synthetic chemistry

Discovery chemist; 1,2 shift to a Development chemist

From Discovery to Chemical Development

Introduction.

 

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 the rest back. I found out later that this being was in charge of running the GMP storage facility, in collaboration with the other department, which explained his reticence in accepting my wondrous gift(s).

A few weeks later I got a call from the chemical entity who was developing my compound, “would I like to have a tour round the pilot plant?” Of course I said yes and got on my heavy bike. My God was I impressed, lots of huge reactors, centrifuges and plastic (not glass) windows with holes in within the safety cells. When I asked why are there holes I was told that it stops the plastic from bursting all over the place in case of an explosion and directs the blast wave towards the outside. Oh! To be seen was lots of piping, valves, control consoles and the like, with the bottom two-thirds of reactors protruding from the ceiling like some kind of monster upside-down mushrooms. One lasting memory was just how clean the whole plant was, you could have eaten your dinner from the floor, very impressive. Little did I know?

The chemist there made several hundred kilos of my precious development compound and then the compound was axed, as they tend to be, and the whole lot was incinerated.

Moving forward in time a few years I found myself in a departmental meeting involved in a “chemical” argument with the boss, never a good thing to have. He was moaning that instead of removing chiral centres in our active series we were putting them in. In retrospect this is probably correct but at the time it lead to more active compounds. Anyway things got quite heated and I left the meeting and phoned the head of chemical development who, in the meantime had become a good friend of mine, and asked him if he had a job for me. Well he said yes, I said yes and a week later I was one of those chemical entities at the other side of the factory site.

I joined a group of 4 other chemists and a group leader. They were all great guys very helpful and got me settled in and started working on changing my chemical outlook. I was given 4 stuffed A4 folders full of information about the pilot plant, SOPs, cGMP and so on, but no project! That changed rather rapidly. A compound was dumped in our group’s lap because the another site did not have the equipment to make the quantities for a phase 2 study, we needed around 2000kgs of the drug substance the day before yesterday. I think it was a nine-step synthesis; I was allocated the middle two steps. I do remember the person, for whom I would be making the material (the last three steps), giving me a piece of paper with exact and I mean exact specifications for the compound I was to deliver to him. I don’t recall them but I remember them being very thorough. I thought how in hell am I going to do this? He needed around 3.5 tons of material for his part of the pilot campaign.

Phone went, group leader on the end. Went to his office and he handed me the laboratory procedure and pilot plant procedures and said do it. Bear in mind that I had been a development chemist for about a week. The first step was a phenolic alkylation with a 10-fold excess of 1,5-dibromopentane, acetone and potassium carbonate at reflux followed by filtration, extraction and product distillation. The second step was also a phenolic alkylation (of the product from the first step), as before, followed by a crystallisation after a solvent change. Sounds easy.

The alkylations were done in a 1000 L reactor, the crystallisation in a 2500 L glass lined reactor. Well the alkylation(s) were no problem went in 99.5% yield. But before the second alkylation could be carried out we had to remove and recover the excess 1,5-dibromopentane. This was done in a molecular distillation set-up that had three columns and was under high vacuum generated with an oil diffusion pump. Here are 2 pictures for those not familiar with this equipment:

 

               

 

 

 

I apologise for the picture quality, but you can see what is meant here. Our distillation bodies were about two meters high and 70cm in diameter, our pump got us down to 10-3mbar. We spent months distilling our 7000 kg of material, to recover the excess 1,5-dibromopentane and eventually get pure product. I forgot to mention that we added carbowax 600 to make the whole mixture less viscous. Actually the distillation was not a problem, it just ran 24 hours a day, 7 days a week. What caused me the biggest headache was the crystallisation of the product from the second alkylation.

