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Aug 22

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

by Quintus | Categories: general chemistry, synthetic chemistry, Uncategorized | (35270 Views)

(-)-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.

 

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  1. BRSM

    Nice post, but be careful what you say about that 1928 Diels-Alder reaction. They actually weren’t the first to do it (Aldebrecht, a student of Thiele did that exact reaction a few years earlier), the dienophile was benzoquinone (not the unlikely tautomer of hydroquinone you’ve drawn), and they got a mixture of mono- and di- adducts. Also, the reaction give the endo- product; be careful with the methylene bridge.

  2. Quintus

    Thanks for the comment. I, being a bit lazy, got the Diels-Alder info from http://en.wikipedia.org/wiki/Diels–Alder_reaction.
    Dammit I forgot to remove the other carbonyl!!

  3. azmanam

    I also wrote about the D-A reaction a while ago :)

    http://www.chemistry-blog.com/2011/09/26/blog-carnival-the-diels-alder-reaction/

  4. Quintus

    Did not realise that. I shall read it tomorrow.

  5. gippgig

    The picture on the right is not the compound on the left (it’s compound C)! In the compound on the left, the configuration of the top right carbon is S (1st priority O, 2nd methyl-bearing C, 3rd methylene C).
    In the retrosynthetic analysis the configuration of the methyl-bearing C is R (1st priority double-bonded or carbonyl C, 2nd OTES-bearing C, 3rd methyl) in all of the structures in the upper row. The OTES should project to the left (yes, it’s hard to draw correctly). The top right structures aren’t quite equivalent since the rightmost has the methyl ester.
    Incidentally, in the example Diels-Alder reaction the product would be racemic (50% both H up, 50% both down), that’s p-methoxybenZyl, & is 1H-MNR inverse electron demand NMR?

    1. Quintus

      Thanks for pointing out the errors. I shall correct them. The error in (R) and (S) I shall blame on ChemDraw not recognising a TES group.
      So I think now all have been corrected. I didn’t alter the acid to the methyl ester as it messes up the scheme

      1. gippgig

        In the structure above the picture the top right C is still labeled R when it is actually S & the text still has p-methoxybenyl.

  1. The Good Ol’ Diels-Alder | Healthcare

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