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.

7 Comments

  1. Interesting post! I believe the lethal dose is off by a factor of 1000.

    • Thanks, perhaps you could report the correct value?
      My maths is not so good any more.

      • Using the numbers you provided, if 50 mg is a lethal dose for a 70 kg person, that would translate to about 700 ug/kg, rather than ng/kg.

  2. Thank you, actually i was a test to see if anyone read it!

  3. Pingback: Improbable Research » Blog Archive » Some say strychnine

  4. Pingback: Chemistry students, can you imagine this? | Hans K.C.'s Journal

  5. Pestisida Nabati Daun Sirsak says:

    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.

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