Based on the procedures I was given I tried it all out in the lab before hand, the compound crystallised nicely from cyclohexane. I don’t remember the quantities but it was done in a 2500 L reactor. So, following my wonderful pilot plant procedure (in which I had remembered to include the anti-static agent), we went to work. It dissolved nicely at reflux; we then had to concentrate it from 2000 L to 1500 L at which point it should have began to crystallise after this the distillation was terminated and the mixture then cooled slowly to 10°C. This all went fine and after 500 L distillate had been collected the soup went cloudy, great I thought, and left the plant to have a well deserved coffee and cigarette. Just sat down, phone goes, “Dr. Quintus the suspension has become a solution again, what do we do next?” said a voice. What now? It should be noted here that the pilot plant operators will not do anything without a procedure, as a novice I had the feeling that if I wrote a procedure for blowing their noses, they would follow it to the letter, this, of course, is cGMP at work. Anyway we removed more solvent, no crystallisation, went down to a volume of 1000 L no crystallisation. Obviously the mixture was supersaturated; at least that’s what I told them. Off to the lab, back with one seed crystal, heaved it in at 25°C, the whole stupid mixture solidified instantly! There was a sort of sickly crunching noise as the stirrer stopped. The crunching noise was the sound of the enamel cracking. Luckily I did not bend the stirrer, but I think that may be a bit harder to achieve, it was bad enough. We eventually added a bit of THF and slowly warmed the mixture up and the solid re-dissolved and it was transferred it to another reactor.

Now I don’t know if you have seen one of these reactors, there is miles of glass attached to the top of it, not to mention condensers, probes, stirrer motor. The lid is attached to the main body with what seemed like thousands of big nuts and bolts, and the whole lot weighs hundreds of kilos. Needless to say I was not very popular with the pilot plant boss. It took them three weeks to dismantle the reactor replace the stirrer and put the whole lot back together again. But never mind, the good news was that I got my yield, plus a few glass splinters, and the compound met the specs I was set, the glass did not interfere in the next step and was removed by a simple filtration.

This may seem trivial now but at the time I got really, shall we say, worried that I would not produce the goods but as it turned out this was nothing. So that was my first foray into the magic world of chemical development. There is a lot more to tell but that is for another day. Of course, if you all wish to read it!

 

 

 

Another Fascinating Structure and a Potent Anti-Cancer agent. (-)-FR 182877

(-)-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 a nice new ring system, for example.

 

The diene is electron rich, and the dienophile electron deficient. This reaction has been studied in great detail throughout the years. Chirality control is easily achieved, as is regio- and stereo-selectivity, and I refer the reader to the many books and reviews published on this topic. One review outlining the use of the Diels-Alder reaction in natural product synthesis is especially worth reading9.

The Inverse Electron Demand Diels-Alder reaction is just the opposite of the above, i.e. electron poor diene, electron rich dienophile. For an interesting description of this reaction please go to the Wiki page, where it is wonderfully described. Substrates containing heteroatoms can also be employed in this reaction.

In the case I present here compound A was deemed to be a suitable substrate for this process, this, because, it was surmised that the HOMO and the LUMO were sufficiently near enough in energy this being brought about by proximity of the electron withdrawing ester group and the electron donating methyl moiety being in close proximity to one another.

Indeed heating compound A for 4 days produced the methyl ester of new ring system as a single isomer in 63% yield. According to Nakada this is the first example of this type of, inverse electron demand intramolecular hetero-Diels-Alder, reaction (IMHDA) to be reported.

However, he was still far away from the desired product and it required some chemical manoeuvring to get there. Deprotection of the methyl ester proved troublesome and they were unable to obtain the carboxylic acid, thus the methyl ester was replaced by a p-methoxybenyl ester (PMB), which is easily removed by employing DDQ, although they used trifluoroacetic acid which simultaneously removed the TES protection.

This ester exchange was not achievable after the IMHDA, which meant that they had go back to the start of the synthesis to introduce it, unfortunately a fact of life. However, they obtained the same Diels-Alder adduct in similar yield with the PMB ester.

Deprotection with TFA in water at 0°C produced the hydroxy acid. Treatment with Mukaiyama’s reagent10 delivered compound C presumably via the desired compound. As predicted the desired ring system was highly reactive and underwent addition of various nucleophiles across the strained double bond.

 

X-ray confirmed the structure of compound C. This new ring system proved to biologically inactive in a variety of cancer cell assays. A 1H-NMR spectrum of the desired compound was obtained from the crude product.

