Pettit isolated the same compound from a different species4. The appearance of this compound in different species of sponge may indicate that it...
After spending some years in medicinal chemistry (CNS) I moved to chemical development. Now this change I can recommend to everyone. In med. chem. you are just another tool for the biologists churning out compounds (methyl, ethyl, futile). I think this says it all, one of my biological colleagues asked me for more of a particular compound and added “make it more soluble the next time.”
You don’t get a real chance to use your chemical knowledge and training, you know all that stuff you learnt at university, some of which may have gone into a thesis. Now, in chemical development that is completely different. There you can actually apply your knowledge to scores of problems, even using physical organic chemistry! For me it was like a breath of fresh air and it re-vitalised my organic chemistry tick. At that time we were responsible for everything, reservation of the pilot plant equipment, ordering the starting materials, carrying out use tests of material from new suppliers1, organisation of all the analytics, all the lab work to produce a lab procedure, all the pilot plant supervision including writing a pilot plant procedure, all the safety studies, proposing and carrying out alternative routes, when required, in fact, everything one can think of we were responsible for. It all boiled down to quality, quantity and delivery (on time).
In a previous post here I recalled some of my experiences my first project, now I recount the second. This compound could loosely be called...
From Discovery to Chemical Development
With the following I want to change the theme of my contributions and go back in history just a little way and recount my change of jobs from Med. Chem. to Chemical Development followed later on by some posts on my development adventures but firstly a bit of background.
I remember when one of my compounds was selected for development. It was quite exciting at the time, my first development compound, it was also my first brush with the people from chemical development, who, I knew were there, but I never really thought about it, until that fateful day when the compound was selected.
As probably every company has we had a standard package which was turned over to these curious people at the other side of the company site, about a 15 minute walk from my lab or 5 minutes with a departmental bicycle (which was an old military reject and had a fixed wheel, no gears and weighed a ton). I set off like one of the Biblical Magi with all the gifts of paperwork and samples, including 1kg of my precious development compound. The person to whom I gave this package to would not accept the kilo sample. He said “I’ll take it but only for lab use”, when asked “why?” he said, “it was not manufactured under cGMP conditions and anyway belonged with pharma drug supply management and as such could not be utilised for anything except normal lab work.” Well that deflated my ego a bit, so I left him with 10g, for lab use, and took...
(-)-FR 182877 and (-) FR 182876 are two structures isolated from Streptomyces sp. No.9885 by researchers at the Fujisawa Pharmaceutical company (now Astelllas)1-5.
These compounds have been known for several years and the academic community has developed various approaches to their total synthesis, for example, references 6 and 7.
Nakada etal8 became interested in the unusual highly strained ring system in (-)-FR182877, shown below.
The picture beneath is a ChemDraw 3D energy minimised structure supposidly highlighting the strained nature of this ring system although I could not find an orientation which made it look good (my ineptitude with ChemDraw 3D).
Nakada became interested in the biological activity of and a synthetic approach to this bicyclic system8. This is a highly strained system owing to the distorted double bond, which is easily oxidised. The route he chose was the utilisation of an inverse electron demand Diels-Alder reaction. The retro-synthetic analysis leading to this approach is as follows: the red arrows are my attempt to indicate the retrosynthetic Diels-Alder reaction, with the blue bonds being those involved.
TES = triethylsilyl.
A brief digression into the realms of cycloaddition chemistry is now required. Diels and his student Alder carried out the seminal work in this area in 1928 and were awarded the Nobel Prize in 1950 for their efforts.
Basically you take a diene and a dienophile heat them and if you have chosen correctly out pops...