Post Tagged with: "complexity"

From Natural Product to Pharmaceutical.

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 is produced by a symbiote.

The biological activity of Halichondrin B is amazing. When evaluated against B-16 melanoma cells it was found to have an IC50 of 0.093ng/mL. Against various cancers, generated in mice, it was shown to be affective at a daily dose of 5ug/kg, which resulted in a doubling of the survival rate. It has also been demonstrated that Halichondrin acts as a microtubule destabiliser and mitoitic spindle poison. It was proven that it is has tremendous in vivo activity against a variety of drug resistant cancers, lung, colon, breast, ovarian to mention a few. Consequently the National Cancer Institute selected it for pre-clinical trials and it’s here that the problems began. According to reference 1 the entire clinical development would require some 10g, and if successful the annual production amount would be between 1-5 kg. Blunt and co-workers managed to isolate 310mg from 1000kg-harvested sponge therefore, the only way to obtain the amounts required is total chemical synthesis. But synthesising 1-5 kg of such a compound would indeed be a mammoth task.

Kishi synthesised this compound7 in 1992 starting from carbohydrate precursors employing the Nozaki-Hiyama-Kishi Ni/Cr reaction, several times, in the long synthetic sequence8, 9. Now as an aside I have used this reaction on scale several times and although it works well its success is very dependant upon the quality of the chromium source and also the presence of other trace transition metals.

In collaboration with Eisai work on the SAR of Halichondrin began. They had a good start: Thanks to the total syntheses of Kishi several advanced intermediates were available for biological screening and one popped out of the screen as being very active:


 The first active lead compound

As one can see the complete left hand side of Halichondrin has gone! However, this compound was not active in vivo. Many derivatives and analogues of this compound were prepared: furans, diols, ketones and so on and a lead emerged from this complex SAR study, ER-076349. The vicinal diol was used as a handle for further refinement and lead ultimately to E7389, the clinical candidate.

It can be synthesised in around 35 steps from simple starting materials.

Going through all this work in a few sentences really belittles the tremendous amount of effort that went into discovery and development of this compound and the people involved are to be applauded for their dedication.

Kishi continues to optimise the synthesis of Eribulin as judged by a recent publication10. Where he describes an approach to the amino-alcohol-tetrahydrofuran part of Eribulin (top left fragment, compound 1 below). The retro-synthetic analysis is shown below. The numbering corresponds to that of Eribulin.

The first generation synthesis consisted of 20 steps and delivered compound 1 about 5% yield, the second-generation route was completed in 12 steps with a yield of 48%. One of the highlights includes a remarkable asymmetric hydrogenation11 with Crabtree’s catalyst12:


This selectivity was not just luck; it seems to quite general, at least in this system. I always wonder how long it took them to stumble across this catalyst, but then I suppose that Eisai like most of the large pharma. companies has a hydrogenation group that probably indulges in catalyst screening.

The C34-C35 diol was obtained by a Sharpless asymmetric hydroxylation, here the diastereoisomeric ratio was not very high, only about 3:1 in favour of the desired isomer. Fortunately the undesired isomer could be removed completely by crystallisation.

This is a remarkable story and references 1 and 2 are worth reading to obtain the complete picture and learn lots of new chemistry as well. Eisai filed a NDA and the FDA approved the compound in 2010 for the treatment of metastatic breast cancer.


  1. Jackson, K. L., Henderson, J. A., Phillips, A. J., Chem. Rev., 2009, 109, 3044-3079.
  2. Yu, M. J. Kishi, Y., Littlefield, B. A., in Anticancer Agents from Natural Products, page 241; Editors Cragg, G. M., Kingston, D. G. I., and Newmann, D. J. Published by CRC press, Taylor and Francis group, Boca Raton, 2005. ISBM 10:0-8493-1863-7.
  3. Lake, R. J. Internal Report, University of Canterbury, February 26, 1988.
  4. Litaudon, M.; Hart, J. B.; Blunt, J. W.; Lake, R. J.; Munro, M. H. G. Tetrahedron Lett. 1994, 35, 9435.
  5. Litaudon, M.; Hickford, S. J. H.; Lill, R. E.; Lake, R. J.; Blunt,J. W.; Munro, M. H. G. J. Org. Chem. 1997, 62, 1868.
  6. Pettit, G. R.; Herald, C. L.; Boyd, M. R.; Leet, J. E.; Dufresne, C.; Doubek, D. L.; Schmidt, J. M.; Cerny, R. L.; Hooper, J. N. A.; Rutzler, K. C. J. Med. Chem. 1991, 34, 3339.
  7. Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y.; Matelich, M. C.; Scola, P. M.; Spero, D. M.; Yoon, S. K. J. Am. Chem. Soc. 1992, 114, 3162.
  8. Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1983, 24, 5281.
  9. (a) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644. (b) Kishi, Y. Pure Appl. Chem. 1992, 64, 343.
  10. Yang, Yu-Rong, Kim Dae-Shik and Kishi Yoshito, Org. Lett., 2009, 11 (20), 4516–4519.
  11. Stork, G.; Kahne, D. E. J. Am. Chem. Soc. 1983, 105, 1072.
  12. Crabtree, R. H.; Felkin, H.; Fellebeen-Khan, T.; Morris, G. E. J. Organomet. Chem. 1979, 168, 183.
By September 15, 2012 5 comments general chemistry, synthetic chemistry

Emergent Complexity: The Fourth Law of Thermodynamics?

The transfer of energy dictates everything on earth from the movement of atoms to the global economy. In high school/first-year chemistry we learn that the rules governing the movement of energy are simply defined by three laws of thermodynamics (four if you count the zeroth law). Yet, this simplicity can be misleading –  as demonstrated by how often the second law is misunderstood, misused and abused. The second law states:

The entropy of closed systems undergoing real processes must increase.

For some people the second law translates to “everything progresses from order to disorder” or “it is impossible for complexity to arise from randomness.” The biggest promoters for this misguided interpretation are advocates for intelligent design and/or irreducible complexity, which are just thinly veiled pseudonyms for creationism. They argue that complex systems like the flagellum or the human eye could not evolve spontaneously because they are complex – A logically precarious stance to take since these claims have been thoroughly debunked by evolutionary biologists.1

A quick bit of reflection on our day-to-day lives produces examples of complexity arising from less complex components. Ants, neurons, and transistors are just some examples of small building blocks that become infinitely more complex systems when combined in the right circumstances.

It is easy to argue that the above examples are the result of agency but there are also many examples of objects naturally arranging themselves into complex structures. In fact, the natural world is very good at arranging atoms.  Diamonds, ice crystals, and polycyclic aromatic hydrocarbons are just a few examples. Ambipolar molecules are an especially useful illustration of this tendency. When these molecules come into contact with water they form beautiful monolayers, bilayers, micelles and other structures.

So, returning to the 2nd law of thermodynamics, the correct interpretation is that complex structures – like those listed above – are possible, but at the cost of increased entropy in the surrounding environment.2

The tendency for a system to self-organize, when given the right circumstance and some energy from the surrounding environment, is one of the most important phenomena we observe. Yet, this transition from energy to order is not obvious when looking at our current laws of thermodynamics. This has led some researchers to suggest it may be possible to formalize a fourth law of thermodynamics that describes how complex systems arise.

Read more ›

By July 18, 2012 15 comments Uncategorized