I think this is a marvellous example of the power of the Diels-Alder reaction in forming ring systems. I stand corrected, but I do not think there are many examples of this reaction employed by industry, especially the big pharma branch. This may be simply due to the nature of the set of investigational drugs currently being examined, which tend to be rather flat molecules with lots of nitrogen and may be better explosives than pharmaceuticals.

References:

  1. Sato, B.; Muramatsu, H.; Miyauchi, M.; Hori, Y.; Takese, S.; Hino, M.; Hashimoto, S; Terano, H. J. Antibiot. 2000, 53, 123–130.
  2. Sato, B.; Nakajima, H.; Hori, Y.; Hino, M.; Hashimoto, S.; Terano, H. J. Antibiot. 2000, 53, 204–206.
  3. Yoshimura, S.; Sato, B.; Kinoshita, T.; Takase, S.; Terano, H. J. Antibiot. 2000, 53, 615–622.
  4. Yoshimura, S.; Sato, B.; Kinoshita, T.; Takase, S.; Terano, H. J. Antibiot. 2002, 55, C1.
  5. Yoshimura, S.; Sato, B.; Takase, S.; Terano, H. J. Antibiot. 2004, 57, 429–435.
  6. Evans, D. A.; Starr, J. T. Angew. Chem. 2002, 114, 1865–1868.
  7. Evans, D. A.; Starr, J. T. J. Am. Chem. Soc. 2003, 125, 13531–13540.
  8. Nakada M. etal, Org. Lett., 2012, 14 (8), 2086–2089.
  9. Nicolaou, K. C. etal Angewandte Chemie Int. Ed. English, 2002, 41, 1668-1698.
  10. Mukaiyama, T.; Usui, M.; Saigo, K. Chem. Lett. 1976, 49–50.

Postscript: after reading a very recent publication by Stössel etal in Organic Process Research and Development, 2012, DOI: 10.1021/op300145k. I can understand why the Diels-Alder reaction is not commonly seen in industry. This interesting analysis should be read by everyone as it highlights the dangers of uncontrolled chemical reactions with an actual example. It also demonstrates that these difficulties may be overcome. Indeed it is being employed in API production see, Stefan Abele, Stefan Höck, Gunther Schmidt, Jacques-Alexis Funel, and Roger Marti Org. Process Res. Dev.201216 (5), 1114–1120.

 

What’s in a name?

(4aR,5aS,8aR,8a1S,15aS)-4a1,5,5a,7,8,8a1,15,15a-octahydro-2H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-14(4aH)-one.

Imagine if Agatha Christie had to write that every time she had to mention the poison used in the murder, or if Hitchcock’s leading man had to vocalise it in the courtroom. Well they’d never get the book or the film down to a manageable size. It’s much easier to say strychnine

From the early eighteen hundreds until the present day strychnine has been the subject of intense study.In a recent review in Angewandte Chemie International edition1  Professor Overmann and Dr. Cannon present the history of this fascinating compound in terms of total chemical synthesis, the title says it all, “Is there no end to the total synthesis of strychnine?” They are to be commended for presenting the complete history of one of the world’s most famous murder tools.

I won’t recount all the total synthesis here, except to pick out a couple of salient highlights. My wish is to give the community a feeling for the effort, which went into the structure elucidation and total synthesis of this remarkable compound. The statistics of strychnine research are truly impressive: In the middle ages people were aware of the properties of the ground nuts of Strychnos nux-vomica and physicians in Germany in the 16th and 17th centuries were also curious about this preparation. In 1818 the active ingredient was isolated and was reported to have a variety of pharmacological properties. However, its only real use was as a poison. Around 50mg is fatal for an adult. So if your average adult is 70kg, this makes a lethal dose of around 700 ng/kg ug/kg, which is toxic. It acts on the central nervous system binding at the glycine receptor chloride channel and causes convulsions and asphyxiation. There is no antidote.

This was one tough nut to crack (pardon the pun), Robinson etal apparently published around 400 papers on the structure determination of strychnine, 400 papers, gracious they must have spent more time writing than experimenting. In those days it was all done by degradation and conversion of the fragments to a known set of compounds and then all put back together in a vast mental effort requiring a supreme knowledge of organic chemistry. Woodward finally solved the structure2 that was later confirmed by x-ray. Some 58 years ago he published the first total synthesis of racemic strychnine, only six years after the structure had been determined3. Forty years after that the first enantioselective route was described by Overman etal4. Here is his retro-synthetic pathway:

 

Above the arrows are the proposed synthetic steps. One of the interesting conversions here is the de-symmetrisiation of the diacetate using shocking conditions. Stirring this compound with electric eels5, or better the acetylcholinesterase produced from the poor creatures, hydrolysed the AcO group on the left as shown;

One can imagine how the reaction vessel must have looked. Further highlights are the use of η3-allylpalladium alkylation and carbonylative cross-coupling reactions.

A [2+2+2] cycloaddition strategy was employed by Vollhard, in his route to racemic strychnine, to construct four of the six rings, in reasonable yield6.

 

From here he had a further six steps to the final product.

Moving right up to date Macmillan published a route7 involving several interesting chemical reactions. He employed an enantioselective organocatalytic promoted sequence to produce an advanced intermediate in 87% yield with 97%ee via the pathway shown here (taken from ref. 1).

 

 

So there is just a part of the more than 200-year-old strychnine story.

Here is an interesting table outlining the synthetic effort, taken from ref. 1 and somewhat abbreviated.

Main Author Year Target No. of Steps Overall Yield (%)
Woodward 1954 (-)-isostrychnine

29

0.0002

Overman 1993 (-)-Wieland-Gumlich aldehyde

25

3

Rawal 1994 (±)-isostrychnine

12

10

Kuehne 1998 (-)-Wieland-Gumlich aldehyde

21

4

Vollhardt 2000 (±)-isostrychnine

14

0.7

Martin 2001 (±)-Wieland-Gumlich aldehyde

16

1

Fukuyama 2004 (-)-Wieland-Gumlich aldehyde

25

1

Reissig 2010 (±)-isostrychnine

9

4

Vanderwal 2011 (±)-Wieland-Gumlich aldehyde

6

2-3

MacMillan 2011 (-)-Wieland-Gumlich aldehyde

12

7

Isostrychnine and the Wieland-Gumlich aldehyde are convertible to strychnine in one step in  low and good yield 28% and 80% respectively.

For more detailed information please refer to the Overman essay and the references therein.

References:

  1.  Overman L. E., Cannon J. S., Angewandte Chemie Int. Ed. English, 2012, 51(18), 4288-4311.
  2.  a) R. B. Woodward, W. J. Brehm, A. L. Nelson, J. Am. Chem. Soc. 1947, 69, 2250; b) R. B. Woodward, W. J. , Brehm, J. Am. Chem.        Soc. 1948, 70, 2107 – 2115.
  3. a) R. B. Woodward, M. P. Cava, W. D. Ollis, A. Hunger, H. U. 
Daeniker, K. Schenker, J. Am. Chem. Soc. 1954, 76, 4749 – 4751; b) R. B. Woodward, M. P. Cava, W. D. Ollis, A. Hunger, H. U. Daeniker, K. Schenker, Tetrahedron 1963, 19, 247 – 288.
  4. a) S. D. Knight, L. E. Overman, G. Pairaudeau, J. Am. Chem. Soc. 1993, 115, 9293 – 9294; b) S. D. Knight, L. E. Overman, G. Pairaudeau, J. Am. Chem. Soc. 1995, 117, 5776 – 5788.
  5.  a) D. R. Deardorff, A. J. Matthews, D. S. McMeekin, C. L. Craney, Tetrahedron Lett., 1986, 27, 1255 –  1256; b) D.R. Deardorff, C. Q.      Windham, C. L. Craney, Org. Synth., 1996, 73, 25 – 35.
  6. M. J. Eichberg, R. L. Dorta, K. Lamottke, K. P. C. Vollhardt, Org. Lett. 2000, 2, 2479 – 2481.
  7. S. B. Jones, B. Simmons, A. Mastracchio, D. W. C. MacMillan, Nature, 2011, 475, 183 – 188.

Natural Product Man

Brandon Findlay recently blogged here about “good research and total synthesis” Well here is something I hope he will enjoy.

I recently became aware that a good friend of mine, Professor Stephen Hanessian, of the University of Montreal in Canada, has been awarded the ACS 2012 Ernest Guenther Award in Natural Products Chemistry. His career spans some 45 years, starting as an industrial research chemist and continuing as a still-active academic 45 years later. As he puts it “I remain an ardent student of our profession. I am motivated by the exhilaration of discovery and the creative possibilities that organic synthesis offers.”

Congratulations Steve.

Very recently he published a JOC perspective in which he outlined his philosophy towards natural product synthesis with a myriad of examples of his own work1. I would like to try and give you all a flavor of his approach here.

Amongst other things Prof. Hanessian is probably well known for his propagation of “The Chiron Approach” to organic synthesis2-6. A chiron is a combination of the words chiral and synthon and represents a small chiral building block, for example, amino acids, terpenes, carbohydrates. This gave rise to an excellent computer assisted synthesis program that recognised these chirons in a complex molecule and suggested synthetic routes. I have used this program personally and found it very helpful for the problem I had at the time. This whole approach is based upon a “visual relational thought process” which is a vital part in the planning and conception of the synthesis of a complex molecule.

Let us examine just some of the extensive number of examples given by Prof. Hanessian in his perspective one, for example, Ionomycin.

The calcium salt of this compound is the folded structure A and looks quite complicated, when one “unfolds it” to a linear sequence, compound B, the stereochemical perspective is much more recognisable, however still a very complex molecule.

 

With a good knowledge of organic chemistry and what one can do experimentally, Professor Hanessian reduced compound B to simple chirons, one of which is glutamic acid a simple cheap readily available chiral starting material. This was then converted to some more advanced intermediates en-route to Ionomycin. It would have taken me a long time to get to glutamic acid as a starting material for the synthesis of this compound.

Chiral C2-symmetric phosphonamides are also a significant part of Prof. Hanessian’s contribution to organic chemistry7,8. These compounds are single diastereoisomers where attack of an electrophile occurs from the less hindered side of the anion. Further reaction, in this variant of the Horner-Emmons, reaction leads to the chiral olefins in good yield and high enantiomeric excess. He is still working hard as judged by his latest publication in Organic Letters9, which I can recommend.

I collaborated with Professor Hanessian for many many years during my industrial sojourn. I always enjoyed his visits to the company; not only for the good food and wine we were presented with but for the stimulating chemical discussions and the new perspectives that he brought to a problem. He made us think and he always enjoyed a lively discussion. Congratulations again on your recognition Stephen.

References

  1. Hanessian, S., J. Org. Chem, 2012, dx.doi.org/10.1021/jo300902m
  2. Hanessian, S.; Giroux, S.; Merner, B. L.;Design and Strategy in Organic Synthesis: From the Chiron Approach to Catalysis; Wiley-VCH: Weinheim, 2012.
  3. Hanessian, S.; Franco, J.; Larouche, B. Pure Appl. Chem. 1990, 62, 1887.
  4. Hanessian, S. Reflections on the Total Synthesis of Natural Products: Art, Craft, Logic, and the Chiron Approach. Pure. Appl. Chem., 1993, 65, 1189.
  5. Hanessian, S. Design and Implementation of Tactically Novel Strategies for Stereochemical Control Using the Chiron Approach. Aldrichimica Acta  1989, 22, 3.
  6. Hanessian, S. Total Synthesis of Natural Products: The “Chiron Approach”; Pergamon: Oxford, 1984.
  7. Hanessian, S.; Delorme, D.; Beaudoin, S.; Leblanc, Y. J. Am. Chem. Soc. 1984, 106, 5754.
  8. Bennani, Y. L.; Hanessian, S. Chem. Rev. 1997, 97, 3161.
  9. Hanessian S., Chénard E., Org. Lett., 2012, 14(12), 3222-3225.
By July 18, 2012 3 comments synthetic chemistry